基本情報

所属

• 保健科学研究院　保健科学部門　病態解析学分野

職名

• 教授

学位

• 博士（医学）（北海道大学）

ホームページURL

http://kaken.nii.ac.jp/d/r/60321957.ja.html

J-Global ID

• 201201075639257251

プロフィール

• 平成2年 北海道大学医学部卒業
  
  平成7年 北海道大学大学院医学研究科博士課程修了

研究キーワード

• 動物モデル   胸腺   自己免疫   T細胞   IL-6   トランスクリプトーム   血管炎   自己反応性T細胞   網羅的遺伝子発現解析   予後予測   ATF-1   シンビスウイルスベクター   末梢血   dominant negative   遺伝子治療   関節リウマチ   血管内皮細胞   CREB   滑膜細胞   壊死性血管炎   トランスクリプトーム解析   自己免疫疾患   HTLV-I   crm1   DNAアレイ   レトロウイルス   ARF   ヒト内在性レトロウイルス   胸腺腫   トランスジェニック   

研究分野

• ライフサイエンス / 実験病理学

担当教育組織

•  学士課程　医学部（保健学科）
•  修士課程　保健科学院
•  博士課程　保健科学院

職歴

• 2012年 北海道大学 教授

所属学協会

• 日本癌学会   日本臨床細胞学会   日本免疫学会   日本リウマチ学会   日本病理学会   

研究活動情報

論文

• Transcription factor Nrf2 activation regulates NETosis, endothelial injury, and kidney disease in myeloperoxidase-positive antineutrophil cytoplasmic antibody-associated vasculitis.

  Yusho Ueda, Daigo Nakazawa, Saori Nishio, Satoka Shiratori-Aso, Takashi Kudo, Atsuko Miyoshi-Harashima, Kanako Watanabe-Kusunoki, Fumihiko Hattanda, Sari Iwasaki, Takahiro Tsuji, Utano Tomaru, Yasuaki Aratani, Mamiko Yamamoto, Akihiro Ishizu, Tatsuya Atsumi

  Kidney international 2024年03月25日 

  Antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) is a systemic autoimmune disease pathologically characterized by vascular necrosis with inflammation. During AAV development, activated neutrophils produce reactive oxygen species (ROS), leading to the aberrant formation of neutrophil extracellular traps (NETs) via NETosis and subsequent fibrinoid vascular necrosis. Nuclear factor-erythroid 2-related factor 2 (Nrf2) functions as an intracellular defense system to counteract oxidative stress by providing antioxidant properties. Herein, we explored the role of Nrf2 in the pathogenesis of AAV. The role and mechanism of Nrf2 in ANCA-stimulated neutrophils and subsequent endothelial injury were evaluated in vitro using Nrf2 genetic deletion and Nrf2 activator treatment. In corresponding in vivo studies, the role of Nrf2 in ANCA-transfer AAV and spontaneous AAV murine models was examined. Pharmacological activation of Nrf2 in vitro suppressed ANCA-induced NET formation via the inhibition of ROS. In contrast, NET formation was enhanced in Nrf2-deficient neutrophils. Furthermore, Nrf2 activation protected endothelial cells from ANC-induced NETs-mediated injury. In vivo, Nrf2 activation ameliorated glomerulonephritis in two AAV models by upregulating antioxidants and inhibiting ROS-mediated NETs. Furthermore, Nrf2 activation restrained the expansion of splenic immune cells, including T lymphocytes and limited the infiltration of Th17 cells into the kidney. In contrast, Nrf2 genetic deficiency exacerbated vasculitis in a spontaneous AAV model. Thus, the pathophysiological process in AAV may be downregulated by Nrf2 activation, potentially leading to a new therapeutic strategy by regulating NETosis.
• 結腸癌の診断と同時期に発症した抗LAMP-2抗体陽性血管炎の1例

  原田 拓弥, 山下 裕之, 上田 聖, 秋山 優弥, 小林 俊昭, 谷口 舞, 西端 友香, 益田 紗季子, 石津 明洋, 金子 礼志

  脈管学 64 1 11 - 12 (一社)日本脈管学会 2024年02月
• Methylprednisolone pulse-enhanced neutrophil extracellular trap formation in mice with imiquimod-induced lupus-like disease, resulting in ischaemia of the femoral head cartilage.

  Hodaka Ogawa, Shunichi Yokota, Yumeka Hosoi, Ayano Shindo, Naho Ogawa, Ryodai Yamamura, Tomohiro Shimizu, Issei Nakade, Suishin Arai, Mai Taniguchi, Yuka Nishibata, Sakiko Masuda, Daigo Nakazawa, Utano Tomaru, Norimasa Iwasaki, Akihiro Ishizu

  Lupus science & medicine 10 2 2023年12月28日 

  OBJECTIVES: Methylprednisolone (mPSL) pulse therapy is an essential option for patients with active systemic lupus erythematosus, but there is a risk of adverse events related to microcirculation disorders, including idiopathic osteonecrosis of the femoral head (ONFH). Recent studies have revealed that excessive neutrophil extracellular traps (NETs) are involved in microcirculation disorders. This study aimed to demonstrate that mPSL pulse could induce NETs in lupus mice and identify the factors contributing to this induction. METHODS: Six mice with imiquimod (IMQ)-induced lupus-like disease and six normal mice were intraperitoneally injected with mPSL on days 39 to 41, and five mice with IMQ-induced lupus-like disease and six normal mice were injected with phosphate-buffered saline. Pathological examinations were conducted to evaluate the ischaemic state of the femoral head and tissue infiltration of NET-forming neutrophils. Proteome analysis was performed to extract plasma proteins specifically elevated in mPSL-administered mice with IMQ-induced lupus-like disease, and their effects on NET formation were assessed in vitro. RESULTS: Mice with IMQ-induced lupus-like disease that received mPSL pulse demonstrated ischaemia of the femoral head cartilage with tissue infiltration of NET-forming neutrophils. Proteome analysis suggested that prenylcysteine oxidase 1 (PCYOX1) played a role in this phenomenon. The reaction of PCYOX1-containing very low-density lipoproteins (VLDL) with its substrate farnesylcysteine (FC) induced NETs in vitro. The combined addition of IMQ and mPSL synergistically enhanced VLDL-plus-FC-induced NET formation. CONCLUSION: PCYOX1 and related factors are worthy of attention to understand the underlying mechanisms and create novel therapeutic strategies for mPSL-mediated microcirculation disorders, including ONFH.
• Bruton's tyrosine kinase is a possible therapeutic target in microscopic polyangiitis.

  Issei Nakade, Yuto Tamura, Fuyu Hashimoto, Yuko Ariza, Shingo Hotta, Hirofumi Fujigaya, Suishin Arai, Mai Taniguchi, Hodaka Ogawa, Yuka Nishibata, Sakiko Masuda, Daigo Nakazawa, Utano Tomaru, Akihiro Ishizu

  Arthritis research & therapy 25 1 215 - 215 2023年11月06日 

  BACKGROUND: Bruton's tyrosine kinase (Btk) is an enzyme expressed in leukocytes other than T lymphocytes and plasma cells and involved in B-cell receptor- and Fcγ receptor (FcγR)-mediated signal transduction. Btk inhibitors potentially suppress autoantibody production due to the expected inhibitory ability of B lymphocyte differentiation into antibody-producing plasma cells and reduce FcγR-mediated neutrophil activation, including the release of neutrophil extracellular traps (NETs). Microscopic polyangiitis (MPA) is a systemic small-vessel vasculitis characterized by the pathogenic autoantibody, antineutrophil cytoplasmic antibody (ANCA) that reacts with myeloperoxidase (MPO). MPO and MPO-ANCA immune complex (IC)-induced FcγR-mediated NETs are critically involved in MPA pathogenesis. This study aimed to demonstrate the therapeutic efficacy of the Btk inhibitor tirabrutinib on MPA. METHODS: Various doses of tirabrutinib or vehicle were orally administered to Sprague-Dawley rats daily. Four weeks later, the number of peripheral B lymphocytes was counted, and Btk phosphorylation in B lymphocytes was evaluated by flow cytometry. Human peripheral blood neutrophils were stimulated by MPO and anti-MPO antibody ICs (MPO and anti-MPO-ICs), and Btk and its downstream Vav phosphorylation were assessed by western blotting. The effects of tirabrutinib on MPO and anti-MPO-IC-induced NET formation were examined in vitro. Wistar Kyoto rats were immunized with human MPO to induce experimental MPA and given drug-free or tirabrutinib-containing feed (0.0037% or 0.012%) from day 0 or 28. All rats were euthanized on day 42 for serological and histological evaluation. RESULTS: Tirabrutinib inhibited Btk phosphorylation without decreasing B lymphocytes in vivo. Neutrophil Btk and Vav were phosphorylated when stimulated with MPO and anti-MPO-ICs. Tirabrutinib suppressed MPO and anti-MPO-IC-induced NET formation in vitro and ameliorated experimental MPA in a dose-dependent manner in vivo. Although MPO-ANCA production was not affected, NET-forming neutrophils in the blood were significantly reduced by tirabrutinib. CONCLUSIONS: The Btk inhibitor tirabrutinib suppressed MPO and anti-MPO-IC-induced NET formation in vitro and ameliorated experimental MPA by reducing NET-forming neutrophils but not decreasing MPO-ANCA titer in vivo. This study suggests that Btk is a possible therapeutic target in MPA.
• Demonstration of equivocal anti-glomerular basement membrane antibody positivity as a non-specific reaction through multiple immunologic assays in a case of pediatric asymptomatic hematuria

  Masayuki Sato, Yuka Nishibata, Sakiko Masuda, Tsunehisa Nagamori, Emi Ishibazawa, Yoichiro Yoshida, Hironori Takahashi, Akihiro Ishizu, Satoru Takahashi

  Clinical Biochemistry 120 110650 - 110650 2023年10月
• Inhibition of Toll-like receptor 4 and Interleukin-1 receptor prevent SARS-CoV-2 mediated kidney injury.

  Daigo Nakazawa, Yohei Takeda, Masatoshi Kanda, Utano Tomaru, Haruko Ogawa, Takashi Kudo, Satoka Shiratori-Aso, Kanako Watanabe-Kusunoki, Yusho Ueda, Atsuko Miyoshi, Fumihiko Hattanda, Saori Nishio, Ryo Uozumi, Akihiro Ishizu, Tatsuya Atsumi

  Cell death discovery 9 1 293 - 293 2023年08月10日 

  Acute kidney injury (AKI) is a common and severe complication of the coronavirus disease 2019 (COVID-19). Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) directly affects the glomerular and tubular epithelial cells to induce AKI; however, its pathophysiology remains unclear. Here, we explored the underlying mechanisms and therapeutic targets of renal involvement in COVID-19. We developed an in vitro human kidney cellular model, including immortalized tubular epithelial and endothelial cell lines, demonstrating that SARS-CoV-2 directly triggers cell death. To identify the molecular targets in the process of SARS-CoV-2-mediated cell injury, we performed transcriptional analysis using RNA sequencing. Tubular epithelial cells were more prone to dying by SARS-CoV-2 than endothelial cells; however, SARS-CoV-2 did not replicate in renal cells, distinct from VeroE6/transmembrane protease serine 2 cells. Transcriptomic analysis revealed increased inflammatory and immune-related gene expression levels in renal cells incubated with SARS-CoV-2. Toll-like receptor (TLR) 3 in renal cells recognized viral RNA and underwent cell death. Furthermore, analysis of upstream regulators identified several key transcriptional regulators. Among them, inhibition of the interleukin-1 receptor (IL-1R) and TLR4 pathways protects tubular epithelial and endothelial cells from injury via regulation of the signal transducer and activator of transcription protein-3/nuclear factor-kB pathway. Our results reveal that SARS-CoV-2 directly injures renal cells via the proinflammatory response without viral replication, and that IL-1R and TLR4 may be used as therapeutic targets for SARS-CoV-2 mediated kidney injury.
• CD47 blockade ameliorates autoimmune vasculitis via efferocytosis of neutrophil extracellular traps.

  Satoka Shiratori-Aso, Daigo Nakazawa, Takashi Kudo, Masatoshi Kanda, Yusho Ueda, Kanako Watanabe-Kusunoki, Saori Nishio, Sari Iwasaki, Takahiro Tsuji, Sakiko Masuda, Utano Tomaru, Akihiro Ishizu, Tatsuya Atsumi

  JCI insight 2023年06月27日 

  Neutrophil extracellular trap (NET) formation contributes to immune defense and is a distinct form of cell death. Excessive NET formation is found in patients with anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV), contributing to disease progression. The clearance of dead cells by macrophages, a process known as efferocytosis, is regulated by the CD47-mediated "don't eat me" signal. Hence, we hypothesized that pathogenic NETs in AAV escape from efferocytosis via the CD47 signaling pathway, resulting in the development of necrotizing vasculitis. Immunostaining for CD47 in human renal tissues revealed high CD47 expression in crescentic glomerular lesions of patients with AAV. In ex vivo studies, ANCA-induced netting neutrophils increased the expression of CD47 with the reduction of efferocytosis. After efferocytosis, macrophages displayed pro-inflammatory phenotypes. The blockade of CD47 in spontaneous crescentic glomerulonephritis-forming/Kinjoh (SCG/Kj) mice ameliorated renal disease and reduced myeloperoxidase (MPO)-ANCA titers with a reduction in NETs formation. Thus, CD47 blockade would protect against developing glomerulonephritis in AAV via restored efferocytosis of ANCA-induced NETs.
• SLEモデルマウスに対するステロイドパルス治療の大腿骨頭血流に与える影響の検証

  横田 隼一, 清水 智弘, 高橋 大介, 岩崎 倫政, 石津 明洋

  日本関節病学会誌 42 3 256 - 256 (一社)日本関節病学会 2023年06月
• 無症候性血尿に対する精査で抗糸球体基底膜抗体が陽性だったが、抗体解析により非特異的反応と考えられた男児例

  佐藤 雅之, 西端 友香, 益田 紗季子, 長森 恒久, 石羽澤 映美, 吉田 陽一郎, 高橋 弘典, 石津 明洋, 高橋 悟

  日本小児腎臓病学会雑誌 36 Suppl. 192 - 192 (一社)日本小児腎臓病学会 2023年05月
• 壊疽性膿皮症の皮膚生検標本を使用したneutrophil extracellular traps(NETs)の検証

  川上 民裕, 横山 華英, 池田 高治, 益田 紗季子, 石津 明洋

  日本皮膚科学会雑誌 133 4 713 - 714 (公社)日本皮膚科学会 2023年04月
• 自己免疫疾患におけるNETosis

  魚住 諒, 石津 明洋

  リウマチ科 69 4 492 - 498 (有)科学評論社 2023年04月
• ANCA関連血管炎に対するアバコパンを含む新規治療 C5a受容体拮抗薬と好中球エラスターゼ阻害剤の好中球活性化抑制比較

  荒井 粋心, 西端 友香, 谷口 舞, 益田 紗季子, 外丸 詩野, 石津 明洋

  日本リウマチ学会総会・学術集会プログラム・抄録集 67回 629 - 629 (一社)日本リウマチ学会 2023年03月
• ANCA関連血管炎に対するアバコパンを含む新規治療 Cathepsin C阻害による好中球細胞外トラップ形成抑制

  西端 友香, 荒井 粋心, 谷口 舞, 益田 紗季子, 外丸 詩野, 石津 明洋

  日本リウマチ学会総会・学術集会プログラム・抄録集 67回 629 - 629 (一社)日本リウマチ学会 2023年03月
• ANCA関連血管炎に対するアバコパンを含む新規治療 好中球細胞外トラップにDNase I抵抗性を付与するタンパクの同定

  谷口 舞, 益田 紗季子, 中村 哲朗, 荒井 粋心, 西端 友香, 外丸 詩野, 石津 明洋

  日本リウマチ学会総会・学術集会プログラム・抄録集 67回 630 - 630 (一社)日本リウマチ学会 2023年03月
• ベーチェット病 ベーチェット病における口内炎の発生原因の解明

  益田 紗季子, 西端 友香, 川邊 智宏, 宮前 多佳子, 外丸 詩野, 石津 明洋

  日本リウマチ学会総会・学術集会プログラム・抄録集 67回 649 - 649 (一社)日本リウマチ学会 2023年03月
• 自己抗体から紐解く疾患の病理病態 ANCA関連血管炎におけるintermolecular epitope spreadingによる抗GBM抗体の産生

  西端 友香, 益田 紗季子, 外丸 詩野, 石津 明洋

  日本病理学会会誌 112 1 196 - 196 (一社)日本病理学会 2023年03月
• SLEモデルマウスへのステロイドパルスは好中球細胞外トラップを誘導する

  小川 帆貴, 横田 隼一, 清水 智弘, 西端 友香, 益田 紗季子, 外丸 詩野, 岩崎 倫政, 石津 明洋

  日本リウマチ学会総会・学術集会プログラム・抄録集 67回 886 - 886 (一社)日本リウマチ学会 2023年03月
• COVID-19関連を含むIgA血管炎皮膚生検標本を使用したNeutrophil Extracellular Traps(NETs)の検証

  川上 民裕, 横山 華英, 池田 高治, 西端 友香, 益田 紗季子, 石津 明洋, 外丸 詩野

  日本皮膚科学会雑誌 133 2 254 - 254 (公社)日本皮膚科学会 2023年02月
• 感染症と血管炎 COVID-19発症後およびCOVID-19ワクチン接種後IgA血管炎の皮膚生検組織における好中球細胞外トラップの沈着 COVID-19非関連IgA血管炎との比較

  益田 紗季子, 西端 友香, 外丸 詩野, 横山 華英, 池田 高治, 川上 民裕, 石津 明洋

  脈管学 63 1 10 - 11 (一社)日本脈管学会 2023年02月
• 無症候性血尿を呈した抗糸球体基底膜(GBM)抗体陽性症例の血清を用いた抗体解析

  西端 友香, 佐藤 雅之, 長森 恒久, 益田 紗季子, 外丸 詩野, 石津 明洋

  脈管学 63 1 13 - 14 (一社)日本脈管学会 2023年02月
• 皮膚血管炎動物モデルの完成

  川上 民裕, 中出 一生, 田村 宥人, 伊藤 吹夕, 西端 友香, 益田 紗季子, 外丸 詩野, 石津 明洋

  脈管学 63 1 15 - 15 (一社)日本脈管学会 2023年02月
• 巨細胞性動脈炎の診断に寄与する新たな超音波所見 生検所見との比較に基づく検討

  工藤 悠輔, 原 花梨, 村山 迪史, 加賀 早苗, 表原 里実, 岩井 孝仁, 進藤 由衣香, 菊池 桃佳, 加藤 将, 外丸 詩野, 松野 吉宏, 石津 明洋

  脈管学 63 1 16 - 16 (一社)日本脈管学会 2023年02月
• Low disease activity of microscopic polyangiitis in patients with anti-myosin light chain 6 antibody that disrupts actin rearrangement necessary for neutrophil extracellular trap formation.

  Miku Yoshinari, Yuka Nishibata, Sakiko Masuda, Daigo Nakazawa, Utano Tomaru, Yoshihiro Arimura, Koichi Amano, Yukio Yuzawa, Ken-Ei Sada, Tatsuya Atsumi, Hiroaki Dobashi, Hitoshi Hasegawa, Masayoshi Harigai, Seiichi Matsuo, Hirofumi Makino, Akihiro Ishizu

  Arthritis research & therapy 24 1 274 - 274 2022年12月16日 

  BACKGROUND: Neutrophil extracellular traps (NETs) are critically involved in microscopic polyangiitis (MPA) pathogenesis, and some patients with MPA possess anti-NET antibody (ANETA). Anti-myosin light chain 6 (MYL6) antibody is an ANETA that affects NETs. This study aimed to determine the significance of anti-MYL6 antibody in MPA. METHODS: The influence of anti-MYL6 antibody on NET formation and actin rearrangement necessary for NET formation was assessed by fluorescent staining. An enzyme-linked immunosorbent assay was established to detect serum anti-MYL6 antibody, and the prevalence of this antibody in MPA was determined. Furthermore, the disease activity and response to remission-induction therapy of MPA were compared between anti-MYL6 antibody-positive and anti-MYL6 antibody-negative MPA patients. RESULTS: Anti-MYL6 antibody disrupted G-actin polymerization into F-actin, suppressing phorbol 12-myristate 13-acetate-induced NET formation. Serum anti-MYL6 antibody was detected in 7 of 59 patients with MPA. The Birmingham vasculitis activity score (BVAS) of anti-MYL6 antibody-positive MPA patients was significantly lower than anti-MYL6 antibody-negative MPA patients. Among the nine BVAS evaluation items, the cutaneous, cardiovascular, and nervous system scores of anti-MYL6 antibody-positive MPA patients were significantly lower than anti-MYL6 antibody-negative MPA patients, although other items, including the renal and chest scores, were equivalent between the two groups. The proportion of patients with remission 6 months after initiation of remission-induction therapy in anti-MYL6 antibody-positive MPA patients was significantly higher than in anti-MYL6 antibody-negative MPA patients. CONCLUSIONS: Collective findings suggested that anti-MYL6 antibody disrupted actin rearrangement necessary for NET formation and could reduce the disease activity of MPA.
• Similar deposition of neutrophil extracellular traps in the dermis among COVID-19-associated IgA vasculitis, post-COVID-19 vaccination IgA vasculitis, and COVID-19-unrelated IgA vasculitis.

  Tamihiro Kawakami, Kae Yokoyama, Takaharu Ikeda, Yuka Nishibata, Sakiko Masuda, Utano Tomaru, Akihiro Ishizu

  The Journal of dermatology 50 5 e151-e152  2022年12月15日
• 正常ラットにヒストン皮下注射後,抗ホスファチジルセリン・プロトロンビン複合体抗体と抗リソソーム膜タンパク質2抗体の静脈注射により,皮膚血管炎の発症に成功した

  川上 民裕, 中出 一生, 田村 宥人, 伊藤 吹夕, 西端 友香, 益田 紗季子, 外丸 詩野, 石津 明洋

  日本皮膚免疫アレルギー学会総会学術大会プログラム・抄録集 52回 215 - 215 (一社)日本皮膚免疫アレルギー学会 2022年12月
• 正常ラットにヒストン皮下注射後,抗ホスファチジルセリン・プロトロンビン複合体抗体と抗リソソーム膜タンパク質2抗体の静脈注射により,皮膚血管炎の発症に成功した

  川上 民裕, 中出 一生, 田村 宥人, 伊藤 吹夕, 西端 友香, 益田 紗季子, 外丸 詩野, 石津 明洋

  日本皮膚免疫アレルギー学会総会学術大会プログラム・抄録集 52回 215 - 215 (一社)日本皮膚免疫アレルギー学会 2022年12月
• A Novel Antineutrophil Extracellular Trap Antibody Targeting Myosin Light Chain 6 in Microscopic Polyangiitis.

  Miku Yoshinari, Fumihiko Hattanda, Yuka Nishibata, Sakiko Masuda, Daigo Nakazawa, Utano Tomaru, Akihiro Ishizu

  The Journal of rheumatology 49 11 1286 - 1288 2022年11月
• Transcriptional dynamics of granulocytes in direct response to incubation with SARS-CoV-2.

  Daigo Nakazawa, Yohei Takeda, Masatoshi Kanda, Utano Tomaru, Haruko Ogawa, Takashi Kudo, Satoka Shiratori-Aso, Kanako Watanabe-Kusunoki, Yusho Ueda, Atsuko Miyoshi, Fumihiko Hattanda, Saori Nishio, Ryo Uozumi, Akihiro Ishizu, Tatsuya Atsumi

  FEBS open bio 2022年10月22日 

  Severe coronavirus disease 2019 (COVID-19) is characterized by acute respiratory distress syndrome and multiple organ dysfunction, in which the host immune response plays a pivotal role. Excessive neutrophil activation and subsequent superfluity of neutrophil extracellular traps (NETs) can lead to tissue damage, and several studies have shown the involvement of neutrophils in severe COVID-19. However, the detailed responses of each neutrophil subset to SARS-CoV-2 infection has not been fully described. To explore this issue, we incubated normal-density granulocytes (NDGs) and low-density granulocytes (LDGs) with different viral titers of SARS-CoV-2. NDGs form NETs with chromatin fibers in response to SARS-CoV-2, whereas LDGs incubated with SARS-CoV-2 display a distinct morphology with condensed nuclei and moderate transcriptional changes. Based on these transcriptional changes, we suggest that AGO2 possibly plays a role in LDG regulation in response to SARS-CoV-2.
• ベーチェット病皮下の血栓性静脈炎におけるNeutrophil Extracellular Trapsの発現

  川上 民裕, 横山 華英, 池田 高治, 西端 友香, 益田 紗季子, 外丸 詩野, 石津 明洋

  アレルギー 71 6-7 870 - 870 (一社)日本アレルギー学会 2022年08月
• ベーチェット病皮膚生検標本を使用したNETsの検証

  川上 民裕, 横山 華英, 池田 高治, 西端 友香, 益田 紗季子, 外丸 詩野, 石津 明洋

  西日本皮膚科 84 4 371 - 371 日本皮膚科学会-西部支部 2022年08月
• ベーチェット病皮下の血栓性静脈炎におけるNeutrophil Extracellular Trapsの発現

  川上 民裕, 横山 華英, 池田 高治, 西端 友香, 益田 紗季子, 外丸 詩野, 石津 明洋

  アレルギー 71 6-7 870 - 870 (一社)日本アレルギー学会 2022年08月
• Cyclophilin D regulates NETosis and inflammation in myeloperoxidase-antineutrophil cytoplasmic antibody-associated vasculitis.

  Takashi Kudo, Daigo Nakazawa, Kanako Watanabe-Kusunoki, Masatoshi Kanda, Satoka Shiratori-Aso, Nobuya Abe, Saori Nishio, Jun-Ichiro Koga, Sari Iwasaki, Takahiro Tsuji, Yuichiro Fukasawa, Miwako Yamasaki, Masahiko Watanabe, Sakiko Masuda, Utano Tomaru, Masaaki Murakami, Yasuaki Aratani, Akihiro Ishizu, Tatsuya Atsumi

  Arthritis & rheumatology (Hoboken, N.J.) 75 1 71 - 83 2022年07月29日 

  OBJECTIVE: Anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) is pathologically characterized by focal fibrinoid necrosis where ANCA-mediated neutrophil extracellular trap (NET) formation and subsequent endothelial necrosis occurs. Cyclophilin D (CypD) plays an important role in mediating cell necrosis and inflammation via opening of mitochondrial permeability transition pores (mPTP). Here, we examined the role of CypD in AAV pathogenesis. METHODS: In vitro, the role and mechanism of CypD in ANCA-stimulated neutrophils were assessed by immunostaining and electron microscopy. A comprehensive RNA sequencing analysis was performed on ANCA-treated murine neutrophils. To investigate the role of CypD in vivo, an-anti-MPO IgG-transfer AAV model or spontaneous AAV model mice were induced in CypD knockout or wild-type mice. RESULTS: In vitro, pharmacological and genetic inhibition of CypD suppressed ANCA-induced NET formation via the suppression of reactive oxygen species/cytochrome c release from the mitochondria. The analysis of RNA sequencing in ANCA-treated murine neutrophils revealed the involvement of inflammatory responses, and CypD deficiency reduced ANCA-induced alterations in gene expression. Furthermore, the upstream regulator analysis revealed the relevance of intracellular calcium (CypD activator) and cyclosporin (CypD inhibitor) in ANCA stimulation, indicating that CypD-dependent mPTP opening is associated with ANCA-induced neutrophil activation and NETosis. In both AAV models, the genetic deletion of CypD ameliorated crescentic glomerulonephritis via the inhibition of CypD-dependent neutrophil and endothelial necrosis. CONCLUSIONS: CypD targeting is a novel and specific therapeutic strategy for AAV via the resolution of necrotizing vasculitis.
• Typical cutaneous small-vessel vasculitis induced by combined injection of antiphosphatidylserine/prothrombin complex antibody and anti-LAMP-2 antibody in normal rats.

  Tamihiro Kawakami, Issei Nakade, Yuto Tamura, Fuyu Ito, Yuka Nishibata, Sakiko Masuda, Utano Tomaru, Akihiro Ishizu

  The Journal of dermatology 49 12 1233 - 1237 2022年07月25日 

  We previously reported that IgA vasculitis and cutaneous arteritis could be dependently associated with the presence of the antiphosphatidylserine/prothrombin complex (anti-PS/PT) antibody and lysosomal-associated membrane protein-2 (LAMP-2). The copy number of LAMP-2 mRNA in skin tissue samples from rats with cutaneous vasculitis induced by intravenous administration of anti-PS/PT antibody after subcutaneous histone injection was significantly higher than in those without cutaneous vasculitis. We found LAMP-2 protein overexpression in neutrophils and vascular endothelial cells of the affected blood vessels in rats with cutaneous vasculitis induced by intravenous administration of anti-PS/PT antibody after cutaneous priming by histones. We found typical cutaneous small-vessel vasculitis in the skin of rats given intravenous injection of both anti-PS/PT antibody and anti-LAMP-2 antibody after cutaneous priming by histones. We suggested that the introduction of skin local histones and anti-PS/PT antibody in serum could move LAMP-2 to the cell surface of neutrophils and vascular endothelial cells, and that anti-LAMP-2 antibody could bridge these cells through antigen-specific binding in typical cutaneous small-vessel vasculitis.
• Expert Perspectives on Pathological Findings in Vasculitis.

  Akihiro Ishizu, Tamihiro Kawakami, Hiroyuki Kanno, Kei Takahashi, Tatsuhiko Miyazaki, Eiji Ikeda, Toshiaki Oharaseki, Yayoi Ogawa, Mitsuho Onimaru, Mie Kurata, Daigo Nakazawa, Eri Muso, Masayoshi Harigai

  Modern rheumatology 2022年05月10日 

  Pathological findings are important in the diagnosis of vasculitis. However, due to the rarity of the disease, standard textbooks usually devote only a few pages to this topic, and this makes it difficult for clinicians not specializing in vasculitis to fully understand the pathological findings in vasculitis. To address the paucity of information, we present representative pathological findings in vasculitis classified in the 2012 Revised International Chapel Hill Consensus Conference Nomenclature of Vasculitides (CHCC2012). The CHCC2012 classifies 26 vasculitides into seven categories: (1) large vessel vasculitis, (2) medium vessel vasculitis, (3) small vessel vasculitis, including antineutrophil cytoplasmic antibody-associated vasculitis and immune complex small vessel vasculitis, (4) variable vessel vasculitis, (5) single-organ vasculitis, (6) vasculitis associated with systemic disease, and (7) vasculitis associated with probable etiology. Moreover, representative pathological findings of vasculitis-related diseases and non-inflammatory vasculopathy not mentioned in the CHCC2012 are also presented. This will be useful for clinicians to refer for typical pathological findings of vasculitis in daily practice.
• Presence of neutrophil extracellular traps in superficial venous thrombosis of Behçet's disease.

  Tamihiro Kawakami, Kae Yokoyama, Takaharu Ikeda, Yuka Nishibata, Sakiko Masuda, Utano Tomaru, Akihiro Ishizu

  The Journal of dermatology 49 7 741 - 745 2022年04月17日 

  Behçet's disease (BD) has a heterogeneous spectrum of disease manifestations featuring the involvement of different organs and can be characterized with different symptoms depending on the clinical department in charge. We retrospectively reviewed BD patients seen at our hospital and investigated the presence of neutrophils producing neutrophil extracellular traps (NET) in those patients. Immunolabeling of myeloperoxidase and histone citrullination proteins was performed on skin biopsies from three BD patients who had skin biopsy-proven superficial vein thrombophlebitis in their erythema nodosum-like lesions. We observed a higher proportion of female patients and a higher incidence of acne-like eruptions among BD patients seen at our dermatology department, while there was a higher incidence of ocular and gastrointestinal involvement among BD patients treated in other departments. We suggest that sex statistical trends could lead to the co-development of different manifestations and may help clinicians choose the best therapeutic approaches, tailoring them to the specific phenotype of the patient rather than one based on single disease manifestations. NET were found in neutrophils of panniculitis concurrent with superficial vein thrombophlebitis. We suggest that the pathogenesis of BD-related thrombosis could be associated with neutrophil activation and NET are released in the panniculitis of affected skin lesions, erythema nodosum-like lesions.
• Phorbol 12-myristate 13-acetate stimulation under hypoxia induces nuclear swelling with DNA outflow but not extracellular trap formation of neutrophils.

  Sakiko Masuda, Kurumi Kato, Misato Ishibashi, Yuka Nishibata, Ayako Sugimoto, Daigo Nakazawa, Satoshi Tanaka, Utano Tomaru, Ichizo Tsujino, Akihiro Ishizu

  Experimental and molecular pathology 125 104754 - 104754 2022年04月 

  Neutrophils stand sentinel over infection and possess diverse antimicrobial weapons, including neutrophil extracellular traps (NETs). NETs are composed of web-like extracellular DNA decorated with antimicrobial substances and can trap and eliminate invading microorganisms. Although phorbol 12-myristate 13-acetate (PMA) is a potent NET inducer, previous studies have demonstrated that not all neutrophils exhibit NET formation even if stimulated by PMA at high concentrations. This study first showed that some neutrophils stimulated by PMA displayed a swollen nucleus but not NET formation and that hypoxic environments suppressed the NET release. Next, characterization of PMA-stimulated neutrophils with a swollen nucleus was accomplished by differentiating between suicidal-type NETosis and apoptosis. Furthermore, the significance of the phenomenon was examined using formalin-fixed, paraffin-embedded human lung disease tissues with and without pneumonia. As a result, histone H3 citrullination, DNA outflow, propidium iodide labeling, resistance to DNase I, and suspended actin rearrangement were characteristics of PMA-stimulated neutrophils with a swollen nucleus distinct from neutrophils that underwent either suicidal-type NETosis or apoptosis. Neutrophils stimulated by PMA under hypoxic conditions secreted matrix metalloproteinase-9 cytotoxic to human lung-derived fibroblasts. Further, deposition of neutrophil-derived citrullinated histone H3+ chromatin substances in pulmonary lesions was greater in patients with pneumonia than in patients without pneumonia and positively correlated with hypoxia-inducible factor-1α expression. The collective findings suggested that neutrophils activated under hypoxic conditions could be putative modulators of hypoxia-related disease manifestations.
• 変貌する糸球体疾患の概念:近年のトピックス 膜性腎症の特異抗原(PLA2R,THSD7A,NELL1,EXT1/2)について最近の話題

  辻 隆裕, 牧田 啓史, 深澤 雄一郎, 加賀 幸斗, 西端 友香, 益田 紗季子, 石津 明洋, 岩崎 沙理

  日本病理学会会誌 111 1 162 - 162 (一社)日本病理学会 2022年03月
• 好中球細胞外トラップにDNase I抵抗性を付与するタンパクの探索

  益田 紗季子, 北野 翔大, 西端 友香, 外丸 詩野, 石津 明洋

  日本病理学会会誌 111 1 214 - 214 (一社)日本病理学会 2022年03月
• SLE・抗リン脂質抗体症候群:基礎 全身性エリテマトーデスへのステロイドパルスが好中球細胞外トラップ形成に及ぼす影響

  小川 帆貴, 横田 隼一, 清水 智弘, 西端 友香, 益田 紗季子, 外丸 詩野, 岩崎 倫政, 石津 明洋

  日本リウマチ学会総会・学術集会プログラム・抄録集 66回 347 - 347 (一社)日本リウマチ学会 2022年03月
• ANCA関連血管炎:基礎研究・予後予測因子 ブルトン型チロシンキナーゼ阻害剤チラブルチニブによるMPO-ANCA関連血管炎誘導モデルの発症抑制

  中出 一生, 西端 友香, 益田 紗季子, 外丸 詩野, 石津 明洋

  日本リウマチ学会総会・学術集会プログラム・抄録集 66回 406 - 406 (一社)日本リウマチ学会 2022年03月
• ANCA関連血管炎:基礎研究・予後予測因子 MPO-ANCA関連血管炎モデルにおける新規好中球機能制御化合物薬の抑制効果

  西端 友香, 益田 紗季子, 外丸 詩野, 石津 明洋

  日本リウマチ学会総会・学術集会プログラム・抄録集 66回 407 - 407 (一社)日本リウマチ学会 2022年03月
• SLE・抗リン脂質抗体症候群:基礎 全身性エリテマトーデスへのステロイドパルスが好中球細胞外トラップ形成に及ぼす影響

  小川 帆貴, 横田 隼一, 清水 智弘, 西端 友香, 益田 紗季子, 外丸 詩野, 岩崎 倫政, 石津 明洋

  日本リウマチ学会総会・学術集会プログラム・抄録集 66回 347 - 347 (一社)日本リウマチ学会 2022年03月
• Possible implication of intermolecular epitope spreading in the production of anti-glomerular basement membrane antibody in anti-neutrophil cytoplasmic antibody-associated vasculitis.

  Yuka Nishibata, Mayu Nonokawa, Yuto Tamura, Rio Higashi, Ku Suzuki, Hideyuki Hayashi, Sakiko Masuda, Daigo Nakazawa, Satoshi Tanaka, Utano Tomaru, Akihiro Ishizu

  Clinical and experimental rheumatology 40 4 691 - 704 2022年02月04日 

  OBJECTIVES: Anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) is sometimes complicated by anti-glomerular basement membrane (GBM) disease. Proteases, including elastase, released from neutrophils activated by ANCA are implicated in the pathogenesis of AAV. Epitopes of anti-GBM antibody exist in the α3-subunit non-collagenous (NC1) domain of collagen type IV [Col (IV)]. This region, called α3(IV)NC1, is structurally cryptic. This study aimed to determine the production mechanism of anti-GBM antibody in AAV. METHODS: We first examined whether α3(IV)NC1 could be revealed by the digestion of formalin-fixed, paraffin-embedded (FFPE) normal kidney sections and Col (IV) by proteases, including neutrophil elastase, using immunohistochemistry (IHC) and enzyme-linked immunosorbent assay (ELISA). Next, the reveal of α3(IV)NC1 and the infiltration of CD11c+ macrophages in the affected kidneys were evaluated by IHC and immunofluorescent staining using FFPE sections. Finally, the production of anti-GBM antibody in AAV rats was determined by ELISA. RESULTS: α3(IV)NC1 was revealed by the digestion of FFPE normal kidney sections and Col (IV) by proteases. Although the reveal of α3(IV)NC1 was observed in sclerotic glomeruli regardless of causative diseases, CD11c+ macrophages near α3(IV)NC1 were characteristics of AAV. Anti-GBM antibody was produced subsequent to ANCA in some AAV rats. IHC demonstrated the reveal of α3(IV)NC1 in affected renal tissues and the infiltration of CD11c+ macrophages around the sites. CONCLUSIONS: The collective findings suggest that, in AAV, proteases released from neutrophils activated by ANCA digest Col (IV) and result in the reveal of α3(IV)NC1, CD11c+ macrophages present GBM epitopes, and then the host's immune system produce anti-GBM antibody.
• 結節性多発動脈炎と皮膚動脈炎の皮膚生検画像の人工知能による鑑別

  柏 航, 加藤 千恵次, 西端 友香, 益田 紗季子, 外丸 詩野, 川上 民裕, 石津 明洋

  脈管学 62 2 8 - 8 (一社)日本脈管学会 2022年02月
• 結節性多発動脈炎と皮膚動脈炎の皮膚生検画像の人工知能による鑑別

  柏 航, 加藤 千恵次, 西端 友香, 益田 紗季子, 外丸 詩野, 川上 民裕, 石津 明洋

  脈管学 62 2 8 - 8 (一社)日本脈管学会 2022年02月
• Involvement of neutrophil extracellular traps in the pathogenesis of glomerulonephritis in a case of systemic lupus erythematosus and antineutrophil cytoplasmic antibody-associated vasculitis overlap syndrome.

  Arisa Senda, Ryutaro Sasai, Kurumi Kato, Yuka Nishibata, Sakiko Masuda, Akihiro Ishizu, Noriko Takahara

  CEN case reports 11 3 339 - 346 2022年01月13日 

  Systemic lupus erythematosus (SLE) and antineutrophil cytoplasmic antibody-associated vasculitis (AAV) are autoimmune diseases that often cause rapidly progressive glomerulonephritis, with neutrophil extracellular traps (NETs) involved in their pathogenesis. However, the involvement of NETs in the renal damage caused by SLE/AAV overlap syndrome has not been clarified yet. In this study, we detected renal deposition of NETs in a patient with SLE/AAV overlap syndrome. In addition, a significantly increased level of NET-inducing activity was observed in the patient's serum, which improved with treatment. On the other hand, a markedly lower level of NET degradation was observed in the patient's serum as compared to healthy subjects' sera, without any posttreatment changes. These findings suggest that NETs may play a role in the pathogenesis of renal injury associated with SLE/AAV overlap syndrome.
• 抗ホスファチジルセリン・プロトロンビン複合体抗体による皮膚血管炎動物モデルの完成

  川上 民裕, 董 宇鵬, 田村 宥人, 吉成 未来, 西端 友香, 益田 紗季子, 石津 明洋, 外丸 詩野

  日本皮膚科学会雑誌 132 1 91 - 91 (公社)日本皮膚科学会 2022年01月
• 抗ホスファチジルセリン・プロトロンビン複合体抗体による皮膚血管炎動物モデルの完成

  川上 民裕, 董 宇鵬, 田村 宥人, 吉成 未来, 西端 友香, 益田 紗季子, 石津 明洋, 外丸 詩野

  日本皮膚科学会雑誌 132 1 91 - 91 (公社)日本皮膚科学会 2022年01月
• Involvement of neutrophil extracellular traps in the pathogenesis of glomerulonephritis in a case of systemic lupus erythematosus and antineutrophil cytoplasmic antibody-associated vasculitis overlap syndrome

  Arisa Senda, Ryutaro Sasai, Kurumi Kato, Yuka Nishibata, Sakiko Masuda, Akihiro Ishizu, Noriko Takahara

  CEN CASE REPORTS 11 3 339 - 346 2022年01月 

  Systemic lupus erythematosus (SLE) and antineutrophil cytoplasmic antibody-associated vasculitis (AAV) are autoimmune diseases that often cause rapidly progressive glomerulonephritis, with neutrophil extracellular traps (NETs) involved in their pathogenesis. However, the involvement of NETs in the renal damage caused by SLE/AAV overlap syndrome has not been clarified yet. In this study, we detected renal deposition of NETs in a patient with SLE/AAV overlap syndrome. In addition, a significantly increased level of NET-inducing activity was observed in the patient's serum, which improved with treatment. On the other hand, a markedly lower level of NET degradation was observed in the patient's serum as compared to healthy subjects' sera, without any posttreatment changes. These findings suggest that NETs may play a role in the pathogenesis of renal injury associated with SLE/AAV overlap syndrome.
• Neutrophil fixation protocols suitable for substrates to detect anti-neutrophil cytoplasmic antibodies by indirect immunofluorescence

  Yuka Nishibata, Shun Matsuzawa, Yosuke Satomura, Takeshi Ohtsuka, Motoki Kuhara, Sakiko Masuda, Utano Tomaru, Akihiro Ishizu

  PATHOLOGY RESEARCH AND PRACTICE 228 2021年12月 

  ABS T R A C T Anti-neutrophil cytoplasmic antibodies (ANCAs) are autoantibodies that recognize neutrophil cytoplasmic an-tigens. The major ANCA antigens are myeloperoxidase and proteinase 3. Necrotizing small vessel vasculitis accompanied by ANCA production is called ANCA-associated vasculitis (AAV). In addition to AAV, ANCA is sometimes produced in patients with connective tissue diseases, such as systemic lupus erythematosus, and in-flammatory bowel diseases. Indirect immunofluorescence (IIF) and enzyme immunoassay (EIA) have been used to detect ANCAs. Recently, the accuracy of EIA has improved and it has become the gold standard for ANCA detection. However, IIF does not lose its role in ANCA detection because EIA cannot detect ANCAs that recognize antigens other than those coated on the plate. For IIF, neutrophil substrates prepared with two different fixations, namely, ethanol fixation and formalin fixation, are used. There is a recommended protocol for ethanol fixation but not for formalin fixation. This study prepared neutrophil substrates according to the recommended protocol for ethanol fixation and protocols in the literature and original protocols for formalin fixation and then examined ANCA specificity and how storage period would influence the number of cells, antigen distribution, and anti -genicity of the substrates. As a result, the number of cells and antigen distribution did not change after storage for up to 2 months regardless of fixation protocols, whereas a time-dependent decline in ANCA antigenicity and a fixation protocol-dependent difference in ANCA specificity were observed. How neutrophils are fixed on the glass slide needs to be checked upon evaluation of ANCAs by IIF.
• Neutrophil fixation protocols suitable for substrates to detect anti-neutrophil cytoplasmic antibodies by indirect immunofluorescence.

  Yuka Nishibata, Shun Matsuzawa, Yosuke Satomura, Takeshi Ohtsuka, Motoki Kuhara, Sakiko Masuda, Utano Tomaru, Akihiro Ishizu

  Pathology, research and practice 228 153661 - 153661 2021年12月 

  Anti-neutrophil cytoplasmic antibodies (ANCAs) are autoantibodies that recognize neutrophil cytoplasmic antigens. The major ANCA antigens are myeloperoxidase and proteinase 3. Necrotizing small vessel vasculitis accompanied by ANCA production is called ANCA-associated vasculitis (AAV). In addition to AAV, ANCA is sometimes produced in patients with connective tissue diseases, such as systemic lupus erythematosus, and inflammatory bowel diseases. Indirect immunofluorescence (IIF) and enzyme immunoassay (EIA) have been used to detect ANCAs. Recently, the accuracy of EIA has improved and it has become the gold standard for ANCA detection. However, IIF does not lose its role in ANCA detection because EIA cannot detect ANCAs that recognize antigens other than those coated on the plate. For IIF, neutrophil substrates prepared with two different fixations, namely, ethanol fixation and formalin fixation, are used. There is a recommended protocol for ethanol fixation but not for formalin fixation. This study prepared neutrophil substrates according to the recommended protocol for ethanol fixation and protocols in the literature and original protocols for formalin fixation and then examined ANCA specificity and how storage period would influence the number of cells, antigen distribution, and antigenicity of the substrates. As a result, the number of cells and antigen distribution did not change after storage for up to 2 months regardless of fixation protocols, whereas a time-dependent decline in ANCA antigenicity and a fixation protocol-dependent difference in ANCA specificity were observed. How neutrophils are fixed on the glass slide needs to be checked upon evaluation of ANCAs by IIF.
• Usefulness of tissue inhibitor of metalloproteinase 1 as a predictor of sustained remission in patients with antineutrophil cytoplasmic antibody-associated vasculitis

  Jun Ishizaki, Ayako Takemori, Kenta Horie, Daisuke Hiraoka, Koichiro Suemori, Takuya Matsumoto, Ken ei Sada, Koichi Amano, Masayoshi Harigai, Yoshihiro Arimura, Hirofumi Makino, Katsuto Takenaka, Nobuaki Takemori, Hitoshi Hasegawa, Yohko Murakawa, Eri Muso, Atsushi Komatsuda, Satoshi Ito, Takao Fujii, Atsushi Kawakami, Izaya Nakaya, Takao Saito, Takafumi Ito, Nobuhito Hirawa, Masahiro Yamamura, Masaaki Nakano, Kosaku Nitta, Makoto Ogura, Taio Naniwa, Shoichi Ozaki, Junichi Hirahashi, Noriyoshi Ogawa, Tatsuo Hosoya, Takashi Wada, Satoshi Horikoshi, Yasushi Kawaguchi, Taichi Hayashi, Masaharu Yoshida, Tsuyoshi Watanabe, Daijo Inaguma, Kazuhiko Tsuruya, Noriyuki Homma, Tsutomu Takeuchi, Naoki Nakagawa, Shinichi Takeda, Ritsuko Katabuchi, Masayuki Iwano, Tatsuya Atsumi, Shoichi Fujimoto, Shogo Banno, Takahiko Sugihara, Masaki Kobayashi, Kunihiro Yamagata, Sakae Homma, Hiroaki Dobashi, Naotake Tsuboi, Akihiro Ishizu, Hitoshi Sugiyama

  Arthritis Research and Therapy 23 1 2021年12月 

  Background: We previously identified tissue inhibitor of metalloproteinase 1 (TIMP-1) as a biomarker of disease activity that distinguished mildly or highly active antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) from remission 6 months after the initiation of remission-induction therapy. In the present study, we investigated whether TIMP-1 is clinically useful as a predictor of relapse and sustained remission in AAV patients with microscopic polyangiitis (MPA) and granulomatosis with polyangiitis (GPA) during maintenance therapy. Methods: The relationship between serum TIMP-1 levels and clinical outcomes in AAV patients receiving maintenance therapy was assessed using the follow-up data of a Japanese large-cohort study (the RemIT-JAV-RPGN study) and data collected from AAV patients on maintenance therapy in our hospital (the MAAV-EU study). Results: In the RemIT-JAV RPGN study, serum levels of TIMP-1 were significantly higher in mildly active AAV patients with MPA and GPA 6 months after the initiation of remission-induction therapy than in patients in remission. Regarding maintenance therapy, elevated levels of TIMP-1 in patients in remission were associated with relapse and/or difficulty reducing the glucocorticoid dosage after 6 to 12 months. In the MAAV-EU study, serum levels of TIMP-1 were elevated in relapsed patients 6 months before relapse, earlier than the increase in serum levels of CRP. Analyses of both studies revealed that approximately 30% of patients in remission with a serum TIMP-1 level ≥ 150 ng/mL relapsed after 6 to 12 months, while the majority of patients with a TIMP-1 level < 150 ng/mL sustained remission for at least 12 months. Conclusion: We herein demonstrated that TIMP-1 is more useful as a predictive biomarker of sustained remission than as a predictor of relapse in maintenance therapy for AAV. TIMP-1 levels < 150 ng/mL are important for the long-term maintenance of remission and may be an indicator for the tapering or cessation of treatment.
• 【新しい手法を駆使した腎臓病研究の最前線】糸球体疾患 ANCAとNETs

  石津 明洋, 益田 紗季子, 西端 友香

  腎と透析 91 5 851 - 855 (株)東京医学社 2021年11月
• 【循環器II-血管・血管腫・弁膜疾患-】小型血管の血管炎

  石津 明洋, 益田 紗季子, 西端 友香

  病理と臨床 39 11 1116 - 1122 (株)文光堂 2021年11月
• 免疫疾患の形態病理学的理解 ヒストン皮下注射と抗ホスファチジルセリン・プロトロンビン複合体抗体静脈注射から完成した皮膚血管炎の動物モデル

  川上 民裕, 田村 宥人, 董 宇鵬, 吉成 未来, 西端 友香, 益田 紗季子, 外丸 詩野, 石津 明洋

  日本臨床免疫学会総会プログラム・抄録集 49回 58 - 58 (一社)日本臨床免疫学会 2021年10月
• 膠原病・自己免疫疾患 皮膚血管炎動物モデルの完成と抗ホスファチジルセリン・プロトロンビン複合体抗体

  川上 民裕, 田村 宥人, 董 宇鵬, 吉成 未来, 西端 友香, 益田 紗季子, 外丸 詩野, 石津 明洋

  アレルギー 70 6-7 809 - 809 (一社)日本アレルギー学会 2021年08月
• Expression of the immunoproteasome subunit β5i in non-small cell lung carcinomas.

  Takayuki Kiuchi, Utano Tomaru, Akihiro Ishizu, Makoto Imagawa, Sari Iwasaki, Akira Suzuki, Noriyuki Otsuka, Yoshihito Ohhara, Ichiro Kinoshita, Yoshihiro Matsuno, Hirotoshi Dosaka-Akita, Masanori Kasahara

  Journal of clinical pathology 74 5 300 - 306 2021年05月 [査読有り][通常論文]
   

  AIM: The immunoproteasome is a specific proteasome isoform whose proteolytic activity enhances the generation of antigenic peptides to be presented by major histocompatibility complex class I molecules to CD8+ T cells. Physiologically, it is expressed abundantly in immune cells and is induced in somatic cells by cytokines, especially interferon-γ. Recently, variable expression of immunoproteasomes has been demonstrated in different types of cancers. However, the clinical significance of immunoproteasome expression in malignant tumours is poorly understood. In this study, we performed clinicopathological evaluation of immunoproteasome subunit β5i in non-small cell lung carcinomas (NSCLCs). METHODS: Tumour tissues were collected from 155 patients with NSCLCs, and immunohistochemical analysis for β5i was performed in relation to the prognosis of patients. RESULTS: High expression of β5i was found in about 20% of all NSCLCs and was found significantly more frequently (40%) in the adenocarcinoma subset. High expression of β5i was associated with a better 5-year relative survival rate in patients with pStage I to II adenocarcinoma and was also a significant and independent favourable prognostic factor in adenocarcinoma patients. In addition, when we performed in vitro analysis using NSCLC cell lines, combined treatment with the immunoproteasome-specific inhibitor ONX0914 and the proteasome inhibitor MG132 enhanced cell death in β5i-expressing NSCLC cell lines. CONCLUSION: The expression of immunoproteasome can be explored as both a prognostic factor and a potential therapeutic target in NSCLCs. Since immunoproteasomes have crucial role in the antigen presentation, further studies may help to provide essential knowledge for therapeutic strategies in anticancer immunotherapy.
• Spontaneously regressed granulomatosis with polyangiitis: A case report.

  Hiroki Ota, Chisa Sato, Akira Igarashi, Sumito Inoue, Sakiko Masuda, Akihiro Ishizu, Masafumi Watanabe

  Respiratory investigation 59 3 372 - 376 2021年05月 [査読有り][通常論文]
   

  A 71-year-old woman presented with chest pain, cough, and back pain. A chest roentgenogram showed multiple nodular shadows in both lungs. She was diagnosed with granulomatosis with polyangiitis (GPA). The multiple nodular shadows in both lungs regressed spontaneously in a few months. There are few reports of spontaneous regression of GPA, and the underlying mechanism is unclear. Neutrophil extracellular traps (NETs) have been recently shown to be involved in GPA. NETs may also be related to the natural regression of GPA.
• Anti-phosphatidylserine/prothrombin complex antibodies in patients with cutaneous vasculitis: Possible involvement in the pathogenesis.

  Tamihiro Kawakami, Yuto Tamura, Yupeng Dong, Miku Yoshinari, Yuka Nishibata, Sakiko Masuda, Utano Tomaru, Akihiro Ishizu

  The Journal of dermatology 48 5 703 - 706 2021年05月 [査読有り][通常論文]
   

  We assessed the IgG and IgM prevalence of anti-phosphatidylserine/prothrombin complex (aPS/PT) antibodies (Abs) in patients with vasculitis using a novel commercial ELISA kit. To examine whether aPS/PT Abs were involved in the pathogenesis of cutaneous vasculitis, inbred wild-type rats were intravenously administered with a rat IgM class aPS/PT monoclonal Ab established previously or with rat immunoglobulins as controls. To express PS on the surface of vascular endothelium, these rats were given a subcutaneous injection of cell-free histones in advance. Serum IgM aPS/PT Ab levels were elevated in patients with systemic vasculitis with skin involvement and cutaneous arteritis compared to those in patients with systemic vasculitis without skin involvement and healthy controls. There was no significant difference in the serum levels of IgG aPS/PT Abs between the patients and healthy controls. Correspondingly, inbred wild-type rats intravenously administered with the aPS/PT monoclonal IgM Ab after appropriate priming-subcutaneous histone injection developed cutaneous vasculitis. Some rats given rat IgM instead of the aPS/PT monoclonal Ab also developed cutaneous vasculitis, whereas vasculitis did not occur in rats given IgG or only priming by histones. We suggested that IgM aPS/PT Abs could be involved in the pathogenesis of cutaneous vasculitis based on these findings.
• 多発血管炎性肉芽腫症(GPA)の自然退縮における,好中球細胞外トラップ(NETs)分解について 当院で経験した1症例を通して

  太田 啓貴, 佐藤 千紗, 五十嵐 朗, 邨野 浩義, 梁 秀鼎, 町田 浩祥, 佐藤 建人, 中野 寛之, 根本 貴子, 西脇 道子, 木村 友美, 山内 啓子, 佐藤 正道, 井上 純人, 渡辺 昌文, 益田 紗季子, 石津 明洋

  日本呼吸器学会誌 10 増刊 241 - 241 (一社)日本呼吸器学会 2021年04月
• 多発血管炎性肉芽腫症(GPA)の自然退縮における,好中球細胞外トラップ(NETs)分解について 当院で経験した1症例を通して

  太田 啓貴, 佐藤 千紗, 五十嵐 朗, 邨野 浩義, 梁 秀鼎, 町田 浩祥, 佐藤 建人, 中野 寛之, 根本 貴子, 西脇 道子, 木村 友美, 山内 啓子, 佐藤 正道, 井上 純人, 渡辺 昌文, 益田 紗季子, 石津 明洋

  日本呼吸器学会誌 10 増刊 241 - 241 (一社)日本呼吸器学会 2021年04月
• RNase in the saliva can affect the detection of severe acute respiratory syndrome coronavirus 2 by real-time one-step polymerase chain reaction using saliva samples.

  Yuka Nishibata, Shota Koshimoto, Kenta Ogaki, Erika Ishikawa, Kosuke Wada, Miku Yoshinari, Yuto Tamura, Ryo Uozumi, Sakiko Masuda, Utano Tomaru, Akihiro Ishizu

  Pathology, research and practice 220 153381 - 153381 2021年04月 [査読有り][通常論文]
   

  Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a single-stranded RNA virus that causes coronavirus disease 2019, which spread worldwide immediately after the first patient infected with this virus was discovered in Wuhan, China, in December 2019. Currently, polymerase chain reaction (PCR) specimens for the detection of SARS-CoV-2 include saliva, nasopharyngeal swabs, and lower respiratory tract-derived materials such as sputum. Initially, nasopharyngeal swab specimens were applied mainly to the PCR detection of SARS-CoV-2. There was a risk of infection to healthcare workers due to coughing or sneezing by the subjects at the time of sample collection. In contrast, saliva specimens have a low risk of droplet infection and are easy to collect, and their application to PCR testing has been promoted. In this study, we have determined the detection limit of SARS-CoV-2 in saliva samples and examined the effects of storage temperature and storage time of saliva samples on the PCR detection results. As a result, 5 × 103 copies of SARS-CoV-2 could be detected in 1 mL phosphate-buffered saline, whereas 5 × 104 copies of SARS-CoV-2 were needed in 1 mL saliva to detect the virus by real-time one-step PCR. Interestingly, SARS-CoV-2 (5 × 103 copies/mL) could be detected in saliva supplemented with an RNase inhibitor. Concerning the saliva samples supplemented with an RNase inhibitor, the optimal temperature for sample storage was -20 °C, and PCR detection was maintained within 48 h without problems under these conditions. These finding suggest that RNase in the saliva can affect the detection of SARS-CoV-2 by PCR using saliva samples.
• Expression of cathepsins B, D and K in thymic epithelial tumours.

  Naoko Yamaguchi, Utano Tomaru, Takayuki Kiuchi, Akihiro Ishizu, Takahiro Deguchi, Noriyuki Otsuka, Satoshi Tanaka, Katsuji Marukawa, Yoshihiro Matsuno, Masanobu Kitagawa, Masanori Kasahara

  Journal of clinical pathology 74 2 84 - 90 2021年02月 [査読有り][通常論文]
   

  AIM: Cathepsins are proteases that regulate a wide range of physiological processes, including protein turnover, cell signalling and antigen presentation. Recent studies have shown that cathepsins are highly upregulated in many types of tumours. Of the 15 cathepsins in humans, cathepsins V and S are abundantly expressed in the thymus, and we previously showed that the immunostaining of these cathepsins could serve as diagnostic markers for thymic epithelial tumours. However, little is known about the expression of other cathepsins in thymic epithelial tumours. To determine the diagnostic implications of cathepsins, we performed immunohistochemical analysis of cathepsin B (CTB), cathepsin D (CTD) and cathepsin K (CTK), all of which have been reported to correlate with the progression of squamous cell carcinoma. METHODS: The association between cathepsin expression and clinicopathological features was evaluated in 122 cases of thymoma and thymic carcinoma. RESULTS: CTB and CTD were frequently expressed in type A and type AB thymomas. In contrast, CTB and CTD were significantly less common in type B thymomas than in type A or AB thymomas. In type AB thymomas, the expression of CTB correlated with histological features, and was found predominantly in the type A component. Notably, CTK was expressed most commonly in thymic carcinomas, and patients who died of the disease showed increased expression of CTK. CONCLUSIONS: The expression of CTB and CTD correlated with the histological subtype of thymoma. In addition, the expression of CTK appears to be useful for the diagnosis of thymic carcinomas and as a prognostic marker.
• 人工知能による結節性多発動脈炎と皮膚動脈炎の皮膚生検画像の鑑別

  新海 隼人, 加藤 千恵次, 川上 民裕, 高橋 啓, 西端 友香, 益田 紗季子, 田中 敏, 外丸 詩野, 石津 明洋

  脈管学 61 1 1 - 2 (一社)日本脈管学会 2021年01月
• OMAAVの上気道生検組織の病理学的特徴

  宮崎 龍彦, 小林 一博, 新居 俊典, 酒々井 夏子, 石津 明洋, 武曾 理恵, 小川 弥生, 中沢 大悟, 黒川 真奈絵

  脈管学 61 1 1 - 1 (一社)日本脈管学会 2021年01月
• 人工知能による結節性多発動脈炎と皮膚動脈炎の皮膚生検画像の鑑別

  新海 隼人, 加藤 千恵次, 川上 民裕, 高橋 啓, 西端 友香, 益田 紗季子, 田中 敏, 外丸 詩野, 石津 明洋

  脈管学 61 1 1 - 2 (一社)日本脈管学会 2021年01月
• Decreased Proteasomal Function Induces Neuronal Loss and Memory Impairment.

  Utano Tomaru, Tomoki Ito, Yu Ohmura, Kei Higashikawa, Syota Miyajima, Ruka Tomatsu, Tsunehito Higashi, Akihiro Ishizu, Yuji Kuge, Mitsuhiro Yoshioka, Masanori Kasahara

  The American journal of pathology 191 1 144 - 156 2021年01月 [査読有り][通常論文]
   

  Alzheimer disease (AD) is a progressive neurodegenerative disorder and the most common type of dementia worldwide. There is considerable evidence of age-related disruption of proteostasis being responsible for the development of AD. The proteasome is a multicatalytic enzyme complex that degrades both normal and damaged proteins, and an age-related decline in its activity has been implicated in age-related pathologies. Although proteasomal dysfunction is assumed to be a key AD hallmark, it remains unclear whether its role in disease onset is causative or secondary. In this study, we demonstrate that mice with proteasomal dysfunction exhibited memory impairment with associated neuronal loss, accumulation of phosphorylated tau, and activation of endoplasmic reticulum (ER) stress-related apoptosis pathways. Impaired proteasomal activity also activated ER stress-related apoptosis pathways in HT-22, a murine hippocampal neuronal cell line. HT-22 cell death, caused by proteasomal inhibition, was prevented by an inhibitor of c-Jun N-terminal kinase, an ER stress-related molecule. Collective evidence suggests that impaired proteasomal activity alters proteostasis, and subsequent ER stress-mediated pathways play pivotal roles in neuronal loss. Because aging decreases proteasomal function, age-related impairment of proteasomes may be involved in the development and progression of AD in elderly patients.
• Association of Neutrophil Extracellular Traps with the Development of Idiopathic Osteonecrosis of the Femoral Head.

  Mayu Nonokawa, Tomohiro Shimizu, Miku Yoshinari, Yamato Hashimoto, Yusuke Nakamura, Daisuke Takahashi, Tsuyoshi Asano, Yuka Nishibata, Sakiko Masuda, Daigo Nakazawa, Satoshi Tanaka, Utano Tomaru, Norimasa Iwasaki, Akihiro Ishizu

  The American journal of pathology 190 11 2282 - 2289 2020年11月 [査読有り][通常論文]
   

  Idiopathic osteonecrosis of the femoral head (ONFH) is defined as necrosis of osteocytes due to a non-traumatic ischemia of the femoral head. Iatrogenic glucocorticoid administration and habitual alcohol intake are regarded as risk factors. It has been suggested that glucocorticoid-induced activation of platelets contributes to the local blood flow disturbance of the femoral head. Both activated platelets and alcohol can induce neutrophil extracellular traps (NETs). To determine the association of NETs with the development of idiopathic ONFH, surgically resected femoral heads of patients with idiopathic ONFH and osteoarthritis were assessed for existence of NET-forming neutrophils by immunofluorescence staining. NET-forming neutrophils were present in small vessels surrounding the femoral head of patients with idiopathic ONFH but not osteoarthritis. Moreover, Wistar-Kyoto rats were intravenously injected with NET-forming neutrophils or neutrophils without NET induction, and then the ischemic state of the tissue around the femoral head was evaluated by immunohistochemistry for hypoxia-inducible factor-1α. NET-forming neutrophils circulated into the tissue around the femoral head, and hypoxia-inducible factor-1α expression in the tissue was higher compared with that of rats intravenously administered with neutrophils without NET induction. Furthermore, ischemic change of osteocytes was observed in the femoral head of rats given an i.v. injection of NET-forming neutrophils. The collective findings suggest that NETs are possibly associated with the development of idiopathic ONFH.
• 特発性大腿骨頭壊死症の発生における好中球細胞外トラップの関与

  清水 智弘, 野々川 茉佑, 西端 友香, 益田 紗季子, 高橋 大介, 浅野 毅, 田中 敏, 外丸 詩野, 岩崎 倫政, 石津 明洋

  日本整形外科学会雑誌 94 8 S1801 - S1801 (公社)日本整形外科学会 2020年09月
• Immunothrombosis in severe COVID-19.

  Daigo Nakazawa, Akihiro Ishizu

  EBioMedicine 59 102942 - 102942 2020年09月 [査読有り][招待有り]
  
• Infliximab-Induced Granulomatous Vasculitis With Amyloid Deposition in the Tongue of a Patient With Behçet Disease.

  Sari Iwasaki, Toshiyuki Watanabe, Takahiro Tsuji, Takuya Otsuka, Keishi Makita, Yuichiro Fukasawa, Akihiro Ishizu

  Journal of clinical rheumatology : practical reports on rheumatic & musculoskeletal diseases 2020年08月20日 [査読有り][通常論文]
  
• 中小型血管炎(ANCA関連血管炎) 抗好中球細胞質抗体(ANCA)に続き抗糸球体基底膜(GBM)抗体が産生されるメカニズム

  西端 友香, 益田 紗季子, 中沢 大悟, 外丸 詩野, 石津 明洋

  日本リウマチ学会総会・学術集会プログラム・抄録集 64回 507 - 507 (一社)日本リウマチ学会 2020年08月
• 中小型血管炎(ANCA関連血管炎) 抗好中球細胞質抗体(ANCA)に続き抗糸球体基底膜(GBM)抗体が産生されるメカニズム

  西端 友香, 益田 紗季子, 中沢 大悟, 外丸 詩野, 石津 明洋

  日本リウマチ学会総会・学術集会プログラム・抄録集 64回 507 - 507 (一社)日本リウマチ学会 2020年08月
• Fluvastatin prevents the development of arthritis in env-pX rats via up-regulation of Rho GTPase-activating protein 12.

  Shun Tanimura, Mutsumi Nishida, Tatsunori Horie, Tamotsu Kamishima, Hitomi Matsumoto, Yutaka Morimura, Yuka Nishibata, Sakiko Masuda, Daigo Nakazawa, Utano Tomaru, Tatsuya Atsumi, Akihiro Ishizu

  Experimental and molecular pathology 115 104454 - 104454 2020年08月 [査読有り][通常論文]
   

  The pleiotropic effects of statins, including an antiarthritic potential, have been noted. This study aimed to determine the efficacy of statins on rheumatoid arthritis (RA) and clarify how statins affect its pathogenesis. Fluvastatin (500 μg/kg/day) or vehicle was given per os to env-pX rats, which carry the human T-cell leukemia virus type I env-pX gene and spontaneously develop destructive arthritis mimicking RA, for 30 days. Blood sampling and ultrasonography (US) of the ankle joints were conducted on days 0, 10, 20, and 30. On day 30, all rats were euthanized, and the ankle joints were subjected to histological analysis. To clarify how fluvastatin affects the pathogenesis of RA, comprehensive serum exosomal microRNA (miRNA) analysis was performed. Gene expression in the primary culture of synovial fibroblasts derived from arthritic rat and human and non-arthritic rat periarticular tissues was determined quantitatively by real-time reverse transcription-polymerase chain reaction (RT-PCR). As a result, the development of arthritis in env-pX rats was significantly suppressed by fluvastatin, which was evident from the viewpoints of serology, US imaging, and histology. Comprehensive serum exosomal miRNA analysis suggested that the expression of Rho GTPase-activating protein 12 (Arhgap12) was decreased in arthritic env-pX rats but increased with the administration of fluvastatin. Corresponding results were obtained by quantitative RT- PCR using primary culture of synovial fibroblasts. The collective findings suggest that fluvastatin prevents the development of arthritis in env-pX rats via the up-regulation of ARHGAP12. This study suggests that ARHGAP12 can be a possible therapeutic target of RA.
• Survey of Japanese dermatological vasculitis specialists on cases of cutaneous arteritis (cutaneous polyarteritis nodosa).

  Takaharu Ikeda, Tamihiro Kawakami, Yoshihiro Arimura, Naoko Ishiguro, Akihiro Ishizu, Fuyu Ito, Toshiko Ito-Ihara, Naoko Okiyama, Sachiko Ono, Kazuo Suzuki, Koji Sugawara, Mariko Seishima, Masanari Kodera, Maiko Tanaka, Minoru Hasegawa, Fukumi Furukawa, Yukie Yamaguchi, Ayumi Yoshizaki

  The Journal of dermatology 47 5 534 - 537 2020年05月 [査読有り][通常論文]
   

  We developed a questionnaire to examine the findings of cutaneous arteritis among dermatological specialists experienced in vasculitis as certified by the Committee for guidelines for the management of vasculitis and vascular disorders of the Japanese Dermatological Association. We sent a questionnaire to 12 dermatological facilities identified through the revised Committee for guidelines for the management of vasculitis and vascular disorders of the Japanese Dermatological Association. Retrospective data obtained from 84 patients at the 12 dermatological facilities between 2012 January 2016 December were evaluated. The 84 patients were categorized into two groups, a systemic steroid treatment group (group 1, n = 52) and a no systemic steroid treatment group (group 2, n = 32). C-reactive protein in group 1 patients was significantly higher than that in group 2 patients. Frequency of fever, arthritis, myalgia- and peripheral neuropathy in group 1 was significantly higher than that in group 2. We propose that these symptoms could serve as early markers for the transfer from cutaneous arteritis to systemic polyarteritis nodosa. We further suggest that patients who are subsequently associated with cerebral hemorrhage and infarction, who are originally diagnosed as having cutaneous arteritis, could progress to systemic polyarteritis nodosa. The study demonstrated that it is important for dermatologists to detect these findings early in order to establish an accurate diagnosis and a timely treatment.
• 腎生検組織におけるNeutrophil Extracellular Traps(NETs)の検討

  岩崎 沙理, 益田 紗季子, 石津 明洋, 大塚 拓也, 牧田 啓史, 深澤 雄一郎, 辻 隆裕

  日本病理学会会誌 109 1 435 - 435 (一社)日本病理学会 2020年03月
• 肺基礎疾患を有する肺炎患者における分解抵抗性好中球細胞外トラップの形成

  益田 紗季子, 石橋 美郷, 加藤 くるみ, 西端 友香, 田中 敏, 外丸 詩野, 辻野 一三, 石津 明洋

  日本病理学会会誌 109 1 308 - 308 (一社)日本病理学会 2020年03月
• Recombinant thrombomodulin ameliorates autoimmune vasculitis via immune response regulation and tissue injury protection.

  Kanako Watanabe-Kusunoki, Daigo Nakazawa, Yoshihiro Kusunoki, Takashi Kudo, Fumihiko Hattanda, Saori Nishio, Sakiko Masuda, Utano Tomaru, Takeshi Kondo, Tatsuya Atsumi, Akihiro Ishizu

  Journal of autoimmunity 108 102390 - 102390 2020年03月 [査読有り][通常論文]
   

  Anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) is characterized by necrotizing vasculitis with the presence of pathogenic ANCA. ANCA can potentially cause neutrophil activation and induce neutrophil extracellular traps (NETs), resulting in endothelial damage as well as activation of autoreactive B cells and alternative complement pathway. Recombinant thrombomodulin (rTM) protects the endothelium from vascular injury during disseminated intravascular coagulation, thus we hypothesized that rTM ameliorates necrotizing vasculitis in AAV. In this study, rTM was administered in an experimental AAV rat model. Treatment of experimental AAV rats with rTM improved pulmonary hemorrhage and glomerulonephritis, with a suppression of ANCA production and NETs formation. In addition, in vitro experiments showed that rTM bound to neutrophils via Mac-1 (macrophage-1 antigen) and inhibited ANCA-induced NETs formation accompanied by a suppression of histone citrullination, leading to a protection of the endothelium from NETs toxicity. Additionally, rTM affected lymphocytes leading to the inhibition of pro-inflammatory cytokine/chemokin in PBMC during the antibody production process, which might indirectly be involved in the reduction of pathogenic ANCA. Our data revealed that the rTM could ameliorate autoimmune vasculitis through a combination of different biological mechanisms.
• OMAAVの上気道生検組織の組織学的パラメーターの解析

  宮崎 龍彦, 小林 一博, 久松 憲治, 酒々井 夏子, 松本 宗和, 武曾 恵理, 小川 弥生, 中沢 大悟, 石津 明洋, 原渕 保明, 岸部 幹

  脈管学 60 2 19 - 19 (一社)日本脈管学会 2020年02月
• 抗GBM抗体が認識するエピトープの表出に関する検討

  西端 友香, 野々川 茉佑, 益田 紗季子, 中沢 大悟, 田中 敏, 外丸 詩野, 石津 明洋

  脈管学 60 2 19 - 19 (一社)日本脈管学会 2020年02月
• Relationship between lysosomal-associated membrane protein-2 and anti-phosphatidylserine/prothrombin complex antibody in the pathogenesis of cutaneous vasculitis.

  Tamihiro Kawakami, Ayaka Kikuchi, Chie Miyabe, Takaharu Ikeda, Sora Takeuchi, Yuto Tamura, Yuka Nishibata, Sakiko Masuda, Daigo Nakazawa, Utano Tomaru, Akihiro Ishizu

  Clinical and experimental rheumatology 2020年01月27日 [査読有り][通常論文]
   

  OBJECTIVES: We investigated the relationship between lysosomal-associated membrane protein-2 (LAMP-2) and anti-phosphatidylserine/prothrombin (PS/PT) antibody in the pathogenesis of cutaneous vasculitis. METHODS: Cell surface LAMP-2 expression of human neutrophils was measured using flow cytometry. Twenty inbred wild-type Wistar-King-Aptekman-Hokudai (WKAH) rats were divided into four groups: Group 1, rabbit IgG injection only as negative control (n=5); Group 2, both histone and rabbit IgG injection (n=5); Group 3, anti-LAMP-2 antibody injection only (n=5); and Group 4, both histone and anti-LAMP-2 antibody injection (n=5). Ten WKAH rats were divided into two groups: Group A, histone, anti-PS/PT antibody, and anti-LAMP-2 antibody injection (n=5), and Group B, histone, anti-PS/PT antibody, and rabbit IgG injection as control (n=5). RESULTS: LAMP-2 expression on human neutrophils was induced by cell-free histone exposure in a dose- and time-dependent manner. Histopathological examination revealed the recruitment of neutrophils in cutaneous small vessels in all Group 4 rats. These observations were not evident in systemic organs other than the skin. LAMP-2 expression on the surface of vascular endothelial cells was evident in Group 2, exclusively in the skin, but not in Group 1. Thrombi were detected in various organs in all Groups A and B rats. However, no apparent thrombi were observed in the skin. CONCLUSIONS: Anti-PS/PT and anti-LAMP-2 antibodies are responsible for independent effector mechanisms in the rats given intravenous injection of cell-free histones. We considered that undetermined factors other than cell-free histones could be required for the induction of cutaneous vasculitis by anti-PS/PT and anti-LAMP-2 antibodies.
• JCS 2017 Guideline on Management of Vasculitis Syndrome - Digest Version.

  Mitsuaki Isobe, Koichi Amano, Yoshihiro Arimura, Akihiro Ishizu, Shuichi Ito, Shinya Kaname, Shigeto Kobayashi, Yoshinori Komagata, Issei Komuro, Kimihiro Komori, Kei Takahashi, Kazuo Tanemoto, Hitoshi Hasegawa, Masayoshi Harigai, Shouichi Fujimoto, Tatsuhiko Miyazaki, Tetsuro Miyata, Hidehiro Yamada, Akitoshi Yoshida, Takashi Wada, Yoshinori Inoue, Haruhito A Uchida, Hideki Ota, Takahiro Okazaki, Mitsuho Onimaru, Tamihiro Kawakami, Reiko Kinouchi, Atsushi Kurata, Hisanori Kosuge, Ken-Ei Sada, Kunihiro Shigematsu, Eiichi Suematsu, Eijun Sueyoshi, Takahiko Sugihara, Hitoshi Sugiyama, Mitsuhiro Takeno, Naoto Tamura, Michi Tsutsumino, Hiroaki Dobashi, Yoshikazu Nakaoka, Kenji Nagasaka, Yasuhiro Maejima, Hajime Yoshifuji, Yoshiko Watanabe, Shoichi Ozaki, Takeshi Kimura, Hiroshi Shigematsu, Keiko Yamauchi-Takihara, Toyoaki Murohara, Shin-Ichi Momomura

  Circulation journal : official journal of the Japanese Circulation Society 84 2 299 - 359 2020年01月24日 [査読有り][通常論文]
  
• Thrombomodulin as a Physiological Modulator of Intravascular Injury.

  Kanako Watanabe-Kusunoki, Daigo Nakazawa, Akihiro Ishizu, Tatsuya Atsumi

  Frontiers in immunology 11 575890 - 575890 2020年 [査読有り][通常論文]
   

  Thrombomodulin (TM), which is predominantly expressed on the endothelium, plays an important role in maintaining vascular homeostasis by regulating the coagulation system. Intravascular injury and inflammation are complicated physiological processes that are induced by injured endothelium-mediated pro-coagulant signaling, necrotic endothelial- and blood cell-derived damage-associated molecular patterns (DAMPs), and DAMP-mediated inflammation. During the hypercoagulable state after endothelial injury, TM is released into the intravascular space by proteolytic cleavage of the endothelium component. Recombinant TM (rTM) is clinically applied to patients with disseminated intravascular coagulation, resulting in protection from tissue injury. Recent studies have revealed that rTM functions as an inflammatory regulator beyond hemostasis through various molecular mechanisms. More specifically, rTM neutralizes DAMPs, including histones and high mobility group box 1 (HMGB1), suppresses excessive activation of the complement system, physiologically protects the endothelium, and influences both innate and acquired immunity. Neutrophil extracellular traps (NETs) promote immunothrombosis by orchestrating platelets to enclose infectious invaders as part of the innate immune system, but excessive immunothrombosis can cause intravascular injury. However, rTM can directly and indirectly regulate NET formation. Furthermore, rTM interacts with mediators of acquired immunity to resolve vascular inflammation. So far, rTM has shown good efficacy in suppressing inflammation in various experimental models, including thrombotic microangiopathy, sterile inflammatory disorders, autoimmune diseases, and sepsis. Thus, rTM has the potential to become a novel tool to regulate intravascular injury via pleiotropic effects.
• Simultaneous development of IgA vasculitis and eosinophilic granulomatosis with polyangiitis.

  Yosuke Asano, Yoshinori Matsumoto, Tatsuhiko Miyazaki, Akihiro Ishizu, Shin Morizane, Keigo Hayashi, Yuriko Yamamura, Sumie Hiramatsu, Yoshia Miyawaki, Michiko Morishita, Keiji Ohashi, Haruki Watanabe, Katsue Sunahori Watanabe, Tomoko Kawabata, Ken-Ei Sada, Hirofumi Makino, Jun Wada

  Modern rheumatology case reports 4 1 63 - 69 2020年01月 [査読有り][通常論文]
   

  Immunoglobulin A (IgA) vasculitis (IgAV) is a small vessel vasculitis presenting cutaneous purpura, arthralgias and/or arthritis, acute enteritis and glomerulonephritis caused by deposition of the IgA1-mediated immune complex. Eosinophilic granulomatosis with polyangiitis (EGPA) is an anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) characterised by eosinophil-rich and granulomatous inflammation in small to medium-sized vessels. Both IgAV and EGPA are classified as autoimmune systemic vasculitis, but the pathogenesis of immune complex-mediated IgAV and that of pauci-immune EGPA are different. Here we report a rare case of simultaneous development of IgAV and EGPA presenting palpable purpura and numbness in a patient with a history of asthma. Histological examination revealed leukocytoclastic vasculitis with deposition of IgA, IgM and C3 in the upper dermis and necrotising vasculitis with eosinophilic infiltration and granulomatous formation in the lower dermis and subcutaneous fat, indicating the existence of IgAV and EGPA. Our case provides evidence of concurrent development of two different types of vasculitis, which may affect disease-associated complications, therapeutic strategy and prognosis.
• A histopathological report of a 16-year-old male with peripheral pulmonary artery stenosis and Moyamoya disease with a homozygous RNF213 mutation.

  Kei Takahashi, Junichi Nakamura, Shinya Sakiyama, Toshitaka Nakaya, Takahiro Sato, Taku Watanabe, Hiroshi Ohira, Keishi Makita, Utano Tomaru, Akihiro Ishizu, Ichizo Tsujino

  Respiratory medicine case reports 29 100977 - 100977 2020年 [査読有り][通常論文]
   

  Peripheral pulmonary artery stenosis (PPAS) is a rare pulmonary vasculopathy characterized by multiple stenoses and obstructions in the peripheral pulmonary arteries. PPAS often develops in children with congenital diseases such as Williams syndrome and Alagille syndrome; however, recent studies have reported PPAS cases in adults with Moyamoya disease (MMD). Recent genetic studies have demonstrated that ring finger protein 213 (RNF213) is a susceptibility gene for MMD. However, the pathophysiology of combined PPAS and MMD and the relationship between the two diseases remain largely unknown. Here we report a case of PPAS in a 16-year-old male, with a history of MMD, who died suddenly at 24. An autopsy was performed, and remarkable pathological changes were identified in the pulmonary arteries and in other arteries. Furthermore, genetic analysis revealed that the patient had a homozygous c.14576G > A (p.R4859K) mutation in RNF213. This is the first report to demonstrate the histopathology of systemic arteriopathy in a case with MMD and PPAS with a confirmed homozygous RNF213 mutation. We also review immunohistochemical data from the case and discuss how RNF213 mutation could have resulted in the observed vascular abnormalities.
• Native myeloperoxidase is required to make the experimental vasculitis model.

  Mayu Nonokawa, Ku Suzuki, Hideyuki Hayashi, Yuka Nishibata, Sakiko Masuda, Daigo Nakazawa, Satoshi Tanaka, Utano Tomaru, Akihiro Ishizu

  Arthritis research & therapy 21 1 296 - 296 2019年12月21日 [査読有り][通常論文]
  
• 【NETsにまつわる様々な病態】自己免疫疾患とNETs

  楠 加奈子, 楠 由宏, 中沢 大悟, 石津 明洋

  Thrombosis Medicine 9 4 296 - 303 (株)先端医学社 2019年12月 

  好中球細胞外トラップ(NETs)は好中球の貪食とは異なる自然免疫機構である。NETsは細胞内殺菌蛋白やヒストンを混合したDNA線維を細胞外に放出して、効率よく微生物を殺菌するが、過剰なNETsの形成やNETsの分解障害は、抗好中球細胞質抗体関連血管炎や全身性エリテマトーデスなどの自己免疫疾患の悪循環病態に関与する。現在まで、様々な自己免疫疾患でNETsを標的とした治療の効果が示されてきており、今後の臨床応用の可能性について解説する。(著者抄録)
• 皮膚血管炎の発症機序における抗リソソーム膜タンパク2抗体(抗LAMP2抗体)と抗ホスファチジルセリン・プロトロンビン複合体抗体(抗PSPT抗体)の役割

  川上 民裕, 宮部 千恵, 池田 高治, 菊池 彩花, 西端 友香, 益田 紗季子, 石津 明洋, 中沢 大悟, 外丸 詩野

  日本皮膚科学会雑誌 129 12 2533 - 2533 (公社)日本皮膚科学会 2019年11月
• Detection of Increased Vascular Signal in Arthritis-Prone Rats Without Joint Swelling Using Superb Microvascular Imaging Ultrasonography.

  Tatsunori Horie, Mutsumi Nishida, Shun Tanimura, Tamotsu Kamishima, Erika Tamai, Yutaka Morimura, Yuka Nishibata, Sakiko Masuda, Daigo Nakazawa, Utano Tomaru, Tatsuya Atsumi, Akihiro Ishizu

  Ultrasound in medicine & biology 45 8 2086 - 2093 2019年08月 [査読有り][通常論文]
   

  This study aimed to determine whether ultrasonography (US) can detect increased vascular signal in the synovial tissue before overt synovitis in rheumatoid arthritis (RA). Env-pX rats that spontaneously develop RA-like synovitis were used. Ankle joints of 15 pre-morbid env-pX rats were observed with power Doppler and superb microvascular imaging (SMI) using an ultrahigh-frequency (8-24 MHz) probe. Signal values were counted as the number of pixels. The total number of vessels and vessel area in the synovial tissue were histologically evaluated. Dilated vessels were determined from the mean value of synovial vessels in three wild-type rats. In all env-pX rats, apparent synovial proliferation was not observed. However, vasodilation was evident. Only SMI values were significantly correlated with the number of dilated vessels (r = 0.585, p = 0.022) but not with the total number of vessels. US with SMI using ultrahigh-frequency probe can detect increased vascular signal in the synovial tissue of arthritis-prone rats.
• 皮膚動脈炎(皮膚型結節性多発動脈炎)の全国アンケート調査結果

  川上 民裕, 有村 義宏, 池田 高治, 石黒 直子, 石津 明洋, 伊藤 吹夕, 猪原 登志子, 沖山 奈緒子, 小野 さち子, 鈴木 和男, 菅原 弘二, 清島 真理子, 小寺 雅也, 田中 麻衣子, 長谷川 稔, 古川 福実, 山口 由衣, 吉崎 歩, 日本皮膚科学会血管炎・血管障害診療ガイドライン改訂委員会

  日本皮膚科学会雑誌 129 9 1901 - 1907 (公社)日本皮膚科学会 2019年08月 [査読有り][通常論文]
   

  本邦における皮膚動脈炎(皮膚型結節性多発動脈炎)の現状を把握するため、日本皮膚科学会血管炎・血管障害診療ガイドライン改訂委員会に所属している全国12施設にアンケート調査を行った。対象は、2012年1月から2016年12月までの5年間である。平均約3年間の観察期間において、発熱・脳出血・脳梗塞が1割強の症例でみられた。また、関節痛・関節炎ありが37%、筋痛・筋炎ありが21%、末梢神経障害ありが33%に認められた。加えて、ステロイド全身投与治療が半数症例で施行されていた。随伴症状を呈した症例は、皮膚限局とは必ずしも言えず、全身性の結節性多発動脈炎への移行の可能性を推測させた。(著者抄録)
• Retinal vasculitis in primary Sjögren's syndrome.

  Toshiyuki Watanabe, Yayoi Marumo, Akihiro Ishizu

  Rheumatology (Oxford, England) 58 7 1244 - 1244 2019年07月01日 [査読有り][通常論文]
  
• The presence of anti-neutrophil extracellular trap antibody in patients with microscopic polyangiitis.

  Fumihiko Hattanda, Daigo Nakazawa, Kanako Watanabe-Kusunoki, Yoshihiro Kusunoki, Haruki Shida, Sakiko Masuda, Saori Nishio, Utano Tomaru, Tatsuya Atsumi, Akihiro Ishizu

  Rheumatology (Oxford, England) 58 7 1293 - 1298 2019年07月01日 [査読有り][通常論文]
   

  OBJECTIVE: Although ANCA is the major autoantibody in patients with ANCA-associated vasculitis, previous studies have suggested the presence of anti-neutrophil extracellular trap (NET) antibody in patients with microscopic polyangiitis (MPA), one type of ANCA-associated vasculitis. In this study, we aimed to determine the prevalence and pathogenic role of anti-NET antibody (ANETA) in MPA. METHODS: We examined the presence or absence of ANETA in sera obtained from 19 MPA patients by indirect immunofluorescence. We compared the clinical parameters, including age, sex, MPO-ANCA, creatinine, CRP, MPO-DNA complexes and vasculitis activity, in ANETA-positive and ANETA-negative MPA patients. We investigated the serum NET induction and degradation abilities of ANETA-positive and ANETA-negative MPA patients with reference to healthy controls (n = 8). Furthermore, we assessed the relationship between ANETA and the effect of IgG depletion on the serum NET degradation ability. RESULTS: ANETA was present in 10 of the 19 MPA patients. There was no significant difference in the clinical parameters in ANCA-positive and ANCA-negative MPA patients. Although the NET induction ability was higher and the NET degradation ability was lower in MPA sera than those in healthy controls, these abilities were not different between ANETA-positive and ANETA-negative MPA sera. Interestingly, the NET degradation ability in some sera with ANETA was markedly increased by IgG depletion. CONCLUSION: Some MPA patients produce ANETA and some ANETA possess an inhibitory function against the serum NET degradation ability. Although further studies are needed, ANETA is worthy of attention in order to understand the pathophysiology of MPA.
• 特発性大腿骨頭壊死症の発生における好中球細胞外トラップの関与

  野々川 茉佑, 西端 友香, 益田 紗季子, 石津 明洋, 清水 智弘, 高橋 大介, 浅野 毅, 岩崎 倫政, 田中 敏, 外丸 詩野

  北海道医学雑誌 94 1 59 - 59 北海道医学会 2019年05月
• Chest High-Resolution CT Findings of Microscopic Polyangiitis: A Japanese First Nationwide Prospective Cohort Study.

  Aika Suzuki, Susumu Sakamoto, Atsuko Kurosaki, Yasuyuki Kurihara, Keita Satoh, Yusuke Usui, Toshihiro Nanki, Yoshihiro Arimura, Hirofumi Makino, Yasunori Okada, Masayoshi Harigai, Kunihiro Yamagata, Hitoshi Sugiyama, Hiroaki Dobashi, Akihiro Ishizu, Naotake Tsuboi, Joichi Usui, Ken-Ei Sada, Sakae Homma

  AJR. American journal of roentgenology 1 - 11 2019年04月11日 [査読有り][通常論文]
   

  OBJECTIVE: The lung is one of the organs possibly involved in microscopic polyangiitis (MPA), and myeloperoxidase (MPO) antineutrophil cytoplasmic antibody (ANCA) is commonly found in patients with MPA. The aim of this study was to assess pulmonary lesions in Japanese patients with MPA. SUBJECTS AND METHODS: This prospective study was based on 144 patients with MPA who were enrolled in the Remission Induction Therapy in Japanese Patients With ANCA-Associated Vasculitis and Rapidly Progressive Glomerulonephritis Study and who underwent chest high-resolution CT (HRCT) imaging at the time of diagnosis during 2011-2014. We reviewed the electronic case report forms of patients with MPA who did and did not have interstitial pneumonia (IP), and the clinical features and laboratory findings of these groups were compared. RESULTS: Abnormal HRCT findings were noted in 134 of the 144 patients (93%). Chest HRCT findings included ground-glass opacity (n = 72; 50%), reticulation (n = 69; 48%), traction bronchiectasis (n = 57; 42%), honeycombing (n = 44; 31%), and emphysema (n = 32; 22%). IP was diagnosed radiologically in 74 patients (51%), 38% of whom had the usual IP (UIP) pattern. Ground-glass opacity, reticulation, traction bronchiectasis, honeycombing, and interlobular septal thickening were frequent in patients with IP (p < 0.05). Patients with MPA with the UIP or possible UIP pattern also had minor findings, such as bronchial wall thickening, consolidation, increased attenuation around honeycombing, and traction bronchiectasis. CONCLUSION: IP (51%) was most commonly observed in Japanese patients with MPA, and 38% of these patients exhibited a UIP pattern. Increased attenuation around honeycombing or traction bronchiectasis was also found.
• 抗GBM抗体が認識するエピトープの表出に関する検討

  西端 友香, 東 里緒, 益田 紗季子, 中沢 大悟, 田中 敏, 外丸 詩野, 石津 明洋

  日本病理学会会誌 108 1 298 - 298 (一社)日本病理学会 2019年04月
• ANCA関連血管炎(AAV)の壊死性病変部における好中球細胞外トラップ(NETs)の存在と病的意義

  益田 紗季子, 野々川 茉佑, 西端 友香, 岩崎 沙理, 辻 隆裕, 田中 敏, 外丸 詩野, 川上 民裕, 石津 明洋

  日本病理学会会誌 108 1 327 - 327 (一社)日本病理学会 2019年04月
• Formation and Disordered Degradation of Neutrophil Extracellular Traps in Necrotizing Lesions of Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis.

  Sakiko Masuda, Mayu Nonokawa, Emika Futamata, Yuka Nishibata, Sari Iwasaki, Takahiro Tsuji, Yutaka Hatanaka, Daigo Nakazawa, Satoshi Tanaka, Utano Tomaru, Tamihiro Kawakami, Tatsuya Atsumi, Akihiro Ishizu

  The American journal of pathology 189 4 839 - 846 2019年04月 [査読有り][通常論文]
   

  Antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) is characterized by the production of ANCAs and systemic necrotizing vasculitis in small vessels. Disordered regulation of neutrophil extracellular traps (NETs) is critically involved in the pathogenesis of AAV. NETs are web-like DNA decorated with antimicrobial proteins; they are extruded from activated neutrophils. The principal degradation factor of NETs in vivo is DNase I; however, NETs resistant to DNase I can persist in tissues and can lead to the production of ANCAs. Deposition of NETs has been demonstrated in glomerular crescents and necrotizing vasculitis in AAV. Here, the amount of NETs in formalin-fixed, paraffin-embedded tissue sections was examined, and the results for AAV were compared with the results for diseases that should be distinguished from AAV. NETs were more abundant in necrotizing vasculitis of AAV than in non-ANCA-associated vasculitis, or in granulomatous angiitis. Pulmonary granulomas in AAV and non-ANCA-associated diseases were further studied. The amount of NETs was significantly greater in necrotizing granulomas of AAV than in granulomas of sarcoidosis without necrosis. Although NETs were formed in necrotizing granulomas of tuberculosis equivalently to those formed in AAV, they were more susceptible to degradation by DNase I than were NETs in AAV. The formation and disordered degradation of NETs in necrotizing lesions are characteristics of AAV and are possibly related to its pathogenesis.
• Epitope recognized by anti-glomerular basement membrane (GBM) antibody in a patient with repeated relapse of anti-GBM disease.

  Yuka Nishibata, Sakiko Masuda, Daigo Nakazawa, Satoshi Tanaka, Utano Tomaru, Mandkhai Nergui, Xiaoyu Jia, Zhao Cui, Ming-Hui Zhao, Kimimasa Nakabayashi, Akihiro Ishizu

  Experimental and molecular pathology 107 165 - 170 2019年04月 [査読有り][通常論文]
   

  The major epitopes recognized by autoantibodies in anti-glomerular basement membrane (GBM) disease are found in the α3-subunit non-collagenous domain of type IV collagen [α3(IV)NC1], which is present in the glomerular and alveolar basement membranes. These epitopes are structurally cryptic, owing to the hexamer formation of the non-collagenous domain of α3, α4, and α5 subunits and are expressed by the dissociation of the hexamer. Anti-GBM disease usually manifests as a single attack (SA), and we rarely see patients who repeatedly relapse. We recently treated a patient with anti-GBM disease who exhibited repeated relapse (RR). Here, we conducted immunohistochemistry of formalin-fixed paraffin-embedded normal kidney sections and immunoblotting using recombinant human α3(IV)NC1 to compare the epitopes recognized by anti-GBM antibodies in the RR patient and SA patients. Although a clear staining of GBM especially in the connecting basement membrane of Bowman's capsule was observed when IgGs of SA patients were used as primary antibodies, such staining was not obtained when IgG of the RR patient was employed. In immunoblotting of α3(IV)NC1 using the IgG of the RR patient as a primary antibody, an 18-kDa band was detected besides the 56.8-kDa band corresponding to the whole-size α3(IV)NC1. Whereas the 56.8-kDa band disappeared after digestion of the recombinant α3(IV)NC1 by protease, the 18-kDa band remained. Furthermore, the 18-kDa band was not detected by a commercially available anti-α3(IV)NC1 monoclonal antibody. These findings suggest that the IgG of the RR patient recognizes the epitope distinct from that recognized by the anti-α3(IV)NC1 monoclonal antibody.
• Pharmaceutical immunoglobulins reduce neutrophil extracellular trap formation and ameliorate the development of MPO-ANCA-associated vasculitis.

  Ryo Uozumi, Risa Iguchi, Sakiko Masuda, Yuka Nishibata, Daigo Nakazawa, Utano Tomaru, Akihiro Ishizu

  Modern rheumatology 30 3 1 - 7 2019年04月01日 [査読有り][通常論文]
   

  OBJECTIVES: Intravenous immunoglobulin (IVIG) therapy is effective against some autoimmune diseases. We examined the effects of pharmaceutical immunoglobulins on the development of MPO-ANCA-associated vasculitis (MPO-AAV). METHODS: Peripheral blood neutrophils were pretreated with 5 mg/ml sulfo-immunoglobulins (IVIG-S) and then exposed to 100 nM phorbol myristate acetate (PMA). Thereafter, neutrophil extracellular traps (NETs) were detected by flow cytometry. Next, Wistar-Kyoto rats were given oral administration of 10 mg/kg/day propylthiouracil for 28 days and intraperitoneal (i.p.) injection of 1 μg PMA on days 0 and 7. These rats were divided into two groups: Group 1 with i.p. injection of 400 mg/kg IVIG-S on days 8-12 and Group 2 with vehicle similarly. ANCA titers were chronologically determined by indirect immunofluorescence. On day 28, all rats were killed to examine NET formation in the peritoneum and the development of AAV. RESULTS: IVIG-S significantly inhibited NET formation induced by PMA in vitro. NET amounts in the peritoneum in Group 1 were significantly smaller than in Group 2, and ANCA titers in Group 1 were significantly lower than in Group 2. The degree of pulmonary hemorrhage in Group 1 was also smaller than in Group 2. CONCLUSION: IVIG-S reduce NET formation and ameliorate the development of MPO-AAV.
• A case report dysregulated neutrophil extracellular traps in a patient with propylthiouracil-induced anti-neutrophil cytoplasmic antibody-associated vasculitis.

  Kanako Watanabe-Kusunoki, Nobuya Abe, Daigo Nakazawa, Kohei Karino, Fumihiko Hattanda, Yuichiro Fujieda, Saori Nishio, Shinsuke Yasuda, Akihiro Ishizu, Tatsuya Atsumi

  Medicine 98 17 e15328  2019年04月 [査読有り][通常論文]
   

  RATIONALE: Neutrophil extracellular traps (NETs) are immune defence systems that release extracellular chromatin and myeloid granules including myeloperoxidase (MPO) to kill pathogens. An experimental animal study recently demonstrated that disordered NETs induced by propylthiouracil (PTU) could contribute to the production of MPO anti-neutrophil cytoplasmic antibody (ANCA) and the development of ANCA-associated vasculitis (AAV). However, the role of dysregulated NETs in the pathogenesis of human AAV remains unclear. PATIENT CONCERNS: We report a 19-year-old woman with Graves' disease on PTU presented fever, polyarthralgia, and lung hemorrhage with high titer of MPO-ANCA. This patient had a variety of atypical ANCAs and disordered NETs in vitro. DIAGNOSES: A diagnosis of PTU-induced AAV (PTU-AAV). INTERVENTIONS: The PTU was discontinued and she was treated with immunosuppressants and plasmapheresis for reducing pathogenic autoantibodies. OUTCOMES: Clinical manifestations including fever, polyarthralgia, and lung hemorrhage were on remission with a decrease of dysregulated NETs. LESSONS: The clinical course of this PTU-AAV case indicated that dysregulated NETs would play a role in the development of ANCA and the pathogenesis of AAV.
• Eosinophilic granulomatosis with polyangiitis mimicking peripheral T-cell lymphoma, not otherwise specified.

  Kawauchi M, Watanabe T, Hattori T, Suzuki A, Ishizu A, Jodo S

  Scandinavian journal of rheumatology 48 2 171 - 172 2019年03月 [査読有り][通常論文]
  
• 抗糸球体基底膜抗体病(抗GBM病)の頻回再発症例の抗GBMが認識するエピトープ

  西端 友香, 東 里緒, 益田 紗季子, 中沢 大悟, 田中 敏, 外丸 詩野, 中林 公正, 石津 明洋

  脈管学 59 3 19 - 19 (一社)日本脈管学会 2019年03月
• ヒストンは好中球細胞上にLAMP2を表出し、抗LAMP2抗体と連携して皮膚小血管炎の発症機序に関与している

  川上 民裕, 竹内 そら, 菊池 彩翔, 西端 友香, 益田 紗季子, 外丸 詩野, 石津 明洋

  脈管学 59 3 22 - 22 (一社)日本脈管学会 2019年03月
• ANCA関連血管炎の壊死性病変部における好中球細胞外トラップの存在と病的意義

  益田 紗季子, 西端 友香, 中沢 大悟, 外丸 詩野, 川上 民裕, 渥美 達也, 石津 明洋

  日本リウマチ学会総会・学術集会プログラム・抄録集 63回 777 - 777 (一社)日本リウマチ学会 2019年03月
• Histopathological classification of anti-neutrophil cytoplasmic antibody-associated glomerulonephritis in a nationwide Japanese prospective 2-year follow-up cohort study.

  Kunihiro Yamagata, Joichi Usui, Michio Nagata, Hitoshi Sugiyama, Ken-Ei Sada, Eri Muso, Masayoshi Harigai, Koichi Amano, Tatsuya Atsumi, Shouichi Fujimoto, Yukio Yuzawa, Masaki Kobayashi, Takao Saito, Takafumi Ito, Nobuhito Hirawa, Sakae Homma, Hiroaki Dobashi, Naotaka Tsuboi, Akihiro Ishizu, Yoshihiro Arimura, Hirofumi Makino, Seiichi Matsuo

  Clinical and experimental nephrology 23 3 387 - 394 2019年03月 [査読有り][通常論文]
   

  BACKGROUND: The prognostic value of the EUVAS-proposed histopathological classification of anti-neutrophil cytoplasmic antibody (ANCA)-associated glomerulonephritis has been evaluated throughout the world. Here, we performed a Japanese nationwide biopsy survey to assess the association between this histopathological classification and renal prognosis after 2-year follow-up in ANCA-associated glomerulonephritis. METHODS: We collected 67 renal biopsy materials of the 321 entries in the RemIT-JAV-RPGN cohort study, and assessed their histologies. Based on the EUVAS-proposed histopathological classification and some histological parameters, we statistically evaluated renal survival and the comparison of renal function for 2 years. RESULTS: Based on the histopathological classification, the largest number of biopsy samples belonged to the Focal class, followed by the Mixed, Crescentic, and Sclerotic classes (n = 30, 19, 10, 8, respectively). Although the number of events might be too low (four patients with renal death) to make this conclusion, the Focal and Mixed classes had higher renal-survival rates compared to the others in the renal-survival curve. Comparing renal function among all classes, the estimated glomerular filtration rate (eGFR) throughout 2-year follow-up period was significantly higher in the Focal class compared to the other 3 classes. The eGFR-values in the Crescentic, Mixed, and Sclerotic classes increased with time. Based on both combined results, the Focal class could be the best prognosis. CONCLUSION: This histopathological classification was valuable for both the stratification of renal function and the estimation of partial renal survival during 2-year follow-up in ANCA-associated glomerulonephritis.
• Author Correction: Pathogenesis and therapeutic interventions for ANCA-associated vasculitis.

  Daigo Nakazawa, Sakiko Masuda, Utano Tomaru, Akihiro Ishizu

  Nature reviews. Rheumatology 15 2 123 - 123 2019年02月 

  In the originally published online version of this article there were errors in the Supplementary Information. All three Supplementary Tables had incorrectly numbered references. These errors have now been corrected in the HTML and PDF versions of the manuscript.
• Pathogenesis and therapeutic interventions for ANCA-associated vasculitis.

  Daigo Nakazawa, Sakiko Masuda, Utano Tomaru, Akihiro Ishizu

  Nature reviews. Rheumatology 15 2 91 - 101 2019年02月 [査読有り][招待有り]
   

  Anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) affects systemic small vessels and is accompanied by the presence of ANCAs in the serum. This disease entity includes microscopic polyangiitis, granulomatosis with polyangiitis, eosinophilic granulomatosis with polyangiitis and drug-induced AAV. Similar to other autoimmune diseases, AAV develops in patients with a predisposing genetic background who have been exposed to causative environmental factors. The mechanism by which ANCAs cause vasculitis involves ANCA-mediated excessive activation of neutrophils that subsequently release inflammatory cytokines, reactive oxygen species and lytic enzymes. In addition, this excessive activation of neutrophils by ANCAs induces formation of neutrophil extracellular traps (NETs). Although NETs are essential elements in innate immunity, excessive NET formation is harmful to small vessels. Moreover, NETs are involved not only in ANCA-mediated vascular injury but also in the production of ANCAs themselves. Therefore, a vicious cycle of NET formation and ANCA production is considered to be involved in the pathogenesis of AAV. In addition to this role of NETs in AAV, some other important discoveries have been made in the past few years. Incorporating these new insights into our understanding of the pathogenesis of AAV is needed to fully understand and ultimately overcome this disease.
• The Diagnostic and Clinical Utility of the Myeloperoxidase-DNA Complex as a Biomarker in Otitis Media With Antineutrophil Cytoplasmic Antibody-associated Vasculitis.

  Shinya Morita, Yuji Nakamaru, Daigo Nakazawa, Masanobu Suzuki, Kimiko Hoshino, Atsushi Fukuda, Fumihiko Hattanda, Kanako Kusunoki, Utano Tomaru, Akihiro Ishizu, Akihiro Homma

  Otology & neurotology : official publication of the American Otological Society, American Neurotology Society [and] European Academy of Otology and Neurotology 40 2 e99-e106  2019年02月 [査読有り][通常論文]
   

  OBJECTIVE: This prospective study aimed to evaluate the diagnostic and clinical utility of the myeloperoxidase (MPO)-DNA complex as a NETosis-derived product in the middle ear fluid of patients with otitis media with antineutrophil cytoplasmic antibody-associated vasculitis (OMAAV). STUDY DESIGN: Prospective study. SETTING: Tertiary referral center. PATIENTS: Twenty-two patients diagnosed with OMAAV. INTERVENTION: Collection of the fluid samples from middle ear. MAIN OUTCOME MEASURE: The levels of the MPO-DNA complex in the fluid samples were quantified using an enzyme-linked immunosorbent assay. RESULTS: Patients with both systemic and localized forms of OMAAV showed significantly higher levels of the MPO-DNA complex compared to the controls (p < 0.001 and p = 0.002, respectively). In particular, they showed significantly higher levels of MPO-DNA complex compared to the controls, regardless of serum antineutrophil cytoplasmic antibody status (p < 0.001 and p < 0.001, respectively) or immunosuppressive therapy (p < 0.001 and p < 0.001, respectively) at the time of sampling. An optical density cutoff value of 0.16 at 405 nm according to the receiver operating characteristic curve showed a sensitivity of 86.4%, specificity of 95.5%, positive predictive value of 95.0% and negative predictive value of 87.5% for the diagnosis of OMAAV. Significant positive correlations were observed between the levels of MPO-DNA complex and the values for air conduction - (r = 0.49, p = 0.022) and bone conduction - pure tone average thresholds (r = 0.45, p = 0.035). CONCLUSIONS: The detection and quantification of the MPO-DNA complex in the otitis media fluid may aid in providing a definite diagnosis as well as predicting the activity and severity of OMAAV.
• Restricted Expression of the Thymoproteasome Is Required for Thymic Selection and Peripheral Homeostasis of CD8+ T Cells.

  Utano Tomaru, Saori Konno, Syota Miyajima, Rikuto Kimoto, Mari Onodera, Shizuka Kiuchi, Shigeo Murata, Akihiro Ishizu, Masanori Kasahara

  Cell reports 26 3 639 - 651 2019年01月15日 [査読有り][通常論文]
   

  The thymoproteasome subunit β5t is specifically expressed in cortical thymic epithelial cells (TECs) and generates unique peptides to support positive selection. In this study, using a mouse model ubiquitously expressing β5t, we showed that aberrant expression of self-peptides generated by β5t affects CD8+ T cell homeostasis, including thymic selection and maintenance of the peripheral naive pool of CD8+ T cells. In mice in which β5t was expressed both in cortical and medullary TECs, the abundance of CD8+ lineage thymocytes was reduced, and extra-thymic expression of β5t caused accumulation of CD8+ T cells with the memory or exhausted phenotype and induced autoreactive T cell responses. We found that thymoproteasomes are essential for positive selection but that the subsequent change in peptide repertoire in the medulla is also crucial for thymic selection and that β5t-derived peptide must be confined to the thymus to avoid autoimmunity in peripheral tissues.
• Detection of Autoreactive Type II NKT Cells: A Pilot Study of Comparison Between Healthy Individuals and Patients with Vasculitis.

  Yusuke Nishioka, Takaomi Sonoda, Haruki Shida, Yoshihiro Kusunoki, Fumihiko Hattanda, Shun Tanimura, Ryo Uozumi, Mai Yamada, Yuka Nishibata, Sakiko Masuda, Daigo Nakazawa, Utano Tomaru, Tatsuya Atsumi, Akihiro Ishizu

  Cytometry. Part A : the journal of the International Society for Analytical Cytology 93 11 1157 - 1164 2018年11月 [査読有り][通常論文]
   

  NKT cells are defined as T cells that recognize hydrophobic antigens presented by class I MHC-like molecules, including CD1d. Among CD1d-restricted NKT cells, type I and type II subsets have been noted. CD1d-restricted type I NKT cells are regarded as pro-inflammatory cells in general. On the contrary, accumulated evidence has demonstrated an anti-inflammatory property of CD1d-restricted type II NKT cells. In our earlier study using a rat model with vasculitis, we demonstrated the pro-inflammatory function of CD1d-restricted type II NKT cells and identified that one such cell recognized P518-532 of rat sterol carrier protein 2 (rSCP2518-532 ), which appeared on vascular endothelial cells presented by CD1d. Based on this evidence, we attempted to detect human CD1d-restricted type II NKT cells in peripheral blood using hSCP2518-532 , the human counterpart of rSCP2518-532, together with a CD1d tetramer in flow cytometry. First, we determined the binding of hSCP2518-532 to CD1d. Next, we detected CD3-positive hSCP2518-532 -loaded CD1d (hSCP2518-532 /CD1d) tetramer-binding cells in peripheral blood of healthy donors. The abundance of TGF-β-producing cells rather than TNF-α-producing cells in CD3-positive hSCP2518-532 /CD1d tetramer-binding cells suggests the anti-inflammatory property of SCP2-loaded CD1d (SCP2/CD1d) tetramer-binding type II NKT cells in healthy individuals. Furthermore, we compared cytokine profile between healthy individuals and patients with vasculitis in a pilot study. Interestingly, the percentage of TGF-β-producing cells in SCP2/CD1d tetramer-binding type II NKT cells in vasculitic patients was significantly lower than that in healthy controls despite the greater number of these cells. Although further studies to clarify the mechanism and significance of this phenomenon are needed, SCP2/CD1d tetramer-binding type II NKT cells in peripheral blood should be examined in more detail to understand the pathophysiology of vasculitides in humans. © 2018 International Society for Advancement of Cytometry.
• Anti-neutrophil extracellular trap antibody in a patient with relapse of anti-neutrophil cytoplasmic antibody-associated vasculitis: A case report

  Haruki Shida, Nobuhiro Hashimoto, Yoshihiro Kusunoki, Fumihiko Hattanda, Yayoi Ogawa, Terumasa Hayashi, Daigo Nakazawa, Sakiko Masuda, Utano Tomaru, Akihiro Ishizu

  BMC Nephrology 19 1 145  2018年06月22日 [査読有り][通常論文]
   

  Background: Neutrophil extracellular traps (NETs) are web-like DNA decorated with antimicrobial proteins, such as myeloperoxidase (MPO), which are extruded from activated neutrophils. Although NETs are essential in innate immunity, an excessive formation of NETs has adverse effects, e.g., induction of anti-neutrophil cytoplasmic antibody (ANCA), to the hosts. Since ANCA can induce NET formation in the primed neutrophils, a positive feedback loop can be formed between NETs and ANCA, which is called "ANCA-NETs vicious cycle." Case presentation: A 79-year-old Japanese woman developed hydralazine-induced pauci-immune necrotizing crescentic glomerulonephritis with MPO-ANCA. Although the illness improved after cessation of hydralazine, MPO-ANCA-associated vasculitis relapsed 16 months later. Remission was achieved 5 months after beginning of administration of prednisone. In order to determine the involvement of ANCA-NETs vicious cycle in this patient, we examined NET degradation and induction activities in sera obtained at the disease onset (Serum A MPO-ANCA, 107 IU/ml), at relapse (Serum B MPO-ANCA, 195 IU/ml), at 3 months after treatment (Serum C MPO-ANCA, 4.5 IU/ml), and at remission (Serum D MPO-ANCA, 2.4 IU/ml). NET degradation activity was low in the all sera. NET induction activity was high in Sera A, B, and C but not in D. Additionally, we demonstrated the presence of anti-NET antibody (ANETA) in Sera B and C but not in A or D. Conclusions: The collective findings suggest NET induction potential of ANETA in the present patient and that the ANETA could contribute to the enhancement of NETs resulting in amplification of the ANCA-NETs vicious cycle.
• ANCA関連血管炎(AAV)の壊死性病変部における好中球細胞外トラップ(NETs)の存在と病的意義

  益田 紗季子, 野々川 茉佑, 西端 友香, 岩崎 沙理, 辻 隆裕, 田中 敏, 外丸 詩野, 川上 民裕, 石津 明洋

  日本病理学会会誌 107 1 330 - 330 (一社)日本病理学会 2018年04月
• 免疫グロブリン大量静注療法(IVIG)は好中球細胞外トラップ(NETs)の抑制によりMPO-ANCA関連血管炎を抑制する

  魚住 諒, 井口 理彩, 益田 紗季子, 西端 友香, 谷村 瞬, 中沢 大悟, 外丸 詩野, 石津 明洋

  日本病理学会会誌 107 1 331 - 331 (一社)日本病理学会 2018年04月
• Elevated Level of Myeloperoxidase-Deoxyribonucleic Acid Complex in the Middle Ear Fluid Obtained from Patients with Otitis Media Associated with Antineutrophil Cytoplasmic Antibody-associated Vasculitis

  Shinya Morita, Yuji Nakamaru, Daigo Nakazawa, Fumihiko Hattanda, Haruki Shida, Yoshihiro Kusunoki, Kanako Watanabe, Sakiko Masuda, Dai Takagi, Masanobu Suzuki, Kimiko Hoshino, Atsushi Fukuda, Utano Tomaru, Akihiro Homma, Akihiro Ishizu

  Otology and Neurotology 39 4 e257 - e262 2018年04月01日 [査読有り][通常論文]
   

  Objective:The purpose was to explore the presence of myeloperoxidase (MPO)-deoxyribonucleic acid (DNA) complex as a surrogate marker of neutrophil extracellular traps (NETs) in the middle ear fluid, and to clarify the correlation between its quantifiable level and hearing outcome in patients with otitis media associated with antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV).Study Design:Prospective study.Setting:Tertiary referral center.Patients:Nine AAV patients presenting with otitis media.Intervention:Collection of the fluid samples from middle ear.Main Outcome Measure:The quantifiable levels of MPO-DNA complex using an enzyme-linked immunosorbent assay.Results:The quantifiable levels of MPO-DNA complex in patients with AAV were significantly higher than those in controls (p < 0.001). In particular, both ANCA-positive and-negative cases indicated higher levels of MPO-DNA complex compared with the controls (p = 0.004 and p = 0.006, respectively). The significant negative correlations were observed between the level of MPO-DNA complex and the functional hearing values for air (r =-0.82, p = 0.009) and bone conduction (r =-0.73, p = 0.028), respectively.Conclusion:This analysis is the first to reveal the presence of elevated levels of MPO-DNA complex in the middle ear fluid, suggesting the pathogenic role of NETs in otitis media associated with AAV. NETs may be a valuable biomarker for use in clinical decision-making and predicting hearing outcome, regardless of ANCA status.
• Brain-derived neurotrophic factor induces angiogenin secretion and nuclear translocation in human umbilical vein endothelial cells

  Ayako Mori, Yusuke Nishioka, Mai Yamada, Yuka Nishibata, Sakiko Masuda, Utano Tomaru, Naoyuki Honma, Takanori Moriyama, Akihiro Ishizu

  Pathology Research and Practice 214 4 521 - 526 2018年04月01日 [査読有り][通常論文]
   

  Brain-derived neurotrophic factor (BDNF) is a well-known humoral protein that induces growth of neurons. Recent studies have suggested that BDNF could act as an angiogenesis inducer similar to vascular endothelial growth factor (VEGF). Angiogenin is a strong mediator of angiogenesis. It has particular characteristics both as a secreted protein and a transcription factor. After being incorporated into the cytoplasm, angiogenin is immediately transferred to the nucleus and then mediates the angiogenic effects of angiogenesis inducers, including VEGF. The aim of this study is to determine the association between BDNF and angiogenin. At first, we determined the secretion of angiogenin from human umbilical vein endothelial cells (HUVEC) induced by BDNF with enzyme-linked immunosorbent assay. Next, we determined BDNF-induced nuclear translocation of angiogenin by immunofluorescent staining. In addition, we examined the mRNA expression of angiogenin in HUVEC before and after BDNF stimulation by quantitative reverse transcriptase-polymerase chain reaction. As a result, we noted that BDNF induced angiogenin secretion and nuclear translocation without an increase in the mRNA expression in HUVEC. Furthermore, we demonstrated that BDNF-induced HUVEC proliferation was significantly suppressed when neomycin, a specific inhibitor of nuclear translocation of angiogenin, was administered. These findings indicate that nuclear translocation of angiogenin is critically involved in BDNF-induced proliferation of HUVEC. In conclusion, angiogenin contributes to angiogenesis induced by BDNF.
• An Autopsy Case of Myeloperoxidase-anti-neutrophil Cytoplasmic Antibody (MPO-ANCA) -associated Vasculitis Accompanied by Cryoglobulinemic Vasculitis Affecting the Kidneys, Skin, and Gastrointestinal Tract.

  Hasegawa J, Wakai S, Kono M, Imaizumi Y, Masuda S, Ishizu A, Honda K

  Internal medicine (Tokyo, Japan) 57 18 2739 - 2745 2018年04月 [査読有り][通常論文]
   

  Anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) and cryoglobulinemic vasculitis (CV) rarely coexist. An 83-year-old woman was admitted with rapidly progressive renal failure, gastrointestinal hemorrhage and purpura with myeloperoxidase (MPO)-ANCA positivity and cryoglobulinemia. Despite intensive immunosuppressive treatment, she died of aspergillus pneumonia. Autopsy revealed necrotizing crescentic glomerulitis in the majority of the glomeruli, accompanied by partially membranoproliferative-like glomerular changes. Immunofluorescence staining revealed the presence of neutrophil extracellular trap (NET) formation in the glomeruli and cutaneous arteries. These pathological findings suggested that MPO-AAV and/or CV caused NET formation, leading to lethal systemic vasculitis.
• CD1d-restricted type II NKT cells reactive with endogenous hydrophobic peptides

  Yusuke Nishioka, Sakiko Masuda, Utano Tomaru, Akihiro Ishizu

  Frontiers in Immunology 9 548  2018年03月15日 [査読有り][通常論文]
   

  NKT cells belong to a distinct subset of T cells that recognize hydrophobic antigens presented by major histocompatibility complex class I-like molecules, such as CD1d. Because NKT cells stimulated by antigens can activate or suppress other immunocompetent cells through an immediate production of a large amount of cytokines, they are regarded as immunological modulators. CD1d-restricted NKT cells are classified into two subsets, namely, type I and type II. CD1d-restricted type I NKT cells express invariant T cell receptors (TCRs) and react with lipid antigens, including the marine sponge-derived glycolipid a-galactosylceramide. On the contrary, CD1d-restricted type II NKT cells recognize a wide variety of antigens, including glycolipids, phospholipids, and hydrophobic peptides, by their diverse TCRs. In this review, we focus particularly on CD1d-restricted type II NKT cells that recognize endogenous hydrophobic peptides presented by CD1d. Previous studies have demonstrated that CD1d-restricted type I NKT cells usually act as pro-inflammatory cells but sometimes behave as anti-inflammatory cells. It has been also demonstrated that CD1d-restricted type II NKT cells play opposite roles to CD1d-restricted type I NKT cells thus, they function as anti-inflammatory or pro-inflammatory cells depending on the situation. In line with this, CD1d-restricted type II NKT cells that recognize type II collagen peptide have been demonstrated to act as anti-inflammatory cells in diverse inflammation-induction models in mice, whereas pro-inflammatory CD1d-restricted type II NKT cells reactive with sterol carrier protein 2 peptide have been demonstrated to be involved in the development of small vessel vasculitis in rats.
• 血管炎1:血管炎のバイオマーカー・病態解析 免疫グロブリン製剤は好中球細胞外トラップ(NETs)の形成抑制を介してMPO-ANCA関連血管炎(MPO-AAV)の発症を抑制する

  魚住 諒, 益田 紗季子, 西端 友香, 谷村 瞬, 中沢 大悟, 外丸 詩野, 石津 明洋

  日本リウマチ学会総会・学術集会プログラム・抄録集 62回 433 - 433 (一社)日本リウマチ学会 2018年03月
• リウマチ性疾患の画像2:関節エコーその他 超高周波プローブを用いたSuperb Micro-vascular Imagingによる超音波検査でのラット足関節の早期関節炎診断

  西田 睦, 谷村 瞬, 神島 保, 西端 友香, 益田 紗季子, 中沢 大悟, 外丸 詩野, 渥美 達也, 石津 明洋

  日本リウマチ学会総会・学術集会プログラム・抄録集 62回 485 - 485 (一社)日本リウマチ学会 2018年03月
• スタチンの関節炎抑制効果とその機序の解明

  谷村 瞬, 西田 睦, 神島 保, 西端 友香, 益田 紗季子, 中沢 大悟, 外丸 詩野, 渥美 達也, 石津 明洋

  日本リウマチ学会総会・学術集会プログラム・抄録集 62回 778 - 778 (一社)日本リウマチ学会 2018年03月
• Vanishing Immunoglobulins: The Formation of Pauci-Immune Lesions in Myeloperoxidase-Antineutrophil Cytoplasmic Antibody-Associated Vasculitis

  Emika Futamata, Sakiko Masuda, Yuka Nishibata, Satoshi Tanaka, Utano Tomaru, Akihiro Ishizu

  Nephron 138 4 328 - 330 2018年03月01日 [査読有り][通常論文]
  
• Targeted proteomics reveals promising biomarkers of disease activity and organ involvement in antineutrophil cytoplasmic antibody-associated vasculitis

  Jun Ishizaki, and for the Research Committee of Intractable Vasculitis Syndrome and the Research Committee of Intractable Renal Disease of the Ministry of Health, Labour and Welfare of Japan, Ayako Takemori, Koichiro Suemori, Takuya Matsumoto, Yoko Akita, Ken-ei Sada, Yukio Yuzawa, Koichi Amano, Yoshinari Takasaki, Masayoshi Harigai, Yoshihiro Arimura, Hirofumi Makino, Masaki Yasukawa, Nobuaki Takemori, Hitoshi Hasegawa, Yohko Murakawa, Eri Muso, Atsushi Komatsuda, Satoshi Ito, Takao Fujii, Atsushi Kawakami, Izaya Nakaya, Takao Saito, Takafumi Ito, Nobuhito Hirawa, Masahiro Yamamura, Masaaki Nakano, Kosaku Nitta, Makoto Ogura, Taio Naniwa, Shoichi Ozaki, Junichi Hirahashi, Noriyoshi Ogawa, Tatsuo Hosoya, Takashi Wada, Satoshi Horikoshi, Yasushi Kawaguchi, Taichi Hayashi, Masaharu Yoshida, Tsuyoshi Watanabe, Daijo Inaguma, Kazuhiko Tsuruya, Noriyuki Homma, Tsutomu Takeuchi, Naoki Nakagawa, Shinichi Takeda, Ritsuko Katabuchi, Masayuki Iwano, Tatsuya Atsumi, Shoichi Fujimoto, Shogo Banno, Takahiko Sugihara, Masaki Kobayashi, Kunihiro Yamagata, Sakae Homma, Hiroaki Dobashi, Naotake Tsuboi, Akihiro Ishizu, Hitoshi Sugiyama

  Arthritis Research and Therapy 19 1 2017年09月29日 [査読有り][通常論文]
   

  Background: Targeted proteomics, which involves quantitative analysis of targeted proteins using selected reaction monitoring (SRM) mass spectrometry, has emerged as a new methodology for discovery of clinical biomarkers. In this study, we used targeted serum proteomics to identify circulating biomarkers for prediction of disease activity and organ involvement in antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV). Methods: A large-scale SRM assay targeting 135 biomarker candidates was established using a triple-quadrupole mass spectrometer coupled with nanoflow liquid chromatography. Target proteins in serum samples from patients in the active and remission (6 months after treatment) stages were quantified using the established assays. Identified marker candidates were further validated by enzyme-linked immunosorbent assay using serum samples (n = 169) collected in a large-cohort Japanese study (the RemIT-JAV-RPGN study). Results: Our proteomic analysis identified the following proteins as biomarkers for discriminating patients with highly active AAV from those in remission or healthy control subjects: tenascin C (TNC), C-reactive protein (CRP), tissue inhibitor of metalloproteinase 1 (TIMP1), leucine-rich alpha-2-glycoprotein 1, S100A8/A9, CD93, matrix metalloproteinase 9, and transketolase (TKT). Of these, TIMP1 was the best-performing marker of disease activity, allowing distinction between mildly active AAV and remission. Moreover, in contrast to CRP, serum levels of TIMP1 in patients with active AAV were significantly higher than those in patients with infectious diseases. The serum levels of TKT and CD93 were higher in patients with renal involvement than in those without, and they predicted kidney outcome. The level of circulating TNC was elevated significantly in patients with lung infiltration. AAV severity was associated with markers reflecting organ involvement (TKT, CD93, and TNC) rather than inflammation. The eight markers and myeloperoxidase (MPO)-ANCA were clustered into three groups: MPO-ANCA, renal involvement (TKT and CD93), and inflammation (the other six markers). Conclusions: We have identified promising biomarkers of disease activity, disease severity, and organ involvement in AAV with a targeted proteomics approach using serum samples obtained from a large-cohort Japanese study. Especially, our analysis demonstrated the effectiveness of TIMP1 as a marker of AAV activity. In addition, we identified TKT and CD93 as novel markers for evaluation of renal involvement and kidney outcome in AAV.
• Measurement of NET formation in vitro and in vivo by flow cytometry

  Sakiko Masuda, Sakika Shimizu, Junji Matsuo, Yuka Nishibata, Yoshihiro Kusunoki, Fumihiko Hattanda, Haruki Shida, Daigo Nakazawa, Utano Tomaru, Tatsuya Atsumi, Akihiro Ishizu

  CYTOMETRY PART A 91A 8 822 - 829 2017年08月 [査読有り][通常論文]
   

  Neutrophil extracellular traps (NETs) are extracellular chromatin fibers adorned with antimicrobial proteins, such as myeloperoxidase (MPO), which are extruded from activated neutrophils. NETosis is the metamorphosis of neutrophils with NET formation that follows decondensation of DNA and rupture of the plasma membrane. Although NETs play important roles in innate immunity, excessive formation of NETs can be harmful to the hosts. Until now, various methods for evaluation of NETs have been reported. Although each has a virtue, the gold standard has not been established. Here we demonstrate a simple, objective, and quantitative method to detect NETs using flow cytometry. This method uses a plasma membrane-impermeable DNA-binding dye, SYTOX Green. SYTOX Green-positive cells were detected in human peripheral polymorphonuclear cells exposed to a NET inducer, phorbol 12-myristate 13-acetate (PMA). The number of SYTOX Green-positive cells was increased depending on the exposure duration and concentrations of PMA. Furthermore, co-localization of MPO and plasma membrane-appendant DNA of SYTOX Green-positive cells was demonstrated. Moreover, a NET inhibitor, diphenylene iodonium, could significantly reduce the number of SYTOX Green-positive cells induced by PMA. The collective evidence suggests that SYTOX Green-positive cells include neutrophils that formed NETs. The established method could detect neutrophils that underwent NETosis but not early apoptosis with equivalence in quantification to another well-used image analysis, which is based on fluorescent staining. Additionally, NETs that were formed in vivo were also detectable by this method. It is conceivable that the established method will bring us better understanding of the relation between NETosis and human diseases. (c) 2017 The Authors. Cytometry Part A published by Wiley Periodicals, Inc. on behalf of ISAC.
• Elevated moesin mRNA level in skin tissue of patients with polyarteritis nodosa based on real time RT-PCR

  Tamihiro Kawakami, Tatsuro Okano, Sora Takeuchi, Yoshinao Soma, Fuyu Ito, Akihiro Ishizu, Yoshihiro Arimura, Kazuo Suzuki

  JOURNAL OF DERMATOLOGICAL SCIENCE 87 1 94 - 97 2017年07月 [査読有り][通常論文]
  
• Establishment of a rat model of thrombosis induced by intravenous injection of anti-phosphatidylserine-prothrombin complex antibody

  Mai Yamada, Tamihiro Kawakami, Kohei Takashima, Yusuke Nishioka, Yuka Nishibata, Sakiko Masuda, Shigeru Yoshida, Utano Tomaru, Akihiro Ishizu

  RHEUMATOLOGY 56 6 1013 - 1018 2017年06月 [査読有り][通常論文]
   

  Objective. Recent studies have suggested that aPS-PT antibody is one of the most relevant autoantibodies to APS. This study aimed to demonstrate the pathogenicity of aPS-PT antibody in vivo. Methods. At first, cultured rat vascular endothelial cells (RECs) were exposed to calf thymus-derived histones. Two hours later, lactate dehydrogenase release from the RECs and expression of PS on the cell surface were assessed. Next, we administered an i.v. injection of calf thymus-derived histones into Wistar rats (12.5 mu g/g weight of 8-week-old female rats), and 2 h later they were given an i.v. injection of aPS-PT mAb (1.25 mg/g weight, n = 6) or an equal dose of rat IgM as controls (n = 5). Three days later, histological examination was conducted. Results. Calf thymus-derived histones (> 12.5 mg/ml) could injure RECs in vitro. Simultaneously, annexin V could bind to the RECs; thereby, this result indicated that cell-free histone exposure of vascular endothelial cells induced cell surface expression of PS, which is naturally present inside the plasma membrane. Thrombosis developed with higher frequency in the rats given an i. v. injection of aPS-PT mAb than in controls. Conclusion. We established a rat model of thrombosis induced by i. v. injection of aPS-PT mAb.
• 血管炎・その他の免疫疾患 皮膚限局の血管炎が重症化した際の抗モエシン抗体の推移について

  岡野 達郎, 竹内 そら, 相馬 良直, 鈴木 浩也, 月田 早智子, 石津 明洋, 鈴木 和男, 川上 民裕

  アレルギー 66 4-5 621 - 621 (一社)日本アレルギー学会 2017年05月
• Prediction of response to remission induction therapy by gene expression profiling of peripheral blood in Japanese patients with microscopic polyangiitis

  Akihiro Ishizu, Utano Tomaru, Sakiko Masuda, Ken-ei Sada, Koichi Amano, Masayoshi Harigai, Yasushi Kawaguchi, Yoshihiro Arimura, Kunihiro Yamagata, Shoichi Ozaki, Hiroaki Dobashi, Sakae Homma, Yasunori Okada, Hitoshi Sugiyama, Joichi Usui, Naotake Tsuboi, Seiichi Matsuo, Hirofumi Makino

  ARTHRITIS RESEARCH & THERAPY 19 1 117  2017年05月 [査読有り][通常論文]
   

  Background: Microscopic polyangiitis (MPA), which is classified as an anti-neutrophil cytoplasmic antibody (ANCA)associated small vessel vasculitis, is one of the most frequent primary vasculitides in Japan. We earlier nominated 16 genes (IRF7, IFIT1, IFIT5, OASL, CLC, GBP-1, PSMB9, HERC5, CCR1, CD36, MS4A4A, BIRC4BP, PLSCR1, DEFA1/DEFA3, DEFA4, and COL9A2) as predictors of response to remission induction therapy against MPA. The aim of this study is to determine the accuracy of prediction using these 16 predictors. Methods: Thirty-nine MPA patients were selected randomly and retrospectively from the Japanese nationwide RemIT-JAV-RPGN cohort and enrolled in this study. Remission induction therapy was conducted according to the Guidelines of Treatment for ANCA-Associated Vasculitis published by the Ministry of Health, Labour, and Welfare of Japan. Response to remission induction therapy was predicted by profiling the altered expressions of the 16 predictors between the period before and 1 week after the beginning of treatment. Remission is defined as the absence of clinical manifestations of active vasculitis (Birmingham Vasculitis Activity Score 2003: 0 or 1 point). Persistent remission for 18 months is regarded as a "good response," whereas no remission or relapse after remission is regarded as a "poor response." Results: "Poor" and "good" responses were predicted in 7 and 32 patients, respectively. Five out of 7 patients with "poor" prediction and 1 out of 32 patients with "good" prediction experienced relapse after remission. One out of 7 patients with "poor" prediction was not conducted to remission. Accordingly, the sensitivity and specificity to predict poor response was 85.7% (6/7) and 96.9% (31/32), respectively. Conclusions: Response to remission induction therapy can be predicted by monitoring the altered expressions of the 16 predictors in the peripheral blood at an early point of treatment in MPA patients.
• 血管炎 ANCA関連血管炎(AAV)における抗NETs抗体の存在と病的意義

  八反田 文彦, 楠 由宏, 志田 玄貴, 中沢 大悟, 西尾 妙織, 益田 紗季子, 外丸 詩野, 渥美 達也, 石津 明洋

  日本リウマチ学会総会・学術集会プログラム・抄録集 61回 431 - 431 (一社)日本リウマチ学会 2017年03月
• SLE・抗リン脂質抗体症候群 抗PSPT抗体による抗リン脂質抗体症候群動物モデルの完成

  川上 民裕, 石津 明洋, 益田 紗季子, 外丸 詩野

  日本リウマチ学会総会・学術集会プログラム・抄録集 61回 605 - 605 (一社)日本リウマチ学会 2017年03月
• フローサイトメトリーによる定量的好中球細胞外トラップ測定法

  益田 紗季子, 西端 友香, 松尾 淳司, 外丸 詩野, 石津 明洋

  日本病理学会会誌 106 1 350 - 350 (一社)日本病理学会 2017年03月
• Expression of cathepsins V and S in thymic epithelial tumors

  Shizuka Kiuchi, Utano Tomaru, Akihiro Ishizu, Makoto Imagawa, Takayuki Kiuchi, Sari Iwasaki, Akira Suzuki, Noriyuki Otsuka, Takahiro Deguchi, Tomohiro Shimizu, Katsuji Marukawa, Yoshihiro Matsuno, Masanori Kasahara

  HUMAN PATHOLOGY 60 66 - 74 2017年02月 [査読有り][通常論文]
   

  Cathepsins are a group of proteolytic enzymes of the endosomal/lysosomal pathway involved in the thymic development of T cells restricted by major histocompatibility complex class II molecules. In the normal thymus, cathepsin V (CTV) and cathepsin S (CTS) are expressed in cortical and medullary epithelial cells, respectively. To investigate whether cathepsins could serve as a diagnostic marker, we performed immunohistochemical analysis for CTV and CTS in 77 cases of thymic epithelial tumors. Almost all cases (59/ 60) of thymoma expressed CTV, whereas 28 of 60 cases of thymoma expressed CTS. Notably, CTS was expressed in most cases of type A and type AB thymomas, but not in type B thymoma. The expression of cathepsins in type AB thymoma showed a clear correlation with histologic features; CTV was found predominantly in the type B component, and CTS was frequently expressed in the type A component. In thymic carcinoma, CTV was expressed in less than half cases (7/17), and the ratio of CTS-positive cases was equivalent to that of thymoma (8/17). Cases of CTV-negative thymic carcinoma tended to have a higher incidence of recurrence than did CTV-positive cases. Although further studies with a larger number of cases are required to confirm the utility of cathepsin immunostaining, CTV and CTS appear to serve as auxiliary diagnostic and/or prognostic markers in thymic epithelial tumors. (C) 2016 Elsevier Inc. All rights reserved.
• Presence of anti-phosphatidylserine-prothrombin complex antibodies and anti-moesin antibodies in patients with polyarteritis nodosa

  Tatsuro Okano, Sora Takeuchi, Yoshinao Soma, Koya Suzuki, Sachiko Tsukita, Akihiro Ishizu, Kazuo Suzuki, Tamihiro Kawakami

  JOURNAL OF DERMATOLOGY 44 1 18 - 22 2017年01月 [査読有り][通常論文]
   

  We measured both serum anti-phosphatidylserine-prothrombin complex (anti-PSPT) antibodies and anti-moesin antibodies, as well as various cytokines (interleukin[ IL]-2, IL-4, IL-5, IL-10, IL-13, IL-17, granulocyte macrophage colony-stimulating factor, c-interferon, tumor necrosis factor-alpha) levels in polyarteritis nodosa (PAN) patients with cutaneous manifestations. All patients showed the presence of a histological necrotizing vasculitis in the skin specimen. They were treated with i.v. cyclophosphamide pulse therapy (IV-CY) and prednisolone therapy or steroid pulse therapy. The immunological assessments were performed on sera collected prior to and after treatment with IV-CY or steroid pulse therapy. We found a significant positive correlation between serum anti-moesin antibodies and both clinical Birmingham Vasculitis Activity Scores and Vasculitis Damage Index. Anti-PSPT antibody and IL-2 levels after treatment in PAN patients were significantly lower than before treatment. In contrast, antimoesin antibody levels were higher following IV-CY or steroid pulse therapy compared with the pretreatment levels. In the treatment-resistant PAN patients (n = 8), anti-PSPT antibody levels after treatment were significantly lower than before treatment. In contrast, anti-moesin antibody levels after treatment in the patients were significantly higher compared with the pretreatment levels. Immunohistochemical staining revealed moesin overexpression in mainly fibrinoid necrosis of the affected arteries in the PAN patients. We suggest that measurement of serum anti-PSPT antibody levels could serve as a marker for PAN and aid in earlier diagnosis of PAN. We also propose that elevated serum anti-moesin antibodies could play some role of the exacerbation in patients with PAN.
• Type II Natural Killer T Cells that Recognize Sterol Carrier Protein 2 Are Implicated in Vascular Inflammation in the Rat Model of Systemic Connective Tissue Diseases

  Yusuke Nishioka, Madoka Yamaguchi, Ai Kawakami, Maya Munehiro, Sakiko Masuda, Utano Tomaru, Akihiro Ishizu

  AMERICAN JOURNAL OF PATHOLOGY 187 1 176 - 186 2017年01月 [査読有り][通常論文]
   

  We previously generated a rat model that developed systemic connective tissue diseases, including synovitis, myositis, and small-vessel vasculitis (SVV), and established a vascular endothelial cell-reactive T-cell clone, VASC-1, from the model. VASC-1 was determined to be a type II natural killer T-cell clone. In this study, we attempted to identify the antigen recognized by VASC-1. The monkey-derived cell line COS-7 was used because VASC-1 does not bind naturally to COS-7, although the amino acid sequences are well conserved between monkey CD1d and rat CD1d. We generated 98 COS-7 clones transfected with miscellaneous rat cDNA and screened them for VASC-1 binding. Consequently, we found one clone, 4D2, which could bind to VASC-1. Sequencing identified the rat cDNA introduced into 4D2 as sterol carrier protein 2 (SCP2). When VASC-1 was co-cultured with SCP2 knockdown rat vascular endothelial cells, VASC-1 binding was reduced significantly. Moreover, we designed a series of rat SCP2 peptides and introduced them into COS-7 cells. On the basis of VASC-1 binding and proliferation, we revealed that the peptide rSCP2(518-532) included the epitope recognized by VASC-1. Furthermore, immunization with rSCP2(518-532) accelerated the development of SVV in the rat model. The collective findings suggest that type II natural killer T cells reactive with autologous SCP2 are implicated in vascular inflammation in the rat model.
• Relationship between power Doppler grade and the pathological blood vessel features in long-standing rheumatoid arthritis

  Katsumi Saito, Asami Abe, Tamotsu Kamishima, Hajime Ishikawa, Kunihiko Wakaki, Akihiro Ishizu

  RHEUMATOLOGY INTERNATIONAL 36 12 1689 - 1690 2016年12月 [査読有り][通常論文]
  
• The Presence of Anti-Lactoferrin Antibodies in a Subgroup of Eosinophilic Granulomatosis with Polyangiitis Patients and Their Possible Contribution to Enhancement of Neutrophil Extracellular Trap Formation

  Haruki Shida, Daigo Nakazawa, Yu Tateyama, Arina Miyoshi, Yoshihiro Kusunoki, Fumihiko Hattanda, Sakiko Masuda, Utano Tomaru, Tamihiro Kawakami, Tatsuya Atsumi, Akihiro Ishizu

  FRONTIERS IN IMMUNOLOGY 7 636  2016年12月 [査読有り][通常論文]
   

  Lactoferrin (Lf) is one of the antigens of antineutrophil cytoplasmic antibodies (ANCA) and functions as an endogenous suppressor of neutrophil extracellular trap (NET) formation. However, the prevalence and pathogenicity of anti-lactoferrin antibodies (aLf) in ANCA-associated vasculitis (AAV) remain unrevealed. This study aimed to examine the significance of aLf in AAV, initially. Sixty-five sera from AAV patients, including 41 microscopic polyangiitis, 5 granulomatosis with polyangiitis, and 19 eosinophilic granulomatosis with polyangiitis (EGPA) patients, were subjected to aLf detection using enzyme-linked immunosorbent assay. Clinical characteristics were compared between aLf-positive and aLf-negative patients. Neutrophils from healthy donors were exposed to suboptimal dose (10 nM) of phorbol myristate acetate (PMA) with aLf followed by evaluation of NET formation. Results demonstrated that 4 out of 65 AAV sera (6.2%) were positive for aLf. All of them were EGPA sera (4/19, 21.1%). In EGPA, the frequency of renal involvement, serum CRP levels, and Birmingham Vasculitis Activity Score (BVAS) in the aLf-positive patients was significantly higher than those in the aLf-negative patients, and the aLf titer correlated positively with the serum CRP level and BVAS. The NET formation was particularly enhanced by combined stimulation of 10 nM PMA and 1 mu g/mL aLf. IgG isolated from sera of the aLf-positive EGPA patients (250 mu g/mL) enhanced NET formation induced by 10 nM of PMA, and the effect was abolished completely by absorption of the aLf. This pilot study suggests that aLf enhance NET formation induced by PMA and are associated with disease activity of EGPA.
• NETosis markers: Quest for specific, objective, and quantitative markers

  Saldko Masuda, Daigo Nakazawa, Haruki Shida, Anna Miyoshi, Yoshihiro Kusunoki, Utano Tomaru, Akihiro Ishizu

  CLINICA CHIMICA ACTA 459 89 - 93 2016年08月 [査読有り][招待有り]
   

  More than 10 years have passed since the discovery of neutrophil extracellular traps (NETs) in 2004. NETs are extracellular web-like DNA decorated with antimicrobial proteins, which are released from activated neutrophils. The state of neutrophils with NET formation is called NETosis. It has been realized that NETosis includes suicidal NETosis and vital NETosis. The former state means cell death of neutrophils, whereas the latter state preserves living neutrophilic functions. Although both suicidal and vital NETosis play essential roles in elimination of microorganisms, excessive formation of NETs, especially the ones derived from suicidal NETosis, can harm the hosts. Therefore, the discovery of NETosis markers and development of evaluation methods are important. In this review, we compare the methods for evaluating NETosis, including immunocytological and immunohistological detection of co-localized neutrophil-derived proteins and extracellular DNA, and citrullinated histones, detection of NET remnants in fluid samples, and flow cytometric detection of cell-appendant NET components, with focus on the specificity, objectivity, and quantitativity. Since the gold standard marker of NETosis or method of NET detection has not been established yet, researchers should choose the most appropriate marker or method in each situation based on the knowledge of the respective virtues and faults. (C) 2016 The Authors. Published by Elsevier B.V. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
• Peptidylarginine Deiminase Inhibitor Suppresses Neutrophil Extracellular Trap Formation and MPO-ANCA Production

  Yoshihiro Kusunoki, Daigo Nakazawa, Haruki Shida, Fumihiko Hattanda, Arina Miyoshi, Sakiko Masuda, Saori Nishio, Utano Tomaru, Tatsuya Atsumi, Akihiro Ishizu

  FRONTIERS IN IMMUNOLOGY 7 1 - 7 2016年06月 [査読有り][通常論文]
   

  Myeloperoxidase-antineutrophil cytoplasmic antibody (MPO-ANCA)-associated vasculitis is a systemic small-vessel vasculitis, wherein. MPO-ANCA plays a critical role in the pathogenesis. Neutrophil extracellular traps (NETs) released from activated neutrophils are composed of extracellular web-like DNA and antimicrobial proteins, including MPO. Diverse stimuli, such as phorbol myristate acetate (PMA) and ligands of toll-like receptors (TLR), induce NETs. Although TLR-mediated NET formation can occur with preservation of living neutrophilic functions (called vital NETosis). PMA-stimulated neutrophils undergo cell death with NET formation (called suicidal NETosis). In the process of suicidal NETosis, histones are citrullinated by peptidylarginine deiminase 4 (PAD4). Since this step is necessary for decondensation of DNA. PAD4 plays a pivotal role in suicidal NETosis. Although NETs are essential for elimination of microorganisms, excessive formation of NETs has been suggested to be implicated in MPO-ANCA production. This study aimed to determine if pan-PAD inhibitors could suppress MPO-ANCA production in vivo. At first, NETs were induced in peripheral blood neutrophils derived from healthy donors (1 x 10(6)/ml) by stimulation with 20 nM PMA with or without 20 mu M propylthiouracil (PTU), an anti-thyroid drug. We then determined that the in vitro NET formation was inhibited completely by 200 mu M Cl-amidine, a pan PAD inhibitor. Next, we established mouse models with MPO-ANCA production. BALB/c mice were given intraperitoneal (i.p.) injection of PMA (50 ng at days 0 and 7) and oral PTU (2.5 mg/day) for 2 weeks. These mice were divided into two groups; the first group was given daily i.p. injection of PBS (200 mu l/day) = 13) and the other group with daily i.p. injection of Cl-amidine (0.3 mg/200 mu l PBS/day) (n = 7). Two weeks later, citrullination as an indicator of NET formation in the peritoneum and serum MPO-ANCA titer was compared between the two groups. Results demonstrated that citrullination in the peritoneum was significantly reduced in the Cl-amidine-treated mice compared with the vehicle-injected control mice (38% reduction). Additionally, the serum MPO-ANCA titer of the Cl-amidine-treated mice (32.3 +/- 31.0 ng/ml) was significantly lower than that in the vehicle-injected mice (132.1 +/- 41.6 ng/ml). The collective findings indicate that excessive formation of NETs may be implicated in MPO-ANCA production in vivo.
• The responses of macrophages in interaction with neutrophils that undergo NETosis

  Daigo Nakazawa, Haruki Shida, Yoshihiro Kusunoki, Arina Miyoshi, Saori Nishio, Utano Tomaru, Tatsuya Atsumi, Akihiro Ishizu

  JOURNAL OF AUTOIMMUNITY 67 19 - 28 2016年02月 [査読有り][通常論文]
   

  Neutrophil extracellular traps (NETs) are net-like chromatin fibers decorated with antimicrobial proteins, which are released from dying neutrophils. The death of neutrophils with NET formation is called NETosis. Although NETs play important roles in the innate immunity, especially in the elimination of microbes, the extracellular release of DNA and intra-cytoplasmic/nuclear proteins can, on the other hand, result in diverse adversities to the hosts. Therefore, NETosis is adequately regulated in vivo. Currently, two mechanisms, namely DNase I-dependent digestion and phagocytosis by macrophages, have been shown as such regulatory mechanisms. In this study, we focused on the interaction of macrophages and neutrophils that underwent NETosis. Results demonstrated that macrophages displayed a phenotype dependent response after degradation of NETs. Several hours after the interaction, M2 macrophages induced a pro-inflammatory response, while M1 macrophages underwent cell death with nuclear decondensation. This nuclear decondensation of M1 macrophages occurred in a peptidylarginine deiminase 4-dependent manner and resulted in a local release of extracellular DNA. Thereafter, M1 macrophages degraded DNA derived from themselves in a caspase-activated DNase-dependent manner resulting in the clearance of extracellular DNA within 24 h. This transient increase and subsequent clearance mechanism of extracellular DNA seems very reasonable in terms of the double-edged sword-like property of NETs. The collective findings demonstrate a novel phenotype- and time-dependent regulation of NETosis by macrophages. (C) 2015 The Authors. Published by Elsevier Ltd.
• Novel monoclonal antibodies that recognize both rat and mouse phosphatidylserine/prothrombin complexes

  Tamihiro Kawakami, Sun Young Yoon, Sora Takeuchi, Yoshinao Soma, Sayo Kuroha, Shigeru Yoshida, Haruki Shida, Daigo Nakazawa, Utano Tomaru, Akihiro Ishizu

  MODERN RHEUMATOLOGY 26 3 470 - 471 2016年 [査読有り][通常論文]
  
• Comparison of severity classification in Japanese patients with antineutrophil cytoplasmic antibody-associated vasculitis in a nationwide, prospective, inception cohort study

  Ken-ei Sada, Masayoshi Harigai, Koichi Amano, Tatsuya Atsumi, Shouichi Fujimoto, Yukio Yuzawa, Yoshinari Takasaki, Shogo Banno, Takahiko Sugihara, Masaki Kobayashi, Joichi Usui, Kunihiro Yamagata, Sakae Homma, Hiroaki Dobashi, Naotake Tsuboi, Akihiro Ishizu, Hitoshi Sugiyama, Yasunori Okada, Yoshihiro Arimura, Seiichi Matsuo, Hirofumi Makino

  MODERN RHEUMATOLOGY 26 5 730 - 737 2016年 [査読有り][通常論文]
   

  Objective: To compare disease severity classification systems for six-month outcome prediction in patients with antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV). Methods: Patients with newly diagnosed AAV from 53 tertiary institutions were enrolled. Six-month remission, overall survival, and end-stage renal disease (ESRD)-free survival were evaluated. Results: According to the European Vasculitis Study Group (EUVAS)-defined disease severity, the 321 enrolled patients were classified as follows: 14, localized; 71, early systemic; 170, generalized; and 66, severe disease. According to the rapidly progressive glomerulonephritis (RPGN) clinical grading system, the patients were divided as follows: 60, grade I; 178, grade II; 66, grade III; and 12, grade IV. According to the Five-Factor Score (FFS) 2009, 103, 109, and 109 patients had <= 1, 2, and >= 3 points, respectively. No significant difference in remission rates was found in any severity classification. The overall and ESRD-free survival rates significantly differed between grades I/II, III, and IV, regardless of renal involvement. Severe disease was a good predictor of six-month overall and ESRD-free survival. The FFS 2009 was useful to predict six-month ESRD-free survival but not overall survival. Conclusions: The RPGN grading system was more useful to predict six-month overall and ESRD-free survival than the EUVAS-defined severity or FFS 2009.
• Circulating Neutrophil Extracellular Trap Levels in Well-Controlled Type 2 Diabetes and Pathway Involved in Their Formation Induced by High-Dose Glucose

  Arina Miyoshi, Mai Yamada, Haruki Shida, Daigo Nakazawa, Yoshihiro Kusunoki, Akinobu Nakamura, Hideaki Miyoshi, Utano Tomaru, Tatsuya Atsumi, Akihiro Ishizu

  PATHOBIOLOGY 83 5 243 - 251 2016年 [査読有り][通常論文]
   

  Objectives: Although intensive therapy for type 2 diabetes (T2D) prevents microvascular complications, 10% of well-controlled T2D patients develop microangiopathy. Therefore, the identification of risk markers for microvascular complications in well-controlled T2D patients is important. Recent studies have demonstrated that high-dose glucose induces neutrophil extracellular trap (NET) formation, which can be a risk for microvascular disorders. Thus, we attempted to determine the correlation of circulating NET levels with clinical/laboratory parameters in well-controlled T2D patients and to reveal the mechanism of NET formation induced by high-dose glucose. Methods: Circulating NET levels represented by myeloperoxidase (MPO)-DNA complexes in the serum of 11 well-controlled T2D patients and 13 healthy volunteers were determined by enzyme-linked immunosorbent assay. The pathway involved in the NET formation induced by high-dose glucose was determined using specific inhibitors. Results: Serum MPO-DNA complex levels were significantly higher in some well-controlled T2D patients in correlation with the clinical/laboratory parameters which have been regarded as risk markers for microvascular complications. The aldose reductase inhibitor, ranirestat, could inhibit the NET formation induced by high-dose glucose. Conclusions: Elevated levels of circulating NETs can be a risk marker for microvascular complications in well-controlled T2D patients. The polyol pathway is involved in the NET formation induced by high-dose glucose. (C) 2016 The Author(s) Published by S. Karger AG, Basel
• Fatal cardiac small-vessel involvement in ANCA-associated vasculitis: an autopsy case report

  Sari Iwasaki, Akira Suzuki, Takashi Fujisawa, Taiju Sato, Shinya Shirai, Mitsunori Kamigaki, Noriyuki Otsuka, Utano Tomaru, Akihiro Ishizu

  CARDIOVASCULAR PATHOLOGY 24 6 408 - 410 2015年11月 [査読有り][通常論文]
   

  An 80-year-old Japanese man, who had fever and generalized fatigue not improved by antibiotics, was admitted to our hospital. Laboratory data indicative of renal dysfunction and antineutrophil cytoplasmic antibody (ANCA) in the serum led to the consideration of ANCA-associated vasculitis as a differential diagnosis. However, before the diagnostic confirmation, he was found dead on the bed. Autopsy revealed necrotizing crescentic glomerulonephritis in the kidneys. In addition, necrotizing granulomatous vasculitis with infiltration of multinucleated giant cells and neutrophils but not eosinophils was present in multiple organs. The direct cause of death was presumed as cardiac arrest by lethal arrhythmia because vasculitic lesions were distributed widely in the cardiac walls, acute congestion was observed in the systemic organs, and other causes of death were ruled out. This report presents the unusual manifestation of cardiac small-vessel involvement in ANCA-associated vasculitis related to sudden death. (C) 2015 Elsevier Inc. All rights reserved.
• Reduction of HLA Class II Expression and Beta-2-Glycoprotein I Presentation By Fluvastatin in Vitro and in Vivo: Possible Mechanism of Statin-Induced-Deprocoagulation in the Antiphospholipid Syndrome

  Toshiyuki Watanabe, Kenji Oku, Olga Amengual, Ryo Hisada, Kazumasa Ohmura, Haruki Shida, Yuka Shimizu, Masaru Kato, Toshiyuki Bohgaki, Tetsuya Horita, Shinsuke Yasuda, Akihiro Ishizu, Hisashi Arase, Tatsuya Atsumi

  ARTHRITIS & RHEUMATOLOGY 67 2015年10月 [査読有り][通常論文]
  
• Decreased expression of thymus-specific proteasome subunit β5t in Down syndrome patients.

  Tomaru U, Tsuji T, Kiuchi S, Ishizu A, Suzuki A, Otsuka N, Ito T, Ikeda H, Fukasawa Y, Kasahara M

  Histopathology 67 2 235 - 244 2015年08月 [査読有り][通常論文]
   

  AimsThe majority of patients with Down syndrome (DS), trisomy 21, have morphologically abnormal thymuses and present with intrinsic immunological abnormalities affecting mainly the cellular immune response. The aim of this study was to examine whether the expression of functionally important molecules is altered in thymic stromal cells in patients with DS. Methods and resultsWe analysed thymic tissues from patients with trisomy 13 (n=4), trisomy 18 (n=14) and trisomy 21 (n=13) for histological alterations, and for the expression of functionally important molecules such as 5t, a thymoproteasome subunit, and cathepsins L and S. In patients with trisomy 13 and trisomy 18, the thymus was morphologically normal or showed only mild depletion of cortical thymocytes. In contrast, the thymus showed variable histological changes in patients with trisomy 21; six of 13 cases showed severe depletion of thymocytes accompanied by the disappearance of thymic lobular architecture. In such thymuses, spindle-shaped keratin-positive cells were densely distributed, and expression of 5t, but not of cathepsin L, was markedly decreased. ConclusionsThe present study suggests that abnormal thymic architecture and decreased expression of functionally important molecules in thymic stromal cells may be involved in immunological abnormalities in DS patients.
• Decreased proteasomal function accelerates cigarette smoke-induced pulmonary emphysema in mice

  Yosuke Yamada, Utano Tomaru, Akihiro Ishizu, Tomoki Ito, Takayuki Kiuchi, Ayako Ono, Syota Miyajima, Katsura Nagai, Tsunehito Higashi, Yoshihiro Matsuno, Hirotoshi Dosaka-Akita, Masaharu Nishimura, Soichi Miwa, Masanori Kasahara

  LABORATORY INVESTIGATION 95 6 625 - 634 2015年06月 [査読有り][通常論文]
   

  Chronic obstructive pulmonary disease (COPD) is a disease common in elderly people, characterized by progressive destruction of lung parenchyma and chronic inflammation of the airways. The pathogenesis of COPD remains unclear, but recent studies suggest that oxidative stress-induced apoptosis in alveolar cells contributes to emphysematous lung destruction. The proteasome is a multicatalytic enzyme complex that plays a critical role in proteostasis by rapidly destroying misfolded and modified proteins generated by oxidative and other stresses. Proteasome activity decreases with aging in many organs including lungs, and an age-related decline in proteasomal function has been implicated in various age-related pathologies. However, the role of the proteasome system in the pathogenesis of COPD has not been investigated. Recently, we have established a transgenic (Tg) mouse model with decreased proteasomal chymotrypsin-like activity, showing age-related phenotypes. Using this model, we demonstrate here that decreased proteasomal function accelerates cigarette smoke (CS)-induced pulmonary emphysema. CS-exposed Tg mice showed remarkable airspace enlargement and increased foci of inflammation compared with wild-type controls. Importantly, apoptotic cells were found in the alveolar walls of the affected lungs. Impaired proteasomal activity also enhanced apoptosis in cigarette smoke extract (CSE)-exposed fibroblastic cells derived from mice and humans in vitro. Notably, aggresome formation and prominent nuclear translocation of apoptosis-inducing factor were observed in CSE-exposed fibroblastic cells isolated from Tg mice. Collective evidence suggests that CS exposure and impaired proteasomal activity coordinately enhance apoptotic cell death in the alveolar walls that may be involved in the development and progression of emphysema in susceptible individuals such as the elderly.
• Activating transcription factor 5 enhances radioresistance and malignancy in cancer cells

  Seiichiro Ishihara, Motoaki Yasuda, Akihiro Ishizu, Masayori Ishikawa, Hiroki Shirato, Hisashi Haga

  ONCOTARGET 6 7 4602 - 4614 2015年03月 [査読有り][通常論文]
   

  Radiotherapy is effective for treating various types of tumors. However, some cancer cells survive after irradiation and repopulate tumors with highly malignant phenotypes that correlate with poor prognosis. It is not known how cancer cells survive and generate malignant tumors after irradiation. Here, we show that activating transcription factor 5 (ATF5) promotes radioresistance and malignancy in cancer cells after irradiation. In the G1-S phase of the cell cycle, cancer cells express high levels of ATF5, which promotes cell cycle progression and thereby increases radioresistance. Furthermore, ATF5 increases malignant phenotypes, such as cell growth and invasiveness, in cancer cells in vitro and in vivo. We have identified a new mechanism for the regeneration of highly malignant tumors after irradiation and shown that ATF5 plays a key role in the process.
• Establishment of a vascular endothelial cell-reactive type II NKT cell clone from a rat model of autoimmune vasculitis

  Chihiro Iinuma, Masashi Waki, Ai Kawakami, Madoka Yamaguchi, Utano Tomaru, Naomi Sasaki, Sakiko Masuda, Yuki Matsui, Sari Iwasaki, Tomohisa Baba, Masanori Kasahara, Takashi Yoshiki, Daniel Paletta, Thomas Herrmann, Akihiro Ishizu

  INTERNATIONAL IMMUNOLOGY 27 2 105 - 114 2015年02月 [査読有り][通常論文]
   

  We previously generated a rat model that spontaneously developed small vessel vasculitis (SVV). In this study, a T cell clone reactive with rat vascular endothelial cells (REC) was established and named VASC-1. Intravenous injection of VASC-1 induced SVV in normal recipients. VASC-1 was a TCR alpha beta/CD3-positive CD4/CD8 double-negative T cell clone with expression of NKG2D. The cytokine mRNA profile under unstimulated condition was positive for IL-4 and IFN-gamma but negative for IL-2 and IL-10. After interaction with REC, the mRNA expression of IL-2, IL-5 and IL-6 was induced in VASC-1, which was inhibited by blocking of CD1d on the REC surface. Although the protein levels of these cytokines seemed to be lower than the detection limit in the culture medium, IFN-gamma was detectable. The production of IFN-gamma from the VASC-1 stimulated with LPS-pre-treated REC was inhibited by the CD1d blockade on the REC. These findings indicated VASC-1 as an NKT cell clone. The NKT cell pool includes two major subsets, namely types I and II. Type I NKT cells are characterized by expression of semi-invariant TCRs and the potential to bind to marine sponge-derived alpha-galactosylceramide (alpha-GalCer) loaded on CD1d; whereas, type II NKT cells do not manifest these characteristics. VASC-1 exhibited a usage of TCR other than the type I invariant TCR alpha chain and did not bind to alpha-GalCer-loaded CD1d; therefore, it was determined as a type II NKT cell clone. The collective evidence suggested that REC-reactive type II NKT cells could be involved in the pathogenesis of SVV in rats.
• Overexpression of TNF-α converting enzyme promotes adipose tissue inflammation and fibrosis induced by high fat diet.

  Matsui Y, Tomaru U, Miyoshi A, Ito T, Fukaya S, Miyoshi H, Atsumi T, Ishizu A

  Experimental and molecular pathology 97 3 354 - 358 2014年12月 [査読有り][通常論文]
   

  Obesity is a state in which chronic low-grade inflammation persists in adipose tissues. Pro-inflammatory cytokines, including TNF-alpha, produced by adipose tissues have been implicated as active participants in the development of obesity-related diseases. Since TNF-alpha converting enzyme (TACE) is the major factor that induces soluble TNF-alpha, TACE has been noted as a pivotal regulator in this field. To reveal the role of TACE in adipose tissue inflammation, TACE-transgenic (TACE-Tg) and wild type (WT) mice were fed with high fat diet (HFD) or control diet for 16 weeks. At 13 weeks after the beginning of the diet, serum TNF-alpha and macrophage-related cytokine/chemokine levels were elevated in TACE-Tg mice fed with HFD (Tg-HFD mice), and the number of the so-called crown-like adipocyte was significantly increased in adipose tissues of Tg-HFD mice at the end of the experiment. Although macrophage infiltration was not detected in the adipose tissues at this time, fibrosis was observed around the crown-like adipocytes. These findings suggested that TACE overexpression induced macrophage infiltration and subsequent fibrosis in adipose tissues under HFD regimen. The collective evidence suggested that TACE could be a therapeutic target of HFD-induced obesity-related adipose tissue inflammation. (C) 2014 Elsevier Inc. All rights reserved.
• [111th Scientific Meeting of the Japanese Society of Internal Medicine: Symposium: 1. Immunity and diseases in internal medicine--Frontier of pathophysiology and treatment; 5) Frontiers in the pathogenesis and treatment of ANCA-associated vasculitis].

  Yamamura M, Sada KE, Harigai M, Fujii T, Ishizu A, Arimura Y, Makino H

  Nihon Naika Gakkai zasshi. The Journal of the Japanese Society of Internal Medicine 103 9 2121 - 2129 2014年09月 [査読有り][招待有り]
  
• Enhanced Formation and Disordered Regulation of NETs in Myeloperoxidase-ANCA-Associated Microscopic Polyangiitis

  Daigo Nakazawa, Haruki Shida, Utano Tomaru, Masaharu Yoshida, Saori Nishio, Tatsuya Atsumi, Akihiro Ishizu

  JOURNAL OF THE AMERICAN SOCIETY OF NEPHROLOGY 25 5 990 - 997 2014年05月 [査読有り][通常論文]
   

  AKI involves early Toll-like receptor (TLR)-driven immunopathology, and resolution of inflammation is needed for rapid regeneration of injured tubule cells. Notably, activation of TLRs also has been implicated in epithelial repair. We hypothesized that TLR signaling drives tubule regeneration after acute injury through the induction of certain ILs. Systematic screening in vitro identified IL-22 as a candidate proregeneratory factor in primary tubular cell recovery, and IL-22 deficiency or IL-22 blockade impaired post-ischemic tubular recovery after AKI in mice. Interstitial mononuclear cells, such as dendritic cells and macrophages, were the predominant source of IL-22 secretion, whereas IL-22 receptor was expressed by tubular epithelial cells exclusively. Depleting IL-22-producing cells during the healing phase impaired epithelial recovery, which could be rescued entirely by reconstituting mice with IL-22. In vitro, necrotic tubular cells and oxidative stress induced IL-22 secretion selectively through TLR4. Although TLR4 blockade during the early injury phase prevented tubular necrosis and AKI, TLR4 blockade during the healing phase suppressed IL-22 production and impaired kidney regeneration. Taken together, these results suggest that necrotic cell-derived TLR4 agonists activate intrarenal mononuclear cells to secrete IL-22, which accelerates tubular regeneration and recovery in AKI.
• Expression of thymoproteasome subunit β5t in type AB thymoma.

  Yamada Y, Tomaru U, Ishizu A, Kiuchi T, Kasahara M, Matsuno Y

  Journal of clinical pathology 67 3 276 - 278 2014年03月 [査読有り][通常論文]
   

  Type AB thymoma is a thymic epithelial tumour composed of lymphocyte-poor type A and lymphocyterich type B components. Although it is categorised as a single entity in the classification of WHO, it shows a broad range of morphology. To investigate whether the functional characteristic of neoplastic cells in type AB thymoma relates to morphological diversity, we performed immunohistochemical analysis using anti-beta 5t antibody in 20 cases of type AB thymoma. beta 5t is a recently discovered proteasomal beta subunit expressed exclusively in cortical thymic epithelial cells and tumour epithelial cells of thymomas with cortical differentiation. Consistent with our previous observation, beta 5t was predominantly expressed in the type B component. When the type B component was divided into three groups morphologically, beta 5t was expressed more frequently in cases with round to polygonal than spindle to oval tumour cells. Furthermore, the ratio of terminal deoxynucleotidyl transferase (TdT)-positive lymphocytes was increased in components with higher expression of beta 5t. These results indicate that the histological diversity of type AB thymoma correlates with expression of a functional marker beta 5t and abundance of TdT-positive lymphocytes.
• Aortic valve aneurysm responsible for acute congestive heart failure and histological findings: A case report

  Hirohito Sugawara, Tomoaki Matsumoto, Hiroyuki Hotta, Daisuke Yoshida, Nobuo Kato, Junichi Ohata, Katsuhisa Ishii, Satoshi Yuda, Tatsuya Murakami, Shingo Shibata, Akihiro Ishizu, Hitoshi Ooiwa, Yukiyasu Fujise, Tomoaki Nakata

  Journal of Cardiology Cases 10 3 100 - 103 2014年 [査読有り][通常論文]
   

  We experienced a case of acute congestive heart failure in a 73-year-old man who had been followed up due to mild-to-moderate aortic stenosis and moderate-to-severe aortic regurgitation. A huge aortic valve aneurysm was found to extend from his right coronary cusp to a left ventricular outflow tract, resulting in moderate subaortic obstruction and severe aortic regurgitation. Surgical repair was performed and a perforated aneurysm of right aortic cusp was identified. Histological examinations suggested that healed infective endocarditis was responsible for the formation of an aneurysm in the aortic valve.< Learning objective: Aortic valve aneurysm is an uncommon complication of infective endocarditis. The infective process of a cardiac valve is thought to augment valvular tissue injury, resulting in aneurysmal formation and perforation of the valvular aneurysm. We report an uncommon case of aortic valve aneurysm that was histologically suggested to be caused by subclinical infective endocarditis. The subaortic obstruction and aortic regurgitation were successfully treated using a surgical procedure.> . © 2014 Japanese College of Cardiology.
• Possible linkage between microscopic polyangiitis and thrombosis via neutrophil extracellular traps

  T. Imamoto, D. Nakazawa, H. Shida, A. Suzuki, N. Otsuka, U. Tomaru, A. Ishizu

  CLINICAL AND EXPERIMENTAL RHEUMATOLOGY 32 1 149 - 150 2014年01月 [査読有り][通常論文]
  
• Ag and IL-2 immune complexes efficiently expand Ag-specific Treg cells that migrate in response to chemokines and reduce localized immune responses

  Ryoko Hamano, Tomohisa Baba, Soichiro Sasaki, Utano Tomaru, Akihiro Ishizu, Mitsuhiro Kawano, Masakazu Yamagishi, Naofumi Mukaida

  European Journal of Immunology 44 4 1005 - 1015 2014年 [査読有り][通常論文]
   

  An intravenous administration of a high-dose antigen (Ag) can induce immune tolerance and suppress the immune response, but the mechanism remains unclear. We recently proved that a combined i.v. administration of OVA and IL-2-anti-IL-2 Ab immune complexes (IL-2 ICs) efficiently expands OVA-specific Treg cells in the thymus and induces their migration into peripheral blood, by using OVA-specific TCR Tg-expressing DO11.10 mice. Here, we demonstrate that the expanded OVA-specific Treg cells rapidly move into the air pouch after OVA injection in DO11.10 mice. The migration was inhibited by blocking the axis of a chemokine receptor, CCR2. Moreover, prior treatment with OVA and IL-2 ICs enhanced OVA-specific Treg-cell migration and inhibited OVA-induced delayed-type hypersensitivity (DTH) reactions in the skin of BM chimeric mice with 15% of T cells expressing OVA-specific TCR. Blocking the CCR2 axis reversed this suppression of DTH in these mice. Furthermore, prior treatment with OVA and IL-2 ICs effectively reduced DTH reactions even in WT mice possessing only a very small population of OVA-specific T cells. Thus, the treatment with Ag and IL-2 ICs can efficiently expand Ag-specific Treg cells with the capacity to migrate and reduce localized immune responses. © 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.
• Severe Pulmonary Hypertension in Adult Pulmonary Langerhans Cell Histiocytosis: The Effect of Sildenafil as a Bridge to Lung Transplantation

  Takayuki Yoshida, Satoshi Konno, Ichizo Tsujino, Takahiro Sato, Hiroshi Ohira, Fengshi Chen, Hiroshi Date, Akihiro Ishizu, Hironori Haga, Mishie Tanino, Masaharu Nishimura

  INTERNAL MEDICINE 53 17 1985 - 1990 2014年 [査読有り][通常論文]
   

  Severe pulmonary hypertension (PH) often develops in patients with pulmonary Langerhans cell histiocytosis (PLCH). Supplemental oxygen treatment is often used, whereas pulmonary arterial hypertension-specific vasodilators are generally considered hazardous because of the possible development of pulmonary edema and deterioration of hypoxia. In the present report, we herein describe a PLCH patient with severe PH in whom sildenafil, a phosphodiesterase 5 (PDE5) inhibitor, substantially improved the pulmonary hemodynamics before lung transplantation. An immunohistochemical study of the resected lung revealed positive staining for PDE5 on the diseased pulmonary arteries. These observations suggest that sildenafil can be a promising therapeutic option for PH in patients with PLCH.
• Treatment for cutaneous arteritis patients with mononeuritis multiplex and elevated C-reactive protein

  Tamihiro Kawakami, Azusa Okudaira, Tatsuro Okano, Sora Takeuchi, Satoko Kimura, Yoshinao Soma, Akihiro Ishizu, Yoshihiro Arimura, Shigeto Kobayashi, Shoichi Ozaki

  JOURNAL OF DERMATOLOGY 40 12 955 - 961 2013年12月 [査読有り][通常論文]
   

  Cutaneous arteritis (cutaneous polyarteritis nodosa, CA) is a necrotizing vasculitis of arteries within the skin. CA is a new classification under single-organ vasculitis, as adopted by the 2012 Chapel Hill consensus conference (CHCC 2012). Some patients originally diagnosed as having CA could develop additional disease manifestations that warrant reclassifying as systemic polyarteritis nodosa (PAN) according to the CHCC 2012. We retrospectively investigated 101 patients with CA seen at our department between 2003 and 2012. There was a significantly higher frequency of inflammatory plaques and leg edema in CA patients with elevated C-reactive protein (CRP) compared to CA patients with normal CRP. Similarly, there were significant differences in the incidence of arthralgia and mononeuritis multiplex between the two patient groups. We found significantly positive correlations between CRP and creatinine titers in serum in all 101 CA patients. Prednisolone was administrated in a significantly greater percentage of patients with elevated CRP compared to patients with normal CRP. Repeated i.v. cyclophosphamide pulse therapy (IV-CY) with prednisolone therapy at an early stage resulted in complete resolution without adverse effects or severe complications. We regard inflammatory plaques and leg edema with elevated serum CRP as an indication of a more severe condition, and treated them effectively with prednisolone. Assuming mononeuritis multiplex and/or arthritis exist with elevated CRP, we propose that earlier treatment by IV-CY with prednisolone should be indicated for CA patients who demonstrate these more severe manifestations to prevent progression to PAN.
• Possible implication of disordered neutrophil extracellular traps in the pathogenesis of MPO-ANCA-associated vasculitis

  Daigo Nakazawa, Utano Tomaru, Akihiro Ishizu

  CLINICAL AND EXPERIMENTAL NEPHROLOGY 17 5 631 - 633 2013年10月 [査読有り][招待有り]
   

  Neutrophil extracellular traps (NETs) are characterized by the presence of extracellular DNA fibers studded with antimicrobial proteins, including myeloperoxidase (MPO). Although NETs play an important role in the innate immune system, the scattered extracellular enzymes, such as MPO, pose risks to the host. Therefore, NETs are strictly regulated by DNase I in the serum, which prevents them from persisting. Recent studies have demonstrated that dysregulation of NETs could be involved in the pathogenesis of autoimmune diseases, including systemic lupus erythematosus. In this review, we interpret the association of disordered NETs with autoimmune diseases, especially propylthiouracil-induced MPO-ANCA-associated vasculitis.
• Lysosomal-associated membrane protein-2 plays an important role in the pathogenesis of primary cutaneous vasculitis

  Sora Takeuchi, Satoko Kimura, Yoshinao Soma, Masashi Waki, Madoka Yamaguchi, Daigo Nakazawa, Utano Tomaru, Akihiro Ishizu, Tamihiro Kawakami

  RHEUMATOLOGY 52 9 1592 - 1598 2013年09月 [査読有り][通常論文]
   

  Methods. Cutaneous vasculitis was observed in similar to 30% of 6-month-old morbid env-pX rats. In contrast, these findings were rare in premorbid env-pX rats under 3 months old. We also examined 85 patients with CPN and 36 adult patients with HSP. Serum anti-LAMP-2 antibody levels were determined using ELISA. Premorbid env-pX rats under 3 months old were given an i.v. injection of anti-LAMP-2 antibody at day 0 and day 7. At day 14, these rats underwent histopathological and direct immunofluorescence examination. Cell surface LAMP-2 expression of rat neutrophils was examined by flow cytometry. Results. Serum anti-LAMP-2 antibody levels were significantly higher in morbid env-pX rats than in wild-type normal rats. In addition, the levels in the cutaneous vasculitis group of morbid env-pX rats were significantly higher than the no cutaneous vasculitis group. Intravenous anti-LAMP-2 antibody injection into premorbid env-pX rats under 3 months old induced infiltration of neutrophils into cutaneous small vessels. Anti-LAMP-2 antibody-binding neutrophils were detected there. LAMP-2 expression on the cell surface of neutrophils in premorbid env-pX rats under PMA stimulation was higher compared with controls. Serum anti-LAMP-2 antibody levels in CPN and HSP were significantly higher than those of healthy controls. Conclusion. These data support a positive relationship between anti-LAMP-2 antibody and cutaneous vasculitis.
• Human papillomavirus 16-positive uterine cervical squamous cell carcinoma with coinfection with human papillomavirus 34 has a lower incidence in lymph node metastasis than that without coinfection with human papillomavirus 34

  Rie Michimata, Hidemichi Watari, Utano Tomaru, Noriaki Sakuragi, Akihiro Ishizu

  Pathobiology 80 5 259 - 264 2013年06月 [査読有り][通常論文]
   

  Our earlier study demonstrated high prevalence of multiple human papillomavirus (HPV) infection in patients with invasive uterine cervical cancer, including squamous cell carcinoma (SCC). HPV 16 is the most predominant genotype related to SCC of the uterine cervix. The aim of this study was to reveal the biological significance of multiple HPV infection concerning the tumor progression of invasive uterine cervical SCC. In the present study, the effects of coinfection with genotypes other than HPV 16 on tumor growth and lymph node metastasis of invasive uterine cervical SCC with HPV 16 infection were examined. Although coinfection with most genotypes did not influence tumor progression, the clinical stage of patients coinfected with HPV 16 and HPV 34 was significantly lower than that of those without HPV 34 coinfection (p = 0.0038). Moreover, no patient coinfected with HPV 16 and HPV 34 manifested lymph node metastasis, but about half of the patient population without HPV 34 coinfection did (p = 0.0299). These findings suggested that coinfection with HPV 34 could prevent the tumor progression of invasive uterine cervical SCC with HPV 16 infection. Copyright © 2013 S. Karger AG, Basel.
• Prediction of Response to Treatment by Gene Expression Profiling of Peripheral Blood in Patients with Microscopic Polyangiitis

  Akihiro Ishizu, Utano Tomaru, Taichi Murai, Tomohiro Yamamoto, Tatsuya Atsumi, Takashi Yoshiki, Wako Yumura, Kunihiro Yamagata, Hidehiro Yamada, Shunichi Kumagai, Manae S. Kurokawa, Machi Suka, Hirofumi Makino, Shoichi Ozaki

  PLOS ONE 8 5 e63182  2013年05月 [査読有り][通常論文]
   

  The JMAAV study was an open-labeled prospective clinical trial, which proposed severity-based treatment protocols for patients with microscopic polyangiitis (MPA). The results suggest that the proposed protocols are useful (remission rate: 89.4%), but are also indicative of relapse or patient demise regardless of the treatment (recurrence rate: 19.0%; mortality rate: 10.6%). The aim of this study is to develop the method to predict response to the treatment in patients with MPA. In the present study, transcriptome analysis was performed using peripheral blood from patients enrolled in the JMAAV study before and 1-week after the beginning of treatment. The gene expression profile before treatment was not directly related to the response to the treatment. However, when the samples from 9 patients with good response (persistent remission for 18 months) were examined, the expression of 88 genes was significantly altered by the treatment. Thirty statistically reliable genes were selected, and then the alteration of expression by the treatment was examined among 22 patients, including 17 with good response, which was defined as persistent remission for 18 months and 5 with poor response, which was defined as relapse after remission or no remission. Discrimination analysis between the alteration of expression of the 30 genes by the treatment and the response identified a combination of 16 genes as the most valuable gene set to predict the response to the treatment. This preliminary study identified IRF7, IFIT1, IFIT5, OASL, CLC, GBP-1, PSMB9, HERC5, CCR1, CD36, MS4A4A, BIRC4BP, PLSCR1, DEFA1/DEFA3, DEFA4, and COL9A2 as the important genes that can predict the response to the treatment in patients with MPA at an early point during the therapy.
• Serum Anti-lysosomal-associated Membrane Protein-2 Antibody Levels in Cutaneous Polyarteritis Nodosa

  Tamihiro Kawakami, Akihiro Ishizu, Yoshihiro Arimura, Yoshinao Soma

  ACTA DERMATO-VENEREOLOGICA 93 1 70 - 73 2013年 [査読有り][通常論文]
   

  Lysosomal-associated membrane protein-2 (LAMP-2) is a target antigen for anti-neutrophil cytoplasmic antibodies (ANCAs), which are closely linked to a subset of primary systemic vasculitides. Cutaneous polyarteritis nodosa (CPN) is a necrotizing vasculitis of small to medium-sized arteries within the skin. We measured levels of serum anti-LAMP-2 antibody in 50 patients with CPN, 8 with microscopic polyangiitis (MPA), and 34 healthy persons. We also investigated the presence of ANCA in patients with CPN using indirect immunofluorescence (BY), a direct ELISA and a capture ELISA specific for myeloperoxidase (MPO) and proteinase 3 (PR3). Serum anti-LAMP-2 antibody levels differed significantly between patients with CPN (0.263 U/ml) and those with MIPA (0.180 U/ml) (p=0.0102). Serum of all patients with CPN was negative for MPO-ANCA and PR3-ANCA by both direct ELISA and capture ELISA. In contrast, IIF assay revealed ANCA in 42 (84.0%) of the 50 CPN patients. Serum anti-LAMP-2 antibody levels in the perinuclear ANCA (P-ANCA) group were significantly elevated compared with the non-ANCA group (p=0.0147). We suggest that anti-LAMP-2 antibody could play an important role in the pathogenesis of CPN in the presence of P-ANCA detected by IIF.
• Overexpression of TNF-α-converting enzyme in fibroblasts augments dermal fibrosis after inflammation.

  Fukaya S, Matsui Y, Tomaru U, Kawakami A, Sogo S, Bohgaki T, Atsumi T, Koike T, Kasahara M, Ishizu A

  Laboratory investigation; a journal of technical methods and pathology 93 1 72 - 80 1 2013年01月 [査読有り][通常論文]
   

  TNF-alpha-converting enzyme (TACE) can cleave transmembrane proteins, such as TNF-alpha, TNF receptors, and epidermal growth factor receptor (EGFR) ligands, to release the extracellular domains from the cell surface. Recent studies have suggested that overexpression of TACE may be associated with the pathogenesis of inflammation and fibrosis. To determine the roles of TACE in inflammation and fibrosis, TACE transgenic (TACE-Tg) mice, which overexpressed TACE systemically, were generated. As the transgene-derived TACE was expressed as an inactive form, no spontaneous phenotype developed in TACE-Tg mice. However, the transgene-derived TACE could be converted to an active form by furin in vitro and by phorbol myristate acetate (PMA) in vivo. Subcutaneous injection of PMA into mice induced inflammatory cell infiltration 1 day later and subsequent dermal fibrosis 7 days later. Interestingly, the degree of dermal fibrosis at day 7 was significantly higher in TACE-Tg mice than in wild-type mice. Correspondingly, PMA increased the expression of type I collagen in the primary culture of dermal fibroblasts derived from TACE-Tg mice. Furthermore, phosphorylated EGFR was increased in the fibroblasts by the PMA treatment. The collective findings suggest that TACE overexpression and activation in fibroblasts could shed off putative EGFR ligands. Subsequently, the soluble EGFR ligands could bind and activate EGFR on fibroblasts, and then increase the type I collagen expression resulting in induction of dermal fibrosis. These results also suggest that TACE and EGFR on fibroblasts may be novel therapeutic targets of dermal fibrosis, which is induced after diverse inflammatory disorders of the skin. Laboratory Investigation (2013) 93, 72-80; doi:10.1038/labinvest.2012.153; published online 12 November 2012
• Possible implication of Fc γ receptor-mediated trogocytosis in susceptibility to systemic autoimmune disease.

  Masuda S, Iwasaki S, Tomaru U, Baba T, Katsumata K, Ishizu A

  Clinical & developmental immunology 2013 345745  2013年 [査読有り][招待有り]
   

  Leukocytes can "gnaw away" the plasma membrane of other cells. This phenomenon, called trogocytosis, occurs subsequent to cell-to-cell adhesion. Currently, two mechanisms of trogocytosis, adhesion molecule-mediated trogocytosis and Fc gamma receptor-(Fc gamma R-) mediated trogocytosis, have been identified. In our earlier study, we established an in vitro model of Fc gamma R-mediated trogocytosis, namely, CD8 translocationmodel from T cells to neutrophils. By using this model, we demonstrated that the molecules transferred to neutrophils via Fc gamma R-mediated trogocytosis were taken into the cytoplasm immediately. This result suggests that the chance of molecules transferred via Fc gamma R-mediated trogocytosis to play a role on the cell surface could be time-limited. Thus, we consider the physiological role of Fc gamma R-mediated trogocytosis as a means to remove antibodies (Abs) that bind with self-molecules rather than to extractmolecules from other cells. This concept means that Fc gamma R-mediated trogocytosis can be a defense mechanism to Ab-mediated autoimmune response. Moreover, the activity of Fc gamma R-mediated trogocytosis was revealed to be parallel to the endocytotic activity of neutrophils, which was critically related to the susceptibility to systemic autoimmune diseases. The collective findings suggest that Fc gamma R-mediated trogocytosis could physiologically play a role in removal of Abs bound to self-antigens and prevent autoimmune diseases.
• Mechanism of Fcγ receptor-mediated trogocytosis-based false-positive results in flow cytometry.

  Masuda S, Iwasaki S, Tomaru U, Sato J, Kawakami A, Ichijo K, Sogo S, Baba T, Katsumata K, Kasahara M, Ishizu A

  PloS one 7 12 e52918  2012年12月 [査読有り][通常論文]
   

  The whole blood erythrocyte lysis method is the most common protocol of sample preparation for flow cytometry (FCM). Although this method has many virtues, our recent study has demonstrated false-positive results when surface markers of monocytes were examined by this method due to the phenomenon called Fc gamma receptor (Fc gamma R)-mediated trogocytosis. In the present study, similar Fc gamma R-mediated trogocytosis-based false-positive results have been demonstrated when granulocytes were focused on instead of monocytes. These findings indicated that not only monocytes but also granulocytes, the largest population with Fc gamma R expression in peripheral blood, could perform Fc gamma R-mediated trogocytosis. Since the capacity of Fc gamma R-mediated trogocytosis was different among blood samples, identification of factors that could regulate the occurrence of Fc gamma R-mediated trogocytosis should be important for the quality control of FCM. Our studies have suggested that such factors are present in the serum. In order to identify the serum factors, we employed the in vitro model of Fc gamma R-mediated trogocytosis using granulocytes. Investigation with this model determined the serum factors as heat-labile molecules with molecular weight of more than 100 kDa. Complements in the classical pathway were initially assumed as candidates; however, the C1 inhibitor did not yield an obvious influence on Fc gamma R-mediated trogocytosis. On the other hand, although immunoglobulin ought to be resistant to heat inactivation, the inhibitor of human anti-mouse antibodies (HAMA) effectively blocked Fc gamma R-mediated trogocytosis. Moreover, the inhibition rates were significantly higher in HAMA(high) serum than HAMA(low) serum. The collective findings suggested the involvement of heterophilic antibodies such as HAMA in the mechanism of false-positive results in FCM due to Fc gamma R-mediated trogocytosis.
• Abnormal conformation and impaired degradation of propylthiouracil-induced neutrophil extracellular traps Implications of disordered neutrophil extracellular traps in a rat model of myeloperoxidase antineutrophil cytoplasmic antibody-associated vasculitis

  Daigo Nakazawa, Utano Tomaru, Akira Suzuki, Sakiko Masuda, Risa Hasegawa, Toshiaki Kobayashi, Saori Nishio, Masanori Kasahara, Akihiro Ishizu

  ARTHRITIS AND RHEUMATISM 64 11 3779 - 3787 2012年11月 [査読有り][通常論文]
   

  Objective Neutrophil extracellular traps (NETs) are composed of DNA and antimicrobial proteins, including myeloperoxidase (MPO). Recent studies have demonstrated that impaired regulation of NETs could trigger an autoimmune response. Propylthiouracil (PTU), an antithyroid drug, is associated with a risk of MPO antineutrophil cytoplasmic antibody (ANCA) production and MPO ANCA-associated vasculitis (MPO AAV). This study was undertaken to clarify the mechanism of MPO ANCA production, using the PTU-induced model of MPO AAV. Methods NETs were induced by treating human neutrophils with phorbol myristate acetate (PMA) in vitro. We examined whether the addition of PTU influenced the NET formation induced by PMA and the degradation of NETs by DNase I, which is regarded as a regulator of NETs. Furthermore, we examined whether NETs generated by the combination of PMA and PTU induced MPO ANCA and MPO AAV in vivo in rats. Results When NETs were induced by PMA with PTU using human neutrophils in vitro, abnormal conformation of NETs was observed. Interestingly, the abnormal NETs were hardly digested by DNase I. Moreover, rats immunized with the abnormal NETs, which had been induced by PMA with PTU using rat neutrophils, produced MPO ANCA and developed pulmonary capillaritis. When rats were given oral PTU with intraperitoneal injection of PMA, pauci-immune glomerulonephritis and pulmonary capillaritis occurred with MPO ANCA production in the serum. Conclusion Our findings indicate that abnormal conformation and impaired degradation of NETs induced by PTU are involved in the pathogenesis of PTU-induced MPO ANCA production and MPO AAV. These findings suggest that disordered NETs can be critically implicated in the pathogenesis of MPO AAV.
• Proteasome subunit β5t expression in cervical ectopic thymoma.

  Tomaru U, Yamada Y, Ishizu A, Kuroda T, Matsuno Y, Kasahara M

  Journal of clinical pathology 65 9 858 - 859 9 2012年09月 [査読有り][通常論文]
  
• Decrease of Peripheral and Intestinal NKG2A-Positive T Cells in Patients with Ulcerative Colitis

  Takehiko Katsurada, Waka Kobayashi, Utano Tomaru, Tomohisa Baba, Shigeru Furukawa, Akihiro Ishizu, Kazuyoshi Takeda, Naoya Sakamoto, Masahiro Asaka, Hiroshi Takeda, Masanori Kasahara

  PLOS ONE 7 9 e44113  2012年09月 [査読有り][通常論文]
   

  To investigate the role of inhibitory natural killer receptors (iNKRs) in inflammatory bowel disease (IBD), we analyzed the expression of NKG2A, one of the iNKRs, on T cells in a mouse colitis model and human IBD. During the active phase of dextran sulfate sodium (DSS)-induced mouse colitis, the frequency of NKG2A+ T cells was significantly decreased in the peripheral blood, and increased in the intestine, suggesting the mobilization of this T cell subset to the sites of inflammation. Administration of anti-NKG2A antibody increased the number of inflammatory foci in DSS-induced colitis, suggesting the involvement of NKG2A+ T cells in this colitis model. In ulcerative colitis (UC) patients, the frequency of peripheral blood NKG2A+ T cells was significantly decreased, compared with Crohn's disease (CD) patients and healthy controls, regardless of clinical conditions such as treatment modalities and disease activity. Notably, in sharp contrast to the DSS-induced mouse colitis model, the frequency of NKG2A+ cells among intestinal T cells was also decreased in UC patients. These results suggest that inadequate local infiltration of NKG2A+ T cells may be involved in the pathogenesis of UC.
• Novel process of intrathymic tumor-immune tolerance through CCR2-mediated recruitment of Sirpα+ dendritic cells: a murine model.

  Baba T, Badr Mel S, Tomaru U, Ishizu A, Mukaida N

  PloS one 7 7 e41154  7 2012年07月 [査読有り][通常論文]
   

  Immune surveillance system can detect more efficiently secretory tumor-specific antigens, which are superior as a target for cancer immunotherapy. On the contrary, immune tolerance can be induced in the thymus when a tumor antigen is massively secreted into circulation. Thus, the secretion of tumor-specific antigen may have contradictory roles in tumor immunity in a context-dependent manner. However, it remains elusive on the precise cellular mechanism of intrathymic immune tolerance against tumor antigens. We previously demonstrated that a minor thymic conventional dendritic cell (cDC) subset, CD8 alpha(-)Sirp alpha(+) cDCs, but not the major subset, CD8 alpha(+)Sirp alpha(-) cDCs can selectively capture blood-borne antigens and crucially contribute to the self-tolerance. In the present study, we further demonstrated that Sirp alpha(+) cDCs can capture a blood-borne antigen leaking inside the interlobular vascular-rich regions (IVRs). Blood-borne antigen selectively captured by Sirp alpha(+) cDCs can induce antigen-specific Treg generation or negative selection, depending on the immunogenicity of the presented antigen. Furthermore, CCR2 expression by thymic Sirp alpha(+) cDCs and abundant expression of its ligands, particularly, CCL2 by tumor-bearing mice prompted us to examine the function of thymic Sirp alpha(+) cDCs in tumor-bearing mice. Interestingly, tumor-bearing mice deposited CCL2 inside IVRs in the thymus. Moreover, tumor formation induced the accumulation of Sirp alpha(+) cDCs in IVRs under the control of CCR2-CCL2 axis and enhanced their capacity to take up antigens, resulting in the shift from Treg differentiation to negative selection. Finally, intrathymic negative selection similarly ensued in CCR2-competent mice once the tumor-specific antigen was secreted into bloodstream. Thus, we demonstrated that thymic Sirp alpha(+) cDCs crucially contribute to this novel process of intrathymic tumor immune tolerance.
• Severity-based treatment for Japanese patients with MPO-ANCA-associated vasculitis: the JMAAV study

  Shoichi Ozaki, Tatsuya Atsumi, Taichi Hayashi, Akihiro Ishizu, Shigeto Kobayashi, Shunichi Kumagai, Yasuyuki Kurihara, Manae S. Kurokawa, Hirofumi Makino, Hiroko Nagafuchi, Kimimasa Nakabayashi, Norihiro Nishimoto, Machi Suka, Yasuhiko Tomino, Hidehiro Yamada, Kunihiro Yamagata, Masaharu Yoshida, Wako Yumura

  MODERN RHEUMATOLOGY 22 3 394 - 404 2012年06月 [査読有り][通常論文]
   

  We (JMAAV [Japanese patients with MPO-ANCA-associated vasculitis] Study Group) performed a prospective, open-label, multi-center trial to evaluate the usefulness of severity-based treatment in Japanese patients with myeloperoxidase-anti-neutrophil cytoplasmic antibodies (MPO-ANCA)-associated vasculitis. Patients with MPO-ANCA-associated vasculitis received a severity-based regimen according to the appropriate protocol: low-dose corticosteroid and, if necessary, cyclophosphamide or azathioprine in patients with mild form; high-dose corticosteroid and cyclophosphamide in those with severe form; and the severe-form regimen plus plasmapheresis in those with the most severe form. We followed up the patients for 18 months. The primary end points were the induction of remission, death, and end-stage renal disease (ESRD). Fifty-two patients were registered, and 48 patients were enrolled in this study (mild form, n = 23; severe form, n = 23; most severe form, n = 2). Among the 47 patients who received the predefined therapies, 42 achieved remission within 6 months, 5 died, and 1 developed ESRD. Disease flared up in 8 of the 42 patients with remission during the 18-month follow-up period. The JMAAV trial is the first prospective trial for MPO-ANCA-associated vasculitis to be performed in Japan. The remission and death rates were comparable to those in several previous clinical trials performed in western counties. The regimen employed in this trial was tailor-made based on patients' disease severity and disease type, and it seems that standardization can be consistent with treatment choices made according to severity.
• Decreased Proteasomal Activity Causes Age-Related Phenotypes and Promotes the Development of Metabolic Abnormalities

  Utano Tomaru, Satomi Takahashi, Akihiro Ishizu, Yukiko Miyatake, Aya Gohda, Sayuri Suzuki, Ayako Ono, Jiro Ohara, Tomohisa Baba, Shigeo Murata, Keiji Tanaka, Masanori Kasahara

  AMERICAN JOURNAL OF PATHOLOGY 180 3 963 - 972 2012年03月 [査読有り][通常論文]
   

  The proteasome is a multicatalytic enzyme complex responsible for the degradation of both normal and damaged proteins. An age-related decline in proteasomal activity has been implicated in various age-related pathologies. The relevance of decreased proteasomal activity to aging and age-related diseases remains unclear, however, because suitable animal models are not available. In the present study, we established a transgenic (Tg) mouse model with decreased proteasomal chymotrypsin-like activity. Tg mice exhibited a shortened life span and developed age-related phenotypes. In Tg mice, polyubiquitinated and oxidized proteins accumulated, and the expression levels of cellular proteins such as Bcl-xL and RNase L were altered. When Tg mice were fed a high-fat diet, they developed more pronounced obesity and hepatic steatosis than did wild-type mice. Consistent with its role in lipid droplet formation, the expression of adipose differentiation-related protein (ADRP) was elevated in the livers of Tg mice. Of note, obesity and hepatic steatosis induced by a high-fat diet were more pronounced in aged than in young wild-type mice, and aged wild-type mice had elevated levels of ADRP, suggesting that the metabolic abnormalities present in Tg mice mimic those in aged mice. Our results proteasomal chymotrypsin-like activity affects longevity and aggravates age-related metabolic disorders, such as obesity and hepatic steatosis. (Am J Pathol(2012, 180:963-972; DOI. 10.1016/j.ajpath.2011.11.012)
• Abundant neutrophil extracellular traps in thrombus of patient with microscopic polyangiitis

  Daigo Nakazawa, Utano Tomaru, Chiho Yamamoto, Satoshi Jodo, Akihiro Ishizu

  FRONTIERS IN IMMUNOLOGY 3 333  2012年 [査読有り][通常論文]
   

  This is a case study of a patient diagnosed with microscopic polyangiitis (MPA) and complicated with deep vein thrombosis (DVT), who died of respiratory failure despite treatment. Autopsy revealed severe crescentic glomerulonephritis and massive alveolar hemorrhage. The thrombus contained abundant neutrophils. Although it is reported that patients with ANCA-associated vasculitis (AAV) have an increased risk of DVT, it remains elusive why they are prone to thrombosis. A recent study has demonstrated the presence of neutrophil extracellular traps (NETs), a newly recognized mode of neutrophil cell-death, in glornerular crescents of MPA patients. Interestingly, NETs were identified in the thrombus as well as in the glomerular crescents in the present case. When compared to other thrombi unrelated to MPA, the amount of NETs was significantly greater in the MPA patient. On the other hand, NETs are critically involved in thrombogenesis because histones within NETs can bind platelets and blood coagulants. Although this is important in regard to containment of microbes within NETs, excessive NETs could cause thrombosis. The collective findings suggest the possibility that thrombosis could be critically associated with MPA via NETs, and that NETs could be a therapeutic target in MPA patients.
• Pathogenesis of Vasculitis in env-pX Rats.

  Ishizu A, Yoshiki T

  Annals of vascular diseases 5 3 296 - 299 2012年 [査読有り][招待有り]
  
• Acute Renal Failure due to Thrombotic Microangiopathy in Patient with Scleroderma: Autopsy Case Report.

  Ishizu A, Fukaya S, Tomaru U, Katsumata K, Suzuki A, Umemoto Y, Furusaki A, Amasaki Y

  Annals of vascular diseases 5 4 458 - 461 2012年 [査読有り][通常論文]
  
• Expression of proteasome subunit β5t in thymic epithelial tumors.

  Yamada Y, Tomaru U, Ishizu A, Kiuchi T, Marukawa K, Matsuno Y, Kasahara M

  The American journal of surgical pathology 35 9 1296 - 1304 9 2011年09月 [査読有り][通常論文]
   

  Recently, a proteasome beta subunit expressed exclusively in thymic cortical epithelial cells was discovered in mice and humans. This subunit, designated beta 5t, is a component of the thymoproteasome, a specialized type of proteasome implicated in thymic positive selection. To investigate whether beta 5t could serve as a marker for the differential diagnosis of thymic epithelial tumors, we performed immunohistochemical analysis using anti-beta 5t antibody in 54 cases of thymic epithelial tumors comprising 41 cases of thymomas and 13 cases of thymic carcinomas. beta 5t was detected in the neoplastic epithelial cells of thymomas. Among the subtypes of thymoma, expression of beta 5t was observed in most cases of type B thymoma (20 of 21) but not in type A thymomas (0 of 3). In type AB thymomas, beta 5t expression was variable (6 of 17). Type B3 thymomas (4 cases) were positive for beta 5t but negative for CD5, c-kit, and glucose transporter 1 (GLUT-1), which are known as diagnostic markers for thymic carcinomas. In contrast, thymic carcinomas were negative for beta 5t (0 of 13) but expressed at least one and usually all of CD5, c-kit, and GLUT-1. Thus, beta 5t and CD5/c-kit/GLUT-1 were differentially expressed in type B3 thymoma and thymic carcinoma. We tested beta 5t expression in 39 cases of tumors arising from other organs, which showed the specific expression of beta 5t in thymic epithelial tumors. This study demonstrates that beta 5t is expressed in most type B and in some type AB thymomas and is a marker useful in differentiating type B3 thymomas from thymic carcinomas when used in combination with other diagnostic markers.
• First prospective trial in Japanese patients with MPO-ANCA-AAV

  Ozaki, Shoichi, Yamada, Hidehiro, Nagafuchi, Hiroko, Makino, Hirofumi, Tomino, Yasuhiko, Yumura, Wako, Kobayashi, Shigeto, Yamagata, Kunihiro, Kumagai, Schun-ichi, Ishizu, Akihiro, Kurokawa, Manae S, Suka, Machi

  CLINICAL AND EXPERIMENTAL Nephrology 164 Suppl. 1 62 - 62 WILEY-BLACKWELL 2011年05月 [査読無し][通常論文]
  
• Plasma-dependent, antibody- and Fcγ receptor-mediated translocation of CD8 molecules from T cells to monocytes.

  Iwasaki S, Masuda S, Baba T, Tomaru U, Katsumata K, Kasahara M, Ishizu A

  Cytometry. Part A : the journal of the International Society for Analytical Cytology 79A 1 46 - 56 1 2011年01月 [査読有り][通常論文]
   

  CD8 alpha beta heterodimers are mainly expressed on cytotoxic T lymphocytes. This study demonstrated the detection of CD8 alpha beta heterodimers on human monocytes by whole blood erythrocyte lysis method in flow cytometry. Results revealed that CD8 alpha beta heterodimers were not produced by monocytes themselves, but were transferred from T cells to monocytes when these cells were coincubated in plasma and with anti-CD8 monoclonal antibody (mAb). For completion of CD8 translocation from T cells to monocytes, cell-to-cell contact between T cells and monocytes, as well as binding of the Fc portion of the anti-CD8 mAb and Fc gamma receptor II (Fc gamma RII) on monocytes were required. Furthermore, the dynamism of cell membrane and cytoskeleton were involved in the mechanism of CD8 translocation. Interestingly, CD3 and alpha beta T cell receptor (TCR) were also transferred from T cells to monocytes accompanied by CD8. These phenomena are consistent with Ab-dependent and Fc gamma R-mediated trogocytosis, which is recently recognized as one of the intercellular communication processes of the immune system. Trogocytosis means exchange of plasma membrane including cell surface molecules in conjugates formed between immune cells. Results of this study could provide another model of trogocytosis and clearly indicated that putative plasma factors were critically implicated in the mechanism of Ab-dependent and Fc gamma R-mediated trogocytosis. (C) 2010 International Society for Advancement of Cytometry
• Complexity of tumor vasculature and molecular targeting therapies

  Mitsuko Furuya, Kiyotaka Nagahama, Akihiro Ishizu, Noriyuki Otsuka, Yoji Nagashima, Ichiro Aoki

  Frontiers in Bioscience - Elite 3 2 549 - 561 2011年01月01日 [査読有り][招待有り]
   

  Malignant solid tumors require blood supply for their uncontrollable progression. Angiogenic blood vessels generally sprout from preexisting vascular cells. In addition, various types of precursor cells also participate in tumor neovascularization. They include endothelial progenitor cells, hematopoietic stem cells and mesenchymal stem cells that are stimulated and attracted into tumor lesion, in which a wide variety of proinflammatory factors are involved. Among key molecules, vascular endothelial growth factor (VEGF) works as a mastermind regulator. Humanized monoclonal antibodies targeting VEGF-mediated signaling pathways are currently used as the most pervasive drugs in several types of progressive tumors. Adverse effects of these drugs include hypertension and proteinuria. Such symptoms are widely observed in preeclamptic patients whose blood contain high amount of natural VEGF antagonist. Vasoactive G protein-coupled receptors (GPCRs)-mediated signalings such as renin-angiotensin system and chemokine axes are also noticed that they may become effective therapeutic targets. In this review, we discuss general view of angiogenic microenvironment in solid tumors, and highlight several key signaling molecules and inhibitory effects of them on the whole system.
• High Prevalence of Multiple Human Papillomavirus Infection in Japanese Patients with Invasive Uterine Cervical Cancer

  Hidemichi Watari, Rie Michimata, Motoaki Yasuda, Akihiro Ishizu, Utano Tomaru, Ying Xiong, Mohamed K. Hassan, Noriaki Sakuragi

  PATHOBIOLOGY 78 4 220 - 226 2011年 [査読有り][通常論文]
   

  Objective: Multiple human papillomavirus (HPV) infection of the uterine cervix has been suggested as a risk factor for persistent HPV infection, resulting in the development of invasive cervical cancer. The aim of this study was to reveal the actual state of multiple HPV infection in Japanese patients with invasive cervical cancer. Methods: Sixty fresh-frozen invasive cervical cancer tissues were examined for genotyping of HPV. The presence of HPV genotypes was determined with an HPV-DNA array, which can discriminate 25 different HPV genotypes with high sensitivity and specificity. Results: Among 60 samples, 59 (96.7%) were positive for HPV. The three common genotypes were HPV-16 (83.3%), HPV-18 (45.0%) and HPV-52 (28.3%). Multiple HPV infection was observed in 47 of 60 samples (78.3%), among which 42 were infected with more than one high-risk genotype (70.0%). Multiple high-risk HPV infection was significantly more prevalent in patients below 40 years old (14/15, 93.3%) than in patients 40 years of age and over (28/45, 62.2%). Conclusion: The HPV-DNA array is the preferred method to detect HPV genotypes. Multiple HPV infection in Japanese patients with invasive cervical cancer seemed to be more frequent than reported in the literature. Copyright (C) 2011 S. Karger AG, Basel
• The incidence and mechanism of sunitinib-induced thyroid atrophy in patients with metastatic renal cell carcinoma

  N. Shinohara, M. Takahashi, T. Kamishima, H. Ikushima, N. Otsuka, A. Ishizu, C. Shimizu, H. Kanayama, K. Nonomura

  BRITISH JOURNAL OF CANCER 104 2 241 - 247 2011年01月 [査読有り][通常論文]
   

  BACKGROUND: To elucidate the incidence and mechanisms of sunitinib-induced thyroid atrophy, we investigated serial volumetric and functional changes, and evaluated histological changes of the thyroid gland in metastatic renal cell carcinoma patients who received sunitinib. METHODS: Thyroid volume (by computed tomography volumetry) and thyroid function were measured at baseline, during the treatment, and at post-treatment periods. Histological evaluation of the thyroid gland was performed in four autopsied patients. RESULTS: The median reduction rate in thyroid volume at last evaluation during sunitinib treatment was 30% in all 17 patients. The incidence of hypothyroidism during sunitinib treatment was significantly higher in the high reduction rate group (n - 8; more than 50% reduction in volume) than in the low reduction rate group (n 9; less than 50% reduction in volume). Half of the patients in the high reduction rate group exhibited a transient thyroid-stimulating hormone suppression, suggesting thyrotoxicosis during sunitinib treatment. Histological evaluation demonstrated atrophy of thyroid follicles and degeneration of follicular epithelial cells without critical diminution of vascular volume in the thyroid gland. CONCLUSION: Thyroid atrophy is frequently observed following sunitinib treatment and may be brought about by sunitinib-induced thyrotoxicosis or the direct effects of sunitinib that lead to degeneration of thyroid follicular cells. British Journal of Cancer (2011) 104, 241-247. doi: 10.1038/sj.bjc.6606029 www.bjcancer.com Published online 14 December 2010 (C) 2011 Cancer Research UK
• Frequency and pattern of expression of the stem cell marker CD133 have strong prognostic effect on the surgical outcome of colorectal cancer patients

  Shusaku Takahashi, Toshiya Kamiyama, Utano Tomaru, Akihiro Ishizu, Toshiyuki Shida, Mineji Osaka, Yutaka Sato, Yutaka Saji, Michitaka Ozaki, Satoru Todo

  ONCOLOGY REPORTS 24 5 1201 - 1212 2010年11月 [査読有り][通常論文]
   

  CD133 has been reported to be a cancer stem cell marker in colorectal cancer (CRC). The aim of this study was to examine the frequency and pattern of CD133 expression by immunohistochemical methods and evaluate their correlation with clinicopathological features, including patient survival (PS) and recurrence. Tissue specimens of 151 CRC patients who underwent surgical treatment for well-differentiated/moderately differentiated adenocarcinoma and stage I-IV tumors (TNM classification) were immunostained for analyzing CD133 expression. The frequency of CD 133 expression was 91.4% (138/151), and the pattern of expression was divided into membranous and cytoplasmic expression. Of the 151 patients, 136 (90.1%) showed membranous expression, whereas 44 (29.1%) showed cytoplasmic expression. Both expression patterns were seen in 42 (27.8%) patients. The frequency of CD133 overexpression (>50% of stained cells) was 27.2% (41/151); univariate analysis showed CD133 overexpression to be significantly associated with PS, but not recurrence, and multivariate analysis indicated it to be an independent prognostic factor. Multivariate analysis showed membranous overexpression (>50% of stained tumor cells on the membrane), which significantly correlated with histology and chemoresistance of recurrent and stage IV tumors, to be an independent prognostic factor for PS and recurrence. However, multivariate analysis did not indicate cytoplasmic expression, which significantly correlated with histology, lymph node metastasis, TNM stage and lymphatic invasion, as an independent prognostic factor for PS and recurrence. Our results demonstrated that evaluation of the frequency and pattern of CD133 expression is useful for predicting prognosis, recurrence, and chemosensitivity in CRC patients.
• Cyclic AMP response element-binding protein is implicated in IL-6 production from arthritic synovial cells

  Akihiro Ishizu, Asami Abe, Yukiko Miyatake, Tomohisa Baba, Chihiro Iinuma, Utano Tomaru, Takashi Yoshiki

  MODERN RHEUMATOLOGY 20 2 134 - 138 2010年04月 [査読有り][通常論文]
   

  Overproduction of interleukin (IL)-6 from synovial cells is critically involved in the pathogenesis of rheumatoid arthritis (RA). Cyclic adenosine monophosphate (AMP) response element-binding protein (CREB), a leucine zipper transcription factor, is expressed at a high level in synovial cells of patients with RA. Although CREB transactivates IL-6 expression in vascular smooth muscle cells, the relation between CREB expression and IL-6 production from arthritic synovial cells remains unclear. In this study, to determine whether CREB is implicated in IL-6 production from arthritic synovial cells, a dominant negative molecule of activation transcription factor 1 (ATF-1) was transfected into synovial cells obtained from arthritic joints of env-pX rats. These transgenic rats carrying the env-pX gene of human T-cell leukemia virus type-1 develop destructive arthritis with high titers of serum rheumatoid factor and are thus regarded as a suitable model of RA. The dominant negative ATF-1 (ATF-1DN) constitutes a heterodimer with CREB and inhibits CREB function, as CREB/ATF-1DN heterodimers no longer bind to the target sequence of CREB. We showed that transfection of ATF-1DN significantly reduced IL-6 production from arthritic synovial cells. These findings suggest that CREB is implicated in IL-6 production from synovial cells and plays an important role in RA pathogenesis.
• 顕微鏡的多発血管炎患者血清ペプチドの網羅的探索

  高桑 由希子, 湯村 和子, 山縣 邦弘, 山田 秀裕, 熊谷 俊一, 石津 明洋, 須賀 万智, 尾崎 承一, 加藤 智啓, 黒川 真奈絵, 大岡 正道, 永井 宏平, 有戸 光美, 佐藤 利行, 末松 直也, 岡本 一起, 永渕 裕子

  日本臨床プロテオーム研究会要旨集 2010 0 97 - 2 日本臨床プロテオーム研究会 2010年
• 顕微鏡的多発血管炎患者血清ペプチドの網羅的探索

  高桑 由希子, 湯村 和子, 山縣 邦弘, 山田 秀裕, 熊谷 俊一, 石津 明洋, 須賀 万智, 尾崎 承一, 加藤 智啓, 黒川 真奈絵, 大岡 正道, 永井 宏平, 有戸 光美, 佐藤 利行, 末松 直也, 岡本 一起, 永渕 裕子

  日本プロテオーム学会大会要旨集 2010 0 97 - 97 日本プロテオーム学会（日本ヒトプロテオーム機構） 2010年
• Human Endogenous Retrovirus-R Env Glycoprotein as Possible Autoantigen in Autoimmune Disease

  Naomi Sasaki, Yayoi Ogawa, Chihiro Iinuma, Utano Tomaru, Kazuaki Katsumata, Noriyuki Otsuka, Masanori Kasahara, Takashi Yoshiki, Akihiro Ishizu

  AIDS RESEARCH AND HUMAN RETROVIRUSES 25 9 889 - 896 2009年09月 [査読有り][通常論文]
   

  It has long been discussed whether endogenous retroviruses (ERVs) are involved in the pathogenesis of autoimmune diseases. Among various human endogenous retroviruses (HERVs), we have focused on HERV-R. To investigate the biological roles of HERV-R, we earlier established transgenic rats carrying the full sequence of the viral genome. In these HERV-R rats, however, no disease occurred. Another trigger that induces autoimmunity may be essential for the recognition of HERV-R products by the immune system. Thus, in this study, we mated HERV-R rats with env-pX rats (transgenic rats carrying the env-pX gene of human T cell leukemia virus type I) that develop autoimmune diseases, and generated double transgenic (DTG)rats. In DTG rats, autoimmune diseases occurred similarly in env-pX rats. Interestingly, deposition of rat IgM but not IgG was observed on the glomerular endothelial cells. Such IgM deposition was never seen in the parental HERV-R or env-pX rats. We considered that in situ formation of immune complexes consisted of the HERV-R env glycoprotein and anti-HERV-R env IgM antibodies (Abs) in DTG rats, according to the following evidence: (1) No dense deposit, representing deposition of circulating immune complexes, was seen on glomerular endothelial cells. (2) IgM Abs reactive with HERV-R env glycoprotein were generated in the serum. (3) HERV-R env glycoprotein was expressed in the kidney, specifically on glomerular endothelial cells. (4) IgM deposition was partly colocalized with the HERV-R env glycoprotein on the glomeruli. These findings strongly suggest that the HERV-R env glycoprotein is recognized as an autoantigen in the host with autoimmune diseases.
• Exclusive expression of proteasome subunit beta 5t in the human thymic cortex

  Utano Tomaru, Akihiro Ishizu, Shigeo Murata, Yukiko Miyatake, Sayuri Suzuki, Satomi Takahashi, Taku Kazamaki, Jiro Ohara, Tomohisa Baba, Sari Iwasaki, Kazunori Fugo, Noriyuki Otsuka, Keiji Tanaka, Masanori Kasahara

  BLOOD 113 21 5186 - 5191 2009年05月 [査読有り][通常論文]
   

  The ubiquitin-proteasome pathway, which degrades intracellular proteins, is involved in numerous cellular processes, including the supply of immunocompetent peptides to the antigen presenting machinery. Proteolysis by proteasomes is conducted by three beta subunits, beta 1, beta 2, and beta 5, of the 20S proteasome. Recently, a novel beta subunit expressed exclusively in cortical thymic epithelial cells was discovered in mice. This subunit, designated beta 5t, is a component of the thymoproteasome, a specialized type of proteasomes implicated in thymic positive selection. In this study, we show that, like its mouse counterpart, human beta 5t is expressed exclusively in the thymic cortex. Human beta 5t was expressed in approximately 80% of cortical thymic epithelial cells and some cortical dendritic cells. Human beta 5t was incorporated into proteasomes with two other catalytically active beta subunits beta 1i and beta 2i, forming 20S proteasomes with subunit compositions characteristic of thymoproteasomes. The present study demonstrates, for the first time, the existence of thymoproteasomes in the human thymic cortex, indicating that thymoproteasome function is likely conserved between humans and mice. (Blood. 2009; 113: 5186-5191)
• [Spontaneous pneumothorax, an unusual manifestation of imatinib-resistant chronic eosinophilic leukemia: an autopsy study].

  Fujimi A, Kanisawa Y, Tanaka S, Okuda T, Sato Y, Doi T, Ohta H, Iwasaki S, Ishizu A, Huang Y

  Nihon Naika Gakkai zasshi. The Journal of the Japanese Society of Internal Medicine 98 4 862 - 865 4 2009年04月 [査読有り][通常論文]
   

  近年，FIP1L1/PDGFRα融合遺伝子（FP遺伝子）陽性の慢性好酸球性白血病（chronic eosinophilic leukemia；CEL）に対するimatinib（IM）の有効性が示され，治療成績は著しく改善しているが長期予後には不明な点も多い．今回，我々はIMに耐性化し終末期に自然気胸を併発したCEL症例を経験した．剖検で好酸球の肺胞への高度の浸潤およびその近傍の線維化，気腫化が確認され，CELの進行が肺実質の破壊をきたし気胸の原因となったと推定された．
  
• Rat CD4(+)CD8(+) macrophages kill tumor cells through an NKG2D-and granzyme/perforin-dependent mechanism

  Tomohisa Baba, Sari Iwasaki, Takako Maruoka, Akira Suzuki, Utano Tomaru, Hitoshi Ikeda, Takashi Yoshiki, Masanori Kasahara, Akihiro Ishizu

  JOURNAL OF IMMUNOLOGY 180 5 2999 - 3006 2008年03月 [査読有り][通常論文]
   

  We previously identified a subpopulation of monocyte/macrophage lineage cells expressing both CD4 and CD8. This subpopulation was expanded in rat peripheral blood and spleen after immunization with adjuvants containing killed tuberculosis germs. CD4(+)CD8(+) monocytes/macrophages obtained from preimmunized rats exhibited a Th1-type cytokine/chemokine profile, expressed high levels of Fas ligand, perforin, granzyme B, and NKR-P2 (rat ortholog of human NKG2D), and killed certain tumor cells. In the present study, we confirmed that CD4(+)CD8(+) monocytes/macrophages are distinct from splenic dendritic cells (DCs) or IFN-producing killer DCs. In vitro cytotoxic assays revealed that CD4(+)CD8(+) macrophages killed tumor cells in a cell-cell contact-dependent manner and that expression of the retinoic acid early transcript 1 (a ligand for NKG2D) made tumor cells susceptible to killing by CD4(+)CD8(+) macrophages. Furthermore, inhibitors of granzyme and perforin significantly decreased cytotoxic activities of CD4(+)CD8(+) macrophages. Consistent with these in vitro findings, preimmunization with adjuvants containing killed tuberculosis germs elevated the expression of granzyme B in tumor-infiltrating CD4(+)CD8(+) macrophages and significantly inhibited the growth of inoculated tumor cells. Our current work demonstrates that CD4(+)CD8(+) macrophages are a unique subpopulation of monocyte/macrophage lineage cells that kill tumor cells in an NKG2D- and granzyme/perforin-dependent mechanism.
• 専門教育に特化したFDの意義--北海道大学医学部保健学科FDワークショップの総括を通して

  境 信哉, 佐藤 洋子, 森山 隆則, 武田 直樹, 竹内 文也, 石津 明洋, 松野 一彦

  高等教育ジャ-ナル 15 89 - 98 北海道大学高等教育機能開発総合センター 2007年12月 

  The Department of Health Sciences, Hokkaido University School of Medicine was inaugurated in October 2004, replacing the former College of Medical Technology. With more advanced and professional education required, the chairman of our department suggested the necessity of original faculty development (FD), specializing in professional education. Consequently, an FD working group (the present FD Practice Commission) was organized in 2005. The group repeatedly discussed the results of a questionnaire survey for teachers, and finally held the first FD workshop in September. The second one was held in September 2006. The results of questionnaire surveys conducted after the first and the second workshops included many positive answers. The FD of our department specializing in professional healthcare education is geared to the professionalism of health sciences and the realities of our department, which is compartmentalized from other FD projects in Hokkaido University. The factor that increases the significance of our FD is that the planning to meet the needs of each teacher and the style in which many teachers can participate in FD are feasible because of the limited scale of our department.
• Enhanced production of p24 Gag protein in HIV-1-infected rat cells fused with uninfected human cells

  Jing Chen, Xudong Zhao, Yurong Lai, Akira Suzuki, Utano Tomaru, Akihiro Ishizu, Akio Takada, Hitoshi Ikeda, Masanori Kasahara, Takashi Yoshiki

  EXPERIMENTAL AND MOLECULAR PATHOLOGY 83 1 125 - 130 2007年08月 [査読有り][通常論文]
   

  Although many human molecules have been suggested to affect replication of human immunodeficiency virus type 1 (HIV-1), the distribution of such cofactors in human cell types is not well understood. Rat W31/D4R4 fibroblasts expressing human CD4 and CXCR4 receptors were infected with HIV-1. The provirus was integrated in the host genome, but only a limited amount of p24 Gag protein was produced in the cells and culture supernatants. Here we found that p24 production was significantly increased by fusing HIV-1-infected W31/D4R4 cells with uninfected human cell lines of T-cell, B-cell, or macrophage lineages. These findings suggest that human cellular factors supporting HIV-1 replication are distributed widely in cells of lymphocyte and macrophage lineages. We also examined whether the amount of p24 produced by rat-human hybrid cells was correlated with expression levels of specific human genes. The results suggested that HP68 and MHC class II transactivator (CIITA) might up- and down-regulate p24 production, respectively. It was also suggested that HIV-1 replication is affected by molecules other than those examined in this study, namely, cyclin T1, cyclin-dependent kinase 9, CRM1, HP68, and CIITA. (c) 2006 Elsevier Inc. All rights reserved.
• Expression of human endogenous retrovirus-R gene links to differentiation of squamous cells

  N. Otsuka, Y. Miyatake, A. Ishizu, S. Tanaka, Y. Yamamoto, H. Ikeda, T. Yoshiki

  AIDS RESEARCH AND HUMAN RETROVIRUSES 22 11 1148 - 1151 2006年11月 [査読有り][通常論文]
   

  To investigate the biological roles of human endogenous retrovirus-R (HERV-R) in vivo, we established transgenic rats carrying the full sequence of the viral genome with control of its own long terminal repeat promoter. The Env protein was expressed on the surface of the epidermis of fetal HERV-R transgenic rats on day 10 of gestation. The epidermal Env expression disappeared by day 18 of gestation. After day 18 of gestation, the Env protein was detected in the prickle layer of the esophageal epithelium of transgenic rats. Interestingly, it was not detected in the basal layer of the epithelium, and the expression in the granular layer was weaker than in the prickle layer. These findings suggest that expression of HERV-R is linked not only to the development but also to the differentiation of squamous cells. Next, we examined alterations in the expression of the HERV-R env gene in cultured human squamous cells after exposure to all-trans retinoic acids ( ATRA). The env expression was increased by ATRA in a dose-dependent manner, while the expression of transglutaminase 1 (TGM1), a terminal marker for squamous differentiation, was decreased. TGM1 is expressed in the granular layer of the squamous epithelium, and ATRA suppresses the differentiation of cultured squamous cells. Thus, these in vitro data also suggest that HERV-R expression is regulated by a mechanism closely related to the differentiation of squamous cells. This study is the first to demonstrate the association of HERV-R expression and differentiation of squamous cells.
• MHC class I-like MILL molecules are beta(2)-microglobulin-associated, GPI-anchored glycoproteins that do not require TAP for cell surface expression

  Mizuho Kajikawa, Tomohisa Baba, Utano Tomaru, Yutaka Watanabe, Satoru Koganei, Sachiyo Tsuji-Kawahara, Naoki Matsumoto, Kazuo Yamamoto, Masaaki Miyazawa, Katsumi Maenaka, Akihiro Ishizu, Masanori Kasahara

  JOURNAL OF IMMUNOLOGY 177 5 3108 - 3115 2006年09月 [査読有り][通常論文]
   

  MILL (MHC class I-like located near the leukocyte receptor complex) is a family of MHC class I-like molecules encoded outside the MHC, which displays the highest sequence similarity to human MICA/B molecules among known class I molecules. In the present study, we show that the two members of the mouse MILL family, MILL1 and MILL2, are GPI-anchored glycoproteins associated with beta(2)-microglobulin (beta(2)m) and that cell surface expression of MILL1 or MILL2 does not require functional TAP molecules. MILL1 and MILL2 molecules expressed in bacteria could be refolded in the presence of beta(2)m, without adding any peptides. Hence, neither MILL1 nor MILL2 is likely to be involved in the presentation of peptides. Immunohistochemical analysis revealed that MILL1 is expressed in a subpopulation of thymic medullary epithelial cells and a restricted region of inner root sheaths in hair follicles. The present study provides additional evidence that MILL is a class I family distinct from MICA/B.
• Role of neuronal interferon-gamma in the development of myelopathy in rats infected with human T-cell leukemia virus type 1

  Y Miyatake, H Ikeda, A Ishizu, T Baba, T Ichihashi, A Suzuki, U Tomaru, M Kasahara, T Yoshiki

  AMERICAN JOURNAL OF PATHOLOGY 169 1 189 - 199 2006年07月 [査読有り][通常論文]
   

  Human T-cell leukemia virus type I (HTLV-1) is the causative agent of not only adult T-cell leukemia but also HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP). Among die rat strains infected with HTLV-1, chronic progressive myelopathy, named HAM rat disease, occurs exclusively in WKAH rats. In the present study, we found that HTLV-1 infection induces interferon (IFN)-gamma production in the spinal cords of HAM-resistant strains but not in those of WKAH rats. Neurons were the major cells that produced IFN-gamma in HTLV-1-infected, HAM-resistant strains. Administration of IFN-gamma suppressed expression of pX, the gene critically involved in the onset of HAM rat disease, in an HTLV-1-immortalized rat T-cell line, indicating that IFN-gamma protects against the development of HAM rat disease. The inability of WKAH spinal cord neurons to produce IFN-gamma after infection appeared to stem from defects in signaling through the interleukin (IL)-12 receptor. Specifically, WKAH-derived spinal cord cells were unable to up-regulate the IL-12 receptor beta 2 gene in response to IL-12 stimulation. We suggest that the failure of spinal cord neurons to produce IFN-gamma through the IL-12 pathway is involved in the development of HAM rat disease.
• Rupture of the thyrocervical trunk branch from the subclavian artery in a patient with neurofibromatosis: a case report

  A Ishizu, T Ooka, T Murakami, T Yoshiki

  CARDIOVASCULAR PATHOLOGY 15 3 153 - 156 2006年05月 [査読有り][通常論文]
   

  Background: Vascular involvement in neurofibromatosis type 1 (NF1) is well recognized; however, rupture of extracranial arteries rarely occurs. We present a case of NF1 with rupture of the thyrocervical trunk, which branched from the right subclavian artery. A 76-year-old woman who has numerous cafe-au-lait spots and soft tumors of the skin manifested a sudden swelling of her neck accompanied with increasing pain. Radiological examinations revealed bleeding from the artery. Methods: Histological and immunohistochemical examinations were carried out using tissues that contained the affected vessel. Results: Proliferation of spindle cells positive for S-100 protein was seen in the adventitia of the ruptured vessel. Intimal thickening by proliferation of fibromuscular cells was also evident with irregularity of the media. Conclusions: These findings suggest that the artery was disrupted by NF in the vascular wall. It is considered that NF in the arterial wall causes dysplasia of the smooth muscle layer in the intima and media and leads to fragility of the vessel. Twelve cases, including the present case, with rupture of extracranial arteries in NF1 have been reported in the past 10 years. two thirds of these occurred in extravisceral sites in which there is a good deal of physical movement. This Suggests that a physiological factor is one of the triggers for arterial rupture, which occurs under a background of vascular fragility in NF1. (C) 2006 Elsevier Inc. All rights reserved.
• Articular tissues expressing the env-pX transgene are required for generation of arthritogenic T cells in human T cell leukemia virus type I transgenic rats

  A. Abe, A. Ishizu, K. Fugo, H. Ikeda, T. Yoshiki

  CLINICAL AND EXPERIMENTAL RHEUMATOLOGY 24 3 313 - 316 2006年05月 [査読有り][通常論文]
   

  Objective. Human T cell leukemia virus type I env-pX transgenic rats (env-pX rats) were used to investigate the pathogenesis of arthritis. Methods. Phenotype of cells infiltrated into arthritic joints in env-pX rats was analyzed using flow cytometry and cell-transfer experiments were done using env-pX and wild-type WKAH rats. Results. The majority of T cells infiltrated into arthritic joints in env-pX rats exhibited a CD4 and activated phenotype. Transfer of these T cells into articular space in wild-type WKAH rats succeeded to induce arthritis similarly seen in env-pX rats. However injection of the cells into sites other than joints did not induce inflammation. Transfer of in vitro-stimulated lymph node cells from disease-free env-pX rats into articular space did not induce arthritis in wild-type WKAH rats. Conclusion. These findings suggest that articular tissues carrying the env-pX transgene are required for generation of arthritogenic T cells in env-pX rats. However the constitutive antigens other than the transgene products are recognized as immunological targets by the arthritogenic T cells in the advanced arthritic joints. Molecules expressed specifically in articular tissues may be needed to maintain the inflammatory cell infiltration.
• CD4(+)/CD8(+) macrophages infiltrating at inflammatory sites: a population of monocytes/macrophages with a cytotoxic phenotype

  T Baba, A Ishizu, S Iwasaki, A Suzuki, U Tomaru, H Ikeda, T Yoshiki, M Kasahara

  BLOOD 107 5 2004 - 2012 2006年03月 [査読有り][通常論文]
   

  We found a population of nonlymphoid cells expressing both CD4 and CD8 in peripheral blood mononuclear cells (PBMCs) of human T-cell leukemia virus type-I pX transgenic rats with autoimmune diseases. These cells, which showed a monocytic phenotype, were also found in wild-type rats, and their number increased by adjuvant-assisted immunization. GM-CSF increased the number of these double-positive (DIP) monocytes in PBMCs. Consistent with the idea that DIP monocytes differentiate into DIP macrophages at sites of inflammation, we found infiltration of DIP macrophages at the site of myosin-induced myocarditis in wild-type rats; these cells exhibited a T-helper 1 (Th1)-type cytokine/chemokine profile and expressed high levels of Fas ligand, perforin, granzyme B, and NKR-P2 (rat orthologue of human NKG2D). Adoptive transfer of GFP-positive spleen cells confirmed hematogenous origin of DIP macrophages. DIP monocytes had a cytotoxic phenotype similar to DID macrophages, indicating that this phenotypic specialization occurred before entry into a tissue. In line with this, DIP monocytes killed tumor cells in vitro. Combined evidence indicates that certain inflammatory stimuli that induce GM-CSF trigger the expansion of a population of DIP monocytes with a cytotoxic phenotype and that these cells differentiate into macrophages at inflammatory sites. Interestingly, human PBMCs also contain DIP monocytes.
• Altered expression of apoptosis-related genes in osteocytes exposed to high-dose steroid hormones and hypoxic stress

  Muneharu Tsuji, Hitoshi Ikeda, Akihiro Ishizu, Yukiko Miyatake, Hiroko Hayase, Takashi Yoshiki

  PATHOBIOLOGY 73 6 304 - 309 2006年 [査読有り][通常論文]
   

  Objective: High-dose steroid hormones cause necrosis of the femoral head. Since steroid hormones function as blood coagulants, we hypothesized that ischemic hypoxia induced by steroid hormones is critical for apoptosis which occurs before necrosis of osteocytes. Methods: We performed an analysis of gene expression in the process of leading osteocytes to apoptosis, using a mouse cell line. Cultured osteocytes were loaded with hypoxic stress with or without exposure to steroid hormones, and the gene expression under these conditions was investigated using a cDNA array and real-time quantitative RT-PCR. Results: The proapoptotic p53 gene was downregulated under a hypoxic (1% O-2) condition without exposure to steroid hormones. On the other hand, the expression of antiapoptotic Bcl-2 gene was increased by exposure to high-dose steroid hormones under a normoxic condition (20% O-2). Interestingly, both proapoptotic (p53 and Bax) and antiapoptotic (Bcl-2 and MDM2) genes were downregulated in osteocytes treated with high-dose steroid hormones in the hypoxic environment. Conclusions: These findings suggest that osteocytes exposed to high-dose steroid hormones appear to be more sensitive to apoptosis in the hypoxic environment than those without exposure to steroid hormones. This concept helps to understand the pathogenesis of idiopathic necrosis of the bone. Copyright (c) 2006 S. Karger AG, Basel.
• Malignant transformation of thymoma in recipient rats by heterotopic thymus transplantation from HTLV-I transgenic rats

  T Tsuji, H Ikeda, T Tsuchikawa, K Kikuchi, T Baba, A Ishizu, T Yoshiki

  LABORATORY INVESTIGATION 85 7 851 - 861 2005年07月 [査読有り][通常論文]
   

  Transgenic rats expressing the pX gene of human T lymphocyte virus type-I ( HTLV-I) under control of the rat lymphocyte-specific protein tyrosine kinase type-I promoter ( lck-pX rats) developed benign epithelial thymomas. When the thymuses of newborn lck-pX rats were transplanted into the subcapsular space of the kidney in other thymectomized lck-pX rats, similar tumors developed in the transplanted thymuses. Following the tumor growth, dissemination in the abdominal cavity and distant metastasis occurred. The tumors were histopathologically similar to the original thymomas, but prominent nuclear atypia and high mitotic activity were present. The Ki-67 index was twice as high as that in the originals. The tumors were transplantable into the subcutis of lck-pX rats, although transplantation of the originals never succeeded. All evidence indicated that malignant transformation of thymoma was induced by the heterotopic transplantation. Expression of the pX transgene in the transformed tumors were significantly reduced. Among host genes, the expression of p16ink4a/ARF, which was significantly upregulated in the originals, was never detected in the transformed tumors. Genomic Southern blots and PCR suggest that homozygous deletion of the p16ink4a/ARF gene may play important roles in malignant transformation in this model. Our model described here is a useful unique model for in vivo malignant transformation.
• Aberrant gene expression by CD25(+)CD4(+) immunoregulatory T cells in autoimmune-prone rats carrying the human T cell leukemia virus type-I gene

  H Hayase, A Ishizu, H Ikeda, Y Miyatake, T Baba, M Higuchi, A Abe, U Tomaru, T Yoshiki

  INTERNATIONAL IMMUNOLOGY 17 6 677 - 684 2005年06月 [査読有り][通常論文]
   

  Transgenic rats expressing the env-pX gene of human T cell leukemia virus type-I under the control of the viral long terminal repeat promoter (env-pX rats) developed systemic autoimmune diseases. Prior to disease manifestation, the immunosuppressive function of CD25(+)CD4(+) T (T-reg) cells was impaired in these rats. Since T cell differentiation appeared to be disordered in env-pX rats, we assumed that the impairment of T-reg cells might be caused by an abortive differentiation in the thymus. However, reciprocal bone marrow transfers between env-pX and wild-type rats revealed that direct effects of the transgene unrelated to the thymus framework induced the abnormality of T-reg cells. To identify molecular changes, comparative analyses were done between env-pX and wild-type T-reg cells. Expression of the Foxp3 gene and cell-surface markers supported a naive phenotype for env-pX T-reg cells. Array analyses of gene expression showed some interesting profiles, e.g. up-regulation of genes associated with the Janus kinase/signal transducer and activator of transcription (JAK/STAT) pathways in env-pX T-reg cells. Additionally, expression of the suppressor of cytokine signaling (SOCS) family genes, which inhibit the JAK/STAT signals, was extremely low in env-pX T-reg cells. These findings suggest that the transgene may mediate the down-regulation of the SOCS family genes and that subsequent excess signals through the JAK/STAT pathways may result in the loss of function of env-pX T-reg cells. We suggest that investigation of the pathology of T-reg cells in our autoimmune-prone rat model may aid in understanding the roles of T-reg cells in human autoimmune diseases.
• Chronic graft-versus-host disease-like autoimmune disorders spontaneously occurred in rats with neonatal thymus atrophy

  T Baba, A Ishizu, H Ikeda, Y Miyatake, T Tsuji, A Suzuki, U Tomaru, T Yoshiki

  EUROPEAN JOURNAL OF IMMUNOLOGY 35 6 1731 - 1740 2005年06月 [査読有り][通常論文]
   

  We earlier reported that the human T cell leukemia virus type-1 pX gene transduced into rat thymic epithelial cells had an impact on biology of the cells. We report here that FW-pX rats born by mating of F344 transgenic rats expressing the pX gene without tissue specificity with nontransgenic Wistar rats developed disorders, including atrophy of the thymus, lymphocytopenia, and inflammatory cell infiltration into multiple organs, similar to events in chronic graft-vs.-host disease (GVHD). Vanishment of thymic epithelial cells especially in the cortex and marked depletion of CD4 CD8 double-positive thymocytes were evident in the neonatal thymus in these rats. The relative abundance of CD8 compared to CD4 T cells may be related to dominant infiltration of CD8 T cells into the affected organs. Additionally, adoptive transfer of FW-pX splenocytes could induce lymphocytic infiltration into sublethally irradiated wild-type syngeneic recipients. Analysis of the expression level of the Foxp3 gene in peripheral blood mononuclear cells revealed that the numbers of immunoregulatory T cells were less in FW-pX rats than in wild-type rats. The collective evidence suggested that the FW-pX rats spontaneously developed chronic GVHD-like autoimmune diseases, following abortive differentiation of T cells in the thymus in early days of the newborn. This rat model may shed light on the pathogenesis of chronic GVHD and also other systemic autoimmune diseases, the etiology of which is unknown.
• Right- and left-sided colorectal cancers display distinct expression profiles and the anatomical stratification allows a high accuracy prediction of lymph node metastasis

  K Komuro, M Tada, E Tamoto, A Kawakami, A Matsunaga, K Teramoto, G Shindoh, M Takada, K Murakawa, M Kanai, N Kobayashi, Y Fujiwara, N Nishimura, J Hamada, A Ishizu, H Ikeda, S Kondo, H Katoh, T Moriuchi, T Yoshiki

  JOURNAL OF SURGICAL RESEARCH 124 2 216 - 224 2005年04月 [査読有り][通常論文]
   

  Accurate preoperative prediction of lymph node metastasis and degree of tumor invasion would facilitate an appropriate decision of the extent of surgical resection of cancers to reduce unnecessary complication or to minimize the risk of recurrence in patients. We analyzed gene expression profiles characteristic of the invasiveness of colorectal carcinoma in a total of 89 cases, using a cDNA array and pattern classification algorithms. We set binary classes for a panel of clinicopathologic parameters, each of which was divided at different levels for categories (discrete) or values (continuous). We searched an optimal combination of genes to discriminate the classes by using of a feature subset selection algorithm, which was applied to a set of genes preselected on the basis of statistical difference in expression (two-sided t test, P <= 0.05). We used a sequential forward feature selection which additively searched a combination of genes, giving a minimal leave-one-out classification error rate of a k-nearest neighbor classifier. In the process of gene preselection, we found a remarkable difference in the expression pattern of genes according to the anatomical location of cancers. The difference was most prominent when the classes were set for cecum, ascending colon, transverse colon, and descending colon (CATD) versus sigmoid colon and rectum (SR). By stratifying these two locations, we were able to extract gene expression profiles characteristic of the classes of the presence versus absence of lymph node metastasis, lymphatic invasion, vascular invasion and degree of mural invasion, and pathological stages, with an accuracy of more than 90%. These results suggest that colorectal cancers harbor distinct molecular pathophysiological statuses according to their right-to-left locations, of which stratification is important for pattern classification of cDNA array data. (C) 2005 Elsevier Inc. All rights reserved.
• Prediction of lymphatic invasion/lymph node metastasis, recurrence, and survival in patients with gastric cancer by cDNA array-based expression profiling

  K Teramoto, M Tada, E Tamoto, M Abe, A Kawakami, K Komuro, A Matsunaga, G Shindoh, M Takada, K Murakawa, M Kanai, N Kobayashi, Y Fujiwara, N Nishimura, K Shirata, T Takahishi, A Ishizu, H Ikeda, J Hamada, S Kondo, H Katoh, T Moriuchi, T Yoshiki

  JOURNAL OF SURGICAL RESEARCH 124 2 225 - 236 2005年04月 [査読有り][通常論文]
   

  Background. We assessed the predictability of various classes of gastric carcinoma defined by clinicopathological parameters, such as invasiveness and clinical outcomes, using cDNA array data obtained from 54 cases. Materials and methods. We searched an optimal combination of genes to discriminate the classes defined with the clinicopathological parameters by using a feature subset selection algorithm, which was applied to a set of genes preselected on the basis of statistical difference in expression (two-sided t test, P <= 0.05). With the selected features (gene set), we evaluated the predictability of each parameter in a leave-one-out cross-validation test. Results. We successfully selected sets of genes for which the classifier predicted better versus worse overall survival (tumor-specific death) and tumor-free survival (recurrence), with respective classification rates of 94 and 92%. A contingency table analysis (chi(2) test) and Cox proportional hazard model analysis revealed that lymph node metastasis is the most important factor (confounding factor) in patients' prognoses and risks of recurrence. The feature subset selection procedure successfully extracted expression patterns characteristic of lymph node metastasis and lymphatic vessel invasion, yielding 92 and 98% prediction accuracies for these respective factors. Conclusion. We conclude that expression profiling using feature subset selection provides a powerful means of stratification of gastric cancer patients in regard to the prognostic factors. Further studies should be warranted to apply this method to personalization of the treatment options. (C) 2005 Elsevier Inc. All rights reserved.
• Differential modulation of gene expression among rat tissues with warm ischemia

  Y Miyatake, H Ikeda, R Michimata, S Koizumi, A Ishizu, N Nishimura, T Yoshiki

  EXPERIMENTAL AND MOLECULAR PATHOLOGY 77 3 222 - 230 2004年12月 [査読有り][通常論文]
   

  The aim of this study is to determine if warm ischemia after surgical extirpation impacts gene expression in tissue samples which will be used for cDNA array analysis. We investigated effects of warm ischemia on gene expression in lung, liver, kidney, and spleen of rats, chronologically, using an original cDNA array, real-time quantitative RT-PCR and inummohistochemistry. Although no visible alteration was found in RNA quality, cDNA array showed that expression of many genes was modulated by warm ischemia within 60 min in these tissues, 19.1% of the tested genes in lung, 11.0% in liver, 5.1% in kidney, and 16.2% in spleen. Quantitative RT-PCR revealed that warm ischemia significantly induced up-regulation of immediate early genes, c-fos, Egr-1, and c-jun, in lung, but not in liver. These findings suggest that genes may show tissue-dependent differential transcriptional response against warm ischemia. Tissue samples obtained from patients during surgery cannot completely escape effects of ischemia. In case of examination by cDNA array analysis, biologists should keep in mind that tissue samples come equipped with particular footprints. (C) 2004 Elsevier Inc. All rights reserved.
• Bone marrow cells carrying the env-pX transgene play a role in the severity but not prolongation of arthritis in human T-cell leukaemia virus type-I transgenic rats: a possible role of articular tissues carrying the transgene in the prolongation of arthritis

  A Abe, A Ishizu, H Ikeda, H Hayase, T Tsuji, Y Miyatake, M Tsuji, K Fugo, T Sugaya, M Higuchi, T Matsuno, T Yoshiki

  INTERNATIONAL JOURNAL OF EXPERIMENTAL PATHOLOGY 85 4 191 - 200 2004年08月 [査読有り][通常論文]
   

  Transgenic rats carrying the env-pX gene of human T-cell leukaemia virus type-I (env-pX rats) were immunized with type II collagen (CII), and chronological alterations of arthritis were compared with findings of collagen-induced arthritis (CIA) in wildtype Wistar-King-Aptekman-Hokudai (WKAH) rats. Arthritis induced by CII in env-pX rats was more severe and persisted longer than CIA in WKAH rats. To determine whether the phenomenon is caused mainly by the transgene-carrying lymphocytes or articular tissues, we immunized lethally irradiated env-pX and WKAH rats with reciprocal bone marrow cell (BMC) transplantation. A severe but transient arthritis was induced by CII in WKAH rats reconstituted by env-pX BMC (w/tB/CII rats). On the other hand, in env-pX rats reconstituted by WKAH BMC, arthritis persisted longer than in w/tB/CII rats, although the degree was less at an early phase after CII immunization. These findings suggest that articular tissues rather than the BMCs carrying the env-pX transgene play a role in the prolongation of arthritis in env-pX rats, although BMCs carrying the transgene are associated with the severity of arthritis. When inflammatory cytokines in synovial cells isolated from env-pX rats before they developed arthritis were examined, interleukin-6 (IL-6) was detected at a higher level than in synovial cells from WKAH rats, thus suggesting the critical role of IL-6 in env-pX arthritis.
• Peripheral pulmonary embolism related to a thrombus of the inferior vena cava triggering fatal adrenal crisis in Sheehan's syndrome

  A Ishizu, C Shimizu, T Tsuji, S Nagai, T Yoshiki

  ENDOCRINE JOURNAL 51 3 387 - 388 2004年06月 [査読有り][通常論文]
  
• Pulmonary Langerhans' cell histiocytosis presenting with an endobronchial lesion

  M Suzuki, T Betsuyaku, M Suga, A Ishizu, M Nishimura, M Oguri

  INTERNAL MEDICINE 43 3 227 - 230 2004年03月 [査読有り][通常論文]
   

  A 19-year-old man visited our hospital complaining of cough, sputum and low-grade fever. Chest radiograph and computed tomography findings suggested that he was suffering from pulmonary Langerhans' cell histiocytosis (PLCH). Bronchoscopy revealed a whitish elevated lesion at the bifurcation of the right upper lobe bronchus, and a specimen of this lesion showed the same pathological findings as pulmonary parenchymal lesions. Although there have been only a few reports of endobronchial LCH without pulmonary parenchymal lesions, this is, to our knowledge, the first case of PLCH with an endobronchial lesion, which was confirmed by bronchoscopy, and disappeared several months later.
• Hematopoietic progenitor cells as possible origins of epithelial thymoma in a human T lymphocyte virus type I pX gene transgenic rat model

  T Tsuchikawa, H Ikeda, K Kikuchi, T Tsuji, T Baba, A Ishizu, Y Tanaka, H Kato, T Yoshiki

  LABORATORY INVESTIGATION 84 2 245 - 252 2004年02月 [査読有り][通常論文]
   

  We earlier reported that Fischer 344/jcl strain (F344) rats carrying a unique pX gene of human T lymphocyte virus type I (HTLV-I) under control of a rat lymphocyte-specific protein tyrosine kinase (p56lck) type I promoter (Ick-pX rats) spontaneously developed epithelial thymomas from the thymic medulla. To investigate the role of bone marrow cells carrying the HTLV-I pX gene in development of thymomas, the bone marrow of normal F344 rats after lethal irradiation was reconstituted by bone marrow mononuclear cells (BMMC) of Ick-pX rats. Epithelial thymomas similar to the original thymoma of Ick-pX rats frequently developed in the nontransgenic recipients within 5 months after the BMMC transplantation. The thymomas expressed the pX gene, thereby indicating the thymoma cells to be of donor BMMC origin. Since the thymoma also developed in nontransgenic recipients reconstituted by BMMC depleted of adherent cells, it is suggested that nonadherent BMMC of donor Ick-pX rats may migrate to and lodge in the thymus of recipient nontransgenic rats then transform into thymoma cells with epithelial characteristics. The thymoma cells were shown to bind to Ulex europaeus Agglutinin-1 (UEA-1) lectin, which binds epithelial cells in the thymic medulla. It was also shown that the nonadherent BMMC fraction used for bone marrow reconstitution contained a number of UEA-1-positive cells. Taken together, UEA-1 positive BMMC may be progenitor cells of the epithelial thymoma. The epithelial thymoma in Ick-pX rats sheds light on epithelial cell development in thymic medulla and for oncogenesis of epithelial thymoma in humans.
• Dexamethasone increased plasminogen activator inhibitor-1 expression on human umbilical vein endothelial cells: An additive effect to tumor necrosis factor-alpha

  Y Yamamoto, A Ishizu, H Ikeda, N Otsuka, T Yoshiki

  PATHOBIOLOGY 71 6 295 - 301 2004年 [査読有り][通常論文]
   

  Objective: In patients with autoimmune diseases, blood vessels may be critically involved at the site of inflammation. For these patients, glucocorticoids (GC) are often used as therapeutics. The aim of this study is to determine the effects of GC on vascular endothelial cells which are under inflammatory conditions. Methods: We examined the molecular expressions in human umbilical vein endothelial cells (HUVEC) induced by dexamethasone (Dex) and tumor necrosis factor (TNF)-alpha. Live cell number of HUVEC under exposure to Dex and TNF-alpha was also assayed. Results: The cDNA array analysis showed that a number of genes were upregulated, but only a few were downregulated by Dex and TNF-alpha, respectively. Among them, thrombomodulin (TM) gene showed the least fold change when HUVEC were stimulated by TNF-alpha. Since TM inhibits blood coagulation, we took notice of molecules associated with coagulation and fibrinolysis. The quantitative real-time RT-PCR revealed that the expression of plasminogen activator inhibitor-1 (PAI-1) gene increased when HUVEC were exposed to Dex and TNF-alpha, respectively, and the corresponding augmentation of its protein expression was confirmed by immunohistochemistry. The expression of PAI-1 gene additively increased when Dex and TNF-alpha were added to stimulate HUVEC. Under our experimental conditions, TNF-alpha induced proliferation of HUVEC. On the other hand, Dex did not change the number of live cells regardless of stimulation by TNF-alpha. Conclusion: TNF-alpha can induce proliferation of vascular endothelial cells with downregulation of the anticoagulation molecule, TM, and upregulation of the anti-fibrinolysis molecule, PAI-1. Dex further increased the expression of PAI-1 gene in the cells stimulated by TNF-alpha, and did not reduce the effect on cell proliferation induced by TNF-alpha. These findings suggest that the balance of blood coagulation versus fibrinolysis may incline to coagulation when Dex and TNF-alpha cooperate on vascular endothelial cells. Copyright (C) 2004 S. Karger AG, Basel.
• In vitro model of suicide gene therapy for alpha-fetoprotein-producing gastric cancer

  H Nakaya, A Ishizu, H Ikeda, M Tahara, J Shindo, R Itoh, T Takahashi, M Asaka, H Ishikura, T Yoshiki

  ANTICANCER RESEARCH 23 5A 3795 - 3800 2003年09月 [査読有り][通常論文]
   

  Background: Gastric adenocarcinoma producing alpha-fetoprotein (AFP) has a very poor prognosis. In search of new therapeutic strategies against AFP-producing gastric cancer, we examined the efficacy of suicide gene therapy, which has been effective on A-FP-producing hepatoma. Materials and Methods: The herpes simplex virus thymidine kinase (HSVtk) gene was transduced into an AFP-producing gastric adenocarcinoma cell line, FU97, using adenovirus vectors carrying the constructed AFP enhancer/promoter element, followed by ganciclovir (GCV) administration. Results: Expression of the transgene was evident in FU97 but not in an AFP-nonproducing gastric adenocarcinoma cell line, MKN28, which meant that AFP enhancer/promoter-specific transcriptional targeting was achieved by the vectors. The viability of FU97 but not Of MKN28 significantly decreased after the suicide gene therapy in vitro. Conclusion: Therapeutic application of the AFP enhancer/promoter-specific transfer of the HSVtk gene followed by GCV administration against AFP-producing gastric cancer deserves attention and further research.
• Primary neuroendocrine carcinoma of the liver diagnosed at autopsy

  A Ishizu, K Yokoyama, T Yoshiki

  JOURNAL OF GASTROENTEROLOGY AND HEPATOLOGY 18 8 1002 - U3 2003年08月 [査読有り][通常論文]
  
• Vaccination of fusion cells of rat dendritic and carcinoma cells prevents tumor growth in vivo

  M Kawada, H Ikeda, T Takahashi, A Ishizu, H Ishikura, H Katoh, T Yoshiki

  INTERNATIONAL JOURNAL OF CANCER 105 4 520 - 526 2003年07月 [査読有り][通常論文]
   

  Several reports on immunotherapy using dendritic cells-based vaccine have been published. We investigated findings using fusion cells (FCs) generated from rat dendritic cells and a syngeneic hepatic cancer cell line with regard to inducing anti-tumor immunity. Vaccination of rats using FCs protected against growth of the subcutaneously implanted tumor in vivo and induced infiltration of CD8(+) T cells into the tumor. At the site of CD8(+) T cell infiltration, there were apoptotic tumor cells. T cells from spleen of FCs-vaccinated rats with protective ability against tumor growth included tumor specific cytotoxic CD8(+) T cells restricted to major histocompatibility complex Class I. In addition, adaptive transfer of in vitro re-stimulated splenic T cells with FCs was effective in preventing tumor growth and in vivo vaccinations of rats with FCs after resection of the subcutaneous implanted tumor inhibited local tumor recurrences. Immunotherapy using FCs appears to be an effective method if used in combination with surgical or other anti-cancer therapies. (C) 2003 Wiley-Liss. Inc.
• Transduction of dominant negative ATF-1 suppresses the pX gene expression in joint fibroblastic cells derived from HTLV-I transgenic rats

  A Ishizu, T Tsuji, A Abe, S Saito, T Takahashi, H Ikeda, D Meruelo, T Yoshiki

  EXPERIMENTAL AND MOLECULAR PATHOLOGY 74 3 309 - 313 2003年06月 [査読有り][通常論文]
   

  Tax (p40Tax) encoded by the env-pX gene of human T-cell leukemia virus type I (HTLV-I) interacts with cyclic adenosine-3',5'-monophosphate response element binding protein/activation transcription factor 1 (CREB/ATF-1) transcription factors of host cells and activates the viral long terminal repeat (LTR) promoter. This molecular interaction induces augmentation of viral gene expression and may result in development of HTLV-I-associated diseases, including adult T-cell leukemia, HTLV-I associated myelopathy/tropical spastic paraparesis. and HTLV-I uveitis. To inhibit this pathway, a dominant negative molecule of ATF-1, ATF-1DN, was used. We transduced ATF-1DN into joint fibroblastic cells derived from transgenic rats carrying the LTR-env-pX-LTR gene of HTLV-I, using the Sindbis virus-based vectors. Expression of the pX gene in cells transduced with ATF-1DN was lower than that in cells with control transfection. A possible application of ATF-1DN to suppress viral gene expression in HTLV-1 infected cells can be considered. (C) 2003 Elsevier Science (USA). All rights reserved.
• Functional alteration of peripheral CD25(+)CD4(+) immunoregulatory T cells in a transgenic rat model of autoimmune diseases

  M Higuchi, A Ishizu, H Ikeda, H Hayase, K Fugo, M Tsujia, A Abe, T Sugaya, A Suzuki, T Takahashi, T Koike, T Yoshiki

  JOURNAL OF AUTOIMMUNITY 20 1 43 - 49 2003年02月 [査読有り][通常論文]
   

  Transgenic rats carrying the env-pX gene of human T cell leukemia virus type-I (env-pX rats) develop various collagen vascular diseases. Since autoantibodies are present in their sera, env-pX rats are considered to be a prototype model for autoimmune diseases. Adoptive transfers of spleen cells from syngenic non-transgenic rats decreased the incidence of diseases in env-pX rats, thus suggesting that normal spleen contains cells, which suppress autoimmune diseases. Murine peripheral CD25(+)CD4(+) T cells play roles in maintaining immunological self-tolerance. To examine if alterations of immunoregulatory cells may be evident in env-pX rats, quantitative and qualitative analyses of splenic CD25(+)CD4(+) T cells were done before these rats developed autoimmune diseases. Env-pX and non-transgenic rats had equivalent number of CD25(+)CD4(+) T cells. However, CD25(+)CD4(+) T cells from env-pX rats did not suppress proliferation of T cells stimulated by anti-CD3 antibodies (Ab) in vitro, whereas those from non-transgenic rats did. Additionally, env-pX CD25(+)CD4(+) T cells showed autologous and anti-CD3 Ab-mediated proliferation, in contrast to the anergic features in non-transgenic rats. These findings appear to be the first evidence that CD25(+)CD4(+) immunoregulatory T cells are altered in animal models, which naturally develop autoimmune diseases. (C) 2003 Elsevier Science Ltd. All rights reserved.
• The role of the thymus in development of necrotizing arteritis in transgenic rats carrying the env-pX gene of human T-cell leukemia virus typed

  K Fugo, A Ishizu, H Ikeda, H Hayase, T Sugaya, M Higuchi, M Tsuji, A Abe, A Suzuki, M Shibata, T Takahashi, T Yoshiki

  AMERICAN JOURNAL OF PATHOLOGY 161 3 755 - 761 2002年09月 [査読有り][通常論文]
   

  Necrotizing arteritis mimicking polyarteritis nodosa occurred in transgenic rats carrying the env-pX gene of human T-cell leukemia virus type I. To investigate the pathogenesis of necrotizing arteritis in these rats (env-pX rats), adoptive transfers of spleen cells and bone marrow cells were done from env-pX rats before they developed arteritis to nontransgenic rats. Necrotizing arteritis occurred in lethally irradiated nontransgenic rats reconstituted by env-pX spleen cells, thus indicating that the env-pX transgene in affected vessels may not be essential for the development of arteritis. In contrast, arteritis was not induced in nontransgenic recipients by adoptive transfers of env-pX bone marrow cells, which suggested that T cells derived from the env-pX thymus may play a role in the development of arteritis. To clarify if the process of differentiation of T cells in the env-pX thymus is crucial to develop necrotizing arteritis, reciprocal exchange of thymus frameworks was done between env-pX and nontransgenic rats. Necrotizing arteritis occurred in nontransgenic rats with an env-pX thymus framework, whereas development of arteritis was suppressed in env-pX rats in which the thymus framework was replaced with a nontransgenic one. This collective evidence shows that the thymus is directly associated with the development of necrotizing arteritis in env-pX rats.
• Clonotypic analysis of T cells accumulating at arthritic lesions in HTLV-I env-pX transgenic rats

  T Sugaya, A Ishizu, H Ikeda, Y Nakamaru, K Fugo, M Higuchi, H Yamazaki, K Imai, T Yoshiki

  EXPERIMENTAL AND MOLECULAR PATHOLOGY 72 1 56 - 61 2002年02月 [査読有り][通常論文]
   

  Human T cell leukemia virus type I (HTLV-I) env-pX transgenic rat, (env-pX rats) develop chronic destructive arthritis resembling rheumatoid arthritis in humans. Immunological characteristics were compared with those of collagen-induced arthritis (CIA). Rheumatoid factor was present in some env-pX rats regardless of the development of arthritis, but not in nontransgenic rats with CIA. All rats with CIA produced anti-type It collagen (IIC) antibody, but never so in env-pX rats with naturally occurring arthritis. Although expansions of oligoclonal T cells were evident in the affected joints, no particular clone was shown to infiltrate into the arthritic lesions in env-pX rats. In contrast to CIA. in which clonal expansions of IIC-specific T cells are implicated, locally expanded T cell clones against various antigens of the joints may play pathogenetic roles in the arthritis seen in env-pX rats. However, complementarity-determining region 3 of the TCR Vbeta gene of T cells accumulating at the affected joints in env-pX rats contained the GGA amino acid sequence, which was reported to be a conserved motif in HTLV-I env-pX transgenic mice with arthritis. These findings suggest that common antigens) might be recognized by T cells accumulating at sites of arthritis in both transgenic rats and mice. (C) Elsevier Science.
• Elution of IgA from kidney tissues exhibiting glomerular IgA deposition and analysis of antibody specificity

  Y Ogawa, A Ishizu, H Ishikura, T Yoshiki

  PATHOBIOLOGY 70 2 98 - 102 2002年 [査読有り][通常論文]
   

  Glomerular IgA deposits were eluted from renal biopsy specimens exhibiting IgA nephropathy (IgAN) by using a combination of citrate buffer and collagenase. Collagenase predigestion of the kidney tissues resulted in increased amounts of IgA eluted by citrate buffer, and the elusion procedure did not attenuate the antigen-binding ability of IgA antibody. When reactivity of the eluted IgA with bacteria components was examined by Western blotting, the most notable reaction was observed for Haemophilus influenzae lysates in the form of a 34 kD-band. The reactivity of IgA eluted from the kidney tissues against the H. influenzae 34 kD antigen was evident in 3 of 5 IgAN cases. However, similar reactivity was also evident in 2 of 6 non-IgAN hepatic diseases exhibiting a glomerular IgA deposition. These findings suggest that antibody specificity of IgA against H. influenzae itself may not be directly associated with glomerular injury, although anti-H. influenzae 34 kD IgA was deposited in the kidney, at least in part, by IgAN. Further investigations into the properties of IgA deposited in the glomerulus are needed. Our improved method for IgA elution from kidney tissues would be useful for analysing the pathogenesis of IgAN. Copyright (C) 2002 S. Karger AG, Basel.
• Anti-Thy-1 monoclonal antibody with specific reactivity with vascular endothelial cells in rat glomeruli

  A Ishizu, Y Ogawa, H Ishikura, T Yoshiki

  ACTA HISTOCHEMICA 103 3 279 - 286 2001年07月 [査読有り][通常論文]
   

  Inoculation with anti-Thy-1 antibodies (Abs) in rats induces glomerulonephritis resembling human mesangiolytic and/or mesangioproliferative diseases. Some anti-Thy-1 monoclonal Abs (mAbs) react with both mesangial and glomerular endothelial cells, whereas others react solely with mesangial cells in rat kidney. These findings suggest that the rat Thy-1 molecule possesses at least 2 variant forms, including a mesangial and a vascular endothelial isoform. However, anti-Thy-1 mAbs with specific reactivity with glomerular endothelial cells have not been available. We describe here a unique anti-rat Thy-1 mAb, TM78-8. The epitope for TM78-8 is closely related, but not identical, to that for OX-7, a commercially available anti-rat Thy-1 mAb. Immunoblotting, immunohistochemistry and immunoelectron microscopy confirm that TM78-8 reacts exclusively with Thy-1 antigens on the surface of vascular endothelial cells in rat glomeruli. TM78-8 may be a suitable marker for rat glomerular endothelial cells as well as for the vascular endothelial isoform of the rat Thy-1 molecule. Intravenous injection of TM78-8 did not induce glomerulonephritis in rats, whereas OX-7 did, indicating that TM78-8 is not nephritogenic. This finding also corresponds with the current consensus that Thy-1 antigens expressed on mesangial cells play an essential role in the development of Thy-1 nephritis.
• Immunological hyperresponsiveness in HTLV-1 LTR-env-pX transgenic rats: A prototype animal model for collagen vascular and HTLV-I-related inflammatory diseases

  Y Nakamaru, A Ishizu, H Ikeda, T Sugaya, K Fugo, M Higuchi, H Yamazaki, T Yoshiki

  PATHOBIOLOGY 69 1 11 - 18 2001年 [査読有り][通常論文]
   

  We have earlier reported that diverse collagen vascular diseases, including arthritis, arteritis, thrombosis, myocarditis, myositis, sialo-/dacryoadenitis and dermatitis develop with the advent of autoantibodies in transgenic rats carrying the LTR-env-pX gene of human T lymphocyte virus type I (LTR-env-pX rats). To clarify the pathogenesis of these collagen vascular diseases, immunological features of LTR-env-pX rats were examined. In LTR-env-pX rats affected with these diseases, expression of CD80/86 on both tissue-infiltrating and peripheral T cells increased, compared with findings in non-transgenic rats with experimental inflammatory diseases. CD80/86 was also upregulated on peripheral T cells in LTR-env-pX rats prior to the development of diseases. Lymphocytes from LTR-env-pX rats showed an increase in autologous proliferation and were hyperreactive against several mitogens, including concanavalin A, immobilized anti-CD3 antibodies, and superantigens in vitro. Anti gen-specific immune response was also enhanced in LTR-env-pX rats. The collective evidence indicates that lymphocytes of LTR-env-pX rats constitutively express surface molecules related to T cell activation and are immunologically hyperresponsive. Bone marrow cell transfer from LTR-env-pX rats to lethally irradiated non-transgenic rats revealed that these immunologically pre-activated and hyperresponsive lymphocytes play a critical role in the pathogenesis of several collagen vascular diseases, especially of dermatitis in LTR-env-pX rats. Copyright (C) 2001 S. Karger AG, Basel.
• Transduction of a murine dominant negative activation transcription factor 1 increases cell surface expression of the class I MHC on a human epidermoid tumor cell line

  A Ishizu, K Sawai, H Ikeda, T Hirano, N Ishiguro, D Meruelo

  INTERNATIONAL IMMUNOLOGY 12 2 161 - 168 2000年02月 [査読有り][通常論文]
   

  The transcription of the MHC class I genes is regulated by interaction of cis-elements, located in the 5' genomic flanking regions, with sequence-specific trans-factors. We have identified a cis-regulatory element, 5'-TGACGCG-3', of the H-2D(d) gene. This cyclic adenosine-3',5'-monophosphate regulatory element (CRE)-like sequence, named H-2 binding factor 1 (H-2 BF1) binding motif, is highly conserved among species. In addition, we found that homo- and heterodimers of activation transcription factor 1 (ATF-1) and CRE binding protein (CREB) associate with the H-2 BF1 binding motif and activate transcription of the H-2D(d) gene. Here we demonstrate that a homologue of ATF-1, originally isolated and designated ATF-1DN, acts as a dominant repressor, blocking the ability of wild-type ATF-1 and CREB to bind to the H-2 BF1 probe in electrophoretic mobility shift assays (EMSA). We have utilized this molecule to analyze the participation of the H-2 BF1 complexes, consisting of the H-2 BF1 binding motif and ATF-1/CREB trans-factors, in the physiological regulation of MHC class I expression in tissue culture cells. A human epidermoid carcinoma cell line, A431, was transfected with ATF-1DN and clones expressing the gene transcripts were selected. When analyzed in the EMSA, nuclear proteins prepared from these clones exhibited a decreased shift of the H-2 BF1 probe corresponding to the levels of the ATF-1DN gene expression. Additionally, MHC class I expression of cells with reduced H-2 BF1 activity was significantly higher than in control cells lacking ATF-1DN. These findings indicate that in these carcinoma cells, the H-2 BF1 complexes negatively regulate the constitutive expression of MHC class I.
• A rare case of acromegaly associated with pachydermoperiostosis

  C Shimizu, M Kubo, H Kijima, R Uematsu, Y Sawamura, A Ishizu, T Koike

  JOURNAL OF ENDOCRINOLOGICAL INVESTIGATION 22 5 386 - 389 1999年05月 [査読有り][通常論文]
   

  Pachydermoperiostosis (PDP) is a rare syndrome manifested clinically by finger clubbing, extremity enlargement, hypertrophic skin changes, and periosteal bone formation. The pathogenesis of the disorder has not been clarified and few endocrine abnormalities were apparent. We report here a 58-year-old man with acromegaly associated with PDP, the features of clubbed fingers, coarse skin, and cutis verticis gyrata. Acromegaly due to GH-producing pituitary adenoma was confirmed in endocrinological and pathological studies. (C) 1999, Editrice Kurtis.
• Reducing cytotoxicity induced by sindbis viral vectors

  K Sawai, H Ikeda, A Ishizu, D Meruelo

  MOLECULAR GENETICS AND METABOLISM 67 1 36 - 42 1999年05月 [査読有り][通常論文]
   

  Sindbis virus has been recognized as a potentially useful virus vector for gene therapy. In an effort to improve its utility and provide cell-targeting capability to gene therapy vectors, we recently developed Sindbis virus vectors possessing chimeric envelopes with cell-specific targeting ability [K. Ohno et al. Nature Biotechnol 15:763-767, 1997; K. Sawai et al. Biochem Biophys Res Commun 248:315-323, 1998]. However, a residual problem associated with Sindbis virus vectors is the apoptotic effect of this virus on infected cells. To address this issue, we have studied the possible role of bcl-2 expression. Bcl-2 expression has been postulated to facilitate the establishment of persistent Sindbis viral infection by blocking virus-induced apoptosis. In this study we produced a Sindbis virus vector capable of expressing human bcl-2 and the reporter gene, lacZ. This chimeric virus (SinRep/lacZ/bcl-2/DH-BB) showed a marked reduction in induced apoptosis in infected cells. For example, after infection with this vector, cell proliferation of BHK cells was 55% of that of uninfected cells 2 days after infection and 40% 3 days after infection. While this reflected a significant degree of apoptosis, the effect was much less pronounced than that seen with wild-type Sindbis virus. Cell proliferation was reduced to 26% 2 days after wild-type virus infection of BHK cells and to only 7% 3 days after infection. Although additional work will be required to eliminate apoptosis induced by Sindbis virus vectors, the studies reported here suggest that such a goal may be achievable after additional modification of the vectors. (C) 1999 Academic Press.
• Morphological aspects of ectopia cordis: Four case reports and a review of the literature

  Takahiro Yamada, Nobuhiko Hoshi, Kazuhiko Okuyama, Hiroaki Negishi, Satoko Sudo, Tatsuro Kishida, Hideto Yamada, Tadashi Sagawa, Hiroaki Fujii, Akihiro Ishizu, Hiroshi Ishikura, Seiichiro Fujimoto

  Journal of Obstetrics and Gynaecology Research 25 4 237 - 243 1999年 [査読有り][通常論文]
   

  Ectopia cordis is a rare congenital anomaly. We present 4 cases of ectopia cordis, 1 of which is the first report of an affected fetus in a triplet pregnancy. The morphological relationship between the types of ectopia cordis and their outcomes were investigated in all 4 cases. In addition, the literature on ectopia cordis in Japan was reviewed and discussed.
• Promotion of early osteoclastogenesis and B lymphopoiesis in the bone marrow of transgenic rats with the env-pX gene of human T-cell lymphotropic virus type I

  H Yamazaki, T Kunisada, A Ishizu, H Ikeda, Miyoshi, I, T Sudo, SI Hayashi, T Yoshiki

  ONCOGENE 17 23 2955 - 2960 1998年12月 [査読有り][通常論文]
   

  Human T-cell lymphotropic virus type I(HTLV-I) is associated with various clinical disorders including adult T cell leukemia, myelopathy, arthropathy. Hypercalcemia resulting from osteoclast activation and a variety of hematopoietic abnormalities have been also observed in HTLV-I infected patients, however, precise mechanism about initial trigger(s) prior to presenting symptoms is still unknown. In this study, to assess effects of HTLV-I on hematopoiesis, we analysed characteristics of early hematopoietic precursors in HTLV-I env-pX transgenic rats. Progenitor cells for osteoclasts were significantly increased even in the marrow of asymptomatic env-pX rats. Progenitors for B cells were also highly enriched, while colony forming cells (CFC) elicited by GM-CSF(CFU-GM) and M-CSF(CFU-M) were comparable to normal littermates. Following arthritis in env-pX transgenic rats, osteoclastogenesis was further augmented and the CFCs were increased. Bone marrow cells carrying adjuvant-induced arthritis retained a constant number of progenitors for osteoclast and B lymphocytes, whereas the number of CFU-CM and CFU-M increased. These results indicate that the env-pX transgene affect early stages of osteoclast and B-cell lineages prior to developing diseases, in contrast, an increase of the CFCs was caused indirectly by arthritis. This study provides a novel standpoint for the mechanisms of pathogenesis by HTLV-I.
• Giant cell granulamatous hypophysitis with remarkable uptake on Gallium-67 scintigraphy

  C Shimizu, M Kubo, H Kijima, A Ishizu, T Katoh, T Koike

  CLINICAL ENDOCRINOLOGY 49 1 131 - 134 1998年07月 [査読有り][通常論文]
   

  We treated a man with giant cell granulomatous hypophysitis with pituitary enlargement, as seen on magnetic resonance imaging, Endocrinological examination revealed panhypopituitarism and diabetes insipidus, Microscopic examination of the specimen obtained by transsphenoidal pituitary biopsy revealed a granulomatous lesion, composed of epitheliod cells, Langhans' multinucleated giant cells, lymphocytes and other chronic inflammatory cells, On whole body gallium-67 scintigraphy, there was extensive uptake in the pituitary gland. Gallium-67 scintigraphy may greatly aid in the diagnosis of granulomatous hypophysitis.
• The regulation of murine H-2D(d) expression by activation transcription factor 1 and cAMP response element binding protein

  N Ishiguro, GD Brown, A Ishizu, D Meruelo

  JOURNAL OF IMMUNOLOGY 160 12 5907 - 5914 1998年06月 [査読有り][通常論文]
   

  Resistance to radiation leukemia virus (RadLV)-induced leukemia is correlated with an increase in H-2D(d) expression on the thymocyte surface. It has been shown that elevated H-2D(d) expression on infected thymocytes is a result of elevated mRNA transcription and that the transcriptional increase is correlated with elevated levels of a DNA binding activity, H-2 binding factor 1 (H-2 BF1), which recognizes the 5'-flanking sequence (5'-TGACGCG-3') of the H-2D(d) gene. Recently, it has been shown that the activation transcription factor 1 (ATF-1) homodimer is one form of the H-2 BF1 complex. Here we demonstrate that the cAMP response element binding protein (CREB) homodimer and the heterodimer of CREB/ATF-1 also recognize the cis regulatory moth and are two additional forms of the H-2 BP1 complex. The levels of mRNA encoding ATF-1 and CREB were both increased in RadLV-infected thymocytes that showed increased levels of H-2 mRNA. Also, all three H-2 BF1 binding activities, ATF-1 homodimer, CREB homodimer, and ATF-1/CREB heterodimer, were increased in RadLV-infected thymocytes that expressed high levels of H-2D(d) Ag on the cell surface. Transfection experiments demonstrated that ATF-1 and CREB activated a reporter plasmid containing the H-2 BF1 motif, These observations strongly suggest that both ATF-1 and CREB are involved in the regulation of H-2 gene expression following RadLV infection of mouse thymocytes.
• Models of HTLV-I-induced diseases. Infectious transmission of HTLV-I in inbred rats and HTVL-I env-pX transgenic rats.

  T Yoshiki, H Ikeda, U Tomaru, O Ohya, T Kasai, I Yamashita, K Morita, H Yamazaki, A Ishizu, Y Nakamaru, K Kikuchi, S Tanaka, A Wakisaka

  Leukemia 11 Suppl 3 245 - 6 1997年04月 

  To examine the pathogenic roles of HTLV-I in HTLV-I-induced diseases, we developed two models; namely HTLV-I carrier rats and HTLV-I env-pX transgenic rats. Among life long HTLV-I carriers in seven rat strains, only WKAH rats with the RT1k haplotype developed chronic progressive myeloneuropathy, resembling HAM/TSP clinically and histologically in humans, designated as HAM rat disease and after long incubation periods. Apoptosis of myelin forming cells, oligodendrocytes and Schwann cells associated with HTLV-I infection appears to be the primary cause of HAM rat disease. Local activation of the pX gene and TNF alpha gene was evident in these rats. WKAH rats transgenic for HTLV-I env-pX gene were established and at age 5 weeks, swelling of the bilateral ankle joints began to develop and histological features of the affected joints resembled findings in cases of rheumatoid arthritis (RA): high-titers of rheumatoid factors were present in these rats. A series of vascular collagen diseases such as polyarteritis nodosa-like angiitis, polymyositis, myocarditis, and Sjögren's syndrome-like sialodenitis together with RA were present, even in one individual animal. These transgenic rats as well as HAM rats appear to be suitable animal models for elucidating pathogenic mechanisms implicated in HTLV-I-induced diseases and also various demyelinating vascular collagen diseases of unknown etiology.
• A wide spectrum of collagen vascular and autoimmune diseases in transgenic rats carrying the env-pX gene of human T lymphocyte virus type I

  H Yamazaki, H Ikeda, A Ishizu, Y Nakamaru, T Sugaya, K Kikuchi, S Yamada, A Wakisaka, N Kasai, T Koike, M Hatanaka, T Yoshiki

  INTERNATIONAL IMMUNOLOGY 9 2 339 - 346 1997年02月 [査読有り][通常論文]
   

  To investigate the pathogenesis of human T lymphocyte virus type I (HTLV-I)-related diseases, the env-pX gene of HTLV-I was introduced into the germline of inbred Wistar-King-Aptekman-Hokudai rats, A wide spectrum of collagen vascular diseases was evident in the transgenic rats, including chronic destructive arthritis similar to rheumatoid arthritis, necrotizing arteritis mimicking polyarteritis nodosa, polymyositis, myocarditis, dermatitis, and chronic sialoadenitis and dacryoadenitis resembling Sjogren's syndrome in humans, Thymic atrophy with the depletion of CD4 and CD8 double-positive thymocytes was also observed, In these animals, a number of autoantibodies, including high titers of rheumatoid factor, were present in the serum, We propose that the HTLV-I env-pX gene region may play a pathogenetic role in the development of collagen vascular and autoimmune diseases associated with autoimmune phenomenon.
• E-SELECTIN EXPRESSION INDUCED BY PANCREAS-CARCINOMA-DERIVED INTERLEUKIN-1-ALPHA RESULTS IN ENHANCED ADHESION OF PANCREAS-CARCINOMA CELLS TO ENDOTHELIAL-CELLS

  M KAJI, H ISHIKURA, T KISHIMOTO, M OMI, A ISHIZU, C KIMURA, T TAKAHASHI, H KATO, T YOSHIKI

  INTERNATIONAL JOURNAL OF CANCER 60 5 712 - 717 1995年03月 [査読有り][通常論文]
   

  Cellular adhesion of sialyl-Lewis-a(SLe(a))-positive pancreas carcinoma to endothelial cells (EC) is augmented by activation of EC via up-regulated E-selectin expression on EC. Cocultivation of pancreas-carcinoma cells, PCI-24, with human umbilical-vein endothelial cells (HUVEC) for 5 hr at the PCI-to-HUVEC ratio of 1:10 induced E-selectin expression on the endothelial-cell surface, augmenting SLe(a)-positive pancreas-carcinoma cell attachment with HUVEC. Culture supernatants of 6 tested pancreas-carcinoma cell lines contained soluble, E-selectin-inducing factor(s). The E-selectin-inducing effect by the supernatants was blocked by the protein-kinase-C inhibitor, H7. Antibodies against SLe(a) and E-selectin but not SLe(x) or ICAM-1 blocked the increased pancreas-carcinoma-to-endothelial attachment. Paraformaldehyde(PFA)-fixed PCI-24 cells also induced E-selectin on vascular endothelial cells upon direct contact with endothelial cells, indicating the presence of a membrane-bound form. The 6 pancreas-carcinoma lines all produced IL-1 alpha mRNA and protein but not IL-1 beta or TNF-alpha protein and/or mRNA. Absorption of IL-1 alpha from the supernatants by IL-1 alpha-specific antibody almost completely abolished E-selectin-inducing activity. Anti-IL-1 alpha antibody also abolished the E-selectin-inducing activity of PFA-fixed PCI. IL-1 alpha production by PCI cells was up-regulated by TNF-alpha. These observations suggest that substance(s) produced by pancreas-carcinoma cells, in this case, IL-1 alpha may contribute to pancreas-carcinoma-cell colonization in non-inflamed, distant locations in vivo, by activating vascular endothelial cells. (C) 1995 Wiley-Liss. Inc.
• IMPORTANCE OF E-SELECTIN (ELAM-1) AND SIALYL LEWIS(A) IN THE ADHESION OF PANCREATIC-CARCINOMA CELLS TO ACTIVATED ENDOTHELIUM

  K IWAI, H ISHIKURA, M KAJI, H SUGIURA, A ISHIZU, C TAKAHASHI, H KATO, T TANABE, T YOSHIKI

  INTERNATIONAL JOURNAL OF CANCER 54 6 972 - 977 1993年07月 [査読有り][通常論文]
   

  Adhesion molecules involved in attachment between human pancreatic carcinoma and activated endothelial cells in vitro were investigated. Basal adhesion occurred between 6 pancreatic carcinoma cell lines and unstimulated human umbilical vein endothelial cells (HUVEC), and augmented basal adhesion to activated HUVEC was only seen when pancreatic cancer cells expressed sialyl Lewis(a) (SLe(a)) and sialyl Lewis(x) (SLe(x)). Activation of HUVEC with interleukin 1-beta (IL-1beta) or tumor necrosis factor-alpha (TNF-alpha), but not with interferon-gamma (IFN-gamma), generated the augmentative basal adhesion. Dose dependence and additive effect were observed in augmentation of the basal adhesion induced by IL-1beta and/or TNF-alpha. Increase in adhesion correlated with up-regulation of the surface E-selectin (or ELAM-1) on HUVEC, and was evident at both 25-degrees-C and 4-degrees-C. Anti-E-selectin and anti-SLe(a) blocked the augmented attachment, whereas anti-SLe(x), an antibody against another known ligand for E-selectin, did not. The collective evidence indicates that attachment between pancreas carcinoma cells and activated endothelial cells is regulated by cytokines such as IL-1beta and TNF-alpha, and is mediated by SLe(a) on pancreas carcinoma and E-selectin on endothelial cells. These molecules may be of significant importance in blood-borne metastasis of pancreatic carcinoma cells to inflamed sites. (C) 1993 Wiley-Liss, Inc.

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  新海隼人, 加藤千恵次, 川上民裕, 高橋啓, 西端友香, 益田紗季子, 田中敏, 外丸詩野, 石津明洋 脈管学(Web) 61 (1) 2021年
• myosin light chain6を認議する抗好中球細胞外トラップ(NETs)抗体はNETs分解阻害活性を持つ

  西端友香, 益田紗季子, 外丸詩野, 石津明洋 日本リウマチ学会総会・学術集会プログラム・抄録集 65th 2021年
• 低酸素環境が好中球細胞外トラップ形成へ与える影響

  益田紗季子, 西端友香, 田中敏, 外丸詩野, 辻野一三, 石津明洋 日本病理学会会誌 110 (1) 2021年
• 多発血管炎性肉芽腫症(GPA)の自然退縮における,好中球細胞外トラップ(NETs)分解について~当院で経験した1症例を通して~

  太田啓貴, 佐藤千紗, 五十嵐朗, 邨野浩義, 梁秀鼎, 町田浩祥, 佐藤建人, 中野寛之, 根本貴子, 西脇道子, 木村友美, 山内啓子, 佐藤正道, 井上純人, 渡辺昌文, 益田紗季子, 石津明洋 日本呼吸器学会誌(Web) 10 2021年
• OMAAVの上気道生検組織の組織学的パラメーターの解析

  宮崎 龍彦, 小林 一博, 久松 憲治, 酒々井 夏子, 松本 宗和, 武曾 恵理, 小川 弥生, 中沢 大悟, 石津 明洋, 原渕 保明, 岸部 幹 脈管学 60 (2) 19 -19 2020年02月 [査読無し][通常論文]
  
• OMAAVの上気道生検組織の組織学的パラメーターの解析

  宮崎龍彦, 小林一博, 久松憲治, 酒々井夏子, 松本宗和, 武曾恵理, 小川弥生, 中沢大悟, 石津明洋, 原渕保明, 岸部幹 脈管学(Web) 60 (2) 2020年
• 抗GBM抗体が認識するエピトープの表出に関する検討

  西端友香, 野々川茉佑, 益田紗季子, 中沢大悟, 田中敏, 外丸詩野, 石津明洋 脈管学(Web) 60 (2) 2020年
• ANCA関連血管炎の病因研究 ANCA関連血管炎における好中球細胞外トラップ

  魚住諒, 魚住諒, 益田紗季子, 石津明洋 炎症と免疫 28 (4) 2020年
• 腎生検組織におけるNeutrophil Extracellular Traps(NETs)の検討

  岩崎沙理, 益田紗季子, 石津明洋, 大塚拓也, 牧田啓史, 深澤雄一郎, 辻隆裕 日本病理学会会誌 109 (1) 2020年
• OMAAVの上気道生検組織の組織学的パラメーターの萌芽的解析

  宮崎 龍彦, 小林 一博, 久松 憲治, 酒々井 夏子, 松本 宗和, 武曾 恵理, 小川 弥生, 中沢 大悟, 石津 明洋 日本病理学会会誌 108 (1) 347 -347 2019年04月 [査読無し][通常論文]
  
• HIGH DOSE IMMUNOGLOBULINS CAN INHIBIT NEUTROPHIL EXTRACELLULAR TRAP FORMATION, EVENTUALLY PREVENT THE DEVELOPMENT OF MPO-ANCA-ASSOCIATED VASCULITIS

  Ryo Uozumi, Sakiko Masuda, Yuka Nishibata, Shun Tanimura, Daigo Nakazawa, Utano Tomaru, Akihiro Ishizu RHEUMATOLOGY 58 2019年03月
• 薬剤起因性自己免疫疾患におけるNETsの関与

  益田紗季子, 石津明洋 月刊リウマチ科 61 (1) 2019年
• 抗糸球体基底膜抗体病(抗GBM病)の頻回再発症例の抗GBMが認識するエピトープ

  西端友香, 東里緒, 益田紗季子, 中沢大悟, 田中敏, 外丸詩野, 中林公正, 石津明洋 脈管学(Web) 59 (3) 2019年
• シクロフィリンDをターゲットとしたANCA関連壊死性血管炎に対する新規治療薬の開発

  工藤孝司, 中沢大悟, 白鳥里佳, 楠加奈子, 西尾妙織, 益田紗季子, 外丸詩野, 石津明洋, 渥美達也 日本臨床免疫学会総会プログラム・抄録集 47th 2019年
• ヒストンは好中球細胞上にLAMP2を表出し,抗LAMP2抗体と連携して皮膚小血管炎の発症機序に関与している

  川上民裕, 竹内そら, 菊池彩翔, 西端友香, 益田紗季子, 外丸詩野, 石津明洋 脈管学(Web) 59 (3) 2019年
• 【膠原病の病理-今日的視点から-】 膠原病の病態形成メカニズムと最新治療 自己寛容破綻と自己抗体産生のメカニズム

  石津 明洋 病理と臨床 36 (6) 514 -517 2018年06月 [査読無し][通常論文]
  
• EFFECTS OF RECOMBINANT THROMBOMODULIN ON EXPERIMENTAL AUTOIMMUNE VASCULITIS VIA THE INHIBITION OF NEUTROPHIL EXTRACELLULAR TRAPS

  Kanako Watanabe, Daigo Nakazawa, Yoshihiro Kusunoki, Fumihiko Hattanda, Saori Nishio, Sakiko Masuda, Utano Tomaru, Tatsuya Atsumi, Akihiro Ishizu NEPHROLOGY DIALYSIS TRANSPLANTATION 33 34 -34 2018年05月
• 抗ホスファチジルセリン-プロトロンビン複合体抗体による血栓症モデル

  山田 真衣, 石津 明洋 リウマチ科 59 (5) 542 -546 2018年05月 [査読無し][通常論文]
  
• 「内科医・小児科医・病理医を招いた血管炎シンポジウム」 血管炎診療の病理診断と皮膚病変

  石津 明洋 日本皮膚科学会雑誌 128 (5) 864 -864 2018年05月 [査読無し][通常論文]
  
• 【MHCクラスIb拘束性T細胞研究の新展開】 【CD1d拘束性T細胞の最近の話題】自己血管内皮細胞反応性type II NKT細胞の血管炎における役割

  西岡 佑介, 石津 明洋 医学のあゆみ 265 (4) 273 -277 2018年04月 [査読無し][通常論文]
   

  血管炎を自然発症するenv-pXラットから、自己血管内皮細胞に反応し、血管炎を惹起するT細胞クローンVASC-1を単離した。フェノタイプおよびジェノタイプ解析から、VASC-1はtype II NKT細胞であると考えられた。VASC-1は血管内皮細胞上のCD1d分子に提示される自己細胞内抗原sterol carrier protein 2(SCP2)のP518-532を認識し、活性化して炎症性サイトカインを放出する。一方、文献的には自己反応性type II NKT細胞の免疫抑制能が示唆されている。自己反応性type II NKT細胞が正常では免疫抑制性に働くとすると、env-pXラットでは機能失調に陥っている可能性があり、そのことが血管炎の発症に関与している可能性が考えられる。(著者抄録)
• 病原性自己抗体と腎・血管障害 ANCAとANCA関連腎炎・血管炎

  石津 明洋 日本病理学会会誌 107 (1) 219 -219 2018年04月 [査読無し][通常論文]
  
• ANCA関連血管炎(AAV)の壊死性病変部における好中球細胞外トラップ(NETs)の存在と病的意義

  益田 紗季子, 野々川 茉佑, 西端 友香, 岩崎 沙理, 辻 隆裕, 田中 敏, 外丸 詩野, 川上 民裕, 石津 明洋 日本病理学会会誌 107 (1) 330 -330 2018年04月 [査読無し][通常論文]
  
• 免疫グロブリン大量静注療法(IVIG)は好中球細胞外トラップ(NETs)の抑制によりMPO-ANCA関連血管炎を抑制する

  魚住 諒, 井口 理彩, 益田 紗季子, 西端 友香, 谷村 瞬, 中沢 大悟, 外丸 詩野, 石津 明洋 日本病理学会会誌 107 (1) 331 -331 2018年04月 [査読無し][通常論文]
  
• PKD1変異を認めたMedullary cystic kidney disease(MCKD)の一例

  岩崎 沙理, 島本 真実子, 藤丸 拓也, 森 崇寧, 蘇原 映誠, 石津 明洋, 今本 鉄平, 石立 尚路, 辻 隆裕, 深澤 雄一郎 日本病理学会会誌 107 (1) 449 -449 2018年04月 [査読無し][通常論文]
  
• 致死的な腹腔内出血を来した顕微鏡的多発血管炎の一剖検例

  伊丹 久実, 木内 隆之, 外丸 詩野, 大塚 紀幸, 田中 敏, 石津 明洋, 笠原 正典 日本病理学会会誌 107 (1) 535 -535 2018年04月 [査読無し][通常論文]
  
• 頸部リンパ節の穿刺吸引細胞診(FNAC)から病変を推定しえたメルケル細胞癌の1例

  下坂 光生, 堀井 恒哉, 小山内 翔祐, 高木 芳武, 石津 明洋 日本臨床細胞学会雑誌 57 (Suppl.1) 178 -178 2018年04月 [査読無し][通常論文]
  
• ANCA関連血管炎の壊死性病変部におけるNETsの存在と病的意義

  益田 紗季子, 野々川 茉佑, 西端 友香, 岩崎 沙理, 辻 隆裕, 田中 敏, 外丸 詩野, 川上 民裕, 石津 明洋 脈管学 58 (3) 35 -35 2018年03月 [査読無し][通常論文]
  
• プロテアーゼによる抗糸球体基底膜抗体病の隔絶抗原の表出

  西端 友香, 植松 千浩, 益田 紗季子, 田中 敏, 外丸 詩野, 石津 明洋 脈管学 58 (3) 36 -37 2018年03月 [査読無し][通常論文]
  
• 病理学的視点から考えるリウマチ性疾患 血管病理から考えるリウマチ性疾患

  石津 明洋 日本リウマチ学会総会・学術集会プログラム・抄録集 62回 235 -235 2018年03月 [査読無し][通常論文]
  
• 血管炎診療の最前線 血管炎病理診断コンサルテーションシステム

  石津 明洋 日本リウマチ学会総会・学術集会プログラム・抄録集 62回 270 -270 2018年03月 [査読無し][通常論文]
  
• 血管炎の病理診断のポイント

  石津 明洋 日本リウマチ学会総会・学術集会プログラム・抄録集 62回 323 -323 2018年03月 [査読無し][通常論文]
  
• 血管炎1:血管炎のバイオマーカー・病態解析 免疫グロブリン製剤は好中球細胞外トラップ(NETs)の形成抑制を介してMPO-ANCA関連血管炎(MPO-AAV)の発症を抑制する

  魚住 諒, 益田 紗季子, 西端 友香, 谷村 瞬, 中沢 大悟, 外丸 詩野, 石津 明洋 日本リウマチ学会総会・学術集会プログラム・抄録集 62回 433 -433 2018年03月 [査読無し][通常論文]
  
• リウマチ性疾患の画像2:関節エコーその他 超高周波プローブを用いたSuperb Micro-vascular Imagingによる超音波検査でのラット足関節の早期関節炎診断

  西田 睦, 谷村 瞬, 神島 保, 西端 友香, 益田 紗季子, 中沢 大悟, 外丸 詩野, 渥美 達也, 石津 明洋 日本リウマチ学会総会・学術集会プログラム・抄録集 62回 485 -485 2018年03月 [査読無し][通常論文]
  
• スタチンの関節炎抑制効果とその機序の解明

  谷村 瞬, 西田 睦, 神島 保, 西端 友香, 益田 紗季子, 中沢 大悟, 外丸 詩野, 渥美 達也, 石津 明洋 日本リウマチ学会総会・学術集会プログラム・抄録集 62回 778 -778 2018年03月 [査読無し][通常論文]
  
• 抗好中球細胞質抗体(ANCA)と好中球細胞外トラップ(NETs)

  益田 紗季子, 石津 明洋 リウマチ科 59 (2) 200 -205 2018年02月 [査読無し][通常論文]
  
• BDNFはHUVECにおけるangiogeninの分泌と核移行を誘導する

  森綾子, 西岡祐介, 山田真衣, 西端友香, 益田紗季子, 外丸詩野, 本間直幸, 森山隆則, 石津明洋 日本血管生物医学会学術集会プログラム・抄録集 26th 2018年
• スタチンの関節炎抑制効果と機序の検討

  谷村瞬, 渥美達也, 西田睦, 堀江達則, 神島保, 玉井絵里香, 森村豊, 西端友香, 益田紗季子, 石津明洋, 外丸詩野 北海道医学雑誌 93 (2) 2018年
• プロテアーゼによる抗糸球体基底膜抗体病の隔絶抗原の表出

  西端友香, 植松千浩, 益田紗季子, 田中敏, 外丸詩野, 石津明洋 脈管学(Web) 58 (3) 2018年
• ANCA関連血管炎の壊死性病変部におけるNETsの存在と病的意義

  益田紗季子, 野々川茉佑, 西端友香, 岩崎沙理, 辻隆裕, 田中敏, 外丸詩野, 川上民裕, 石津明洋 脈管学(Web) 58 (3) 2018年
• 【血管炎の臨床UPDATE】 血管炎の分類と病因

  石津 明洋 医学のあゆみ 263 (6) 481 -484 2017年11月 [査読無し][通常論文]
   

  血管が一次的に炎症性に障害される疾患を血管炎という。血管炎は、(1)大型血管炎、(2)中型血管炎、(3)小型血管炎、(4)多様な血管を侵す血管炎、(5)単一臓器血管炎、(6)全身性疾患関連血管炎、(7)推定病因を有する血管炎、に分類され、小型血管炎はさらに、(1)抗好中球細胞質抗体(ANCA)関連血管炎と、(2)免疫複合体性小型血管炎に細分される。血管炎の病因は不明であるが、他の膠原病・自己免疫疾患と同様に、血管炎はなんらかの遺伝要因を有する人に種々の環境要因が加わることにより発症すると考えられている。日本人集団における血管炎発症に関与する遺伝子としてHLA遺伝子、IL12B遺伝子、IRF5遺伝子などが報告されている。また、環境要因としては感染、薬剤、喫煙、空気中の微小結晶などが血管炎発症に関連することが示唆されている。(著者抄録)
• 【免疫学の基本的知識およびリウマチ性疾患との関連について理解する】 好中球とNETosis

  八反田 文彦, 中沢 大悟, 石津 明洋 リウマチ科 58 (5) 467 -473 2017年11月 [査読無し][通常論文]
  
• スタチン製剤の関節炎抑制効果と機序の検討

  谷村 瞬, 渥美 達也, 西田 睦, 堀江 達則, 神島 保, 齋藤 克己, 西端 友香, 益田 紗季子, 石津 明洋, 外丸 詩野 北海道医学雑誌 92 (2) 105 -105 2017年11月 [査読無し][通常論文]
  
• 皮膚科領域でみる血管炎の病理組織像からのアプローチ

  石津 明洋 Journal of Environmental Dermatology and Cutaneous Allergology 11 (4) 296 -299 2017年10月 [査読無し][通常論文]
   

  皮膚血管炎の病理組織学的所見は、白血球破砕性血管炎と結節性多発動脈炎(PAN)型壊死性動脈炎に大別される。白血球破砕性血管炎をきたす疾患には、皮膚固有のものの他、IgA血管炎、抗好中球細胞質抗体(ANCA)関連血管炎、薬剤やがんに関連する血管炎などがある。壊死性動脈炎には、PANの皮膚限局型に相当する皮膚動脈炎と、PANの部分症として皮膚の動脈が標的となる場合がある。白血球破砕性血管炎は、病因論的には免疫複合体の血管壁への沈着が関与するものと、ANCAが関与するものに大別される。ANCAによる血管障害機序として、従来ANCA-サイトカインシークエンスが提唱されてきたが、近年の研究の進展により、ANCAの産生原因やANCAを介した血管障害に好中球細胞外トラップ(NETs)の関与が明らかとなってきており、ANCA関連血管炎では、NETsとANCAの悪循環が生じている。PAN型壊死性動脈炎の病因は不明である。(著者抄録)
• Superb micro-vascular imaging法のシグナル強度と関節内血管径の関係性 関節リウマチの実験動物モデル(Relationship between Superb Micro-vascular Imaging Signal Quantity and Vessel Diameter in the Joints: Experimental Animal Models of Rheumatoid Arthritis)

  玉井 絵里香, 神島 保, 森村 豊, 堀江 達則, 谷村 瞬, 西田 睦, 石津 明洋, 外丸 詩野 日本放射線技術学会雑誌 73 (9) 855 -855 2017年09月 [査読無し][通常論文]
  
• 好中球細胞外トラップ(NETs)の基礎と臨床

  石津 明洋 臨床化学 46 (Suppl.1) 129 -129 2017年09月 [査読無し][通常論文]
  
• 血管炎症候群における自己抗体

  石津 明洋 日本臨床免疫学会会誌 40 (4) 279 -279 2017年08月 [査読無し][通常論文]
   

    自己抗体には病変形成の結果として産生されるものもあるが，血管炎症候群では病原性自己抗体が出現する特徴がある．そのような自己抗体のひとつがANCA関連血管炎におけるMPO-ANCAである．我々は，抗甲状腺薬であるPTUを投与された患者の約30％にMPO-ANCAが産生されることに着目し，MPO-ANCAの産生に好中球細胞外トラップ（NETs）の制御異常が関与していることを明らかにした．NETsは本来，感染防御に不可欠な自然免疫機構であるが，自己損傷の恐れもあるため，役割を果たした後は血清中のDNase Iにより速やかに分解される．我々は，ヒト好中球をPMAで刺激してNETsを誘導する際に，PTUを添加すると，DNase Iに対して抵抗性のNETsが形成されることを見出した．さらに，PTUの存在下で形成させたDNase I抵抗性のNETsをWKYラットに免疫すること，または，PTUの経口投与下で腹腔内にPMAを注射して，生体内でDNase I抵抗性のNETsを形成させることにより，MPO-ANCAが産生され，そのラットに小型血管炎が発症することを報告した．また，PTUとPMAを用いて作製したMPO-ANCA産生モデルマウスに，NETs形成阻害作用を持つPAD阻害剤を投与することにより，MPO-ANCAの産生が抑制されることも確認した．分解されず，生体内に残存するNETsに含まれるMPOが，何らかの理由によりCD4 T細胞に自己抗原として認識され，B細胞を刺激して病原性自己抗体であるMPO-ANCAが産生される可能性が考えられる．

• 【血管生物学と疾患】 日常業務でよく遭遇する血管病変の最新知見 血管炎の最新研究知見と病理(ANCA関連血管炎を中心に)

  石津 明洋 病理と臨床 35 (8) 713 -716 2017年08月 [査読無し][通常論文]
  
• 核内因子の放出によって誘導される血栓形成・炎症反応 好中球NETsと血管炎

  石津 明洋 日本動脈硬化学会総会プログラム・抄録集 49回 130 -130 2017年06月 [査読無し][通常論文]
  
• 多発血管炎の新展開 各領域における最近のトピックス 自己血管内皮細胞反応性type II NKT細胞の機能異常と血管炎

  石津 明洋 アレルギー 66 (4-5) 390 -390 2017年05月 [査読無し][通常論文]
  
• 血管炎・その他の免疫疾患 皮膚限局の血管炎が重症化した際の抗モエシン抗体の推移について

  岡野 達郎, 竹内 そら, 相馬 良直, 鈴木 浩也, 月田 早智子, 石津 明洋, 鈴木 和男, 川上 民裕 アレルギー 66 (4-5) 621 -621 2017年05月 [査読無し][通常論文]
  
• 自己免疫疾患とNETosis

  楠 由宏, 益田 紗季子, 外丸 詩野, 石津 明洋 リウマチ科 57 (4) 437 -442 2017年04月 [査読無し][通常論文]
  
• 【病理診断に直結した組織学】 筋骨格系 脈管(血管・リンパ管)

  石津 明洋 病理と臨床 35 (臨増) 54 -60 2017年04月 [査読無し][通常論文]
  
• _7 RAT TYPE II NKT CELL CLONE PATHOGENIC FOR SMALL VESSEL VASCULITIS RECOGNIZES STEROL CARRIER PROTEIN 2

  Yusuke Nishioka, Madoka Yamaguchi, Ai Kawakami, Maya Munehiro, Sakiko Masuda, Utano Tomaru, Akihiro Ishizu RHEUMATOLOGY 56 30 -31 2017年03月 [査読無し][通常論文]
  
• AN AUTOPSY CASE OF SJOGREN SYNDROME PRESENTED RENAL AND CNS INVOLVEMENT OF SUSPECTED CRYOGLOBULINEMIC VASCULITIS

  Sari Iwasaki, Takahiro Tsuji, Yasushi Ishii, Mitsuru Yanai, Mayuko Akimoto, Hiroshi Kataoka, Akihiro Ishizu, Yuichiro Fukazawa RHEUMATOLOGY 56 2017年03月 [査読無し][通常論文]
  
• THE EFFECT OF PEPTIDYLARGININE DEIMINASE INHIBITOR ON NET FORMATION AND MPO-ANCA PRODUCTION IN MOUSE MODEL

  Yoshihiro Kusunoki, Daigo Nakazawa, Haruki Shida, Fumihiko Hattanda, Arina Miyoshi, Sakiko Masuda, Saori Nishio, Utano Tomaru, Tatsuya Atsumi, Akihiro Ishizu RHEUMATOLOGY 56 112 -113 2017年03月 [査読無し][通常論文]
  
• ESTABLISHMENT OF ANTI-RAT PHOSPHATIDYLSERINE/PROTHROMBIN MONOCLONAL ANTIBODIES AND A THROMBOTIC RAT MODEL INDUCED BY INTRAVENOUS INJECTION OF THE ANTIBODY

  Mai Yamada, Tamihiro Kawakami, Kohei Takashima, Yusuke Nishioka, Yuka Nishibata, Sakiko Masuda, Shigeru Yoshida, Akihiro Ishizu RHEUMATOLOGY 56 2017年03月 [査読無し][通常論文]
  
• RELATIONSHIP OF ANTI-PHOSPHATIDYLSERINE-PROTHROMBIN COMPLEX ANTIBODIES AND ANTI-MOESIN ANTIBODIES IN PATIENTS WITH POLYARTERITIS NODOSA

  Tamihiro Kawakami, Tatsuro Okano, Sora Takeuchi, Yoshinao Soma, Koya Suzuki, Sachiko Tsukita, Akihiro Ishizu, Kazuo Suzuki RHEUMATOLOGY 56 28 -28 2017年03月 [査読無し][通常論文]
  
• USEFULNESS OF CONCOMITANT CYCLOPHOSPHAMIDE FOR TREATMENT OF GENERALIZED OR SEVERE PATIENTS WITH MICROSCOPIC POLYANGIITIS OR GRANULOMATOSIS WITH POLYANGIITIS IN JAPAN

  Ken-ei Sada, Masayoshi Harigai, Joichi Usui, Naotake Tsuboi, Hiroaki Dobashi, Akihiro Ishizu, Hitoshi Sugiyama, Kunihiro Yamagata, Sakae Homma, Yasunori Okada, Yoshihiro Arimura, Seiichi Matsuo, Hirofumi Makino RHEUMATOLOGY 56 151 -152 2017年03月 [査読無し][通常論文]
  
• PATHOLOGICAL ANALYSIS ON THE ROLE OF SMALL VESSEL VASCULITIS AND TUBULO-INTERSTITIAL LESIONS IN ANCA-ASSOCIATED NEPHRITIS

  Yayoi Ogawa, Kensuke Joh, Eri Muso, Nobuo Kondo, Yoshitake Takagi, Akihiro Ishizu RHEUMATOLOGY 56 37 -37 2017年03月 [査読無し][通常論文]
  
• PATHOLOGICAL ANALYSIS OF ANTI-GBM GLOMERULONEPHRITIS

  Yayoi Ogawa, Nobuo Kondo, Yoshitake Takagi, Akihiro Ishizu RHEUMATOLOGY 56 83 -83 2017年03月 [査読無し][通常論文]
  
• MOESIN MRNA LEVEL IN FORMALIN-FIXED AND PARAFFIN-EMBEDDED SKIN BIOPSY SPECIMEN OF PATIENTS WITH POLYARTERITIS NODOSA BASED ON REAL TIME RT-PCR

  Tamihiro Kawakami, Tatsuro Okano, Sora Takeuchi, Yoshinao Soma, Fuyu Ito, Akihiro Ishizu, Yoshihiro Arimura, Kazuo Suzuki RHEUMATOLOGY 56 62 -62 2017年03月 [査読無し][通常論文]
  
• 自己抗体の病因的意義と臨床的意義 抗好中球細胞質抗体(ANCA)と好中球細胞外トラップ(NETs)

  石津 明洋 日本リウマチ学会総会・学術集会プログラム・抄録集 61回 212 -212 2017年03月 [査読無し][通常論文]
  
• 血管炎 ANCA関連血管炎(AAV)における抗NETs抗体の存在と病的意義

  八反田 文彦, 楠 由宏, 志田 玄貴, 中沢 大悟, 西尾 妙織, 益田 紗季子, 外丸 詩野, 渥美 達也, 石津 明洋 日本リウマチ学会総会・学術集会プログラム・抄録集 61回 431 -431 2017年03月 [査読無し][通常論文]
  
• 血管炎 皮膚動脈炎から結節性多発動脈炎への移行とモエシンとの関連

  川上 民裕, 石津 明洋, 有村 義宏 日本リウマチ学会総会・学術集会プログラム・抄録集 61回 431 -431 2017年03月 [査読無し][通常論文]
  
• SLE・抗リン脂質抗体症候群 抗PSPT抗体による抗リン脂質抗体症候群動物モデルの完成

  川上 民裕, 石津 明洋, 益田 紗季子, 外丸 詩野 日本リウマチ学会総会・学術集会プログラム・抄録集 61回 605 -605 2017年03月 [査読無し][通常論文]
  
• ANCA関連血管炎を発症した全身性エリテマトーデスの一例

  古崎 章, 天崎 吉晴, 石津 明洋 日本リウマチ学会総会・学術集会プログラム・抄録集 61回 761 -761 2017年03月 [査読無し][通常論文]
  
• プロテアソーム機能低下モデルマウスにおける脳機能障害の解析

  外丸 詩野, 伊藤 智樹, 大村 優, 石津 明洋, 笠原 正典 日本病理学会会誌 106 (1) 323 -323 2017年03月 [査読無し][通常論文]
  
• フローサイトメトリーによる定量的好中球細胞外トラップ測定法

  益田 紗季子, 西端 友香, 松尾 淳司, 外丸 詩野, 石津 明洋 日本病理学会会誌 106 (1) 350 -350 2017年03月 [査読無し][通常論文]
  
• 糸球体係蹄内にFoam cellが目立った糖尿病性腎症の一例

  岩崎 沙理, 辻 隆裕, 石井 保志, 秋元 真祐子, 西尾 沙織, 石津 明洋, 深澤 雄一郎 日本病理学会会誌 106 (1) 382 -382 2017年03月 [査読無し][通常論文]
  
• ウェブ版血管炎病理アトラスの作成について

  石津 明洋 脈管学 57 (2) 21 -21 2017年02月 [査読無し][通常論文]
  
• 血管炎の実験動物モデル 抗PSPT抗体は、正常ラットに血栓を発症させる

  川上 民裕, 山田 真衣, 高島 滉平, 西岡 佑介, 西端 友香, 益田 紗季子, 吉田 繁, 外丸 詩野, 石津 明洋 脈管学 57 (2) 22 -22 2017年02月 [査読無し][通常論文]
  
• 抗PSPT抗体は,正常ラットに血栓を発症させる

  川上民裕, 山田真衣, 高島滉平, 西岡佑介, 西端友香, 益田紗季子, 吉田繁, 外丸詩野, 石津明洋 脈管学(Web) 57 (2) 2017年
• 診療の秘訣 ノロウイルス胃腸炎を契機に発症した上腸間膜静脈血栓症

  石津 明洋 Modern Physician 37 (1) 96 -96 2017年01月 [査読無し][通常論文]
  
• ANCA関連血管炎の病態メカニズム

  石津 明洋 日本臨床免疫学会会誌 39 (6) 491 -496 2016年12月 [査読無し][通常論文]
   

  血清中の抗好中球細胞質抗体(anti-neutrophil cytoplasmic antibody:ANCA)陽性を特徴とする血管炎をANCA関連血管炎という.ANCAには疾患マーカーとしての意義があるのみならず,病原性がある.これまでANCAが血管炎を引き起こす機序として,ANCA-サイトカインシークエンス説が提唱されてきたが,近年の研究により,ANCAによる好中球の過剰な活性化には,サイトカインの異常産生に加え,好中球細胞外トラップ(neutrophil extracellular traps:NETs)の形成誘導も含まれることが明らかとなってきた.本総説では,ANCA関連血管炎の病態形成における好中球,好酸球,マクロファージ/樹状細胞,補体,B細胞/形質細胞,T細胞,サイトカイン/ケモカイン/細胞増殖因子の役割について概説する.(著者抄録)
• MPO-ANCA関連血管炎におけるNETs-ANCA悪循環

  志田 玄貴, 八反田 文彦, 三次 有奈, 楠 由宏, 中沢 大悟, 佐藤 遥, 橋本 展洋, 林 晃正, 益田 紗季子, 石津 明洋, 外丸 詩野 北海道医学雑誌 91 (2) 85 -86 2016年11月 [査読無し][通常論文]
  
• 血管炎の診断と治療の未来像 皮膚科領域でみる血管炎の病理組織像からのアプローチ

  石津 明洋 Journal of Environmental Dermatology and Cutaneous Allergology 10 (4) 321 -321 2016年10月 [査読無し][通常論文]
  
• 皮膚動脈炎(皮膚型結節性多発動脈炎)難治症例における血中マーカーの検討

  岡野 達郎, 竹内 そら, 相馬 良直, 鈴木 浩也, 月田 早智子, 石津 明洋, 鈴木 和男, 川上 民裕 Journal of Environmental Dermatology and Cutaneous Allergology 10 (4) 463 -463 2016年10月 [査読無し][通常論文]
  
• プロテアソームとCD8+ T細胞レパトアの形成

  外丸 詩野, 石津 明洋, 宮島 祥太, 木内 静香, 笠原 正典 MHC: Major Histocompatibility Complex 23 (2Suppl.) 95 -95 2016年10月 [査読無し][通常論文]
  
• 【ANCA関連血管炎-最近の話題-】 好中球細胞外トラップ

  益田 紗季子, 石津 明洋 アレルギーの臨床 36 (5) 419 -423 2016年05月 [査読無し][通常論文]
   

  ANCA関連血管炎において、ANCAは主要な病原因子である。このANCAの産生およびANCAを介した血管障害メカニズムに、好中球細胞外トラップ(Neutrophil Extracellular Traps:NETs)が関与することが明らかとなってきた。感染刺激を受けた好中球は活性化され、NETsを放出して細胞死に至る。NETsは対感染防御において不可欠であるものの、その制御異常はANCAの産生原因となる。また、産生されたANCAにはNETs誘導活性があり、NETsには血管障害活性がある。NETsはANCA関連血管炎の病因ならびに病態形成に重要な役割を果たしている。(著者抄録)
• 血管炎新分類(CHCC2012)と皮膚血管炎の位置づけ病理医の視線で

  石津 明洋 日本皮膚科学会雑誌 126 (5) 811 -811 2016年05月 [査読無し][通常論文]
  
• ANCA関連血管炎の臨床病理学的特徴と好中球細胞外トラップNETs

  石津 明洋 日本病理学会会誌 105 (1) 251 -251 2016年04月 [査読無し][通常論文]
  
• 自己血管内皮細胞反応性小型血管炎惹起性type II NKT細胞が認識する分子の同定

  西岡 佑介, 山口 まどか, 川上 愛, 宗廣 真矢, 山田 真衣, 益田 紗季子, 外丸 詩野, 石津 明洋 日本病理学会会誌 105 (1) 353 -353 2016年04月 [査読無し][通常論文]
  
• CD8+ T細胞の胸腺選択にプロテアソームβ5サブユニットが与える影響

  宮島 祥太, 外丸 詩野, 石津 明洋, 木内 静香, 笠原 正典 日本病理学会会誌 105 (1) 375 -375 2016年04月 [査読無し][通常論文]
  
• 巨大結腸症および左横隔膜弛緩症の増悪により死亡した剖検例の肺病変

  岩崎 沙理, 桑原 健, 岡本 賢三, 齋藤 拓志, 西浦 洋一, 中村 友彦, 清水 亜衣, 池田 仁, 石津 明洋, 鈴木 昭 日本病理学会会誌 105 (1) 390 -390 2016年04月 [査読無し][通常論文]
  
• 抗糸球体基底膜抗体腎炎の病理組織学的検討(Pathological analysis of anti-GBM glomerulonephritis)

  小川 弥生, 高木 芳武, 石津 明洋, 近藤 信夫 日本病理学会会誌 105 (1) 434 -434 2016年04月 [査読無し][通常論文]
  
• 胸腺上皮性腫瘍におけるカテプシンV及びカテプシンSの発現

  木内 静香, 外丸 詩野, 石津 明洋, 大塚 紀幸, 今川 誠, 岩崎 沙理, 鈴木 昭, 丸川 活司, 松野 吉宏, 笠原 正典 日本病理学会会誌 105 (1) 471 -471 2016年04月 [査読無し][通常論文]
  
• 非小細胞肺癌における免疫プロテアソームサブユニットβ5iの発現

  木内 隆之, 外丸 詩野, 石津 明洋, 今川 誠, 岩崎 沙理, 鈴木 昭, 松野 吉宏, 笠原 正典 日本病理学会会誌 105 (1) 534 -534 2016年04月 [査読無し][通常論文]
  
• 肺移植施行後に日和見感染症により死亡に至った肺ランゲルハンス細胞組織球症の一例

  四宮 万里絵, 松林 里佳, 外丸 詩野, 木内 隆之, 大塚 紀幸, 石津 明洋, 笠原 正典 日本病理学会会誌 105 (1) 585 -585 2016年04月 [査読無し][通常論文]
  
• 膵臓EUS-FNA迅速細胞診で乳癌転移と診断し得た一例

  志田 啓, 川田 将也, 石津 明洋, 西海 豊寛, 大森 優子, 菅原 亨, 大坂 育美, 平野 勇志, 小山田 ゆみ子, 武田 広子 日本臨床細胞学会雑誌 55 (Suppl.1) 197 -197 2016年04月 [査読無し][通常論文]
  
• 【自己抗体産生機序の新展開】 抗好中球細胞質抗体と好中球細胞外トラップ

  石津 明洋 医学のあゆみ 256 (12) 1209 -1213 2016年03月 [査読無し][通常論文]
   

  抗好中球細胞質抗体(ANCA)は、ミエロペルオキシダーゼやプロテナーゼ3などの好中球細胞質抗原に対する自己抗体であり、ANCA関連血管炎における病原性の主体である。近年の研究により、その産生メカニズムに好中球細胞外トラップ(NETs)の関与があることが明らかとなってきた。感染刺激を受けた好中球は活性化され、やがて細胞死に至る。その際、好中球はDNAと細胞質内蛋白を混合し、NETsとよばれる網状構造物を細胞外に放出する。NETsは感染防御において重要な役割を果たしているものの、細胞内抗原を細胞外に曝露している状態でもあり、適切に処理されなければ、免疫系に認識され、自己抗体の産生が誘導されうる。本稿では、NETsを介したANCAの産生機序について解説する。(著者抄録)
• 血管炎 抗ラクトフェリン抗体は好酸球性多発血管炎性肉芽腫症において好中球細胞外トラップの形成を促進し、疾患活動性に関与する

  志田 玄貴, 中沢 大悟, 八反田 文彦, 楠 由宏, 益田 紗季子, 外丸 詩野, 川上 民裕, 渥美 達也, 石津 明洋 日本リウマチ学会総会・学術集会プログラム・抄録集 60回 479 -479 2016年03月 [査読無し][通常論文]
  
• 血管炎 Peptigylarginine deiminase 4阻害薬は好中球細胞外トラップの形成阻害を介してMPO-ANCA産生を抑制する

  楠 由宏, 中沢 大悟, 志田 玄貴, 八反田 文彦, 益田 紗季子, 外丸 詩野, 西尾 妙織, 渥美 達也, 石津 明洋 日本リウマチ学会総会・学術集会プログラム・抄録集 60回 479 -479 2016年03月 [査読無し][通常論文]
  
• 血管炎 皮膚動脈炎から結節性多発動脈炎への移行と血中抗モエシン抗体との関連

  川上 民裕, 石津 明洋 日本リウマチ学会総会・学術集会プログラム・抄録集 60回 479 -479 2016年03月 [査読無し][通常論文]
  
• 前向きコホート研究RemIT-JAV-RPGNにおける抗好中球細胞質抗体(ANCA)関連血管炎の寛解に関する検討

  佐田 憲映, 針谷 正祥, 臼井 丈一, 山縣 邦弘, 本間 栄, 土橋 浩章, 石津 明洋, 杉山 斉, 岡田 保典, 有村 義宏, 槇野 博史 日本リウマチ学会総会・学術集会プログラム・抄録集 60回 532 -532 2016年03月 [査読無し][通常論文]
  
• 自己免疫と自己炎症の接点 NETosisとマクロファージの相互作用

  石津 明洋 日本小児科学会雑誌 120 (2) 200 -200 2016年02月 [査読無し][通常論文]
  
• 血管病研究の最新知見 抗モエシン抗体と皮膚動脈炎との関与 全身性結節性多発動脈炎へ移行が想定される症例に関して

  岡野 達郎, 竹内 そら, 相馬 良直, 鈴木 和男, 鈴木 浩也, 月田 早智子, 石津 明洋, 川上 民裕 脈管学 56 (1) 13 -14 2016年02月 [査読無し][通常論文]
  
• Wegener肉芽腫症(GPA)とNecrotizing sarcoid granulomatosis(NSG)との鑑別に苦慮した一例

  岩崎 沙理, 岡本 賢三, 小島 哲弥, 藤田 裕美, 清水 亜衣, 鈴木 昭, 石津 明洋 脈管学 56 (1) 18 -18 2016年02月 [査読無し][通常論文]
  
• 標本レビュー:Cogan症候群の大動脈病変

  石津 明洋 脈管学 56 (1) 19 -19 2016年02月 [査読無し][通常論文]
  
• 医学用語解説 好中球細胞外トラップ(NETs)

  石津 明洋 炎症と免疫 24 (2) 163 -165 2016年02月 [査読無し][通常論文]
  
• 【NETsの臨床における意義】 NETsと血管炎

  石津 明洋 日本血栓止血学会誌 27 (1) 42 -48 2016年02月 [査読無し][通常論文]
   

  感染刺激を受けた好中球は活性化され,やがて細胞死に至る.その際,好中球はDNAと細胞質内タンパクを混合し,これを細胞外に網状に放出する.これが好中球細胞外トラップ(neutrophil extracellular traps:NETs)である.NETsは感染防御において重要な役割を果たしているものの,細胞外に放出されたミエロペルオキシダーゼ(myeloperoxidase:MPO)などの細胞質内タンパクは自身を障害する恐れもあるため,生体内におけるNETsの形成は厳密に制御されている.しかしながら,何らかの原因でNETsが適切に除去されない状況では,MPOに対するトレランスの破綻が誘導され,血管炎惹起性自己抗体であるMPO-ANCAが産生される.また,産生されたMPO-ANCAにはNETs誘導活性があるため,MPO-ANCA関連血管炎ではNETsとANCAを介した悪循環が形成されている.NETsはANCA関連血管炎の病因ならびに病態形成に重要な役割を果たしている.(著者抄録)
• 【ANCA関連血管炎(AAV)】 MPO-ANCAによる血管傷害のメカニズム

  志田 玄貴, 石津 明洋 リウマチ科 54 (6) 581 -585 2015年12月 [査読無し][通常論文]
  
• 【膠原病研究 アップデート】 血管炎症候群

  石津 明洋 アレルギー・免疫 22 (12) 1740 -1747 2015年11月 [査読無し][通常論文]
   

  血管炎症候群の国際分類であるCHCC2012分類では、26疾患が「大型血管炎」「中型血管炎」「小型血管炎」など7つのカテゴリーに分類されている。ここでは、近年の研究によって病因・病態の理解が大きく進んだ高安動脈炎、ANCA関連血管炎、抗GBM病を取り上げる。高安動脈炎では、疾患感受性に関わるIL12B遺伝子領域の遺伝子多型が同定された。ANCA関連血管炎では、ANCAの病原性や産生メカニズム、新たな対応抗原に関する研究が進展している。抗GBM病では、抗GBM抗体のエピトープが明らかにされた。(著者抄録)
• 腹水にみられたGoblet cell carcinoidの一例

  小山内 翔祐, 堀井 恒哉, 石川 麻美, 勘野 真紀, 鈴木 昭, 石津 明洋 北海道臨床細胞学会会報 24 57 -60 2015年10月 [査読無し][通常論文]
   

  Goblet cell carcinoid(以下GCC)は虫垂に好発する比較的稀な腫瘍である.今回我々は,腹水中にGCCの細胞が出現した症例を経験したので,その細胞像を中心に報告する.症例は30歳代女性.帝王切開後の腹部痛を主訴に近医を受診し,腹水を指摘され精査目的に当院紹介となった.試験開腹術が施行され開腹時腹水の細胞診では,リンパ球,マクロファージを背景に,核小体の腫大する核偏在性の異型細胞を孤立散在性に多数認め,印環型の腫瘍細胞も多く見られた.また,わずかながらロゼット様の構造を示す細胞配列を認め,Chromogranin AとPASの重染色では同一の細胞に神経内分泌顆粒と粘液の存在が確認された.術中の所見として,腹腔内播種が高度であり広範囲に癒着を認めたため,腫瘍減量手術も困難と判断され大網の硬結部の一部を摘出し閉腹している.組織像は,細胞診同様に偏在性の異型核を有する腫瘍細胞が個細胞性に浸潤・増殖しており,印環型の腫瘍細胞も多く認められた.免疫組織化学染色によりGCCと診断され,原発としては虫垂が推定された.GCCは細胞像において通常の腺癌との鑑別を要するが,ロゼット様の構造を呈する細胞配列に着目し,免疫染色を併用して診断することが有用と考える.(著者抄録)
• 気管支鏡下細胞診で非上皮系悪性腫瘍を推定した肺癌肉腫の1例

  佐藤 穣, 大坂 峰司, 伊丹 弘恵, 石津 明洋 日本臨床細胞学会雑誌 54 (Suppl.2) 576 -576 2015年10月 [査読無し][通常論文]
  
• 【腎と免疫】 ANCA関連腎炎

  中沢 大悟, 石津 明洋 腎と透析 78 (5) 727 -732 2015年05月 [査読無し][通常論文]
  
• MPO-ANCA関連血管炎に対するPAD4阻害薬の効果

  楠 由宏, 中沢 大悟, 三次 有奈, 志田 玄貴, 外丸 詩野, 西尾 妙織, 渥美 達也, 石津 明洋 日本腎臓学会誌 57 (3) 507 -507 2015年04月 [査読無し][通常論文]
  
• 高血糖による好中球細胞外トラップ(neutrophil extracellular traps:NETs)の形成亢進

  三次 有奈, 山田 真衣, 舘山 ゆう, 楠 由宏, 志田 玄貴, 中沢 大悟, 中村 昭伸, 外丸 詩野, 三好 秀明, 渥美 達也, 石津 明洋 糖尿病 58 (Suppl.1) S -392 2015年04月 [査読無し][通常論文]
  
• その他のアレルギー疾患・免疫疾患 リウマトイド血管炎患者とモデルラットで認めた血中抗ホスファチジルセリン・プロトロンビン複合体抗体上昇

  川上 民裕, 竹内 そら, 相馬 良直, 川上 愛, 外丸 詩野, 石津 明洋 アレルギー 64 (3-4) 490 -490 2015年04月 [査読無し][通常論文]
  
• 悪性腹膜中皮腫との鑑別に苦慮したatypical mesothelial proliferationの1例

  石川 麻美, 堀井 恒哉, 小山内 翔祐, 勘野 真紀, 大塚 紀幸, 外丸 詩野, 石津 明洋, 高木 芳武 日本臨床細胞学会雑誌 54 (Suppl.1) 279 -279 2015年04月 [査読無し][通常論文]
  
• ANCA関連血管炎と好中球細胞外トラップ(neutrophil extracellular traps:NETs)を正しく理解する 抗好中球細胞質抗体(ANCA) 好中球細胞外トラップ(NETs)の悪循環

  中沢 大悟, 楠 由宏, 志田 玄貴, 西尾 妙織, 外丸 詩野, 渥美 達也, 石津 明洋 脈管学 55 (2) 35 -35 2015年03月 [査読無し][通常論文]
  
• リウマトイド血管炎を発症した患者とモデルラットでは血中抗ホスファチジルセリン・プロトロンビン複合体抗体が上昇している

  川上 民裕, 竹内 そら, 相馬 良直, 川上 愛, 外丸 詩野, 石津 明洋 脈管学 55 (2) 40 -40 2015年03月 [査読無し][通常論文]
  
• リウマチ性多発筋痛症や多発性筋炎との鑑別を要した壊死性血管炎の1例

  岩崎 沙理, 高瀬 崇宏, 竿尾 光祐, 鈴木 昭, 石津 明洋 脈管学 55 (2) 41 -41 2015年03月 [査読無し][通常論文]
  
• ANCA関連血管炎のUpdate MPO-ANCA関連血管炎におけるNETs-ANCA悪循環

  石津 明洋 日本リウマチ学会総会・学術集会プログラム・抄録集 59回 223 -223 2015年03月 [査読無し][通常論文]
  
• 血管炎 動物モデル全身に血栓形成を誘導させる新規抗リン脂質抗体の作成に成功した

  川上 民裕, 志田 玄貴, 中沢 大悟, 外丸 詩野, 石津 明洋 日本リウマチ学会総会・学術集会プログラム・抄録集 59回 351 -351 2015年03月 [査読無し][通常論文]
  
• 血管炎 抗ラクトフェリン抗体の病原性

  志田 玄貴, 中沢 大悟, 外丸 詩野, 川上 民裕, 渥美 達也, 石津 明洋 日本リウマチ学会総会・学術集会プログラム・抄録集 59回 351 -351 2015年03月 [査読無し][通常論文]
  
• 胸腺T細胞選択におけるプロテアソームキモトリプシン様活性サブユニットの役割

  宮島 祥太, 外丸 詩野, 石津 明洋, 木内 静香, 大井 智貴, 笠原 正典 日本病理学会会誌 104 (1) 284 -284 2015年03月 [査読無し][通常論文]
  
• プロテアソーム機能低下マウスにおける記銘力障害の解析

  伊藤 智樹, 外丸 詩野, 大村 優, 戸松 留花, 石津 明洋, 笠原 正典 日本病理学会会誌 104 (1) 322 -322 2015年03月 [査読無し][通常論文]
  
• 高血糖による好中球細胞外トラップ(neutrophil extracellular traps:NETs)の形成亢進

  三次 有奈, 山田 真衣, 舘山 ゆう, 楠 由宏, 志田 玄貴, 中沢 大悟, 外丸 詩野, 三好 秀明, 渥美 達也, 石津 明洋 日本病理学会会誌 104 (1) 379 -379 2015年03月 [査読無し][通常論文]
  
• 気胸を反復し肺部分切除を契機に診断に至ったBHD症候群の一例

  岩崎 沙理, 古屋 充子, 桑原 博昭, 大槻 雄士, 石津 明洋, 桑原 健, 鈴木 昭 日本病理学会会誌 104 (1) 407 -407 2015年03月 [査読無し][通常論文]
  
• ダウン症患者の胸腺におけるプロテアソームサブユニットβ5tの発現低下

  木内 静香, 外丸 詩野, 辻 隆裕, 石津 明洋, 鈴木 昭, 大塚 紀幸, 伊藤 智樹, 池田 仁, 深澤 雄一郎, 笠原 正典 日本病理学会会誌 104 (1) 460 -460 2015年03月 [査読無し][通常論文]
  
• 壁在結節を伴う卵巣粘液産生腺癌の3例

  河内 麻里亜, 横山 達也, 大塚 紀幸, 藤本 俊郎, 池田 仁, 高木 芳武, 石津 明洋, 外丸 詩野, 笠原 正典 日本病理学会会誌 104 (1) 522 -522 2015年03月 [査読無し][通常論文]
  
• TypeB胸腺腫、胸腺癌におけるカテプシンの発現

  安部 樹太朗, 有賀 茜, 外丸 詩野, 木内 静香, 石津 明洋, 大塚 紀幸, 清水 知浩, 丸川 活司, 松野 吉宏, 笠原 正典 日本病理学会会誌 104 (1) 528 -528 2015年03月 [査読無し][通常論文]
  
• P3-006 フルバスタチンはHLA classIIによるβ-2グリコプロテインIの抗原提示を抑制する

  渡邊 俊之, 堀田 哲也, 保田 晋助, 石津 明洋, 荒瀬 尚, 渥美 達也, 奥 健志, アメングアル オルガ, 久田 諒, 大村 一将, 志田 玄貴, 清水 裕香, 加藤 将, 坊垣 暁之 日本臨床免疫学会会誌 38 (4) 326b -326b 2015年 [査読無し][通常論文]
   

  【背景】HLA-DRB1*07:01は抗リン脂質抗体症候群（APS）の疾患感受性遺伝子である．近年，我々はβ2-グリコプロテインI（β2GPI）／HLA class II複合体が抗β2GPI抗体の対応抗原であることを報告した．スタチン製剤はいくつかのAPSモデルで抗β2GPI抗体による向血栓細胞活性化を抑制し，血栓症抑制効果が期待されていたが，その機序は不明である．【目的】抗β2GPI抗体による血栓傾向に対するスタチン製剤の抑制的作用機序を解明する．【方法】不死化ヒト臍帯静脈血管内皮細胞（HUEhT-1）とヒト単球系細胞（THP-1）にβ2GPIとHLA-DRA*01:01/DRB1*07:01（HLA-DR7）の遺伝子を導入した後，フルバスタチンを添加し，細胞表面のHLA-DRとβ2GPIの発現およびヒトモノクローナル抗β2GPI依存性抗カルジオリピン抗体（EY2C9）の結合能を解析した．APS自然発症ラットであるenv-pXラットにフルバスタチンを投与し，β2GPI依存性抗カルジオリピン抗体（aCL）を測定した．【結果】HUEhT-1とTHP-1の両細胞表面において，β2GPIの発現およびEY2C9の結合はHLA-DR7発現細胞で亢進していた．フルバスタチンの添加により，HLA-DRとβ2GPIの細胞表面への発現およびEY2C9の結合は抑制され，メバロン酸によりフルバスタチンの作用は拮抗された．またフルバスタチン投与によりenv-pXラットのaCLは有意に低下した．【結語】スタチン製剤はHLA class IIの発現低下を介した自己抗原提示の抑制効果を示すため，APSへの治療効果が予想される．
• Lung cancer cells after irradiation indicate viability and malignancy dependent on activating transcription factor 5.

  S. Ishihara, M. Yasuda, A. Ishizu, H. Haga MOLECULAR BIOLOGY OF THE CELL 25 2014年12月 [査読無し][通常論文]
  
• BEP療法中にアメーバ性大腸炎・肝膿瘍をきたした1例

  杉下 圭治, 毛利 学, 竹内 一郎, 石津 明洋 泌尿器外科 27 (12) 1979 -1979 2014年12月 [査読無し][通常論文]
  
• Churg-Strauss症候群による多発小腸穿孔により死亡した症例

  石津 明洋, 外丸 詩野, 江辺 広志, 浄土 智, 藤咲 淳 脈管学 54 (12) 208 -208 2014年12月 [査読無し][通常論文]
  
• 半月体性糸球体腎炎に加え多臓器で肉芽腫性血管炎を呈したMPO-ANCA関連血管炎の一剖検例

  岩崎 沙理, 藤澤 孝志, 鈴木 昭, 石津 明洋 脈管学 54 (12) 215 -215 2014年12月 [査読無し][通常論文]
  
• MPO-ANCA関連血管炎患者におけるneutrophil extracelular traps(NETs)の制御異常

  中沢 大悟, 志田 玄貴, 西尾 妙織, 渥美 達也, 吉田 雅治, 外丸 詩野, 石津 明洋 脈管学 54 (12) 221 -221 2014年12月 [査読無し][通常論文]
  
• 好中球細胞外トラップの異常とMPO-ANCA関連血管炎

  石津 明洋 日本小児腎臓病学会雑誌 27 (2) 81 -85 2014年11月 [査読無し][通常論文]
   

  MPO-ANCA関連血管炎(MPO-AAV)は、myeloperoxidase(MPO)を抗原とする抗好中球細胞質抗体(ANCA)の出現とともに、糸球体をはじめとする小型血管が侵される壊死性血管炎である。MPO-ANCA自体の病原性が確認されているが、その産生機序は不明であった。我々は好中球細胞外トラップneutrophil extracellular traps(NETs)の異常がMPO-ANCA産生の原因となることを報告した。活性化された好中球はNETsを形成する。NETsは重要な生体防御システムであるが、適切に処理されなければ、DNAとともに細胞外に放出されたMPOが自己抗原となり、MPO-ANCA産生が誘導される。一方、MPO-ANCAにはNETs誘導活性があるなど、MPO-AAV患者ではNETsの過剰に陥りやすい状況があり、NETsとMPO-ANCA介した悪循環が病態を形成している。(著者抄録)
• Scheele法による膀胱拡大術50年後に利用回腸に発生した腺癌の一例

  杉下 圭治, 毛利 学, 西村 陽子, 竹内 一郎, 石津 明洋, 篠原 信雄 日本泌尿器科学会雑誌 105 (4) 207 -211 2014年10月01日 [査読無し][通常論文]
   

  70歳女性。50年前に結核性萎縮膀胱に対してScheele法による回腸利用膀胱拡大術を受けた。肉眼的血尿を主訴に受診し、CTおよび膀胱鏡で膀胱回腸吻合部の回腸側に隆起性腫瘍を認めた。生検では悪性所見を認めなかったが、経過観察中に腫瘍増大傾向あり膀胱部分切除術を施行。病理組織は腺癌であった。術後再発による水腎症、イレウスを発症し、術後8ヵ月で死去。膀胱拡大術後の悪性腫瘍は本邦では自験例を含め43例の報告があり、拡大術後癌発症までは平均33年と長期である。自験例は術後50年後の発症で43例中最長であった。(著者抄録)
• 【臨床医のための血管炎の知識 up-to-date】 《血管炎の最近のトピックス》 血管炎の新たなバイオマーカー

  石津 明洋 Modern Physician 34 (9) 1075 -1079 2014年09月 [査読無し][通常論文]
   

  ＜ポイント＞ANCAの新たな対応抗原として、LAMP-2とモエシンが注目されている。MPO-ANCA関連血管炎の新たなバイオマーカー候補として、アポリポ蛋白質A-I(ApoAI)のC末端13アミノ酸残基(AC13)が同定された。MPO-ANCA関連血管炎の治療アウトカムを治療後の早期に予測する末梢血遺伝子16個が抽出された。MPO-ANCAの産生原因としてNETsの異常が確認され、血清中のNETs(DNA-MPO複合体)がANCA関連血管炎の新たなバイオマーカーとなる可能性がある。大型血管炎の新たなバイオマーカーとして、血清中のPTX3と抗Prx2抗体の有用性が報告されている。(著者抄録)
• 免疫と内科疾患 その病態と治療最前線 抗好中球細胞質抗体(ANCA)関連血管炎の病態と治療の最前線

  山村 昌弘, 佐田 憲映, 針谷 正祥, 藤井 隆夫, 石津 明洋, 有村 義宏, 槇野 博史 日本内科学会雑誌 103 (9) 2121 -2129 2014年09月 [査読無し][通常論文]
  
• 鑑別に苦慮した胸腺腫瘍の1例

  桑原 健, 岩崎 沙理, 桑原 博昭, 外丸 詩野, 笠原 正典, 石津 明洋, 松野 吉宏, 鈴木 昭 日本病理学会会誌 103 (2) 46 -46 2014年09月 [査読無し][通常論文]
  
• 術前診断にて胆管細胞癌との鑑別が困難であった肝孤立性壊死性結節の1手術例

  宮坂 大介, 山口 晃司, 山田 徹, 宮谷内 健吾, 松永 明宏, 新関 浩人, 須永 道明, 池田 淳一, 石津 明洋 日本消化器外科学会雑誌 47 (7) 395 -402 2014年07月 [査読無し][通常論文]
   

  肝孤立性壊死性結節は,中心壊死,硝子化線維性組織,弾性繊維を特徴とするまれな良性病変とされるが,術前診断困難で,発症機序も不明である.今回,胆管細胞癌などを疑ったが確診に至らず肝切除術を行い,肝孤立性壊死性結節と診断した1例を経験したので報告する.症例は64歳の男性で,他科でのCTで肝腫瘍影および肝胆道系酵素上昇を指摘され紹介となった.肝S4に3cm弱の境界不明瞭な腫瘍影を認め,超音波で等エコー,MRIでT1WI低信号,T2WI高信号,造影CT,MRI,超音波では早期濃染を認めず,辺縁部に弱い造影効果を示した.他臓器に悪性所見を認めず,胆管細胞癌などを疑い肝内側区域切除術を施行したところ,病変部は肝孤立性壊死性結節,背景肝は原発性胆汁性肝硬変と診断された.11年前に肝S4に7cm大の限局性結節性過形成もしくは炎症性偽腫瘍を疑う所見を指摘されていた経緯があり,あわせて報告する.(著者抄録)
• ENHANCED FORMATION AND DISORDERED REGULATION OF NETS IN MPO-ANCA-ASSOCIATED VASCULITIS

  Nakazawa Daigo, Shida Haruki, Tomaru Utano, Yoshida Masaharu, Nishio Saori, Atsumi Tatsuya, Ishizu Akihiro NEPHROLOGY 19 149 -150 2014年05月 [査読無し][通常論文]
  
• 顕微鏡的多発血管炎と血栓症はMPO-ANCAと好中球細胞外トラップを介して関連する

  今本 鉄平, 中沢 大悟, 志田 玄貴, 鈴木 昭, 大塚 紀幸, 外丸 詩野, 石津 明洋 北海道医学雑誌 89 (1) 91 -91 2014年05月 [査読無し][通常論文]
  
• 好中球細胞外トラップの異常とMPO-ANCA関連血管炎

  石津 明洋 日本小児腎臓病学会雑誌 27 (1Suppl.) 84 -84 2014年04月 [査読無し][通常論文]
  
• 【血管炎】 血管炎の発症機序とNETs

  中沢 大悟, 西尾 妙織, 外丸 詩野, 渥美 達也, 石津 明洋 日本腎臓学会誌 56 (2) 117 -123 2014年03月 [査読無し][通常論文]
   

  顕微鏡的多発血管炎(Microscopic polyangiitis:MPA)は、ミエロペルオキシダーゼ(myeloperoxidase:MPO)を対応抗原とする抗好中球細胞質抗体(anti-neutrophil cytoplasmic antibody:ANCA)陽性を特徴とし、腎臓、肺、神経を好発部位として全身の小型血管に炎症を起こす血管炎である。詳細な発症機序は不明であったが、近年、好中球の殺菌機構である好中球細胞外トラップ(neutrophil extracellular traps:NETs)がMPO-ANCAの産生や炎症の悪循環病態を招くことがわかってきた。NETsは好中球内の殺菌蛋白やDNAを細胞外に放出して微生物を捕捉・殺菌する強力な免疫機構であるが、NETsの制御異常はNETs成分に対する免疫寛容破綻の原因となり、MPO-ANCAの産生を誘導する。一方MPO-ANCAは、炎症性サイトカインによって活性化された好中球に作用し、血管炎の活動性に比例してNETsを誘導し、誘導されたNETsはさまざまな原因で分解・制御されにくい状態にある。それゆえ、NETsを制御することが本疾患に対する特異的な治療になる可能性がある。本稿では、NETsと本疾患との関連についての基礎研究ならびに臨床研究の最新の報告をまとめ、血管炎の新たな病態機序について考察する。(著者抄録)
• ANCA関連血管炎のアップデート ANCAによる血管傷害機序

  石津 明洋 日本リウマチ学会総会・学術集会プログラム・抄録集 58回 219 -219 2014年03月 [査読無し][通常論文]
  
• 胸腺におけるプロテアソームキモトリプシン様活性サブユニットの発現とT細胞選択

  木内 静香, 外丸 詩野, 紺野 沙織, 石津 明洋, 宮島 祥太, 平川 彩香, 笠原 正典 日本病理学会会誌 103 (1) 247 -247 2014年03月 [査読無し][通常論文]
  
• プロテアソーム機能異常と脳機能の低下

  伊藤 智樹, 外丸 詩乃, 大村 優, 石津 明洋, 笠原 正典 日本病理学会会誌 103 (1) 400 -400 2014年03月 [査読無し][通常論文]
  
• 高齢男性でみられたEBV陽性肝脾γδT細胞リンパ腫の一例

  竹中 淳規, 大塚 紀幸, 藤田 裕美, 中馬 誠, 外丸 詩野, 石津 明洋, 笠原 正典 日本病理学会会誌 103 (1) 407 -407 2014年03月 [査読無し][通常論文]
  
• 腹壁への直接浸潤を来たしたG-CSF産生膀胱癌の一例

  杉下 圭治, 西村 陽子, 毛利 学, 竹内 一郎, 石津 明洋 泌尿器外科 27 (2) 249 -249 2014年02月 [査読無し][通常論文]
  
• 痙攣発作を呈した異所性灰白質の1成人例 病理学的考察

  濱田 晋輔, 相馬 広幸, 本間 早苗, 濱田 啓子, 武井 麻子, 森若 文雄, 田代 邦雄, 石津 明洋 臨床神経学 54 (1) 91 -91 2014年01月 [査読無し][通常論文]
  
• 血管炎症候群の新しい考え方(第7回) 血管炎の新たな発症機構 「好中球の網」NETs

  中沢 大悟, 志田 玄貴, 西尾 妙織, 渥美 達也, 吉田 雅治, 外丸 詩野, 石津 明洋 分子リウマチ治療 7 (1) 34 -38 2014年01月 [査読無し][通常論文]
   

  好中球の殺菌機構であるneutrophil extracellular traps(NETs)がさまざまな自己免疫疾患と関連することが指摘されるようになったが、そのなかでもとくに抗好中球細胞質抗体(ANCA)産生を特徴とする顕微鏡的多発血管炎(MPA)が密接な関係にある。NETsは、殺菌蛋白やDNAを細胞外に放出して微生物を捕捉・殺菌する強力な免疫機構であるが、ANCAは、感染微生物がなくとも好中球に作用してNETsを誘導する。このNETs誘導活性は、血管炎の活動性に比例し、また誘導されたNETsは、本疾患患者ではさまざまな原因で制御されない背景にある。すなわち、ANCAはNETsを誘導して血管炎を引き起こし、そのNETsはANCAの対応抗原を含んだまま制御不能で存続するというNETsとANCAを介した悪循環が、MPAの病態を形成している。(著者抄録)
• von Recklinghausen病による動脈破裂の病理組織学的検討

  木内 隆之, 外丸 詩野, 高田 明生, 石津 明洋 脈管学 53 (December) 222 -223 2013年12月 [査読無し][通常論文]
  
• Pulmonary veno-occlusive disease(PVOD)の一剖検例

  山田 洋介, 大塚 紀幸, 大平 洋, 辻野 一三, 深谷 進司, 外丸 詩野, 石津 明洋 脈管学 53 (December) 242 -243 2013年12月 [査読無し][通常論文]
  
• 自己抗体研究の新たな展開(第7回) 血管炎症候群 抗好中球細胞質抗体

  石津 明洋 分子リウマチ治療 6 (4) 209 -213 2013年10月 [査読無し][通常論文]
   

  抗好中球細胞質抗体(ANCA)には、cytoplasmic ANCA(C-ANCA);proteinase 3-ANCA(PR3-ANCA)と、perinuclear ANCA(P-ANCA);myeloperoxidase-ANCA(MPO-ANCA)がある。PR3-ANCAは多発血管炎性肉芽腫症(Wegener肉芽腫症)で陽性となり、MPO-ANCAは顕微鏡的多発血管炎や好酸球性多発血管炎性肉芽腫症(Churg-Strauss症候群)で陽性となる。MPO-ANCAの病原性は抗原エピトープに依存すると考えられるが、エピトープとの結合を阻害する血清因子の存在も報告されている。MPO-ANCAの産生には、好中球細胞外トラップ(NETs)が関与している可能性がある。グラム陰性菌のFimHと分子相同性を有するlysosomal membrane protein-2やMPOと分子相同性を有するmoesinなどの新規抗原に対するANCAと血管炎との関連も注目されている。(著者抄録)
• 脳死肺移植を施行した重症の肺高血圧を伴う肺ランゲルハンス細胞組織球症の一例

  吉田 貴之, 今野 哲, 辻野 一三, 佐藤 隆博, 大平 洋, 長井 桂, 谷野 美智枝, 羽賀 博典, 石津 明洋, 陳 豊史, 伊達 洋至, 西村 正治 日本サルコイドーシス/肉芽腫性疾患学会雑誌 33 (サプリメント号) 52 -52 2013年10月 [査読無し][通常論文]
  
• MPO-ANCAのaffinityとNETs誘導率はMPO-ANCA関連血管炎の疾患活動性を反映する

  中沢 大悟, 石川 康暢, 柴崎 跡也, 西尾 妙織, 渥美 達也, 外丸 詩野, 吉田 雅治, 石津 明洋 北海道医学雑誌 88 (4-5) 160 -160 2013年09月 [査読無し][通常論文]
  
• 急性腹症を契機に発見された回盲部腸間膜原発solitary fibrous tumorの1例

  京極 典憲, 岩井 和浩, 佐藤 暢人, 飯村 泰昭, 狭間 一明, 石津 明洋 日本臨床外科学会雑誌 74 (8) 2194 -2199 2013年08月 [査読無し][通常論文]
   

  症例は33歳,男性.急激な下腹部痛を主訴に救急搬送され,下腹部全体に腫瘤を触知した.腹部CT検査では20cm大の造影効果に乏しい巨大な腫瘤,およびfree airを認めたため緊急手術を施行した.術中所見では腫瘤は回盲部腸間膜を主座とし,回腸に浸潤していたため回盲部切除術を施行した.病理組織学検査では腫瘍は長紡錘形細胞がpatternless patternを呈しつつ増殖していた.免疫染色ではCD34(+),c-kit(-),desmin(-),S-100(-)でありsolitary fibrous tumor(SFT)と診断された.腫瘍は回腸に穿通しており同部から穿孔したものと考えられた.SFTは成人に発生するまれな繊維性腫瘍であり,全身の様々な部位で発生するとされている.本症例のように急性腹症を呈した報告はなく,貴重な症例と考え若干の文献的考察を加え報告する.(著者抄録)
• 上行結腸壊死の診断に超音波検査が有用であったアメーバ性大腸炎の1例

  高瀬 亜希, 佐藤 真美, 石津 明洋, 木下 静江, 松浦 宏樹, 佐藤 祐輔, 武藤 修一 超音波検査技術 38 (3) 304 -304 2013年06月 [査読無し][通常論文]
  
• 潰瘍性大腸炎における末梢血および大腸粘膜固有層NKG2A+ T細胞の減少

  桂田 武彦, 小林 和夏, 外丸 詩野, 馬場 智久, 古川 滋, 石津 明洋, 竹田 和由, 坂本 直哉, 浅香 正博, 武田 宏司, 笠原 正典 北海道醫學雜誌 = Acta medica Hokkaidonensia 88 (2) 104 -104 2013年04月01日
• Abundant neutrophil extracellular traps in thrombus of patient with microscopic polyangiitis

  D. Nakazawa, U. Tomaru, S. Jodo, S. Nishio, T. Atsumi, A. Ishizu PRESSE MEDICALE 42 (4) 755 -755 2013年04月 [査読無し][通常論文]
  
• Prediction of outcome of treatment by gene expression profiling of peripheral blood in patients with microscopic polyangiitis

  A. Ishizu, U. Tomaru, T. Murai, T. Yamamoto, T. Atsumi, T. Yoshiki, H. Makino, S. Ozaki PRESSE MEDICALE 42 (4) 733 -733 2013年04月 [査読無し][通常論文]
  
• 血管炎症候群の新しい考え方(第4回) 血管炎の予後は予測できるか 予測因子検索の道

  石津 明洋, 外丸 詩野, 村井 太一, 山本 智宏, 吉木 敬 分子リウマチ治療 6 (2) 82 -86 2013年04月 [査読無し][通常論文]
   

  JMAAV試験では、MPO-ANCA関連血管炎の重症度別治療プロトコールの有用性が検討された。その結果、策定したプロトコールにもとづいて治療をおこなった場合、89.4%という高い確率で寛解が得られることが示された。一方、約20%の症例が再燃し、研究期間中の死亡率は約10%であった。われわれは、MPO-ANCA関連血管炎のさらなる予後改善を目的として、JMAAV試験に登録された症例の治療前および治療開始1週間後の末梢血について網羅的遺伝子発現解析(トランスクリプトーム解析)をおこなった。治療後に寛解し、その後も寛解が維持された症例において、88個の遺伝子が治療前後で統計学的に有意な発現変化を示した。このうち、治療後に発現が低下した遺伝子は66個、治療後に発現が上昇した遺伝子は22個であった。これらのなかから、MPO-ANCA関連血管炎の治療反応性を治療開始後の早期に予測する16個の遺伝子を抽出した。(著者抄録)
• 炎症・免疫機構の新基軸と疾病の病理 好中球細胞外トラップ(NETs)の異常とMPO-ANCA関連血管炎の発症

  中沢 大悟, 外丸 詩野, 西尾 妙織, 渥美 達也, 笠原 正典, 石津 明洋 日本病理学会会誌 102 (1) 185 -185 2013年04月 [査読無し][通常論文]
  
• 血管炎の発症メカニズム 自己血管内皮細胞反応性NKT細胞による血管炎発症モデル

  川上 愛, 飯沼 千景, 脇 雅, 山口 まどか, 外丸 詩野, 笠原 正典, 吉木 敬, 石津 明洋 日本病理学会会誌 102 (1) 198 -198 2013年04月 [査読無し][通常論文]
  
• プロテアソームの発現異常における免疫応答の変化

  紺野 沙織, 外丸 詩野, 岸本 栞奈, 石津 明洋, 笠原 正典 日本病理学会会誌 102 (1) 330 -330 2013年04月 [査読無し][通常論文]
  
• 顕微鏡的多発血管炎と血栓症はMPO-ANCAと好中球細胞外トラップを介して関連する

  今本 鉄平, 中沢 大悟, 大塚 紀幸, 外丸 詩野, 笠原 正典, 石津 明洋 日本病理学会会誌 102 (1) 502 -502 2013年04月 [査読無し][通常論文]
  
• HELLP症候群に合併したhepatic ruptureの一剖検例

  山本 岳, 藤井 真理子, 大塚 紀幸, 光部 兼六郎, 櫻井 宏治, 外丸 詩野, 石津 明洋, 笠原 正典 日本病理学会会誌 102 (1) 502 -502 2013年04月 [査読無し][通常論文]
  
• リツキシマブ投与後に日和見感染症を併発した顕微鏡的多発血管炎の一剖検例

  味藤 静, 外丸 詩野, 大塚 紀幸, 石津 明洋, 笠原 正典 日本病理学会会誌 102 (1) 503 -503 2013年04月 [査読無し][通常論文]
  
• 血管炎 聖マリアンナ医科大学皮膚科で経験した皮膚型結節性多発動脈炎101例の集計

  川上 民裕, 石津 明洋, 有村 義宏, 小林 茂人, 尾崎 承一 日本リウマチ学会総会・学術集会・国際リウマチシンポジウムプログラム・抄録集 57回・22回 371 -371 2013年03月 [査読無し][通常論文]
  
• 血管炎 顕微鏡的多発血管炎(MPA)患者に合併した深部静脈血栓における過剰なNETs形成

  中沢 大悟, 外丸 詩野, 浄土 智, 渥美 達也, 石津 明洋 日本リウマチ学会総会・学術集会・国際リウマチシンポジウムプログラム・抄録集 57回・22回 434 -434 2013年03月 [査読無し][通常論文]
  
• 【血管炎-基礎と臨床のクロストーク-】 ANCA関連血管炎の病因・病理、診断・治療 ANCA関連血管炎(AAV)の基礎研究から臨床へのアプローチ ANCA関連血管炎の病因とそのバイオマーカー プロピルチオウラシルとNETsの異常形成・分解異常

  中沢 大悟, 外丸 詩野, 西尾 妙織, 渥美 達也, 石津 明洋 日本臨床 71 (増刊1 血管炎) 244 -249 2013年02月 [査読無し][通常論文]
  
• 【血管炎-基礎と臨床のクロストーク-】 最新の研究トピックス AP-VAS 2012から 血管炎の基礎研究 自己反応性NKT細胞と血管炎

  飯沼 千景, 脇 雅, 山口 まどか, 外丸 詩野, 石津 明洋 日本臨床 71 (増刊1 血管炎) 502 -505 2013年02月 [査読無し][通常論文]
  
• 大腸癌における造影超音波検査と再発予測について

  武藤 修一, 大西 俊介, 小西 康平, 江藤 和範, 宮本 秀一, 高橋 亜希, 福島 拓, 高橋 一宏, 石津 明洋, 武田 宏司 日本癌治療学会誌 47 (3) 2250 -2250 2012年10月 [査読無し][通常論文]
  
• 急性腹症にて発症した回盲部原発solitary fibrous tumorの1例

  京極 典憲, 岩井 和浩, 河合 典子, 溝田 知子, 細井 勇人, 佐藤 暢人, 狭間 一明, 渡邉 幹夫, 石津 明洋 日本臨床外科学会雑誌 73 (増刊) 848 -848 2012年10月 [査読無し][通常論文]
  
• 大腸癌における術前超音波検査結果とその後の予後の検討

  武藤 修一, 武田 宏司, 大西 俊介, 福島 拓, 高橋 一宏, 宮本 秀一, 石津 明洋, 浅香 正博 日本消化器病学会雑誌 109 (臨増大会) A822 -A822 2012年09月 [査読無し][通常論文]
  
• プロテアソームの機能低下は老化, 脂肪代謝の異常を引き起こす

  外丸 詩野, 高橋 里美, 石津 明洋, 宮武 由甲子, 合田 文, 鈴木 小百合, 小野 綾子, 小原 次郎, 馬場 智久, 村田 茂穂, 田中 啓二, 笠原 正典 北海道醫學雜誌 = Acta medica Hokkaidonensia 87 (4) 207 -207 2012年08月01日
• インフリキシマブで治療した再発腸管ベーチェット病の1例

  山本 知穂, 神田 真聡, 古川 將太, 江辺 広志, 山本 浩平, 佐藤 力, 浄土 智, 藤咲 淳, 石津 明洋 北海道医学雑誌 87 (4-5) 211 -211 2012年08月 [査読無し][通常論文]
  
• 深部静脈血栓症を伴った顕微鏡的多発血管炎(MPA)の一剖検例 MPAと血栓の関連について

  中沢 大悟, 外丸 詩野, 山本 知穂, 浄土 智, 石津 明洋 北海道医学雑誌 87 (4-5) 212 -212 2012年08月 [査読無し][通常論文]
  
• Presence of anti-LAMP-2 antibody induces cutaneous vasculitis of rats

  Tamihiro Kawakami, Sora Takeuchi, Satoko Kimura, Yoshinao Soma, Masashi Waki, Madoka Yamaguchi, Daigo Nakazawa, Utano Tomaru, Akihiro Ishizu JOURNAL OF DERMATOLOGY 39 49 -49 2012年06月 [査読無し][通常論文]
  
• ABNORMAL CONFORMATION AND IMPAIRED DEGRADATION OF NEUTROPHIL EXTRACELLULAR TRAPS INDUCED BY PROPYLTHIOURACIL ARE IMPLICATED IN THE PATHOGENESIS OF MPO-ANCA-ASSOCIATED VASCULITIS

  Daigo Nakazawa, Saori Nishio, Sekiya Shibasaki, Utano Tomaru, Ishizu Akihiro NEPHROLOGY DIALYSIS TRANSPLANTATION 27 442 -442 2012年05月 [査読無し][通常論文]
  
• 乳腺アポクリン癌9例の検討

  佐藤 暢人, 岩井 和浩, 狭間 一明, 浅野 賢道, 飯村 泰昭, 京極 典憲, 石津 明洋 日本乳癌学会総会プログラム抄録集 20回 504 -504 2012年05月 [査読無し][通常論文]
  
• PTUによる好中球細胞外トラップの形成・分解障害はMPO-ANCA関連血管炎を誘導する

  中沢 大悟, 西尾 妙織, 柴崎 跡也, 石津 明洋 日本腎臓学会誌 54 (3) 245 -245 2012年04月 [査読無し][通常論文]
  
• 血漿因子に依存し, 抗体およびFcγ受容体が媒介するT細胞から単球へのCD8分子の移動

  岩崎 沙理, 益田 紗季子, 馬場 智久, 外丸 詩野, 勝俣 一晃, 笠原 正典, 石津 明洋 北海道醫學雜誌 = Acta medica Hokkaidonensia 87 (2) 68 -68 2012年04月01日 [査読無し][通常論文]
  
• プロテアソームサブユニットβ5tの胸腺腫における発現

  山田 洋介, 外丸 詩野, 石津 明洋, 木内 隆之, 丸川 活司, 松野 吉宏, 笠原 正典 北海道医学雑誌 87 (2-3) 71 -71 2012年04月 [査読無し][通常論文]
  
• 血管炎(2) 自己血管内皮細胞反応性NKT細胞による血管炎発症モデル

  石津 明洋, 外丸 詩野, 吉木 敬 日本リウマチ学会総会・学術集会・国際リウマチシンポジウムプログラム・抄録集 56回・21回 330 -330 2012年03月 [査読無し][通常論文]
  
• 血管炎(2) プロピルチオウラシルによるNETs(neutrophil extracellular traps)の形成および分解障害とMPO-ANCAの産生 MPO-ANCA関連血管炎の発症機序

  中沢 大悟, 外丸 詩野, 石津 明洋 日本リウマチ学会総会・学術集会・国際リウマチシンポジウムプログラム・抄録集 56回・21回 331 -331 2012年03月 [査読無し][通常論文]
  
• 血管炎(3) 皮膚型結節性多発動脈炎における血中抗LAMP-2抗体は上昇している

  川上 民裕, 石津 明洋, 有村 義宏 日本リウマチ学会総会・学術集会・国際リウマチシンポジウムプログラム・抄録集 56回・21回 387 -387 2012年03月 [査読無し][通常論文]
  
• プロテアソーム機能の低下とCOPDに対する病理作用

  山田 洋介, 外丸 詩野, 木内 隆之, 石津 明洋, 松野 吉宏, 笠原 正典 日本病理学会会誌 101 (1) 279 -279 2012年03月 [査読無し][通常論文]
  
• プロテアソーム活性の低下が腫瘍微小環境に与える影響 腫瘍増殖の抑制効果について

  小野 綾子, 外丸 詩野, 石津 明洋, 小原 次郎, 紺野 沙織, 笠原 正典 日本病理学会会誌 101 (1) 283 -283 2012年03月 [査読無し][通常論文]
  
• 成人T細胞白血病(ATL)の病態における上皮細胞の役割の検討

  宮武 由甲子, 外丸 詩野, Sheehy Noreen, 石津 明洋, Hall William W, 笠原 正典 日本病理学会会誌 101 (1) 291 -291 2012年03月 [査読無し][通常論文]
  
• TNFα変換酵素(TACE)の過剰発現が糖および脂質代謝へ及ぼす影響

  松井 由希, 深谷 進司, 外丸 詩野, 渥美 達也, 笠原 正典, 石津 明洋 日本病理学会会誌 101 (1) 314 -314 2012年03月 [査読無し][通常論文]
  
• 胸腺プロテアソームの発現異常がT細胞分化に与える影響について

  小原 次郎, 外丸 詩野, 鈴木 小百合, 紺野 沙織, 村田 茂穂, 田中 啓二, 石津 明洋, 笠原 正典 日本病理学会会誌 101 (1) 435 -435 2012年03月 [査読無し][通常論文]
  
• 肺腺癌に伴うトルソー症候群により肺高血圧症を合併した一剖検例

  今本 鉄平, 大塚 紀幸, 山田 洋介, 外丸 詩野, 高階 太一, 石津 明洋, 笠原 正典 日本病理学会会誌 101 (1) 439 -439 2012年03月 [査読無し][通常論文]
  
• Expression of Thymoproteasome Subunit beta 5t in Type AB Thymoma

  Y. Yamada, U. Tomaru, K. Kubota, A. Ishizu, T. Kiuchi, T. Mitsuhashi, Y. Matsuno, M. Kasahara LABORATORY INVESTIGATION 92 493A -493A 2012年02月 [査読無し][通常論文]
  
• Expression of Thymoproteasome Subunit beta 5t in Type AB Thymoma

  Y. Yamada, U. Tomaru, K. Kubota, A. Ishizu, T. Kiuchi, T. Mitsuhashi, Y. Matsuno, M. Kasahara MODERN PATHOLOGY 25 493A -493A 2012年02月 [査読無し][通常論文]
  
• 自己免疫の基礎病態 自己血管内皮細胞反応性血管炎惹起性T細胞の認識分子の同定(Identification of the vascular endothelial antigen recognized by T cells pathogenic for vasculitis)

  山口 まどか, 一條 加奈, 飯沼 千景, 脇 雅, 川上 愛, 佐々木 直美, 外丸 詩野, 笠原 正典, 石津 明洋 日本免疫学会総会・学術集会記録 40 83 -83 2011年11月 [査読無し][通常論文]
  
• プロテアソームサブユニットβ5tの胸腺腫における発現

  外丸 詩野, 山田 洋介, 木内 隆之, 丸川 活司, 松野 吉宏, 黒田 徹, 石津 明洋, 笠原 正典 日本病理学会会誌 100 (2) 37 -37 2011年09月 [査読無し][通常論文]
  
• プロテアソーム活性の低下が腫瘍微小環境に与える影響 腫瘍増殖の抑制効果について(Proteasomal inhibition on the tumor microenvironment affects tumor proliferation)

  小野 綾子, 外丸 詩野, 石津 明洋, 小原 次郎, 紺野 沙織, 笠原 正典 日本癌学会総会記事 70回 337 -337 2011年09月 [査読無し][通常論文]
  
• 正常血圧性強皮症腎クリーゼの病理所見

  石津 明洋, 深谷 進司, 外丸 詩野, 古崎 章, 天崎 吉晴 北海道医学雑誌 86 (4-5) 241 -241 2011年08月 [査読無し][通常論文]
  
• 血管炎 自己血管内皮細胞反応性T細胞による血管炎発症モデル

  石津 明洋, 外丸 詩野, 吉木 敬 日本リウマチ学会総会・学術集会・国際リウマチシンポジウムプログラム・抄録集 55回・20回 439 -439 2011年06月 [査読無し][通常論文]
  
• 関節リウマチ経過中に強皮症と血栓性微小血管症(TMA)を併発し急激な経過を呈した1例

  古崎 章, 安田 泉, 天崎 吉晴, 石津 明洋 日本リウマチ学会総会・学術集会・国際リウマチシンポジウムプログラム・抄録集 55回・20回 571 -571 2011年06月 [査読無し][通常論文]
  
• A model of vasculitis induced by autoreactive T cells against vascular endothelial cells

  Akihiro Ishizu, Chihiro Iinuma, Masashi Waki, Madoka Yamaguchi, Naomi Sasaki, Utano Tomaru, Takashi Yoshiki CLINICAL AND EXPERIMENTAL IMMUNOLOGY 164 128 -128 2011年05月 [査読無し][通常論文]
  
• プロピルチオウラシル(PTU)投与によるMPO-ANCA関連血管炎のモデル開発と病態解析

  中沢 大悟, 西尾 妙織, 柴崎 跡也, 小池 隆夫, 石津 明洋 日本腎臓学会誌 53 (3) 379 -379 2011年05月 [査読無し][通常論文]
  
• 【病理診断に役立つ分子生物学】 (第2部)病理診断医になじみのある疾患関連分子 ANCA(anti-neutrophil cytoplasmic autoantibody) 解説編

  石津 明洋 病理と臨床 29 (臨増) 92 -93 2011年04月 [査読無し][通常論文]
  
• 【病理診断に役立つ分子生物学】 (第2部)病理診断医になじみのある疾患関連分子 ANCA(anti-neutrophil cytoplasmic autoantibody) 診断編

  石津 明洋 病理と臨床 29 (臨増) 94 -97 2011年04月 [査読無し][通常論文]
  
• 転移性髄膜癌腫症との鑑別が困難であったprimary diffuse leptomeningeal gliomatosisの1例

  中野 史人, 矢部 一郎, 秋本 幸子, 石津 明洋, 田中 伸哉, 笠原 正典, 佐々木 秀直 臨床神経学 51 (3) 197 -202 2011年03月 [査読無し][通常論文]
   

  症例は65歳女性である。進行する歩行障害のため当科受診。認知機能低下、左上肢と両下肢に深部覚障害、開脚不安定歩行をみとめ、MRIにて左中頭蓋窩に腫瘤性病変と脳幹表面の造影像、脊髄表面の造影像と腫瘤性病変をみとめたため転移性髄膜癌腫症がうたがわれた。髄液細胞診をふくめて全身検索をおこなったが、生前には確定診断にいたらず、剖検にてprimary diffuse leptomeningeal gliomatosis(PDLG)と病理診断された。PDLGはまれな疾患で生前診断は困難であるが、転移性髄膜癌腫症類似の画像所見を呈し、全身検査で原発巣をみとめない症例で、PDLGを鑑別するには髄膜生検も検討する必要がある。(著者抄録)
• プロピルチオウラシル(PTU)投与によるMPO-ANCA関連血管炎のモデル開発と病態解析

  中沢 大悟, 長谷川 梨沙, 一條 加奈, 西尾 妙織, 外丸 詩野, 石津 明洋 日本病理学会会誌 100 (1) 315 -315 2011年03月 [査読無し][通常論文]
  
• 自己血管内皮細胞反応性T細胞による血管炎発症モデル

  脇 雅, 桜沢 貴代, 飯沼 千景, 山口 まどか, 外丸 詩野, 石津 明洋 日本病理学会会誌 100 (1) 316 -316 2011年03月 [査読無し][通常論文]
  
• Fcγ受容体を介したtrogocytosisの意義と制御機構の解析

  益田 紗季子, 岩崎 沙理, 佐藤 樹里, 外丸 詩野, 笠原 正典, 石津 明洋 日本病理学会会誌 100 (1) 316 -316 2011年03月 [査読無し][通常論文]
  
• プロテアソーム機能の低下と喫煙負荷がもたらす老化関連呼吸器系疾患の病態解明

  山田 洋介, 外丸 詩野, 木内 隆之, 高橋 里実, 石津 明洋, 松野 吉宏, 笠原 正典 日本病理学会会誌 100 (1) 332 -332 2011年03月 [査読無し][通常論文]
  
• プロテアソームの機能異常による病理作用 脂質代謝や脂肪肝との関連性について

  高橋 里美, 外丸 詩野, 合田 文, 小野 綾子, 小原 次郎, 宮武 由甲子, 村田 茂穂, 田中 啓二, 石津 明洋, 笠原 正典 日本病理学会会誌 100 (1) 333 -333 2011年03月 [査読無し][通常論文]
  
• TNFα変換酵素の過剰発現による炎症・線維化病態への影響

  松井 由希, 深谷 進司, 外丸 詩野, 渥美 達也, 笠原 正典, 石津 明洋 日本病理学会会誌 100 (1) 344 -344 2011年03月 [査読無し][通常論文]
  
• BCG接種後に判明した慢性肉芽腫症の一剖検例

  定本 圭弘, 大塚 紀幸, 藤田 裕美, 菊地 慶介, 外丸 詩野, 石津 明洋, 笠原 正典 日本病理学会会誌 100 (1) 494 -494 2011年03月 [査読無し][通常論文]
  
• 胸腺プロテアソームの異所性発現によるT細胞分化の異常

  小原 次郎, 外丸 詩野, 鈴木 小百合, 高橋 里美, 宮武 由甲子, 村田 茂穂, 田中 啓二, 石津 明洋, 笠原 正典 日本病理学会会誌 100 (1) 496 -496 2011年03月 [査読無し][通常論文]
  
• von Recklinghausen病による動脈破裂の病理組織学的検討(第二報)

  木内 隆之, 高田 明生, 池田 仁, 外丸 詩野, 石津 明洋 日本病理学会会誌 100 (1) 501 -501 2011年03月 [査読無し][通常論文]
  
• 悪性が強く疑われた傍神経節腫の一例

  前鼻 健志, 広部 恵美, 田口 圭介, 井上 隆太, 栗村 雄一郎, 笹尾 拓巳, 佐藤 俊介, 伊藤 直樹, 石津 明洋 泌尿器外科 24 (1) 113 -113 2011年01月 [査読無し][通常論文]
  
• Circulating fibrocyteの性質異常とケロイド病態との関連性 創傷モデルマウスを用いた検討

  長尾 宗朝, 小山 明彦, 村尾 尚規, 小浦場 祥夫, 古川 洋志, 山本 有平, 外丸 詩野, 石津 明洋 日本形成外科学会会誌 30 (11) 649 -649 2010年11月 [査読無し][通常論文]
  
• 【血管炎症候群の新展開】 トランスクリプトミクスによる血管炎関連因子の探索

  石津 明洋, 外丸 詩野, 村井 太一, 山本 智宏, 吉木 敬 炎症と免疫 18 (5) 509 -513 2010年08月 [査読無し][通常論文]
   

  JMAAVは、わが国におけるMPO-ANCA関連血管炎の標準的治療プロトコール策定を目的として設立された多施設共同研究組織である。われわれは、MPO-ANCA関連血管炎の病因・病態を明らかにするために、JMAAVに登録された症例の治療前および治療開始1週間後の末梢血をサンプルとして、網羅的遺伝子発現解析(トランスクリプトーム解析)をおこなった。治療後に寛解し、その後も寛解が維持された症例において、88個の遺伝子が治療前後で統計学的に有意な発現変化を示した。このうち、治療後に発現が減少した遺伝子は66個、治療後に発現が増加した遺伝子は22個であった。これらのなかから、治療開始後の早期にMPO-ANCA関連血管炎の治療後の予後を予測する16個の遺伝子を抽出した。(著者抄録)
• 好酸球性肉芽腫性血管炎により小腸壊死を呈したが、アレルギー症状や好酸球増加を認めず、診断に苦慮した症例

  石津 明洋, 高橋 利幸, 外丸 詩野, 深谷 進司, 堀田 彰一, 森田 高行, 古崎 章, 天崎 吉晴 北海道医学雑誌 85 (4) 281 -281 2010年07月 [査読無し][通常論文]
  
• The incidence and the mechanism of sunitinib-induced thyroid atrophy in patients with metastatic renal cell carcinoma

  N. Shinohara, M. Takahashi, T. Kamishima, H. Ikushima, N. Otsuka, A. Ishizu, A. Sazawa, H. Kanayama, K. Nonomura JOURNAL OF CLINICAL ONCOLOGY 28 (15) 2010年05月 [査読無し][通常論文]
  
• 動脈破裂をきたしたvon Recklinghausen病の2症例 破裂血管におけるhypoxia-inducible factor-1a発現の検討

  木内 隆之, 外丸 詩野, 高田 明生, 武藤 修一, 大岡 智学, 村上 達哉, 宮武 司, 大場 淳一, 青木 秀俊, 石津 明洋 脈管学 50 (2) 220 -221 2010年04月 [査読無し][通常論文]
  
• ヒト末梢血に検出されるCD8陽性単球・顆粒球の解析

  益田紗季子, 岩崎沙理, 馬場智久, 勝俣一晃, 外丸詩野, 笠原正典, 石津明洋 日本病理学会会誌 99 (1) 217 -217 2010年03月26日 [査読無し][通常論文]
  
• OP-052-5 発現頻度・発現パターンから見た大腸癌における癌幹細胞マーカーCD133の臨床的意義についての検討(腫瘍基礎-2,一般口演,第110回日本外科学会定期学術集会)

  高橋 周作, 神山 俊哉, 島田 信吾, 工藤 岳秋, 廣瀬 邦弘, 佐治 裕, 崎浜 秀康, 尾崎 倫孝, 外丸 詩野, 石津 明洋, 藤堂 省 日本外科学会雑誌 111 (2) 372 -372 2010年03月05日 [査読無し][通常論文]
  
• 造影エコーと大腸癌の組織診断とCEA値についての検討

  武藤 修一, 武田 宏司, 小原 俊央, 上畠 寧子, 山本 洋一, 石津 明洋, 松重 亜希, 浅香 正博 日本消化器病学会雑誌 107 (臨増総会) A360 -A360 2010年03月 [査読無し][通常論文]
  
• 血管炎・APS 血管炎惹起性T細胞クローンの樹立と解析

  石津 明洋, 外丸 詩野, 吉木 敬 日本リウマチ学会総会・学術集会・国際リウマチシンポジウムプログラム・抄録集 54回・19回 543 -543 2010年03月 [査読無し][通常論文]
  
• 血管炎・APS JMAAVトランスクリプトーム解析

  石津 明洋, 外丸 詩野, 吉木 敬, 湯村 和子, 山縣 邦弘, 山田 秀裕, 熊谷 俊一, 黒川 真奈絵, 須賀 万智, 尾崎 承一, Japanese study, group for, MPO-ANCA-associated vasculitis(JMAAV 日本リウマチ学会総会・学術集会・国際リウマチシンポジウムプログラム・抄録集 54回・19回 543 -543 2010年03月 [査読無し][通常論文]
  
• 顕微鏡的多発血管炎患者血清ペプチドの網羅的探索

  高桑 由希子, 黒川 真奈絵, 大岡 正道, 湯村 和子, 山縣 邦弘, 山田 秀裕, 熊谷 俊一, 石津 明洋, 須賀 万智, 尾崎 承一, 加藤 智啓, 増子 佳世 日本リウマチ学会総会・学術集会・国際リウマチシンポジウムプログラム・抄録集 54回・19回 678 -678 2010年03月 [査読無し][通常論文]
  
• MPO-ANCA関連血管炎における疾患活動性とQOLへの影響

  須賀 万智, 永渕 裕子, 湯村 和子, 山縣 邦弘, 山田 秀裕, 熊谷 俊一, 石津 明洋, 黒川 真奈絵, 尾崎 承一 日本リウマチ学会総会・学術集会・国際リウマチシンポジウムプログラム・抄録集 54回・19回 710 -710 2010年03月 [査読無し][通常論文]
  
• 発現頻度・発現パターンから見た大腸癌における癌幹細胞マーカーCD133の臨床的意義についての検討

  高橋 周作, 神山 俊哉, 島田 信吾, 工藤 岳秋, 廣瀬 邦弘, 佐治 裕, 崎浜 秀康, 尾崎 倫孝, 外丸 詩野, 石津 明洋, 藤堂 省 日本外科学会雑誌 111 (臨増2) 372 -372 2010年03月 [査読無し][通常論文]
  
• TNFα変換酵素(TACE)トランスジェニックマウスの解析

  深谷 進司, 外丸 詩野, 松井 由希, 保田 晋助, 堀田 哲也, 片岡 浩, 渥美 達也, 小池 隆夫, 笠原 正典, 石津 明洋 日本病理学会会誌 99 (1) 206 -206 2010年03月 [査読無し][通常論文]
  
• 血管炎惹起性T細胞クローンの樹立と解析

  飯沼 千景, 脇 雅, 山口 まどか, 佐々木 直美, 外丸 詩野, 石津 明洋 日本病理学会会誌 99 (1) 210 -210 2010年03月 [査読無し][通常論文]
  
• プロテアソームサブユニットβ5tの胸腺腫における発現

  山田 洋介, 外丸 詩野, 木内 隆之, 丸川 活司, 笠原 正典, 石津 明洋, 松野 吉宏 日本病理学会会誌 99 (1) 216 -216 2010年03月 [査読無し][通常論文]
  
• ヒト末梢血に検出されるCD8陽性単球・顆粒球の解析

  益田 紗季子, 岩崎 沙理, 馬場 智久, 勝俣 一晃, 外丸 詩野, 笠原 正典, 石津 明洋 日本病理学会会誌 99 (1) 217 -217 2010年03月 [査読無し][通常論文]
  
• 胸腺プロテアソームの異所性発現によるT細胞分化の異常

  鈴木 小百合, 外丸 詩野, 高橋 里実, 小原 次郎, 風巻 拓, 小野 綾子, 宮武 由甲子, 村田 茂穂, 田中 啓二, 石津 明洋, 笠原 正典 日本病理学会会誌 99 (1) 217 -217 2010年03月 [査読無し][通常論文]
  
• プロテアソームの機能異常による病理作用

  高橋 里実, 外丸 詩野, 鈴木 小百合, 小野 綾子, 宮武 由甲子, 風巻 拓, 小原 次郎, 村田 茂穂, 田中 啓二, 石津 明洋, 笠原 正典 日本病理学会会誌 99 (1) 225 -225 2010年03月 [査読無し][通常論文]
  
• von Recklinghausen病による動脈破裂の病理組織学的検討

  木内 隆之, 外丸 詩野, 高田 明生, 石津 明洋 日本病理学会会誌 99 (1) 367 -367 2010年03月 [査読無し][通常論文]
  
• 腎癌患者へのSunitinib投与が引き起こす甲状腺機能障害の発症機序

  篠原 信雄, 高橋 正幸, 神島 保, 生島 仁史, 大塚 紀幸, 石津 明洋, 丸山 覚, 安部 崇重, 佐澤 陽, 金山 博臣, 野々村 克也 日本癌治療学会誌 44 (2) 456 -456 2009年09月 [査読無し][通常論文]
  
• MPO-ANCA陽性であったが糸球体腎炎や血管炎は確認されず、間質性肺炎に感染症を合併して死亡した症例

  石津 明洋, 岩崎 沙理, 外丸 詩野, 武田 広子, 大塚 紀幸, 富居 一範, 笠原 正典, 清水 健一, 南須原 康行, 西村 正治 北海道医学雑誌 84 (5) 403 -403 2009年09月 [査読無し][通常論文]
  
• 弛張熱で発症した原発性胆汁性肝硬変、自己免疫性肝炎合併シェーグレン症候群の1例

  河野 通仁, 佐藤 力, 野本 博司, 谷口 聡, 田村 元男, 山根 康昭, 浄土 智, 藤咲 淳, 石津 明洋, 大塚 紀幸, 富居 一範 北海道医学雑誌 84 (5) 403 -404 2009年09月 [査読無し][通常論文]
  
• モデル動物の解析による自己免疫疾患発症機序の多面的理解

  石津 明洋 日本病理学会会誌 98 (2) 16 -16 2009年09月 [査読無し][通常論文]
  
• ヒト末梢血におけるCD8陽性単球の解析

  岩崎 沙理, 益田 紗季子, 馬場 智久, 勝俣 一晃, 外丸 詩野, 笠原 正典, 石津 明洋 臨床病理 57 (補冊) 136 -136 2009年07月 [査読無し][通常論文]
  
• 当科で経験した耳下腺導管癌の1例

  前田 昌紀, 黒田 徹, 富居 一範, 外丸 詩野, 石津 明洋 耳鼻咽喉科臨床 補冊 (補冊124) 134 -134 2009年06月 [査読無し][通常論文]
  
• 好酸球の広範な肺浸潤により気胸を呈したimatinib耐性化慢性好酸球性白血病の剖検例

  藤見 章仁, 蟹沢 祐司, 田中 信悟, 奥田 敏徳, 佐藤 康裕, 土居 忠, 太田 英敏, 岩崎 沙理, 石津 明洋, 黄 勇澤 日本内科学会雑誌 98 (4) 862 -865 2009年04月 [査読無し][通常論文]
   

  70歳男性。患者は丘疹と咳嗽で発症し、RT-PCR法でFIP1L1/PDGFRα融合遺伝子(FP遺伝子)陽性が判明し耐性化慢性好酸球性白血病(CEL)と診断された。imatinib(IM)少量投与で血液学的寛快となったものの、投与開始13ヵ月後に好酸球の再出現と発熱、倦怠感が著明となって入院となり、末梢血からFP遺伝子が検出されCEL再発と診断された。治療としてIMを増量が行なわれたが、次第に体液貯留傾向と低酸素血症を呈し、X線では左肺尖部に空洞性病変が認められた。更にその後、胸痛、呼吸困難が生じ、高度の気胸も認められ、直ちに持続ドレナージが行なわれた。だが、効果は乏しく、胸腔鏡下胸膜縫縮術を行なうことで気胸は改善したが、全身状態は徐々に悪化し、患者は最終的に第92病日目に死亡となった。尚、剖検所見では好酸球の肺胞への高度浸潤、肺胞の線維化と気腫化が認められ、この好酸球浸潤は全臓器、特に心室壁に線維化、出血を伴う浸潤巣で確認された。以上より、本症例の直接死因は好酸球浸潤による心筋障害と考えられた。
• 下血を契機として発見され、腸重積を呈した小腸GISTの1例

  石 忠明, 羽田 政平, 山本 洋一, 武藤 修一, 旭 よう, 工藤 岳秋, 高橋 周作, 廣瀬 邦弘, 佐治 裕, 久保 公三, 石津 明洋 日本消化器病学会雑誌 106 (臨増総会) A455 -A455 2009年03月 [査読無し][通常論文]
  
• 血管炎 MPO-ANCA関連血管炎患者末梢血のトランスクリプトーム解析

  石津 明洋, 外丸 詩野, 岩崎 沙理, 吉木 敬, 尾崎 承一 日本リウマチ学会総会・学術集会・国際リウマチシンポジウムプログラム・抄録集 53回・18回 209 -209 2009年03月 [査読無し][通常論文]
  
• MPO-ANCA関連血管炎患者末梢血のトランスクリプトーム解析

  石津 明洋, 外丸 詩野, 岩崎 沙理, 飯沼 千景, 村井 太一, 山本 智宏, 吉木 敬, 尾崎 承一 日本病理学会会誌 98 (1) 211 -211 2009年03月 [査読無し][通常論文]
  
• 胸腺プロテアソームの発現とT細胞分化に関する検討

  鈴木 小百合, 外丸 詩野, 石津 明洋, 高橋 里実, 小原 次郎, 風巻 拓, 宮武 由甲子, 村田 茂穂, 田中 啓二, 笠原 正典 日本病理学会会誌 98 (1) 277 -277 2009年03月 [査読無し][通常論文]
  
• ヒト末梢血に検出されるCD8陽性単球の解析

  岩崎 沙理, 馬場 智久, 益田 紗季子, 勝俣 一晃, 外丸 詩野, 笠原 正典, 石津 明洋 日本病理学会会誌 98 (1) 279 -279 2009年03月 [査読無し][通常論文]
  
• 自己血管内皮細胞反応性ラットT細胞の解析

  飯沼 千景, 佐々木 直美, 岩崎 沙理, 外丸 詩野, 石津 明洋 日本病理学会会誌 98 (1) 292 -292 2009年03月 [査読無し][通常論文]
  
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  外丸 詩野, 石津 明洋, 高橋 里実, 鈴木 小百合, 小原 次郎, 風巻 拓, 宮武 由甲子, 村田 茂穂, 田中 啓二, 笠原 正典 日本病理学会会誌 98 (1) 368 -368 2009年03月 [査読無し][通常論文]
  
• 分子標的薬sunitinib投与症例における甲状腺萎縮の病理学的解析

  中村 静香, 大塚 紀幸, 鈴木 昭, 富居 一範, 外丸 詩野, 笠原 正典, 石津 明洋 日本病理学会会誌 98 (1) 400 -400 2009年03月 [査読無し][通常論文]
  
• env-pX ラットの血管炎発症機序

  石津 明洋, 吉木 敬 脈管学 : 日本脈管学会機関誌 : the journal of Japanese College of Angiology 49 (1) 17 -20 2009年02月25日 [査読無し][通常論文]
  
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  石津 明洋, 外丸 詩野, 村井 太一, 吉木 敬, 尾崎 承一 脈管学 : 日本脈管学会機関誌 : the journal of Japanese College of Angiology 49 (1) 45 -51 2009年02月25日 [査読無し][通常論文]
  
• 【中小型血管炎の新展開】 env-pXラットの血管炎発症機序

  石津 明洋, 吉木 敬 脈管学 49 (1) 17 -20 2009年02月 [査読無し][通常論文]
  
• 【中小型血管炎の新展開】 MPO-ANCA関連血管炎の予後予測因子の探索

  石津 明洋, 外丸 詩野, 村井 太一, 吉木 敬, 尾崎 承一 脈管学 49 (1) 45 -51 2009年02月 [査読無し][通常論文]
  
• リツキシマブ投与後に日和見感染症を併発して死亡した顕微鏡的多発血管炎の一剖検例

  外丸 詩野, 富居 一範, 武田 広子, 小川 弥生, 堀田 哲也, 深谷 進司, 橋本 陶子, 石津 明洋 北海道医学雑誌 84 (1) 62 -62 2009年01月 [査読無し][通常論文]
  
• 潰瘍性大腸炎における末梢血および大腸粘膜内NKG2A+T細胞の減少

  桂田 武彦, 外丸 詩野, 笠原 正典, 馬場 智久, 古川 滋, 武田 宏司, 浅香 正博, 田中 淳司, 石津 明洋 北海道医学雑誌 84 (1) 62 -62 2009年01月 [査読無し][通常論文]
  
• 血管炎症候群の診療ガイドライン

  尾崎 承一, 安藤 太三, 居石 克夫, 磯部 光章, 太田 敬, 小林 茂人, 重松 宏, 種本 和雄, 中島 康雄, 中林 公正, 能勢 眞人, 松永 尚文, 宮田 哲郎, 由谷 親夫, 吉田 雅治, 吉田 晃敏, 有村 義宏, 石津 明洋, 岩井 武尚, 岡崎 貴裕, 岡田 宗正, 片岡 浩, 金子 一成, 川名 誠司, 木田 一成, 小林 泰之, 古森 公浩, 坂本 一郎, 椎谷 紀彦, 重松 邦広, 高橋 淳士, 滝澤 始, 長岡 泰司, 長澤 浩平, 野島 美久, 橋本 博史, 濱口 真吾, 廣村 桂樹, 深谷 修作, 正木 久男, 松本 常男, 山田 秀裕, 吉田 俊治, 熊谷 俊一, 小池 隆夫, 笹嶋 唯博, 福井 次矢, 堀江 稔 Circulation journal : official journal of the Japanese Circulation Society 72 (0) 1253 -1346 2008年11月20日 [査読無し][通常論文]
  
• 血管炎症候群の診療ガイドライン(循環器病の診断と治療に関するガイドライン(2006-2007年度合同研究班報告))

  尾崎 承一, 安藤 太三, 居石 克夫, 磯部 光章, 太田 敬, 小林 茂人, 重松 宏, 種本 和雄, 中島 康雄, 中林 公正, 能勢 眞人, 松永 尚文, 宮田 哲郎, 由谷 親夫, 吉田 雅治, 吉田 晃敏, 有村 義宏, 石津 明洋, 岩井 武尚, 岡崎 貴裕, 岡田 宗正, 片岡 浩, 金子 一成, 川名 誠司, 木田 一成, 小林 泰之, 古森 公浩, 坂本 一郎, 椎谷 紀彦, 重松 邦広, 高橋 淳士, 滝澤 始, 長岡 泰司, 長澤 浩平, 野島 美久, 橋本 博史, 濱口 真吾, 廣村 桂樹, 深谷 修作, 正木 久男, 松本 常男, 山田 秀裕, 吉田 俊治, 熊谷 俊一, 小池 隆夫, 笹嶋 唯博, 福井 次矢, 堀江 稔 Circulation journal : official journal of the Japanese Circulation Society 72 (0) 1253 -1318 2008年11月20日 [査読無し][通常論文]
  
• 血管炎症候群の診療ガイドライン(ダイジェスト版,循環器病の診断と治療に関するガイドライン(2006-2007年度合同研究班報告))

  尾崎 承一, 安藤 太三, 居石 克夫, 磯部 光章, 太田 敬, 小林 茂人, 重松 宏, 種本 和雄, 中島 康雄, 中林 公正, 能勢 眞人, 松永 尚文, 宮田 哲郎, 由谷 親夫, 吉田 雅治, 吉田 晃敏, 有村 義宏, 石津 明洋, 岩井 武尚, 岡崎 貴裕, 岡田 宗正, 片岡 浩, 金子 一成, 川名 誠司, 木田 一成, 小林 泰之, 古森 公浩, 坂本 一郎, 椎谷 紀彦, 重松 邦広, 高橋 淳士, 滝澤 始, 長岡 泰司, 長澤 浩平, 野島 美久, 橋本 博史, 濱口 真吾, 廣村 桂樹, 深谷 修作, 正木 久男, 松本 常男, 山田 秀裕, 吉田 俊治, 熊谷 俊一, 小池 隆夫, 笹嶋 唯博, 福井 次矢, 堀江 稔 Circulation journal : official journal of the Japanese Circulation Society 72 (0) 1319 -1346 2008年11月20日 [査読無し][通常論文]
  
• 循環器病の診断と治療に関するガイドライン(2006-2007年度合同研究班報告) 血管炎症候群の診療ガイドライン

  尾崎 承一, 安藤 太三, 居石 克夫, 磯部 光章, 太田 敬, 小林 茂人, 重松 宏, 種本 和雄, 中島 康雄, 中林 公正, 能勢 眞人, 松永 尚文, 宮田 哲郎, 由谷 親夫, 吉田 雅治, 吉田 晃敏, 有村 義宏, 石津 明洋, 岩井 武尚, 岡崎 貴裕, 岡田 宗正, 片岡 浩, 金子 一成, 川名 誠司, 木田 一成, 小林 泰之, 古森 公浩, 坂本 一郎, 椎谷 紀彦, 重松 邦広, 高橋 淳士, 滝澤 始, 長岡 泰司, 長澤 浩平, 野島 美久, 橋本 博史, 濱口 真吾, 廣村 桂樹, 深谷 修作, 正木 久男, 松本 常男, 山田 秀裕, 吉田 俊治, 熊谷 俊一, 小池 隆夫, 笹嶋 唯博, 福井 次矢, 堀江 稔, 日本循環器学会 Circulation Journal 72 (Suppl.IV) 1253 -1346 2008年11月 [査読無し][通常論文]
  
• 脾動脈に発生し、腹腔内出血以外の臨床所見を呈したSegmental Arterial Mediolysis(SAM)の2例

  石津 明洋, 山口 潤, 岩井 和浩, 近藤 信夫, 佐藤 英俊, 吉木 敬 脈管学 48 (5) 477 -478 2008年10月 [査読無し][通常論文]
  
• Churg-Strauss Syndrome(CSS)-associated Eosinophilic Endomyocarditisの一例

  石津 明洋, 平林 鑑, 保田 晋介, 三山 博史, 筒井 裕之, 吉木 敬 脈管学 48 (5) 483 -483 2008年10月 [査読無し][通常論文]
  
• MPO-ANCA関連血管炎患者末梢血のトランスクリプトーム解析

  石津 明洋, 外丸 詩野, 村井 太一, 西平 順, 吉木 敬, 尾崎 承一 脈管学 48 (5) 489 -490 2008年10月 [査読無し][通常論文]
  
• リツキシマブ投与後に日和見感染症を併発して死亡した顕微鏡的多発血管炎の一剖検例

  外丸 詩野, 武田 広子, 小川 弥生, 堀田 哲也, 深谷 進司, 橋本 陶子, 富居 一範, 石津 明洋 脈管学 48 (5) 494 -494 2008年10月 [査読無し][通常論文]
  
• 顕微鏡的多発血管炎の肺病変について

  斉藤 永秀, 岩崎 沙理, 外丸 詩野, 石津 明洋 脈管学 48 (5) 496 -496 2008年10月 [査読無し][通常論文]
  
• 顕微鏡的多発血管炎患者末梢血のトランスクリプトーム解析

  石津 明洋, 外丸 詩野, 村井 太一, 吉木 敬, 尾崎 承一 日本病理学会会誌 97 (2) 23 -23 2008年09月 [査読無し][通常論文]
  
• 肺限局型MPO-ANCA関連血管炎と考えられた一剖検例

  外丸 詩野, 武田 広子, 岩崎 沙理, 大塚 紀幸, 富居 一範, 笠原 正典, 清水 健一, 南須原 康行, 西村 正治, 石津 明洋 日本病理学会会誌 97 (2) 33 -33 2008年09月 [査読無し][通常論文]
  
• 保健医療専門職教育に特化したFaculty Development Workshopの報告

  佐藤 洋子, 境 信哉, 森山 隆則, 武田 直樹, 竹内 文也, 石津 明洋, 松野 一彦 医学教育 39 (Suppl.) 87 -87 2008年07月 [査読無し][通常論文]
  
• O05-04 術前悪性胸膜中皮腫が疑われた,壁側胸膜原発腺癌の1例(胸膜中皮腫,第25回日本呼吸器外科学会総会)

  妻鹿 成治, 川崎 亮輔, 浅野 賢道, 狭間 一明, 岩井 和浩, 大塚 紀幸, 石津 明洋 日本呼吸器外科学会雑誌 22 (3) 419 -419 2008年04月18日 [査読無し][通常論文]
  
• 血管炎症候群研究の進歩 自己血管内皮細胞反応性ラットT細胞の解析

  石津 明洋, 外丸 詩野, 飯沼 千景, 岩崎 沙理, 佐々木 直美, 馬場 智久, 笠原 正典, 吉木 敬 日本リウマチ学会総会・学術集会・国際リウマチシンポジウムプログラム・抄録集 52回・17回 156 -156 2008年04月 [査読無し][通常論文]
  
• 潰瘍性大腸炎におけるNKG2A陽性T細胞の減少と病態への関与

  外丸 詩野, 石津 明洋, 笠原 正典 日本リウマチ学会総会・学術集会・国際リウマチシンポジウムプログラム・抄録集 52回・17回 280 -280 2008年04月 [査読無し][通常論文]
  
• 術前悪性胸膜中皮腫が疑われた、壁側胸膜原発腺癌の1例

  妻鹿 成治, 川崎 亮輔, 浅野 賢道, 狭間 一明, 岩井 和浩, 大塚 紀幸, 石津 明洋 日本呼吸器外科学会雑誌 22 (3) 419 -419 2008年04月 [査読無し][通常論文]
  
• 炎症研究の新しい展開 CD4/CD8 double positiveマクロファージの発見と自然免疫系における新しいエフェクター細胞としての展開

  馬場 智久, 岩崎 浩理, 外丸 詩野, 池田 仁, 吉木 敬, 笠原 正典, 向田 直史, 石津 明洋 日本病理学会会誌 97 (1) 142 -142 2008年03月 [査読無し][通常論文]
  
• 自己免疫病発症機構の新たな概念 自己血管内皮細胞反応性ラットT細胞の解析

  石津 明洋, 外丸 詩野, 岩崎 沙理, 飯沼 千景, 佐藤 亜矢, 佐々木 直美, 馬場 智久, 笠原 正典, 吉木 敬 日本病理学会会誌 97 (1) 169 -169 2008年03月 [査読無し][通常論文]
  
• 創傷治癒に関わる新見解 ケロイド体質とCirculating fibrocyte

  長尾 宗朝, 外丸 詩野, 石津 明洋, 岩崎 沙理, 馬場 智久, 笠原 正典, 小山 明彦, 小浦場 祥夫, 古川 洋志, 山本 有平 日本病理学会会誌 97 (1) 201 -201 2008年03月 [査読無し][通常論文]
  
• 胸腺プロテアソームの発現とT細胞分化に関する検討

  外丸 詩野, 石津 明洋, 宮武 由甲子, 高橋 里実, 小原 次郎, 村田 茂穂, 田中 啓二, 笠原 正典 日本病理学会会誌 97 (1) 203 -203 2008年03月 [査読無し][通常論文]
  
• ヒト末梢血におけるCD8陽性単球の解析

  岩崎 沙理, 馬場 智久, 勝俣 一晃, 外丸 詩野, 笠原 正典, 石津 明洋 日本病理学会会誌 97 (1) 203 -203 2008年03月 [査読無し][通常論文]
  
• 潰瘍性大腸炎における末梢血および大腸粘膜内NKG2A+T細胞の減少

  桂田 武彦, 外丸 詩野, 馬場 智久, 古川 滋, 武田 宏司, 田中 淳司, 浅香 正博, 石津 明洋, 笠原 正典 日本病理学会会誌 97 (1) 233 -233 2008年03月 [査読無し][通常論文]
  
• MPO-ANCA関連血管炎患者末梢血のトランスクリプトーム解析

  石津 明洋, 外丸 詩野, 村井 太一, 西平 順, 吉木 敬, 尾崎 承一 日本病理学会会誌 97 (1) 261 -261 2008年03月 [査読無し][通常論文]
  
• ヒト組織におけるプロテアソームサブユニットβ5t発現に関する検討

  外丸 詩野, 石津 明洋, 宮武 由甲子, 鈴木 小百合, 風巻 拓, 村田 茂穂, 田中 啓二, 笠原 正典 日本病理学会会誌 97 (1) 309 -309 2008年03月 [査読無し][通常論文]
  
• ヒト組織におけるプロテアソームサブユニットβ5t発現に関する検討

  風巻 拓, 外丸 詩野, 石津 明洋, 鈴木 小百合, 笠原 正典 日本病理学会会誌 97 (1) 392 -392 2008年03月 [査読無し][通常論文]
  
• 潰瘍性大腸炎における末梢血中NKG2A陽性T細胞の減少と病態への関与

  桂田 武彦, 外丸 詩野, 鈴木 昭, 笠原 正典, 古川 滋, 武田 宏司, 浅香 正博, 田中 淳司, 石津 明洋 北海道医学雑誌 82 (6) 441 -441 2007年11月 [査読無し][通常論文]
  
• Churg-Strauss syndrome(CSS)-associated eosinophilic endocarditisの一例

  石津 明洋, 外丸 詩野, 平林 鑑, 三山 博史, 筒井 裕之, 保田 晋介, 吉木 敬 北海道医学雑誌 82 (6) 441 -442 2007年11月 [査読無し][通常論文]
  
• 腹部CT上の大動脈壁肥厚を契機に診断しえた側頭動脈炎の1例

  斉藤 真由子, 山本 元久, 小原 美琴子, 鈴木 知佐子, 苗代 康可, 山本 博幸, 高橋 裕樹, 篠村 恭久, 石津 明洋 日本内科学会雑誌 96 (10) 2276 -2278 2007年10月10日 [査読無し][通常論文]
   

  67歳女性。患者は全身倦怠感、体重減少を主訴に近医を受診、炎症反応高値を指摘され、著者らの施設へ紹介入院となった。所見では軽度の開口障害を認め、胸腹部造影CTで大動脈壁肥厚がみられたことから大動脈炎が疑われた。浅側頭動脈生検にて側頭動脈炎と診断し、プレドニゾロン投与を開始したところ、速やかに倦怠感および炎症反応は消失し、2ヵ月後のCTでは大動脈壁肥厚の減少が確認された。
• 術前悪性胸膜中皮腫が疑われた、壁側胸膜原発腺癌の1例

  妻鹿 成治, 川崎 亮輔, 浅野 賢道, 狭間 一明, 岩井 和浩, 大塚 紀幸, 石津 明洋 日本臨床外科学会雑誌 68 (9) 2422 -2422 2007年09月 [査読無し][通常論文]
  
• 抗腫瘍免疫反応の免疫調節 CD4+/CD8+マクロファージはNKG2D及びグランザイム/パーフォリン依存性メカニズムを介して殺腫瘍細胞作用を示す(Immunoregulation of Anti-tumor Immune Responses CD4+/CD8+ macrophages kill tumor cells through an NKG2D-and granzyme/perforin-dependent mechanism)

  石津 明洋, 馬場 智久, 岩崎 沙理, 外丸 詩野, 笠原 正典, 吉木 敬 日本癌学会総会記事 66回 74 -74 2007年08月 [査読無し][通常論文]
  
• 脳死と臓器移植に関する学生の認識・近親者が脳死と判定されたらどうするか?について

  中村 仁志夫, 阿部 歩, 山田 淑子, 石津 明洋, 佐藤 洋子 医学教育 38 (Suppl.) 107 -107 2007年06月 [査読無し][通常論文]
  
• 潰瘍性大腸炎における末梢血中NKG2A陽性T細胞の減少と病態への関与

  外丸 詩野, 石津 明洋, 笠原 正典 日本リウマチ学会総会・学術集会・国際リウマチシンポジウムプログラム・抄録集 51回・16回 338 -338 2007年04月 [査読無し][通常論文]
  
• 自己血管内皮細胞反応性ラットT細胞の解析

  石津 明洋, 外丸 詩野, 岩崎 沙理, 笠原 正典, 吉木 敬 日本リウマチ学会総会・学術集会・国際リウマチシンポジウムプログラム・抄録集 51回・16回 373 -373 2007年04月 [査読無し][通常論文]
  
• CD4/CD8 double positiveマクロファージによる抗腫瘍メカニズムの解明

  馬場 智久, 岩崎 沙理, 石津 明洋, 鈴木 昭, 外丸 詩野, 池田 仁, 吉木 敬, 笠原 正典 日本病理学会会誌 96 (1) 205 -205 2007年02月 [査読無し][通常論文]
  
• 新しいマウスNKG2Dリガンドの同定と解析

  吉田 繁, 富居 一範, 高田 明生, 宮武 由甲子, 鈴木 昭, 石津 明洋, 外丸 詩野, 笠原 正典 日本病理学会会誌 96 (1) 205 -205 2007年02月 [査読無し][通常論文]
  
• 生殖細胞特異的に発現する新規MHC class I様分子の解析

  富居 一範, 吉田 繁, 宮武 由甲子, 高田 明生, 鈴木 昭, 石津 明洋, 外丸 詩野, 笠原 正典 日本病理学会会誌 96 (1) 206 -206 2007年02月 [査読無し][通常論文]
  
• 自己血管内皮細胞反応性ラットT細胞の解析

  石津 明洋, 外丸 詩野, 馬場 智久, 佐々木 直美, 岩崎 沙理, 笠原 正典, 吉木 敬 日本病理学会会誌 96 (1) 222 -222 2007年02月 [査読無し][通常論文]
  
• 潰瘍性大腸炎における末梢血中NKG2A陽性T細胞の減少と病態への関与

  桂田 武彦, 外丸 詩野, 古川 滋, 武田 宏司, 田中 淳司, 浅香 正博, 鈴木 昭, 石津 明洋, 笠原 正典 日本病理学会会誌 96 (1) 226 -226 2007年02月 [査読無し][通常論文]
  
• Micronodular thymoma with lymphoid hyperplasia(MNT)の一例

  古西 崇寛, 山田 綾子, 富居 一範, 鈴木 昭, 外丸 詩野, 石津 明洋, 笠原 正典 日本病理学会会誌 96 (1) 355 -355 2007年02月 [査読無し][通常論文]
  
• 自然免疫から獲得免疫へのリンク CD4/CD8 double positive(DP)macrophageの機能

  馬場 智久, 石津 明洋 Annual Review免疫 2007 124 -131 2006年12月 [査読無し][通常論文]
  
• メソトレキセート(MTX)関連リンパ増殖性疾患と考えられた症例

  石津 明洋, 外丸 詩野, 鈴木 昭, 金井 直樹 北海道医学雑誌 81 (6) 562 -562 2006年11月 [査読無し][通常論文]
  
• NK細胞とMHC受容体 新たなマウスNKG2D ligand様分子の同定とその機能に関する解析

  富居 一範, 吉田 繁, 宮武 由甲子, 鈴木 昭, 石津 明洋, 外丸 詩野, 笠原 正典 日本免疫学会総会・学術集会記録 36 253 -253 2006年11月 [査読無し][通常論文]
  
• Churg-Strauss症候群により僧帽弁弁尖の著明な肥厚をきたした重症僧帽弁狭窄症の一例

  平林 鑑, 南田 大朗, 長津 明久, 三山 博史, 三浦 真健, 古本 智夫, 小野塚 久夫, 岡本 洋, 筒井 裕之, 杉木 宏司, 村下 十志文, 石津 明洋 Circulation Journal 70 (Suppl.III) 1187 -1187 2006年10月 [査読無し][通常論文]
  
• Churg-Strauss症候群により僧帽弁弁尖の著明な肥厚をきたした重症僧帽弁狭窄症の一例

  平林 鑑, 南田 大朗, 長津 明久, 三山 博史, 三浦 真健, 古本 智夫, 小野塚 久夫, 岡本 洋, 筒井 裕之, 杉木 宏司, 村下 十志文, 石津 明洋 Circulation Journal 70 (Suppl.III) 1187 -1187 2006年10月 [査読無し][通常論文]
  
• P-181 DNAアレイによる子宮頸部擦過細胞診検体および浸潤癌組織検体におけるHPVの検出(婦人科(子宮頸部)-(9),一般演題・示説,第45回 日本臨床細胞学会秋期大会)

  森脇 征史, 渡利 英道, 道又 理恵, 石津 明洋, 小田 秦也, 保坂 昌芳, 藤堂 幸治, 武田 真人, 蝦名 康彦, 櫻木 範明 日本臨床細胞学会雑誌 45 (2) 503 -503 2006年09月22日 [査読無し][通常論文]
  
• DNAアレイによる子宮頸部擦過細胞診検体および浸潤癌組織検体におけるHPVの検出

  森脇 征史, 渡利 英道, 道又 理恵, 石津 明洋, 小田 泰也, 保坂 昌芳, 藤堂 幸治, 武田 真人, 蝦名 康彦, 櫻木 範明 日本臨床細胞学会雑誌 45 (Suppl.2) 503 -503 2006年09月 [査読無し][通常論文]
  
• CD4/CD8 double positiveマクロファージの抗腫瘍メカニズムの検討

  馬場 智久, 岩崎 沙理, 石津 明洋, 外丸 詩野, 鈴木 昭, 池田 仁, 吉木 敬, 笠原 正典 日本癌学会総会記事 65回 329 -329 2006年09月 [査読無し][通常論文]
  
• 関節リウマチとCREB

  石津 明洋 日本臨床免疫学会会誌 = Japanese journal of clinical immunology 29 (4) 215 -215 2006年08月31日 [査読無し][通常論文]
  
• 創薬から見た免疫疾患の新たな治療ターゲット 関節リウマチとCREB

  石津 明洋 日本臨床免疫学会会誌 29 (4) 215 -215 2006年08月 [査読無し][通常論文]
  
• 潰瘍性大腸炎患者の末梢血Tリンパ球における抑制性NKレセプター発現の検討

  桂田 武彦, 外丸 詩野, 鈴木 昭, 石津 明洋, 古川 滋, 武田 宏司, 田中 淳司, 浅香 正博, 笠原 正典 日本病理学会会誌 95 (1) 196 -196 2006年04月 [査読無し][通常論文]
  
• CD4/CD8 double positiveマクロファージの抗腫瘍活性の検討

  馬場 智久, 岩崎 沙理, 石津 明洋, 鈴木 昭, 外丸 詩野, 池田 仁, 吉木 敬, 笠原 正典 日本病理学会会誌 95 (1) 201 -201 2006年04月 [査読無し][通常論文]
  
• 血管炎惹起性ラットT細胞の樹立と解析

  佐々木 直美, 石津 明洋, 外丸 詩野, 鈴木 昭, 笠原 正典, 吉木 敬 日本病理学会会誌 95 (1) 228 -228 2006年04月 [査読無し][通常論文]
  
• HTLV-I持続感染ラットの脊髄症発症におけるNeuronal IFN-γの役割

  宮武 由甲子, 石津 明洋, 池田 仁, 馬場 智久, 鈴木 昭, 外丸 詩野, 笠原 正典, 吉木 敬 日本病理学会会誌 95 (1) 231 -231 2006年04月 [査読無し][通常論文]
  
• 子宮頸部病理検体において検出されるHPVジェノタイプと臨床病理学的因子の関連

  道又 理恵, 尾川 直樹, 石津 明洋, 外丸 詩野, 鈴木 昭, 笠原 正典, 吉木 敬 日本病理学会会誌 95 (1) 291 -291 2006年04月 [査読無し][通常論文]
  
• リバビリン併用インターフェロン療法開始後,急速に肝不全をきたして死亡したHCVとHIVの重複感染例

  三次 有奈, 浅野 拓行, 石津 明洋, 外丸 詩野, 鈴木 昭, 池田 仁, 笠原 正典 日本病理学会会誌 95 (1) 382 -382 2006年04月 [査読無し][通常論文]
  
• Granulomatous slack skinの一例

  石井 生, 久田 敦史, 鈴木 昭, 近藤 信夫, 外丸 詩野, 石津 明洋, 笠原 正典 日本病理学会会誌 95 (1) 385 -385 2006年04月 [査読無し][通常論文]
  
• 動物モデルでの自己免疫疾患の解析 血管炎惹起性ラットT細胞の樹立と解析

  石津 明洋, 佐々木 直美, 外丸 詩野, 笠原 正典, 吉木 敬 日本リウマチ学会総会・学術集会・国際リウマチシンポジウムプログラム・抄録集 50回・15回 160 -160 2006年03月 [査読無し][通常論文]
  
• 自己免疫状態におけるヒト内在性レトロウイルスHERV-Rの抗原性について

  石津 明洋, 佐々木 直美, 田中 敏, 大塚 紀幸, 鈴木 昭, 外丸 詩野, 池田 仁, 笠原 正典, 吉木 敬 日本免疫学会総会・学術集会記録 35 35 -35 2005年11月 [査読無し][通常論文]
  
• 細胞傷害活性をもつCD4/CD8 double positiveマクロファージの解析

  馬場 智久, 石津 明洋, 外丸 詩野, 鈴木 昭, 池田 仁, 吉木 敬, 笠原 正典 日本免疫学会総会・学術集会記録 35 124 -124 2005年11月 [査読無し][通常論文]
  
• HTLV-I感染ラットにおける脊髄症の発症にはニューロンでのIL-12を介したIFN-γの産生不応答が関与する

  宮武 由甲子, 池田 仁, 石津 明洋, 外丸 詩野, 鈴木 昭, 吉木 敬, 笠原 正典 日本免疫学会総会・学術集会記録 35 177 -177 2005年11月 [査読無し][通常論文]
  
• 原疾患の増悪に対するステロイド増量後に大動脈瘤破裂をきたして死亡した皮膚筋炎の症例

  佐々木 直美, 石津 明洋, 鈴木 昭, 外丸 詩野, 笠原 正典, 保田 晋助, 桜井 典之 北海道医学雑誌 80 (5) 537 -537 2005年09月 [査読無し][通常論文]
  
• DNAアレイ法を用いた子宮頸癌症例のHPVジェノタイピング

  道又 理恵, 尾川 直樹, 石津 明洋, 渡利 英道, 鈴木 昭, 外丸 詩野, 櫻木 範明, 笠原 正典, 吉木 敬 日本癌学会総会記事 64回 93 -93 2005年09月 [査読無し][通常論文]
  
• HTLV-I感染によるHAMラット病の発症はニューロンにおけるIL-12を介したIFN-γの反応性に依存する

  宮武 由甲子, 池田 仁, 馬場 智久, 道又 理恵, 鈴木 昭, 外丸 詩野, 石津 明洋, 吉木 敬, 笠原 正典 日本癌学会総会記事 64回 343 -343 2005年09月 [査読無し][通常論文]
  
• DNA array法を用いた子宮頸部浸潤癌組織中ヒトパピローマウイルス(HPV)の検出

  渡利 英道, 道又 理恵, 石津 明洋, 安田 元昭, 櫻木 範明 日本癌治療学会誌 40 (2) 534 -534 2005年09月 [査読無し][通常論文]
  
• 【関節リウマチの動物モデルでの新しい治療】 転写因子CREBを標的とした関節炎の治療

  石津 明洋 分子リウマチ 2 (3) 194 -198 2005年08月 [査読無し][通常論文]
  
• 血管炎のモデル動物 (第1土曜特集 血管炎の基礎と臨床) -- (基礎)

  石津 明洋 医学のあゆみ 214 (1) 9 -12 2005年07月02日 [査読無し][通常論文]
  
• 【血管炎の基礎と臨床】 基礎 血管炎のモデル動物

  石津 明洋 医学のあゆみ 214 (1) 9 -12 2005年07月 [査読無し][通常論文]
   

  ヒト血管炎は障害される血管のサイズにより大型・中型・小型血管炎に分類される.また,その病理組織像は内皮下および中膜にフィブリノイド壊死を伴うもの,主として中・外膜に肉芽腫を形成するもの,血栓形成を伴うものなど多彩である.病因として宿主の遺伝的素因に加えて微生物抗原あるいは自己抗原が重要であると推定されており,これまでにII型・III型・IV型アレルギーの関与や血管攣縮,血管機能修飾などが血管炎発症にかかわる免疫学的・非免疫学的機構として解析されてきた.このような多因子疾患の病因の究明やその予防法,治療薬の開発にはモデル動物が欠かせない.本稿ではこれまでに研究されてきた血管炎のモデル動物を紹介するとともに,これらモデル動物における血管炎の発症機構を概説する(著者抄録)
• 膠原病研究の新たな展開 分子病態と制御モデル HTLV-I pX遺伝子導入ラットと正常Wistarラットの交配種における胸腺異常とchronic GVHD様疾患の発症

  石津 明洋, 馬場 智久, 外丸 詩野, 池田 仁, 吉木 敬 日本リウマチ学会総会・学術集会・国際リウマチシンポジウムプログラム・抄録集 49回・14回 116 -116 2005年04月 [査読無し][通常論文]
  
• ラットモデルを用いた壊死性血管炎発症機序の解析

  佐々木 直美, 石津 明洋, 鈴木 昭, 外丸 詩野, 笠原 正典, 吉木 敬 日本病理学会会誌 94 (1) 213 -213 2005年03月 [査読無し][通常論文]
  
• HTLV-I pX遺伝子導入ラットと正常Wistarラットの交配種における胸腺異常と免疫病理

  馬場 智久, 石津 明洋, 鈴木 昭, 外丸 詩野, 池田 仁, 笠原 正典, 吉木 敬 日本病理学会会誌 94 (1) 219 -219 2005年03月 [査読無し][通常論文]
  
• ヒトCD4,CCR5,MHC class II transactivator遺伝子導入ラットの作製と末梢血単核球へのHIV-1の感染

  鈴木 昭, 陳 晶, 馬場 智久, 外丸 詩野, 石津 明洋, 池田 仁, 笠原 正典, 吉木 敬 日本病理学会会誌 94 (1) 225 -225 2005年03月 [査読無し][通常論文]
  
• T細胞による抗原提示と免疫制御

  外丸 詩野, 山野 嘉久, 鈴木 昭, 石津 明洋, 吉木 敬, 笠原 正典 日本病理学会会誌 94 (1) 370 -370 2005年03月 [査読無し][通常論文]
  
• HIV・HCV重複感染の治療経過中,急速に致死的肝不全を来した血友病Aの1例

  曽我部 進, 橋野 聡, 小野澤 真弘, 守田 玲菜, 太宰 昌佳, 夏井坂 光輝, 小野 雄司, 泉山 康, 中馬 誠, 近藤 健, 髭 修平, 大野 稔子, 渡部 恵子, 石津 明洋, 浅香 正博 日本エイズ学会誌 7 (1) 37 -42 2005年02月 [査読無し][通常論文]
   

  35歳男性.血友病Aに対し使用した血液製剤でHIV・HCVに感染し,1990年よりAZT+ddI投与を開始した.以後,服薬コンプライアンスの問題から,2001年にAZT+3TC+NFV変更,2003年1月よりRTV+LPVに変更した.同年9月からHAART+IFN+リバビリンを併用療法を開始したところ,1ヵ月後より乳酸アシドーシス(LA)が出現した.投薬を中止し,各種対症療法を行ったが,食道静脈瘤の悪化・破裂による循環不全と肝不全にて併用療法開始2ヵ月後に死亡した.原因としては,HAARTとリバビリンの併用によるLA,LPV/RTVまたはNRTIによる薬剤性肝障害,慢性C型肝炎の急激な悪化の3点が考えられた
• incidentalに発見された非機能性膵内分泌腫瘍の2例

  広瀬 邦弘, 渡辺 正明, 高橋 周作, 佐治 裕, 今野 哲朗, 石津 明洋 北海道外科雑誌 49 (2) 191 -191 2004年12月 [査読無し][通常論文]
  
• HTLV-I感染によるHAMラット病感受性および抵抗性は脊髄における宿主の対ウイルス反応性に依存する

  宮武 由甲子, 池田 仁, 鈴木 昭, 馬場 智久, 道又 理恵, 外丸 詩野, 石津 明洋, 吉木 敬 日本免疫学会総会・学術集会記録 34 95 -95 2004年11月 [査読無し][通常論文]
  
• T細胞による抗原提示と免疫制御機構

  外丸 詩野, 山野 嘉久, 石津 明洋, 吉木 敬 日本免疫学会総会・学術集会記録 34 100 -100 2004年11月 [査読無し][通常論文]
  
• HTLV-IpX遺伝子導入ラットと正常Wistarラットの交配種における胸腺異常とchronic GVHD様疾患の発症

  馬場 智久, 石津 明洋, 宮武 由甲子, 鈴木 昭, 外丸 詩野, 池田 仁, 吉木 敬 日本免疫学会総会・学術集会記録 34 278 -278 2004年11月 [査読無し][通常論文]
  
• 【自己免疫疾患の病態形成に関する新たな細胞・分子・遺伝子】 HTLV-I env-pX遺伝子導入ラットにおけるCD25+CD4+T細胞機能異常と自己免疫疾患の発症

  石津 明洋 臨床免疫 42 (4) 415 -420 2004年10月 [査読無し][通常論文]
  
• ストレス環境下における培養骨細胞のapoptosis関連遺伝子の発現に関する検討

  辻 宗啓, 池田 仁, 石津 明洋, 吉木 敬 北海道医学雑誌 79 (4) 476 -476 2004年07月 [査読無し][通常論文]
  
• Sweet病に合併した食道癌の1切除例

  加藤 弘明, 本原 敏司, 黒川 貴則, 敷島 裕之, 金子 行宏, 本多 加奈, 近藤 仁, 村松 哲理, 安田 泉, 石津 明洋, 前田 和男 北海道外科雑誌 49 (1) 57 -57 2004年06月 [査読無し][通常論文]
  
• 免疫の多様性 自己免疫疾患モデルとしてのHTLV-I env-pX遺伝子導入ラット

  石津 明洋, 早瀬 広子, 宮武 由甲子, 富居 一範, 樋口 正人, 阿部 麻美, 外丸 詩野, 池田 仁, 吉木 敬 日本病理学会会誌 93 (1) 163 -163 2004年05月 [査読無し][通常論文]
  
• ペプチド/HLA複合体の抗原特異的T細胞による獲得 抗原提示の新しい増幅メカニズム

  外丸 詩野, 山野 嘉久, 石津 明洋, 池田 仁, 吉木 敬 日本病理学会会誌 93 (1) 239 -239 2004年05月 [査読無し][通常論文]
  
• HTLV-1 pXトランスジェニックラットと正常Wistarラットの交配種における全身性炎症性疾患の発症

  馬場 智久, 石津 明洋, 宮武 由甲子, 外丸 詩野, 池田 仁, 吉木 敬 日本病理学会会誌 93 (1) 240 -240 2004年05月 [査読無し][通常論文]
  
• ストレス環境下における培養骨細胞のapoptosis関連遺伝子の発現に関する検討

  辻 宗啓, 吉木 敬, 池田 仁, 石津 明洋 日本病理学会会誌 93 (1) 241 -241 2004年05月 [査読無し][通常論文]
  
• HTLV-I感染によるHAM感受性ラット及び抵抗性ラットの脊髄における遺伝子発現の解析

  宮武 由甲子, 外丸 詩野, 石津 明洋, 池田 仁, 吉木 敬 日本病理学会会誌 93 (1) 249 -249 2004年05月 [査読無し][通常論文]
  
• HTLV-IトランスジェニックラットにおけるCD4+CD25+regulatory T cellの解析

  早瀬 広子, 石津 明洋, 宮武 由甲子, 外丸 詩野, 池田 仁, 吉木 敬 日本病理学会会誌 93 (1) 294 -294 2004年05月 [査読無し][通常論文]
  
• ヒト大腸癌培養株DLD-1細胞とその5-FU耐性株の比較

  伊藤 僚子, 吉木 敬, 池田 仁, 石津 明洋, 外丸 詩野 日本病理学会会誌 93 (1) 304 -304 2004年05月 [査読無し][通常論文]
  
• リウマチ性疾患を発症するHTLV-I遺伝子導入ラットにおける免疫制御性CD25+4+T細胞の解析

  早瀬 広子, 石津 明洋, 宮武 由甲子, 外丸 詩野, 池田 仁, 吉木 敬 日本リウマチ学会総会・学術集会・国際リウマチシンポジウムプログラム・抄録集 48回 172 -172 2004年03月 [査読無し][通常論文]
  
• ストレス環境下における培養骨細胞のapoptosis関連遺伝子の発現に関する検討

  辻 宗啓, 池田 仁, 石津 明洋, 吉木 敬 日本リウマチ学会総会・学術集会・国際リウマチシンポジウムプログラム・抄録集 48回 277 -277 2004年03月 [査読無し][通常論文]
  
• 転写因子CREBを標的とした関節リウマチの遺伝子治療モデル

  石津 明洋, 馬場 智久, 早瀬 広子, 外丸 詩野, 池田 仁, 吉木 敬 日本リウマチ学会総会・学術集会・国際リウマチシンポジウムプログラム・抄録集 48回 317 -317 2004年03月 [査読無し][通常論文]
  
• 【自己免疫疾患における分子標的遺伝子治療の展望】 CREB分子

  石津 明洋 臨床免疫 40 (6) 654 -658 2003年12月 [査読無し][通常論文]
  
• HTLV-1トランスジェニックラットにおけるCD25+4+ regulatory T cellの解析

  早瀬 広子, 石津 明洋, 宮武 由甲子, 外丸 詩野, 池田 仁, 吉木 敬 日本免疫学会総会・学術集会記録 33 42 -42 2003年11月 [査読無し][通常論文]
  
• 肝原発悪性炎症性偽腫瘍の一例

  佐治 裕, 廣瀬 邦弘, 高橋 周作, 五十川 晋, 石津 明洋 日本臨床外科学会雑誌 64 (増刊) 685 -685 2003年10月 [査読無し][通常論文]
  
• コラーゲン関節炎誘導によるHTLV-I env-pX遺伝子導入ラットの関節炎発症及び持続機序の検討

  阿部 麻美, 石津 明洋, 辻 宗啓, 早瀬 広子, 菅谷 寿晃, 鈴木 昭, 高橋 利幸, 池田 仁, 吉木 敬 北海道医学雑誌 78 (5) 468 -468 2003年09月 [査読無し][通常論文]
  
• 痒疹を伴い,鼠径リンパ節を主病巣とした木村病の1例

  岸部 麻里, 岸山 和敬, 新里 順勝, 石津 明洋, 飛澤 慎一 日本皮膚科学会雑誌 113 (10) 1566 -1566 2003年09月 [査読無し][通常論文]
  
• 遺伝子発現プロファイル・パターン識別による膵癌の個性診断の試み

  松永 明宏, 多田 光宏, 西村 訓弘, 白田 勝利, 石津 明洋, 浜田 淳一, 宮本 正樹, 川上 明子, 近藤 哲, 池田 仁, 加藤 紘之, 守内 哲也, 吉木 敬 日本癌学会総会記事 62回 175 -175 2003年08月 [査読無し][通常論文]
  
• 遺伝子発現プロファイル・パターン識別による膵癌の個性診断の試み

  松永 明宏, 多田 光宏, 西村 訓弘, 白田 勝利, 石津 明洋, 浜田 淳一, 宮本 正樹, 川上 明子, 近藤 哲, 池田 仁, 加藤 紘之, 守内 哲也, 吉木 敬 日本癌学会総会記事 62回 175 -175 2003年08月 [査読無し][通常論文]
  
• cDNA microarrayを用いた胃癌における特徴的遺伝子発現プロフィールの検討

  寺本 賢一, 多田 光宏, 西村 訓弘, 白田 勝利, 川上 明子, 宮本 正樹, 浜田 淳一, 石津 明洋, 近藤 哲, 池田 仁, 加藤 紘之, 守内 哲也, 吉木 敬 日本癌学会総会記事 62回 210 -210 2003年08月 [査読無し][通常論文]
  
• 遺伝子発現プロフィールパターン識別による大腸癌の個性診断の試み

  小室 一輝, 多田 光宏, 川上 明子, 白田 勝利, 西村 訓弘, 石津 明洋, 浜田 淳一, 宮本 正樹, 近藤 哲, 池田 仁, 加藤 紘之, 守内 哲也, 吉木 敬 日本癌学会総会記事 62回 210 -211 2003年08月 [査読無し][通常論文]
  
• cDNAアレイを用いた食道扁平上皮癌における遺伝子発現解析

  田本 英司, 多田 光宏, 西村 訓弘, 白田 勝利, 石津 明洋, 浜田 淳一, 宮本 正樹, 川上 明子, 近藤 哲, 池田 仁, 加藤 紘之, 守内 哲也, 吉木 敬 日本癌学会総会記事 62回 211 -211 2003年08月 [査読無し][通常論文]
  
• HTLV-1 pXトランスジェニックラット胸腺腫の悪性化とp16遺伝子異常の解析

  辻 隆裕, 池田 仁, 外丸 詩野, 石津 明洋, 吉木 敬 日本癌学会総会記事 62回 241 -241 2003年08月 [査読無し][通常論文]
  
• HTLV-1 Env領域におけるCD8+T細胞エピトープの同定 抗原特異的Tリンパ球の新たな検出法

  外丸 詩野, 山野 嘉久, 石津 明洋, 池田 仁, 吉木 敬 日本癌学会総会記事 62回 242 -242 2003年08月 [査読無し][通常論文]
  
• 肝細胞癌における遺伝子発現プロファイル

  金井 基錫, 多田 光宏, 川上 明子, 白田 勝利, 西村 訓弘, 石津 明洋, 濱田 淳一, 宮本 正樹, 近藤 哲, 池田 仁, 加藤 紘之, 守内 哲也, 吉木 敬 日本癌学会総会記事 62回 348 -348 2003年08月 [査読無し][通常論文]
  
• ウイルス誘発のモデル動物 (血管炎研究がめざすあらたな展開) -- (血管炎発症機構の解析研究)

  石津 明洋, 吉木 敬 医学のあゆみ 206 (2) 143 -145 2003年07月12日 [査読無し][通常論文]
  
• 【血管炎研究がめざすあらたな展開】 ウイルス誘発のモデル動物

  石津 明洋, 吉木 敬 医学のあゆみ 206 (2) 143 -145 2003年07月 [査読無し][通常論文]
   

  ヒト血管炎の病理組織像は,内皮下及び中膜のフィブリノイド壊死を伴うもの,主として中外膜に肉芽腫を形成するもの,血栓形成を伴うものなど多彩である.病因としては宿主の遺伝的素因に加えて微生物抗原或いは自己抗原が重要であると推定されている.そこで,これまでに研究されてきた血管炎のモデル動物の中から,発症にウイルスが関与するモデルを紹介した
• 自己免疫疾患の分子病理 HTLV-I env-pX遺伝子導入ラットに認める免疫異常と自己免疫疾患の発症

  石津 明洋, 富居 一範, 早瀬 広子, 樋口 正人, 阿部 麻美, 辻 宗啓, 辻 隆裕, 高橋 利幸, 池田 仁, 吉木 敬 日本病理学会会誌 92 (1) 167 -167 2003年04月 [査読無し][通常論文]
  
• コラーゲン関節炎誘導によるHTLV-I env-pX遺伝子導入ラットの関節炎発症及び持続機序の検討

  阿部 麻美, 石津 明洋, 辻 宗啓, 早瀬 広子, 菅谷 壽晃, 鈴木 昭, 辻 隆裕, 高橋 利幸, 池田 仁, 吉木 敬 日本病理学会会誌 92 (1) 223 -223 2003年04月 [査読無し][通常論文]
  
• 異所性移植によるHTLV-I pXトランスジェニックラット胸腺腫の悪性転化とその遺伝子解析

  辻 隆裕, 池田 仁, 石津 明洋, 高橋 利幸, 吉木 敬 日本病理学会会誌 92 (1) 244 -244 2003年04月 [査読無し][通常論文]
  
• HERV-RトランスジェニックラットにおけるEnv蛋白発現と抗原性の解析

  大塚 紀幸, 田中 敏, 山本 友希代, 石津 明洋, 池田 仁, 吉木 敬 日本病理学会会誌 92 (1) 256 -256 2003年04月 [査読無し][通常論文]
  
• 検体採取後の室温放置によるcDNAアレイ解析結果への影響

  宮武 由甲子, 池田 仁, 石津 明洋, 高橋 利幸, 吉木 敬 日本病理学会会誌 92 (1) 285 -285 2003年04月 [査読無し][通常論文]
  
• TNF-α及びステロイド投与によるヒト培養血管内皮細胞の遺伝子発現への影響

  山本 友希代, 池田 仁, 石津 明洋, 辻 隆裕, 高橋 利幸, 吉木 敬 日本病理学会会誌 92 (1) 291 -291 2003年04月 [査読無し][通常論文]
  
• リウマチの動物モデルと遺伝子治療 Dominant Negative ATF-1を組み込んだシンビスウイルスベクターによる関節リウマチの遺伝子治療モデル

  石津 明洋 リウマチ 43 (2) 235 -235 2003年03月 [査読無し][通常論文]
  
• HTLV-I env-pX遺伝子導入ラットに認める関節炎の発症ならびに持続機序に関する検討

  阿部 麻美, 石津 明洋, 辻 宗啓, 早瀬 広子, 菅谷 壽晃, 鈴木 昭, 高橋 利幸, 池田 仁, 吉木 敬 リウマチ 43 (2) 411 -411 2003年03月 [査読無し][通常論文]
  
• 外陰部に発症した乳房外Paget病の1例

  島田 裕子, 坂井 紀夫, 青柳 哲, 村田 純子, 石津 明洋 苫小牧市立病院医誌 16 (1) 31 -33 2003年03月 [査読無し][通常論文]
   

  80歳女.外陰部の紅斑を主訴とした.10年前から外陰部に自覚症状を伴わない皮疹が出現し,抗真菌外用薬を処方されていたが改善しなかった.また,陳旧性心筋梗塞,糖尿病,高血圧,甲状腺機能低下,右大腿深部静脈血栓症のため内科に入院中であった.紅斑の病理組織学的所見で表皮の基底層に類円形の核と胞体の明るい大型の異型細胞が胞巣状に増殖し,生検部位では明らかな基底層の破壊は認めなかった.異型細胞の一部はPAS染色・アルシアンブルー染色・CEA陽性であった.以上より,外陰部に発症した乳房外Paget病と診断し,臨床検査所見よりT1N0M0,病期IAと診断した.治療としては本来ならば局所切除あるいは化学療法を選択すべきであるが,切除術を行う場合,直腸への進展があるため人工肛門造設を行わざるを得ずQOLを著しく損なうこと,80歳と高齢であり,陳旧性心筋梗塞,糖尿病,高血圧と合併症が多いことから手術療法あるいは化学療法は施行できないと判断し,放射線療法を選択する予定である
• Tissue specific expression of the Env protein in fetus rats carrying a full length HERV-R gene.

  N Otsuka, H Ikeda, S Tanaka, A Ishizu, T Yoshiki AIDS RESEARCH AND HUMAN RETROVIRUSES 19 S67 -S67 2003年 [査読無し][通常論文]
  
• Comparative characterization of CD25+CD4+T cells between HTLV-I transgenic and wild type rats.

  H Hayase, A Ishizu, M Higuchi, A Abe, M Tsuji, H Ikeda, T Yoshiki AIDS RESEARCH AND HUMAN RETROVIRUSES 19 S38 -S39 2003年 [査読無し][通常論文]
  
• Malignant transformation of epithelial thymoma developed in HTLV-I pX transgenic rat by heterotopic transplantation and its molecular analysis.

  T Tsuji, H Ikeda, A Ishizu, T Takahashi, T Yoshiki AIDS RESEARCH AND HUMAN RETROVIRUSES 19 S71 -S72 2003年 [査読無し][通常論文]
  
• A transgenic rat model of HTLV-I induced immunological diseases: Effect of the env-pX transgene to effector cells and target tissues in collagen induced arthritis.

  H Ikeda, A Abe, A Ishizu, H Hayase, T Yoshiki AIDS RESEARCH AND HUMAN RETROVIRUSES 19 S68 -S68 2003年 [査読無し][通常論文]
  
• HTLV-I env-pX遺伝子導入ラットにおける関節炎発症機序に関する検討

  阿部 麻美, 石津 明洋, 辻 宗啓, 早瀬 広子, 菅谷 寿晃, 鈴木 昭, 高橋 利幸, 池田 仁, 吉木 啓 北海道医学雑誌 78 (1) 91 -91 2003年01月 [査読無し][通常論文]
  
• 異所性移植によるHTLV-1 pXトランスジェニックラット胸腺腫の悪性化とその解析

  辻 隆裕, 池田 仁, 菊地 和徳, 土川 貴裕, 富居 一範, 石津 明洋, 高橋 利幸, 吉木 敬 日本癌学会総会記事 61回 58 -58 2002年10月 [査読無し][通常論文]
  
• ヒト卵巣癌の腹膜播種株の樹立とcDNAアレイ法を用いた遺伝子発現の変化の検討

  伊藤 僚子, 古屋 充子, 田原 正彦, 石津 明洋, 高橋 利幸, 池田 仁, 吉木 敬 日本癌学会総会記事 61回 118 -118 2002年10月 [査読無し][通常論文]
  
• AFPプロモーターで発現するHSVtk遺伝子の導入によるAFP産生胃癌細胞の自殺遺伝子治療モデル

  仲屋 裕樹, 石津 明洋, 高橋 利幸, 池田 仁, 石倉 浩, 吉木 敬 日本癌学会総会記事 61回 475 -475 2002年10月 [査読無し][通常論文]
  
• HTLV-1 env-pX遺伝子導入ラットに認める関節炎の発症ならびに持続機序に関する検討

  阿部 麻美, 石津 明洋, 辻 宗啓, 早瀬 広子, 菅谷 寿晃, 鈴木 昭, 高橋 利幸, 池田 仁, 吉木 敬 日本免疫学会総会・学術集会記録 32 296 -296 2002年10月 [査読無し][通常論文]
  
• 外科的切除にて診断された縦隔原発悪性リンパ腫の1例

  加藤 弘明, 宮崎 康政, 敷島 裕之, 金子 行宏, 小泉 和輝, 石津 明洋, 本原 敏司 北海道外科雑誌 47 (1) 63 -63 2002年06月 [査読無し][通常論文]
  
• ラット樹状細胞と腫瘍細胞との融合細胞を用いた抗腫瘍免疫誘導の試み

  川田 将也, 池田 仁, 高橋 利幸, 石津 明洋, 石倉 浩, 近藤 哲, 加藤 紘之, 吉木 敬 日本外科学会雑誌 103 (0) 653 -653 2002年03月10日 [査読無し][通常論文]
  
• ERV3トランスジェニックラットにおけるヒトレトロウイルス外被蛋白発現と免疫機能の解析

  大塚 紀幸, 田中 敏, 山本 友希代, 石津 明洋, 池田 仁, 吉木 敬 日本病理学会会誌 91 (1) 201 -201 2002年03月 [査読無し][通常論文]
  
• HTLV-I env-px遺伝子導入ラットにおける関節炎発症機序に関する検討

  阿部 麻美, 石津 明洋, 辻 宗啓, 早瀬 広子, 菅谷 尋晃, 池田 仁, 吉木 敬 リウマチ 42 (2) 386 -386 2002年03月 [査読無し][通常論文]
  
• HTLV-I env-pX遺伝子導入ラットの関節炎発症機序に関する検討

  阿部 麻美, 石津 明洋, 辻 宗啓, 早瀬 広子, 菅谷 寿晃, 池田 仁, 吉木 敬 日本病理学会会誌 91 (1) 201 -201 2002年03月 [査読無し][通常論文]
  
• ラット樹状細胞と腫瘍細胞との融合細胞を用いた抗腫瘍免疫誘導の検討

  川田 将也, 池田 仁, 高橋 利幸, 石津 明洋, 石倉 浩, 吉木 敬 日本病理学会会誌 91 (1) 224 -224 2002年03月 [査読無し][通常論文]
  
• HTLV-I pXトランスジェニックラットに発生した腫瘍における遺伝子発現の検討

  辻 隆裕, 菊地 和徳, 土川 貴裕, 宮武 由甲子, 石津 明洋, 高橋 利幸, 池田 仁, 吉木 敬 日本病理学会会誌 91 (1) 224 -224 2002年03月 [査読無し][通常論文]
  
• 【リウマチ性疾患とウイルス】 ウイルス遺伝子導入ラットとリウマチ性病態

  石津 明洋, 吉木 敬 リウマチ科 27 (3) 213 -217 2002年03月 [査読無し][通常論文]
  
• PVeBV療法が奏効した進行性精巣腫瘍の一例

  佐野 洋, 豊田 健一, 阿部 彌理, 石津 明洋 泌尿器外科 15 (3) 269 -269 2002年03月 [査読無し][通常論文]
  
• 【免疫疾患 state of arts】 病態に関する基礎的研究の進歩 HAM/TSPのラットモデル

  石津 明洋, 吉木 敬 医学のあゆみ 別冊 (免疫疾患-state of arts Ver.2) 331 -335 2002年03月 [査読無し][通常論文]
   

  HAM/TSP(HTLV-1関連ミエロパチー/熱帯性痙性脊髄対麻痺)はHTLV-Iによる脊髄症である.HAM/TSPのラットモデルとなるHTLV-I持続感染ラット及びHTLV-I遺伝子導入ラットについて概説した
• 卵巣成人型顆粒膜細胞腫の1例

  小田切 哲二, 佐藤 修, 花谷 馨, 佐治 裕, 春原 伸行, 池田 仁, 石津 明洋 苫小牧市立病院医誌 15 (1) 10 -15 2002年03月 [査読無し][通常論文]
   

  stage Iaと診断されたが術後2日目から左頸部リンパ節腫大が起こり,遠隔転移が術後早期に発見された52歳症例を経験した.AGCTの再発例及び進行例では確立された治療法は無いのが現状であるが,藤本等の卵巣成人型顆粒膜細胞腫の予後因子の報告を元に検討した.核分裂活性(MC)が13/10HPF・脈管侵襲が中等度であることから,予後不良であることが予想され,今後治療において厳重管理が必要である
• 【リウマチ科診療マニュアル】 基礎知識 モデル動物からみたリウマチ性疾患

  辻 宗啓, 石津 明洋, 池田 仁, 吉木 敬 リウマチ科 27 (Suppl.1) 101 -106 2002年02月 [査読無し][通常論文]
  
• HTLV-I遺伝子導入ラットに認める壊死性血管炎の発症機序に関する研究 (厚生労働省S)

  吉木敬, 石津明洋, 池田仁, 富居一範, 早瀬広子, 辻宗啓, 阿部麻美 難治性血管炎に関する調査研究 平成13年度総括研究報告書 2002年
• 異所性移植によるHTLV-I pXトランスジェニックラット胸腺腫の悪性化とその解析

  辻隆裕, 池田仁, 菊地和徳, 土川貴裕, 富居一範, 石津明洋, 高橋利幸, 吉木敬 日本癌学会総会記事 61st 2002年
• 自己免疫疾患の病因・病態解析と新たな治療法の開発に関する研究

  小池 隆夫, 竹内 勤, 鍔田 武志, 西本 憲弘, 広瀬 幸子, 松下 祥, 宮坂 信之, 石津 明洋, 江口 勝美, 加藤 智啓, 佐々木 毅, 篠原 隆司, 菅井 進, 田中 良哉, 徳永 勝士, 西村 孝司, 橋本 博史, 原 まさ子, 平形 道人, 松浦 栄次, 簑田 清次, 三村 俊英 日本臨床免疫学会会誌 = Japanese journal of clinical immunology 24 (6) 347 -354 2001年12月31日 [査読無し][通常論文]
  
• HTLV-Iトランスジェニックラットにおける壊死性血管炎発症機序の解析

  早瀬 広子, 池田 仁, 富居 一範, 辻 宗啓, 阿部 麻美, 石津 明洋, 吉木 敬 日本免疫学会総会・学術集会記録 31 76 -76 2001年12月 [査読無し][通常論文]
  
• ERV3トランスジェニックラットにおけるヒトレトロウイルス外被蛋白発現の解析

  大塚 紀幸, 田中 敏, 山本 友希代, 石津 明洋, 池田 仁, 吉木 敬 日本免疫学会総会・学術集会記録 31 116 -116 2001年12月 [査読無し][通常論文]
  
• HTLV-I pXトランスジェニックラットに発生する上皮型胸腺腫は骨髄細胞に由来する

  辻 隆裕, 池田 仁, 土川 貴裕, 菊地 和徳, 富居 一範, 石津 明洋, 吉木 敬 日本免疫学会総会・学術集会記録 31 145 -145 2001年12月 [査読無し][通常論文]
  
• HTLV-1 pXトランスジェニックラットに発症する腫瘍の腫瘍化機構の解析

  辻 隆裕, 池田 仁, 菊地 和徳, 土川 貴裕, 富居 一範, 石津 明洋, 高橋 利幸, 吉木 敬 日本癌学会総会記事 60回 303 -303 2001年09月 [査読無し][通常論文]
  
• ラット樹状細胞と腫瘍細胞との融合細胞を用いた抗腫瘍免疫誘導の試み

  川田 将也, 池田 仁, 高橋 利幸, 石津 明洋, 加藤 紘之, 石倉 浩, 吉木 敬 日本癌学会総会記事 60回 489 -489 2001年09月 [査読無し][通常論文]
  
• HTLV-I LTR-env-pXトランスジェニックラットにおける臓器特異的自己免疫疾患の発症機序に関する検討

  富居 一範, 池田 仁, 樋口 正人, 辻 宗啓, 阿部 麻美, 石津 明洋, 吉木 敬 北海道医学雑誌 76 (5) 363 -363 2001年09月 [査読無し][通常論文]
  
• lck-pXトランスジェニックラットに発生する胸腺腫細胞の由来に関する検討

  土川 貴裕, 池田 仁, 菊地 和徳, 辻 隆裕, 石津 明洋, 高橋 利幸, 近藤 哲, 加藤 紘之, 吉木 敬 日本呼吸器外科学会雑誌 15 (5) 巻頭2 -巻頭3 2001年07月 [査読無し][通常論文]
  
• Pathogenesis implicated in the necrotizing arteritis in transgenic rats carrying HTLV-I LTR-env-pX gene

  ISHIZU Akihiro リウマチ 41 (2) 259 -259 2001年04月17日
• HTLV-1 LTR-env-pXトランスジェニックラットにおける臓器特異的自己免疫疾患の発症機序に関する検討

  富居 一範, 池田 仁, 樋口 正人, 辻 宗啓, 阿部 麻美, 石津 明洋, 吉木 敬 リウマチ 41 (2) 472 -472 2001年04月 [査読無し][通常論文]
  
• SF3c-4 膵癌高腹膜播種性転移株の樹立とその遺伝子解析

  田原 正彦, 池田 仁, 川田 将也, 和田 隆宜, 石津 明洋, 高橋 利幸, 近藤 哲, 吉木 敬, 加藤 紘之 日本外科学会雑誌 102 (0) 72 -72 2001年03月10日 [査読無し][通常論文]
  
• PP1246 HTLV-IpXトランスジェニックラットの胸腺腫瘍発生機序の解析

  土川 貴裕, 池田 仁, 菊地 和徳, 辻 隆裕, 石津 明洋, 近藤 哲, 加藤 紘之, 吉木 敬 日本外科学会雑誌 102 (0) 535 -535 2001年03月10日 [査読無し][通常論文]
  
• ERV3トランスジェニックラットにおけるヒトレトロウイルス外被蛋白発現の解析

  大塚 紀幸, 田中 敏, 山本 友希代, 石津 明洋, 柴田 雅彦, 池田 仁, 吉木 敬 日本病理学会会誌 90 (1) 156 -156 2001年03月 [査読無し][通常論文]
  
• HTLV-I pXトランスジェニックラットに好発する上皮性胸腺腫は骨髄単核球由来細胞から発生する

  土川 貴裕, 池田 仁, 菊地 和徳, 辻 隆裕, 富居 一範, 石津 明洋, 高橋 利幸, 吉木 敬 日本病理学会会誌 90 (1) 146 -146 2001年03月 [査読無し][通常論文]
  
• HTLV-I LTR-env-pXトランスジェニックラットにおける自己免疫疾患発症に関する検討

  富居 一範, 池田 仁, 樋口 正人, 辻 宗啓, 阿部 麻美, 石津 明洋, 吉木 敬 日本病理学会会誌 90 (1) 156 -156 2001年03月 [査読無し][通常論文]
  
• 膵癌高腹膜転移株の樹立とそれに関する遺伝子解析

  田原 正彦, 池田 仁, 石倉 浩, 川田 将也, 石津 明洋, 高橋 利幸, 吉木 敬 日本病理学会会誌 90 (1) 149 -149 2001年03月 [査読無し][通常論文]
  
• HTLV-IpXトランスジェニックラットの胸腺腫瘍発生機序の解析

  土川 貴裕, 池田 仁, 菊地 和徳, 辻 隆裕, 石津 明洋, 近藤 哲, 加藤 紘之, 吉木 敬 日本外科学会雑誌 102 (臨増) 535 -535 2001年03月 [査読無し][通常論文]
  
• 膵癌高腹膜播種性転移株の樹立とその遺伝子解析

  田原 正彦, 池田 仁, 川田 将也, 和田 隆宜, 石津 明洋, 高橋 利幸, 近藤 哲, 吉木 敬, 加藤 紘之 日本外科学会雑誌 102 (臨増) 72 -72 2001年03月 [査読無し][通常論文]
  
• 当院における過去6年間の剖検症例の概要

  阿部 雅一, 亀谷 勝春, 寺邑 弘, 松永 徹, 羽根川 立人, 山下 真知子, 石津 明洋, 高橋 利幸, 池田 仁, 清水 道生, 吉木 敬 函館中央病院医誌 5 (5) 6 -8 2001年03月 [査読無し][通常論文]
   

  16歳以上の死亡患者1473名のうち41名(男22名,女19名,平均66.9歳)に剖検を行い,疾患臓器は消化器52%,血液疾患15%,呼吸器8%であった.主病変における非正診は,腫瘍性疾患24例中2例で,脾腫瘍を疑った腎細胞癌例と,鬱血性心不全として加療した腫瘍び漫性浸潤による心不全例であった.非腫瘍疾患17例での非正診は2例で,不明熱とした置換弁膜の亜急性細菌性弁膜炎による敗血症例と,腸閉塞で入院し急死した上腸間膜静脈血栓症に伴う小腸壊死症例であった.死因又は重大な合併症に関する非正診は41例中2例3病変で,腹部大動脈瘤破裂,胸部大動脈破裂,肺結核であった
• HTLV-I LTR-env-pX遺伝子導入ラット(env-pXラット)に認める血管炎の発症機序の解析と治療 (厚生労働省S)

  吉木敬, 石津明洋, 池田仁, 富居一範, 樋口正人, 辻宗啓, 阿部麻美 難治性血管炎に関する調査研究 平成12年度総括研究報告書 2001年
• HTLV-I LTR-env-pXトランスジェニックラットにおける臓器特異的自己免疫疾患の発症機序に関する検討

  富居一範, 池田仁, 樋口正人, 辻宗啓, 阿部麻美, 石津明洋, 吉木敬 リウマチ 41 (2) 2001年
• HTLV-I pXトランスジェニックラットに発症する腫ようの腫よう化機構の解析

  辻隆裕, 池田仁, 菊地和徳, 土川貴裕, 富居一範, 石津明洋, 高橋利幸, 吉木敬 日本癌学会総会記事 60th 2001年
• Functional abnormality of CD25+CD4+T cells in HTLV-I LTR-env-pX transgenic rats; A model for collagen vascular diseases in humans.

  A Ishizu, M Higuchi, K Fugo, M Tsuji, A Abe, H Ikeda, T Yoshiki AIDS RESEARCH AND HUMAN RETROVIRUSES 17 S46 -S46 2001年 [査読無し][通常論文]
  
• Pathogenesis of autoimmune diseases in transgenic rats carrying HTLV-I LTR-env-px gene.

  K Fugo, A Ishizu, M Higuchi, M Tsuji, A Abe, H Ikeda, T Yoshiki AIDS RESEARCH AND HUMAN RETROVIRUSES 17 S46 -S46 2001年 [査読無し][通常論文]
  
• Expression of the env protein in transgenic rats carrying the full length HERV-R gene

  N Otsuka, H Ikeda, S Tanaka, A Ishizu, T Yoshiki AIDS RESEARCH AND HUMAN RETROVIRUSES 17 S17 -S17 2001年 [査読無し][通常論文]
  
• 肝血管肉腫破裂の1例

  高橋 収, 高橋 透, 岩井 和浩, 水戸 康文, 鈴木 善法, 辻野 栄作, 坂井 俊哉, 加藤 紘之, 石津 明洋 日本消化器外科学会雑誌 34 (5) 490 -494 2001年 [査読無し][通常論文]
   

  症例は68歳の女性. 右季肋部痛を主訴に近医を受診した. 血液検査で貧血と血小板減少を認め, さらにCT検査で肝右葉を中心とした占居性病変を認めたため当院に紹介された. 入院後, 血管造影検査を含めた諸検査を進めた結果, 巨大肝血管腫あるいは肝血管肉腫と診断した. 入院第14病日に突然, 腹痛が出現し, 超音波検査にて肝腫瘍の破裂と診断されたため経カテーテル的動脈塞栓術を施行した. しかし, その後も貧血が進行したため, 緊急手術に踏み切り肝右葉切除術を施行した. S_4, S_<2,3>に腫瘍が遺残したが緊急避難的手術と考え切除しなかった. 術後の病理検査にて肝血管肉腫の診断を得た. 患者の周術期の経過は順調であったが, その後, 残肝腫瘍が急速に増大し, 第53病日目に死亡した. 肝血管肉腫は, 肝原発悪性腫瘍の中でまれな疾患であるが, 肝血管腫との鑑別を含め, 外科治療上, 多くの問題を提起するものと考え報告した.
• 【血管炎の基礎と臨床】 血管炎のモデル動物

  石津 明洋, 吉木 敬 最新医学 55 (12) 2611 -2615 2000年12月 [査読無し][通常論文]
   

  血管炎を自然発症するモデル動物として,(NZB×NZW)F1マウス,SL/Niマウス,MRL/lprマウス,HTLV-Iトランスジェニックラットなどが解析されてきた.これら動物モデルに共通する病因は,遺伝子に内在化したレトロウイルスである.内在性レトロウイルスは自己免疫の標的としてふるまうのみならず,宿主遺伝子の欠失や活性化を誘導することにより,ヒト血管炎の発症に関与している可能性がある
• HTLV-I pXトランスジェニックラットに発生する上皮型胸腺腫は骨髄に由来する

  辻 隆裕, 池田 仁, 土川 貴裕, 菊地 和徳, 富居 一範, 石津 明洋, 柴田 雅彦, 吉木 敬 日本免疫学会総会・学術集会記録 30 120 -120 2000年11月 [査読無し][通常論文]
  
• トランスジェニックラットを用いたヒト内在性レトロウイルスERV3の病原性の解析

  大塚 紀幸, 田中 敏, 山本 友希代, 石津 明洋, 柴田 雅彦, 池田 仁, 吉木 敬 日本免疫学会総会・学術集会記録 30 65 -65 2000年11月 [査読無し][通常論文]
  
• 膵癌高腹膜転移株の樹立とそれに関する遺伝子解析

  田原 正彦, 池田 仁, 石倉 浩, 和田 隆宜, 川田 将也, 高橋 利幸, 石津 明洋, 柴田 雅彦, 吉木 敬 日本癌学会総会記事 59回 534 -534 2000年09月 [査読無し][通常論文]
  
• 肝様腺癌及び胃癌に関する染色体4q上のLOHのMicrosatellite解析

  和田 隆宜, 柴田 雅彦, 矢野 智之, 高橋 利幸, 石津 明洋, 岸本 充, 池田 仁, 加藤 紘之, 石倉 浩, 吉木 敬 日本癌学会総会記事 59回 365 -365 2000年09月 [査読無し][通常論文]
  
• HTLV-I pXトランスジェニックラットに発生する胸腺腫の由来についての検討

  辻 隆裕, 池田 仁, 菊地 和徳, 土川 貴裕, 富居 一範, 石津 明洋, 柴田 雅彦, 吉木 敬 日本癌学会総会記事 59回 287 -287 2000年09月 [査読無し][通常論文]
  
• HTLV-1 LTR-env-pXトランスジェニックラットにおける自己免疫疾患発症の抑制に関する検討

  辻 宗啓, 池田 仁, 富居 一範, 樋口 正人, 鈴木 昭, 石津 明洋, 柴田 雅彦, 吉木 敬 北海道医学雑誌 75 (5) 365 -365 2000年09月 [査読無し][通常論文]
  
• 新しい血管炎発症モデル

  石津 明洋 日本病理学会会誌 89 (2) 12 -12 2000年09月 [査読無し][通常論文]
  
• リウマチ性疾患の病因とレトロウイルス

  石津 明洋 リウマチ 40 (2) 242 -242 2000年04月26日 [査読無し][通常論文]
  
• ERV3遺伝子導入ラットを用いたヒト内在性レトロウイルスの病因論的解析

  石津 明洋, 田中 敏, 山本 友希代, 大塚 紀幸, 柴田 雅彦, 池田 仁, 吉木 敬 リウマチ 40 (2) 526 -526 2000年04月 [査読無し][通常論文]
  
• HTLV-I LTR-env-pXトランスジェニックラットの胸腺,リンパ節,脾臓におけるCD25+CD4+ T細胞分画の動態の検討及び脾細胞投与の試み

  樋口 正人, 池田 仁, 富居 一範, 菅谷 壽晃, 石津 明洋, 柴田 雅彦, 吉木 敬 リウマチ 40 (2) 525 -525 2000年04月 [査読無し][通常論文]
  
• リウマチ性疾患の病因と新しい治療戦略 リウマチ性疾患の病因とレトロウイルス

  石津 明洋 リウマチ 40 (2) 242 -242 2000年04月 [査読無し][通常論文]
  
• ヒト内在性レトロウイルスERV3トランスジェニックラットにおける導入遺伝子の発現と抗原性の解析

  大塚 紀幸, 田中 敏, 山本 友希代, 石津 明洋, 柴田 雅彦, 池田 仁, 吉木 敬 日本病理学会会誌 89 (1) 192 -192 2000年03月 [査読無し][通常論文]
  
• 肝様腺癌に関する染色体4q上のLOHのmicrosatellite解析

  和田 隆宜, 池田 仁, 田原 正彦, 矢野 智之, 小西 茂, 高橋 利幸, 石津 明洋, 柴田 雅彦, 石倉 浩, 吉木 敬 日本病理学会会誌 89 (1) 180 -180 2000年03月 [査読無し][通常論文]
  
• HTLV-I pXトランスジェニックラットに好発する上皮性胸腺腫は骨髄由来の細胞から発生する

  土川 貴裕, 池田 仁, 菊地 和徳, 辻 隆裕, 富居 一範, 石津 明洋, 柴田 雅彦, 吉木 敬 日本病理学会会誌 89 (1) 183 -183 2000年03月 [査読無し][通常論文]
  
• 自己免疫疾患を発症するHTLV-I LTR-env-pXトランスジェニックラットの解析 リンパ組織におけるCD25+CD4+T細胞分画の動態の検討

  樋口 正人, 池田 仁, 富居 一範, 菅谷 壽晃, 石津 明洋, 柴田 雅彦, 吉木 敬 日本病理学会会誌 89 (1) 192 -192 2000年03月 [査読無し][通常論文]
  
• 膵癌高腹膜播種株の樹立と遺伝子解析

  田原 正彦, 池田 仁, 和田 隆宜, 川田 将也, 高橋 利幸, 石津 明洋, 柴田 雅彦, 石倉 浩, 吉木 敬 日本病理学会会誌 89 (1) 292 -292 2000年03月 [査読無し][通常論文]
  
• HTLV-1 pXトランスジェニックラットに発生する胸腺腫の由来についての検討

  辻隆浩, 池田仁, 菊地和徳, 土川貴裕, 富居一範, 石津明洋, 柴田雅彦, 吉木敬 Japanese Journal of Cancer Research 91 (Supplement (Sept)) 2000年
• HTLV-I env-pX遺伝子導入ラットにおける自己免疫疾患発症機構の解析と治療 (厚生省S)

  吉木敬, 柴田雅彦, 石津明洋, 池田仁, 富居一範, 樋口正人 難治性血管炎に関する調査研究班 平成11年度研究報告書 2000年
• Cytokine regulation of env gene expression of human endogenous retrovirus-R in human vascular endothelial cells

  K Katsumata, H Ikeda, M Sato, A Ishizu, Y Kawarada, H Kato, A Wakisaka, T Koike, T Yoshiki CLINICAL IMMUNOLOGY 93 (1) 75 -80 1999年10月 [査読無し][通常論文]
   

  To determine whether human endogenous retroviruses are implicated in the pathogenesis of inflammatory vascular diseases of unknown etiology, we examined mRNA expression of a human endogenous retrovirus, HERV-R, which has a long open reading frame in the env region, in cultured human vascular endothelial and smooth muscle cells stimulated in the presence of various cytokines, mRNA of HERV-R was always evident in these cells but not in fibroblastic cells. Levels of expression in vascular endothelial cells were significantly regulated by treatment with tumor necrosis factor-alpha, interleukin (IL)-1 alpha, and IL-1 beta as up-regulators and interferon-gamma as a down-regulator. These observations are interpreted to mean that HERV-R expression may be up- or down-regulated at sites of inflammation in vessels in vivo and hence may play a pathogenetic role in inflammatory vascular diseases in humans, perhaps similar to endogenous retroviruses in mouse models of polyarteritis nodosa in humans. (C) 1999 Academic Press.
• 患者腎組織から抽出したIgAの抗体特異性の解析

  小川 弥生, 石倉 浩, 石津 明洋, 深澤 雄一郎, 佐藤 英俊, 神田 誠, 小林 邦彦, 吉木 敬 日本免疫学会総会・学術集会記録 29 30 -30 1999年10月 [査読無し][通常論文]
  
• IgA腎症患者腎組織から抽出したIgA抗体の抗体特異性の解析

  小川 弥生, 石倉 浩, 石津 明洋, 深澤 雄一郎, 神田 誠, 佐藤 英俊, 小林 邦彦, 吉木 敬 日本病理学会会誌 88 (1) 199 -199 1999年03月 [査読無し][通常論文]
  
• HTLV-env-pXトランスジェニックラットにみられる破骨細胞およびB細胞系譜への影響

  山崎 英俊, 宮本 顕友, 池田 仁, 石津 明洋, 國貞 隆弘, 林 眞一, 吉木 敬 日本リンパ網内系学会会誌 = The journal of the Japanese Society of Lymphoreticular Tissue 38 (4) 203 -209 1998年12月22日 [査読無し][通常論文]
   

  Human T-cell lymphotropic virus type I (HTLV-I) is associated with various clinical disorders including adult T cell leukemia, myelopathy, arthropathy. Hypercalcemia resulting from osteoclast activation and a variety of hematopoietic abnormalities have been also observed in HTLV-I infected patients, however, precise mechanism about initial trigger(s) prior to presenting symptoms is still unknown. In this study, to assess effects of HTLV-I on hematopoiesis, we analyzed characteristics of early hematopoietic precursors and cell surface molecules of lymphocyte in HTLV-I env-pX transgenic rats. Progenitor cells for osteoclasts were significantly increased even in the marrow of asymptomatic env-pX rats. Progenitors for B cells were also highly enriched, while colony forming cells (CFC) elicited by GM-CSF (CFU-GM) and M-CSF (CFU-M) were comparable to normal littermates. Following arthritis in env-pX transgenic rats, osteoclastogenesis was further augmented and the CFCs were increased. Bone marrow cells carrying adjuvant-induced arthritis retained a constant number of progenitors for osteoclast and B lymphocytes, whereas the number of CFU-GM and CFU-M increased. In env-pX rats without arthritis the expression of CD80/86 and ICAM-I were upregulated on the surface of peripheral lymphocytes, compared with those of normal rats and rats with adjuvant-induced arthritis. These results indicate that the env-pX transgene affect early stages of osteoclast and B-cell lineages and lymphocytes prior to developing diseases, in contrast, an increase of the CFCs was caused indirectly by arthritis. This study provides a novel standpoint for the mechanisms of pathogenesis by HTLV-I.
• HTLV-I LTR-env-pXトランスジェニックラットに認められる自己免疫疾患の発症機序の解析

  富居 一範, 池田 仁, 菅谷 壽晃, 石津 明洋, 中丸 裕爾, 菊地 和徳, 田中 敏, 脇坂 明美, 吉木 敬, 山崎 英俊 北海道医学雑誌 73 (5) 531 -531 1998年09月 [査読無し][通常論文]
  
• 【遺伝子改変動物を用いたリンパ網内系研究の新展開】 HTLV-I env-pXトランスジェニックラットにみられる破骨細胞及びB細胞系譜への影響

  山崎 英俊, 宮本 顕友, 池田 仁, 石津 明洋, 國貞 隆弘, 林 眞一, 吉木 敬 日本リンパ網内系学会会誌 38 (4) 203 -209 1998年07月 [査読無し][通常論文]
   

  env-pXラットの血液細胞系譜にみられた現象を,二つに分類することができる.破骨細胞及びB細胞に対する影響はenv-pX遺伝子による直接的な影響,顆粒球やマクロファージに対する影響は疾患発症による二次的なものと考えられた.また,発症以前より免疫担当細胞であるT細胞やB細胞が活性化されていることから,遺伝子導入による標的臓器の変化が発症に関与するばかりでなく,導入遺伝子による免疫細胞側の変化が,疾患の発症の直接の引き金になりうると考えられる.env-pXラットはHTLV-I関連疾患の発症機序解明のための有用なモデル動物である.しかしながら,実際にenv-pXラットで観察された事象がヒトの疾患発症に対応するのかという問題が残されている
• HTLV_1env_pXトウンスジェニックラットにおける破骨細胞とB細胞の分化、増殖への影響

  山崎 英俊, 宮本 顕友, 池田 仁, 石津 明洋, 國貞 隆弘, 林 眞一, 吉木 敬 日本リンパ網内系学会会誌 = The journal of the Japanese Society of Lymphoreticular Tissue 38 (2) 97 -97 1998年04月20日 [査読無し][通常論文]
  
• 自己免疫疾患発症モデルHTLV-I LTR-env-pXラットにおける血管炎発症機序に関する検討 (厚生省S)

  菅谷寿晃, 池田仁, 富居一範, 石津明洋, 中丸裕爾, 山崎英俊, 脇坂明美, 小池隆夫, 吉木敬 免疫疾患調査研究班難治性血管炎分科会 平成9年度研究報告書 1998年
• 【難治性血管炎】 血管炎の動物モデル

  石津 明洋, 吉木 敬 臨床科学 33 (11) 1466 -1471 1997年11月 [査読無し][通常論文]
  
• HTLV-I env-pXトランスジェニックラットに認めるcollagen vascular diseasesの発症機序 骨髄細胞移入による検討

  石津 明洋 日本病理学会会誌 86 (1) 202 -202 1997年04月 [査読無し][通常論文]
  
• 46XYの表現形女性に発生した性腺芽腫の1例

  石倉 浩, 石津 明洋, 吉木 敬 病院病理 14 (2) 131 -131 1997年03月 [査読無し][通常論文]
  
• リンパ系特異的プロモーターを用いたHTLV-IpXトランスジェニックラットにおける胸腺腫ようの発生

  菊地和徳, 池田仁, 田中敏, 石津明洋, 菅谷寿晃, 富居一範, 脇坂明美, 吉木敬 日本免疫学会総会・学術集会記録 27 1997年
• HTLV-ILTR-env-pXトランスジェニックラットの末梢血および炎症局所T細胞に関する検討

  菅谷寿晃, 池田仁, 石津明洋, 菊地和徳, 田中敏, 中丸裕爾, 富居一範, 山崎英俊, 吉木敬 日本免疫学会総会・学術集会記録 27 1997年
• Interleukin-1 alpha regulates Thy-1 expression on rat vascular endothelial cells

  A Ishizu, H Ishikura, Y Nakamaru, K Kikuchi, T Koike, T Yoshiki MICROVASCULAR RESEARCH 53 (1) 73 -78 1997年01月 [査読無し][通常論文]
   

  We recently reported that Thy-1, a surface molecule induced on the rat endothelium, regulates vascular permeability at sites of inflammation. Although the rat inferior vena cava (IVC) did not express Thy-1 in vivo, cultured endothelial cells from the IVC did express Thy-1, thereby suggesting that the expression was acquired during cultivation of the cells in vitro, possibly by autoactivation by cytokine-like substances. Interleukin (IL)-1 alpha but not tumor necrosis factor (TNF)-alpha or interferon (IFN)-gamma was detected in culture supernatants of rat endothelial cells (REC) by ELISA. The production of IL-1 alpha by REC was augmented by exogenously added IL-1 alpha, thereby implying the presence of autocrine regulation by IL-1 alpha. The unaltered expression of Thy-1 by exogenously added IL-1 alpha suggests that Thy-1 expression on REC had already been maximally induced by autologous cytokines; the expression of Thy-1 on REC was lowered by inhibiting protein kinase C and by depleting IL-1 alpha activity from culture supernatants. Although cytokine-like regulators, other than IL-1 alpha, TNF-alpha, or IFN-gamma, produced by REC may also modulate the expression of Thy-1, it is at least in part mediated by IL-1 alpha in vitro. Moreover, Thy-1 expression was induced on rat vascular endothelium at the subcutis where recombinant IL-1 alpha was injected. The evidence indicates that IL-1 alpha functions as one regulator responsible for the induction of Thy-1 on REC, in vitro as well as in vivo. (C) 1997 Academic Press.
• Induced expression of thy-1 molecules on dermal endothelial cells in skin allografts

  E Takeuchi, H Ishikura, A Ishizu, H Harada, H Kato, K Yasuda, T Yoshiki PATHOLOGY RESEARCH AND PRACTICE 193 (9) 623 -627 1997年 [査読無し][通常論文]
   

  We obtained evidence in a foregoing study that inducible Thy-1 on vascular endothelial cells functions as a possible vascular permeability modulator in the rat. We now report on the regulation and function of endothelial Thy-1 in skin allograft rejection in the rat. While no obvious expression of Thy-1 antigen on the vasculature can be seen in normal organs, dermal endothelial cells do express Thy-1 during allogeneic skin graft rejection and Freund's complete adjuvant (FCA)-induced inflammation. The antigen was weakly induced on tubular epithelial, but not on endothelial cells during kidney allograft rejection, and not in FCA-induced inflammation of the kidney. In contrast, Thy-1 antigen was not induced in the rejected lung or in FCA-induced inflammation of the lung. This pattern of Thy-1 regulation was transcriptionally regulated. Administration of anti-Thy-1 antibodies generated increased vascular permeability in skin allografts, although this procedure did not modulate survival of the grafts.
• Interleukin (IL)-6 as a pancreas carcinoma-derived vascular permeability regulator in vitro

  M Omi, H Ishikura, A Ishizu, T Takahashi, H Kato, T Yoshiki PATHOLOGY RESEARCH AND PRACTICE 192 (11) 1107 -1112 1996年11月 [査読無し][通常論文]
   

  The interaction between pancreas adenocarcinoma and vascular endothelial cells in vitro was investigated. Culture media of pancreas carcinoma cells PCI-10, but not PCI-24, induced an augmented albumin permeability across the endothelial monolayer, an event which was blocked by the calmodulin antagonist, W-7. Only marginal inhibitory effects were obtained using protein kinase inhibitors, H-7 and HA-1004. When cytokine production by pancreas carcinoma cells was examined, production of IL-6 in large amounts by PCI-10, but not by PCI-24 cells was evident. As recombinant IL-6 generated a dose-dependent permeability increase, and as this effect was inhibited by W-7, we considered that the enhancement of vascular permeability was mediated by this cytokine. The activity of culture supernatants for enhanced permeability was almost completely absorbed by the addition of an antibody specific for IL-6. Tumor-derived IL-6 as a soluble mediator regulates vascular permeability in vitro, and the production of this factor by pancreas adenocarcinoma cells presumably modulates biologic behavior.
• 接着分子と動脈硬化 基礎と臨床 血管炎と接着分子 Thy-1と血管内皮細胞傷害

  石津 明洋, 吉木 敬 現代医療 28 (10) 2693 -2696 1996年10月 [査読無し][通常論文]
  
• Collagen vascular diseasesを発症するHTLV-I env-pXトランスジェニックラットの免疫学的解析

  石津 明洋 日本病理学会会誌 85 (1) 143 -143 1996年03月 [査読無し][通常論文]
  
• Thy-1の発現調節機構 臓器特異性,細胞特異性に関する検討

  石津 明洋 日本病理学会会誌 85 (1) 132 -132 1996年03月 [査読無し][通常論文]
  
• Thy-1 induced on rat endothelium regulates vascular permeability at sites of inflammation

  A Ishizu, H Ishikura, Y Nakamaru, E Takeuchi, C Kimura, T Koike, T Yoshiki INTERNATIONAL IMMUNOLOGY 7 (12) 1939 -1947 1995年12月 [査読無し][通常論文]
   

  We investigated the role of surface adhesion molecules on endothelial cells in regulating vascular permeability, in vitro and in vivo. Cultured rat endothelial cells (REC) express Thy-1, intercellular adhesion molecule-1 (ICAM-1), CD44 and RT1A. Permeability of albumin across the REC monolayer increased through the interaction of Thy-1 and anti-Thy-1 mAb, but not through ICAM-1 and anti-ICAM-1, CD44 and anti-CD44, and RT1A and anti-RT1A mAb. This anti-Thy-1-effect was completely inhibited when the calmodulin antagonist W-7 and the protein kinase inhibitor H-7 was combined, while the IL-6-mediated increase in REC permeability was blocked by either W-7 or H-7, independently. The anti-Thy-1-mediated permeability increase was additively augmented when IL-6 was admired. These data suggest that intracellular signaling pathways of anti-Thy-1- and IL-6-mediated permeability regulation may be overlapping to some extent but are largely independent. As anti-Thy-1-treatment generated rearrangement of vimentin filaments within REC, alteration of the cytoskeleton distribution may possibly correlate with the regulation of permeability. Although Thy-1-expression on rat vascular endothelium in vivo was not evident, it was induced at sites of Freund's complete adjuvant-induced dermatitis. The administered anti-Thy-1 mAb exclusively located on vascular endothelial surface at the sites of inflammation. Vascular permeability in inflamed skin tissues was significantly augmented when anti-Thy-1 but not anti-ICAM-1, anti-CD44 or anti-RT1A mAb was administered i.v., without affecting populations of inflammatory cells. The collective evidence suggests that Thy-1 induced on rat endothelium is one important regulatory event in vascular permeability at sites of inflammation.
• HTLV-I ENV-PX TRANSGENIC RATS - PROTOTYPE ANIMAL-MODEL FOR COLLAGEN VASCULAR DISEASES

  H YAMAZAKI, H IKEDA, A ISHIZU, H SHIKISHIMA, K KIKUCHI, A WAKISAKA, M HATANAKA, T YOSHIKI JOURNAL OF ACQUIRED IMMUNE DEFICIENCY SYNDROMES AND HUMAN RETROVIROLOGY 10 (2) 225 -225 1995年10月 [査読無し][通常論文]
  
• 血管内皮細胞におけるThyー1の発現と機能 : 血管透過性の調節に関する検討

  石津 明洋 北海道医学雑誌 70 (5) 687 -696 1995年09月 [査読無し][通常論文]
   

  接着とシグナル伝達の両者を媒介する血管内皮細胞上の接着分子,Thy-1,ICAM-1,およびCD44を,それぞれに対するモノクローナル抗体で刺激した時の血管透過性変化についてin vitroおよびin vivoの検討を行なった. 1)培養ラット血管内皮細胞およびラット皮膚炎症部位の血管内皮細胞にThy-1発現が認められた. 2)培養ラット血管内皮細胞のThy-1発現はIL-1β処理により増強した.同時に血管内皮細胞のThy-1発現を減弱する因子の存在も示唆された. 3)血管内皮細胞に発現されたThy-1を抗Thy-1抗体を結合させることで刺激すると,in vitroおよびin vivoのいずれにおいても血管透過性亢進が誘導された. 4)抗Thy-1抗体により誘導される内皮細胞透過性亢進は,抗体結合による内皮細胞傷害性や増殖修飾作用によらず,カルモジュリンや各種プロテインキナーゼなどの細胞内シグナル伝達物質により媒介されている
• STRAIN COMBINATION-DEPENDENT GENESIS OF NECROTIZING ARTERITIS IN ANTI-ICAM-1 ANTIBODY-PERFUSED RENAL-ALLOGRAFTS IN THE RAT

  K KANAGAWA, H ISHIKURA, A ISHIZU, C KIMURA, T SEKI, T KOYANAGI, T YOSHIKI PATHOLOGY INTERNATIONAL 45 (3) 196 -201 1995年03月 [査読無し][通常論文]
   

  Rat kidneys were perfused with anti-intercellular adhesion molecule-1 (anti-ICAM-1) monoclonal antibody prior to allotransplantation. In the two strain combinations examined, LEJ-to-WKAH transplants resulted in accelerated graft loss, and no prolongation of graft survival, The accelerated graft loss was the result of frequent occurrence of necrotizing arteritis within the grafts, In contrast, TO-to-WKAH transplants resulted in no change in graft survival and no arteritis, Necrotizing vasculitis in the LEJ-to-WKAH grafts was characterized by fibrinoid necrosis, collection of cellular infiltrates and serum macromolecular protein entrapment, The F(ab')(2) form of anti-ICAM-1 antibody partially preserved the antibody's capacity to accelerate graft loss, Therefore, although endothelial injury by Fc-mediated cytotoxicity may be involved in vascular damage, other mechanisms also come into play. The amount and distribution pattern of ICAM-1 antigen were identical in both TO and LEJ strains, Intravenous anti-ICAM-1 antibody administration combined with lipopolysaccharide, Poly(I)-Poly(C), warm ischemia to the kidney, or subcutaneous immunization with allogeneic spleen cells, but without renal transplantation, did not generate necrotizing vasculitis or proteinuria, These observations plus our previous data on the rat liver transplantation model clearly show that graft perfusion with anti-ICAM-1 monoclonal antibody invokes extensive vascular damage within allografts by Fc-mediated and Fc-independent mechanisms, depending on the donor-to-host combination.
• HTLV-I ENV-PX TRANSGENIC RATS - PROTOTYPE ANIMAL-MODEL FOR COLLAGEN VASCULAR-DISEASE

  A ISHIZU, H YAMAZAKI, H IKEDA, H SHIKISHIMA, K KIKUCHI, A WAKISAKA, T YOSHIKI AIDS RESEARCH AND HUMAN RETROVIRUSES 11 S152 -S152 1995年 [査読無し][通常論文]
  
• 糸球体腎炎の実験モデル ループス腎炎

  石津 明洋, 小池 隆夫 腎と透析 37 (増刊) 367 -369 1994年11月 [査読無し][通常論文]
  
• 病態時の血管と接着分子 血管炎 抗接着分子抗体による血管障害

  石津 明洋, 吉木 敬 現代医療 26 (9) 3171 -3174 1994年09月 [査読無し][通常論文]
  
• 血管内皮細胞 流血細胞の接着調節 内皮細胞への好中球の接着と相互作用

  石津 明洋, 石倉 浩 血管と内皮 4 (2) 162 -167 1994年04月 [査読無し][通常論文]
  
• 抗内皮細胞表面分子抗体による内皮機能の修飾と疾患

  石津 明洋 日本病理学会会誌 83 (1) 221 -221 1994年03月 [査読無し][通常論文]
  
• 経過中1度も高血糖症状を認めなかった糖尿病性腎症の1例

  石津 明洋, 中村 桜子, 布施川 尚 腎と透析 31 (4) 799 -803 1991年10月 [査読無し][通常論文]
  

特許

• 特開2009-095340:自己免疫疾患の被験者に対する治療効果の予測方法  2009年05月07日

  尾崎 承一, 石津 明洋, 外丸 詩野, 吉木 敬, 村井 太一  学校法人 聖マリアンナ医科大学, 国立大学法人 北海道大学, 株式会社ジェネティックラボ  200903053651772399

受賞

• 2009年11月 日本病理学会 学術研究賞
   

  受賞者: 石津明洋
• 2005年04月 日本病理学会 学術奨励賞
   

  受賞者: 石津明洋

共同研究・競争的資金等の研究課題

• Inflammagingにおける炎症・老化細胞の解析とバイオマーカーへの展開

  日本学術振興会：科学研究費助成事業

  研究期間 : 2022年04月 -2026年03月 

  代表者 : 外丸 詩野, 石津 明洋
• MPO-ANCA関連血管炎発症機序の全貌解明と新規治療法の開発を目指して

  日本学術振興会：科学研究費助成事業

  研究期間 : 2021年04月 -2024年03月 

  代表者 : 石津 明洋, 益田 紗季子, 外丸 詩野, 中沢 大悟

   

  ①MPO-ANCAはどのように好中球を活性化するのかについて、TNF-αでプライミングした好中球に液相または抗原固相により免疫複合体を形成した状態でMPO-ANCAを反応させ、好中球細胞外トラップ（NETs）の形成と細胞内シグナル分子のリン酸化を指標として好中球の活性化を評価した。その結果、どちらの場合もMPO-ANCAはNETsを誘導したが、抗原固相により免疫複合体を形成した状態で好中球に反応させた場合にシグナル分子がリン酸化されることを確認した。 ②MPO-ANCAにより誘導されるNETsに血管炎惹起性はあるかについて、MPO-ANCA誘導モデルの病変糸球体にNETsの沈着があることを証明した。 ③MPO-ANCA関連血管炎（MPO-AAV）におけるNETs除去障害の原因は何かについて、MPO-AAVの肺病変部に認められたDNase I抵抗性NETsと結核の肺病変部に認められたDNase I感受性NETs、そしてin vitroで誘導したDNase I感受性あるいは抵抗性NETsを用いてプロテオーム解析を行った。NETsにDNase I抵抗性をもたらす候補タンパク18種を抽出し、これらのリコンビナントタンパクをNETs誘導時に添加したところ、5つのタンパクで通常のNETsではなく類円形のDNase I抵抗性NETsが形成された。さらに、そのうちの一つのタンパクに対する阻害抗体をNETs誘導時に加えると、類円形NETsおよび通常型NETsの形成が抑制された。 これらの知見に基づき、MPO-AAVの病態形成機序に即した分子標的治療を開発するため、前臨床試験を開始した。
• 自己免疫惹起性T細胞の分子病理学的解析と診断・治療への展開

  日本学術振興会：科学研究費助成事業

  研究期間 : 2018年04月 -2022年03月 

  代表者 : 外丸 詩野, 辻 隆裕, 石津 明洋

   

  免疫系は病原体から体を守るために重要な生体防御システムであるが、免疫応答の異常により自己の組織が攻撃されることで免疫難病である自己免疫疾患や炎症性疾患を発症する。本研究では、新規に開発したubiquitous self-antigensを発現する遺伝子改変マウ（USAs-Tg）を用い、自己免疫惹起炎症細胞の検出や病態評価に有用なバイオマーカーを開発を目指した研究を行なった。炎症病巣にPD-1+Lag-3+Tim-3+CTLA-4-の形質を示す炎症関連メモリーT細胞の浸潤を認めること、炎症惹起細胞の分化には抗原提示細胞の活性化状態が影響を与えることが明らかとなった。
• 糖尿病血管障害の発症における好中球細胞外トラップの関与について

  日本学術振興会：科学研究費助成事業

  研究期間 : 2015年04月 -2017年03月 

  代表者 : 石津 明洋, 外丸 詩野

   

  高濃度グルコースへの暴露は、好中球細胞外トラップ（NETs）の形成を亢進させた。同じ浸透圧のマンニトールや2-デオキシグルコースではNETsの形成は亢進しなかった。ポリオール経路に関わるアルドース還元酵素の阻害薬が、高濃度グルコースにより誘導されるNETs形成を有意に阻害した。血清中のNETsは、コントロール良好な糖尿病患者で健常者に比べて有意に上昇していた。糖尿病患者では高血糖のためNETs形成が亢進し、これにはグルコース代謝のポリオール経路が関与している。糖尿病患者は、コントロールが良好であっても、食後高血糖により生体内でNETs形成が亢進している可能性が示唆された。
• 顕微鏡的多発血管炎の克服に向けた基礎・臨床包括的アプローチ

  日本学術振興会：科学研究費助成事業

  研究期間 : 2014年04月 -2017年03月 

  代表者 : 石津 明洋, 外丸 詩野, 有村 義宏, 佐田 憲映

   

  In vitroでのNETs形成は、ヒストン脱イミノ化に不可欠なPADの阻害薬Cl-amidineにより有意に抑制された。In vivoでも、Cl-amidineにより腹膜NETsの形成、血中MPO-ANCA産生が有意に抑制された。 治療前後の末梢血の遺伝子（IRF7, IFIT1, IFIT5, OASL, CLC, GBP-1, PSMB9, HERC5, CCR1, CD36, MS4A4A, BIRC4BP, PLSCR1, DEFA1/DEFA3, DEFA4, COL9A2）の発現変化を指標とすることで、MPAの治療反応性不良群を感度85.7%、特異度96.9%で予測可能であった。
• プロテアソーム機能低下と老齢病態の形成に関する研究

  日本学術振興会：科学研究費助成事業

  研究期間 : 2013年04月 -2016年03月 

  代表者 : 外丸 詩野, 石津 明洋

   

  老化によるプロテアソーム機能の低下はヒトを含む多くの動物種で観察されており，老化関連疾患の病態形成に関与していることが明らかになっている。ストレス応答に働くプロテアソームの機能異常はストレスに対する脆弱性を高め，変性タンパク質の蓄積，細胞老化を引き起こす。マウスモデルによる解析で，プロテアソーム機能低下マウスに短寿命や老化の表現型を認めた。本マウスに高脂肪食やタバコ煙等の環境因子を負荷すると，ヒト老化関連疾患に類似した脂肪代謝の異常や肺気腫を認めた。プロテアソームの機能低下は個体老化の重要な要因であり，様々な環境要因による細胞ストレスが相加的に疾患の病態形成に働くことが明らかとなった。
• 病理学的アプローチより紐解くクラミジア感染症の難治化予測診断マーカーの探索

  日本学術振興会：科学研究費助成事業

  研究期間 : 2013年04月 -2015年03月 

  代表者 : 中村 眞二, 松尾 淳司, 石津 明洋, 山口 博之, 伊藤 晋

   

  クラミジア(Ct)は，約10%程度の感染がみられる性感染症のポプュラーな原因菌である．このCtを無治療でいると，一部の感染者に繊維化を伴う卵管閉塞など難治化することが知られているが，その理由は不明である．IL-1やPGE2などの炎症性メディエーターの動態を検索し，Ct感染症の難治化の原因を検討した結果，間質の浸潤細胞にIL-1・IL-1Ra・PGE2の陽性細胞を認めたが，Ct感染の有無による所見の差は無かった．Ct感染患者では，扁平及び腺上皮細胞にIL-1αとPGE2の強く発現されていた．この結果はPGE2が炎症を慢性化し難治化への誘因の１つとして重要な働きをしていること示唆している．
• 自己血管内皮細胞反応性NKT細胞による中小型血管炎発症モデル

  文部科学省：科学研究費補助金(挑戦的萌芽研究)

  研究期間 : 2012年 -2012年 

  代表者 : 石津 明洋

   

  中小型血管炎を発症するモデルラットから単離したT細胞クローンVASC-1はラット培養血管内皮細胞（REC）と反応して活性化し、小型血管炎を誘導する。RECと反応することによるVASC-1の活性化は抗CD1d抗体により阻害されたので、VASC-1はNKT細胞であるといえる。VASC-1はtype I NKT細胞にinvariantなTCRを発現していないこと、ならびにtype I NKT細胞が結合するα-galactosylceramideに結合しないことから、type II NKT細胞と考えられた。小型血管炎の発症に自己血管内皮細胞反応性type II NKT細胞が関与していると考えられる。
• プロテアソームの機能異常とその病理作用

  文部科学省：科学研究費補助金(基盤研究(C))

  研究期間 : 2010年 -2012年 

  代表者 : 外丸 詩野, 石津 明洋

   

  プロテアソームはユビキチンシステムと連動してユビキチン化タンパク質の分解を制御・実行する複合体であり、細胞周期、DNA修復、シグナル伝達、タンパク質の品質管理、ストレス応答、免疫応答などの多様な生命現象に関与している。本研究ではプロテアソームの機能異常と病態形成のメカニズムを解明するために、酵素活性の弱いサブユニットであるβ5tを全身発現させた遺伝子導入マウス(β5t-Tg)を用いた研究を進めている。期間中に(A)プロテアソーム機能の低下と老化・老齢病態、および、(B)β5tの異常発現と免疫疾患、の2つの病態メカニズムを明らかにする研究を展開しているが、本年度は特に(A)プロテアソーム機能の低下と老化・老齢病態に焦点を当てて研究を進めることで、以下の成果を得た。(1)β5t-Tgでは背骨の彎曲や皮下脂肪織量の低下等、老化に伴う表現型を伴った短寿命が認められた。(2)β5t-Tgでは細胞寿命に関わる多数の分子(Bcl-xL、RNaseLなど)の発現異常が認められた。(3)β5t-Tgではユビキチン化タンパク質や酸化変性タンパク質が増加していた。(4)β5t-Tgに高脂肪食を投与することで、コントロールに比べ有意な肥満や脂肪肝が誘導された。(5)β5t-Tgでは脂肪代謝に関わる分子であるADRPの発現異常が観察された。現在、β5t-Tgを用いた老齢病態モデルとして喫煙マウスの表現...
• 血管炎発症機序の解明と新しい分子標的治療法および病態診断法の開発

  文部科学省：科学研究費補助金(基盤研究(C))

  研究期間 : 2008年 -2010年 

  代表者 : 石津 明洋, 外丸 詩野, 岩崎 沙理

   

  中・小型血管炎を発症するenv-pXラットから自己血管内皮細胞反応性血管炎惹起性T 細胞を単離した。このT細胞の標的分子や血管傷害機構を明らかにすることにより、血管炎の新しい分子標的治療法の開発が可能となる。また、顕微鏡的多発血管炎患者の治療前および治療開始1週間後の末梢血を用いて、網羅的遺伝子発現解析を行った。治療前後の末梢血における16個の遺伝子の発現変化を調べることにより、患者予後を治療開始後の早期に予測できる可能性が示された。
• 胸腺フレームワークの分子異常と壊死性血管炎の発症に関する研究

  文部科学省：科学研究費補助金(基盤研究(C))

  研究期間 : 2005年 -2006年 

  代表者 : 石津 明洋, 佐々木 直美

   

  env-pXラットでは、骨髄由来のT細胞が胸腺で分化成熟する過程において何らかのセレクション異常が生じ、自己免疫性血管炎が発症すると考えられている。発症前のenv-pXラットにwild type血管内皮細胞を免疫することにより、血管炎の発症が促進された。このことから、env-pXラットの血中には自己の血管内皮細胞に反応し血管炎を惹起するT細胞が存在することが示唆された。次に、免疫ラットのリンパ節細胞をin vitroでwild type血管内皮細胞を用いて繰り返し刺激することにより、自律性増殖を示すCD4陽性T細胞(PC4)を得た。PC4をwild typeラットに静注したところ、肺に血管壁の破綻と周囲への炎症細胞浸潤を伴う血管病変が確認された。以上より、env-pXラットから自己の血管内皮細胞に反応し血管炎を惹起するT細胞を樹立できたと考えられる。PC4はT細胞受容体の使用頻度がVβ8.2、8.6、16に限られたオリゴクローナルなT細胞集団であり、そのサイトカインプロファイルはIFN-γとIL-2が陽性、IL-4とIL-10が陰性のTh1フェノタイプを示した。血管内皮細胞と共培養することによるPC4の増殖はMHCクラスIIに対する抗体により完全に阻害された。しかしながら、この共培養系において血管内皮細胞はMHCクラスIIを発現しておらず、抗原提示細胞として機能しているのはP...
• MILL分子群による免疫監視機構の解析

  文部科学省：科学研究費補助金(特定領域研究)

  研究期間 : 2005年 -2006年 

  代表者 : 笠原 正典, 石津 明洋, 外丸 詩野

   

  NKG2Dリガンドは癌細胞やウイルス感染細胞などで発現されるストレス誘導性のMHCクラスI様分子であり,NK細胞,CD8_+T細胞による免疫監視において重要な役割を果たしている.マウスでは,既知のリガンドとして,RAE-1α,-β,-γ,-δ,-ε,H60(Histocompatibility-60),MULT-1が知られている.本年度は,ヒトのNKG2Dリガンド分子の一つであるMICA-MICB分子と最も近縁なマウスのMHCクラスI様分子MILL(MHCclass I-like located near the leukocyte recptor complex)がNKG2Dのリガンドとして機能するか否かを検討するとともに,新しいマウスNKG2Dリガンドの同定を試みた.その結果,MILLは配列的にはNKG2Dのリガンドとして機能することが予想されたにもかかわらず,NKG2D-Ig融合タンパク質と結合しないことが示された.さらに,MILLはβ2ミクログロブリンと会合するGPIアンカー型タンパク質であり,この点でもMICA・MICB分子とは異なっていることが判明した.この結果を受けて新しいマウスNKG2Dリガンドを探索した結果,2個のMHCクラスI様分子がNKG2Dリガンドとして同定された.これらのNKG2Dリガンドは既知のリガンドの中ではH60と最も相似性が高かったため,H6...
• 転写因子CREBを標的とした関節リウマチ制御の基礎的検討

  文部科学省：科学研究費補助金(若手研究(B))

  研究期間 : 2003年 -2004年 

  代表者 : 石津 明洋

   

  ヒトT細胞白血病ウイルスI型(HTLV-I)のLTR-env-pX遺伝子を導入したトランスジェニックラット(env-pXラット)はヒト関節リウマチ(RA)類似の関節炎を発症する。本研究ではenv-pXラットの関節炎病態に導入遺伝子を発現する滑膜組織が重要な役割を果たしていることを明らかにした。ヒトRAにおいても、滑膜の増殖や同細胞が産生するIL-6、IL-8などの炎症性サイトカインが病態に深く関わっている。本研究では、RAの分子制御を目的として、滑膜細胞の増殖や炎症性サイトカイン産生を転写レベルで制御するCREBに注目した。CREBはロイシンジッパー構造をもつ転写因子で、同じ分子ファミリーに属するATF-1と二量体を形成して標的となるDNA塩基配列に結合し、遺伝子転写活性を発揮する。そこで、CREBを競合的に阻害するDominant Negative ATF-1(ATF-1DN)を作製し、env-pXラット由来の関節滑膜細胞に遺伝子導入して、CREBにより転写調節される細胞周期関連分子や炎症性サイトカインの発現変化を検討した。細胞周期関連分子ではcyclin Dには明らかな変化はなかったが、ATF-1DNの導入によりCDK4の発現が減少した。炎症性サイトカインではIL-8ファミリーのGroには変化がなかった一方、IL-6の発現が減少した。また、生体内におけるATF-1DNの関...
• ヒト内在性レトロウイルスの発現と自己免疫疾患への関与に関する研究

  文部科学省：科学研究費補助金(基盤研究(C))

  研究期間 : 2003年 -2004年 

  代表者 : 池田 仁, 外丸 詩野, 外丸 詩野, 吉木 敬, 石津 明洋, 鈴木 昭

   

  本研究では、ヒトの内在性レトロウイルスの病原性を明らかにするため、樹立したヒト内在性レトロウイルスHERV-R遺伝子のトランスジェニックラット(HERV-Rラット)をモデルとして、導入HERV-R遺伝子のEnv蛋白発現やその抗原性について検討を行った。その結果、以下の成果を得た。1)導入遺伝子は予測された8個の糖鎖を有する85kDaのEnv糖タンパクとして発現し、ホルモン標的組織であるハーダー腺や前立腺ほか表皮、唾液腺など組織特異的に発現を示すことが明らかになった。2)トランスジェニックラットから正常ラットへの皮膚移植を用いて検討を行った結果、約50日後にその多くが脱落し、免疫の標的分子になっていることが明らかになった3)HERV-Rラットと、別に樹立した自己免疫疾患のプロトタイプであるヒト感染性レトロウイルスHTLV-1の遺伝子導入ラット(env-pXラット)とのダブルトランスジェニックラットを作製し、自己免疫疾患発症ラットにおける内在性レトロウイルスの発現と病態修飾、疾患発症の有無について検討した。その結果、ダブルトランスジェニックラットではラットの生存期間が短縮傾向にあり、HERV-R抗原の高発現が観察されるハーダー腺へのIgM型自己抗体の沈着や腎糸球体の血栓形成が観察された。4)以上の結果から、自己免疫疾患において内在性レトロウイルスの抗原発現が病態を修飾している可能...
• 動物モデルを用いたHTLV-1発がん機構の解析

  文部科学省：科学研究費補助金(特定領域研究)

  研究期間 : 2003年 -2003年 

  代表者 : 吉木 敬, 石津 明洋, 池田 仁, 志田 壽利, 外丸 詩野

   

  lckプロモーターの制御下にヒトT細胞白血病ウイルスI型(HTLV-I)のpX遺伝子を発現するlck-pXラットは上皮型胸腺腫を発症する。このラットの腎被膜下に腫瘍化前のlck-pXラット胸腺を移植することにより、胸腺腫の悪性化と考えられる現象が観察された。この悪性胸腺腫では、オリジナルの胸腺腫で認められるp16とARFの発現が認められず、p16/ARF領域遺伝子の欠失が本腫瘍の悪性化に中心的な役割を果たしていると考えられた。HTLV-Iが原因となる成人T細胞白血病(ATL)は一般にキャリア状態から腫瘍化し、くすぶり型や慢性型といった低悪性度のATLから急性型やリンパ腫型といった高悪性度のATLへと進展する経過をたどる。高悪性度のATLへの移行の際にはp16やp53の遺伝子異常を高率に伴っていることが知られている。従って、lck-pXラットでの胸腺腫の悪性化はヒトATLの急性転化でみられる現象の一部を観察している可能性がある。良性腫瘍の状態から高悪性度腫瘍の状態までを連続的に観察できる本実験系はHTLV-I関連腫瘍の悪性化機構を解明する上で有用なin vivoモデルである。一方、HTLV-Iがヒト以外の動物で効率よく増殖できないのは、ウイルス粒子の形成に必要なRexの働きを支持する宿主因子CRM1が、ヒト以外の動物ではHTLV-Iに対して低い支持活性しか示さないためであると考...
• ヒトレトロウイルス感染症の新しい疾患モデル動物の開発と解析に関する研究

  文部科学省：科学研究費補助金(基盤研究(A))

  研究期間 : 2002年 -2003年 

  代表者 : 吉木 敬, 高橋 利幸, 石津 明洋, 池田 仁, 外丸 詩野

   

  HTLV-IやHIV-1などヒトレトロウイルスの感染から疾患発症に至るウイルスと宿主の相互作用の解明を目指し、ラットをモデルとして以下の成果を得た。1.HTLV-I関連脊髄症発症系ラットの脊髄では、感染後、ウイルスに防御的に働くINF-γ発現が増強せず、その結果ウイルス遺伝子の発現増強を許し、一連のアポトーシス関連遺伝子の発現変化を招き、脊髄症が発症する可能性を示した。2.自己免疫疾患発症HTLV-I env-pX遺伝子導入ラットでは疾患発症前からCD4CD25陽性免疫抑制性T細胞に機能障害があり、免疫抑制に関与するCTLA-4、GITR、Foxp3、SOCS発現が半減していた。また、本ラットに認める関節炎の発症には導入遺伝子をもつリンパ球が深く関与するものの、炎症の持続には導入遺伝子の作用によりIL-6を高産生する滑膜細胞側の要因がより重要であることを示した。3.良性胸腺腫発生lck-pXラットの発症前胸腺を正常ラット腎被膜下に移植すると、悪性胸腺腫が発生することを見出した。この悪性胸腺腫では良性で高発現のp16やARFなど細胞周期を負に制御する遺伝子の発現がなく、この形質転換が悪性化に関与していると考えられた。4.HIV-1受容体であるヒトCD4、CCR5/CXCR4およびHIV-1発現に関与するヒトcyclin T1やC2TAを発現するラット細胞様を樹立し、HIV-1感...
• 動物モデルを用いたHTLV-I発がん機構の解析

  文部科学省：科学研究費補助金(特定領域研究)

  研究期間 : 2002年 -2002年 

  代表者 : 吉木 敬, 高橋 利幸, 池田 仁, 志田 壽利, 石津 明洋

   

  ヒトT細胞白血病ウイルスI型(HTLV-I)がヒト以外の動物細胞で効率よく増殖できないのは、ウイルス粒子の形成に必要なRexの働きを支持する宿主細胞性因子CRM1のうち、ヒト型のもののみHTLV-Iに有効に作用するためであると考えられる。本研究では、マイクロインジェクション法により,ヒトcrm1遺伝子をラット受精卵に導入した。導入遺伝子にはプロモーター領域を含むヒトcrm1 BACクローン、およびマウスMHCクラスIプロモーターの下流にヒトcrm1のcDNAを結合したコンストラクトを用いた。得られた遺伝子導入ラットはHTLV-Iに対する高い感染感受性を持つことが期待される。このラットにHTLV-Iを感染させ、現在、経過を観察中である。また、すでに作製したHTLV-I遺伝子導入ラットを用いて、HTLV-Iによる細胞腫癌化機構ならびに悪性化機構を解析した。lckプロモーターの制御下にHTLV-I pX遺伝子を発現するlck-pXラットは上皮型胸腺腫を発症する。このラットの腎被膜下に腫瘍化前のlck-pXラット胸腺を移植することにより、約6ヶ月間の観察期間で、胸腺腫の悪性化と考えられる現象が認められた。この悪性化胸腺腫では、細胞周期を負に制御するp16とARFの発現が全例でほとんど認められず、p16/ARF領域の異常が本腫瘍の悪性化に中心的な役割を果たしているものと考えられた。HT...
• モデル動物を用いたHTLV-I発がんおよび関連疾患発症機構の解析

  文部科学省：科学研究費補助金(特定領域研究(C))

  研究期間 : 2001年 -2001年 

  代表者 : 吉木 敬, 高橋 利幸, 池田 仁, 志田 壽利, 石津 明洋

   

  HTLV-Iによる発がん機構を解析するため新たな動物モデルを開発した。また、従来の動物モデルを用いてHTLV-I関連疾患発症機構を解析した。1.ヒトcrm1遺伝子導入ラットの作製とそれを用いた新しいHTLV-I持続感染モデルの樹立HTLV-Iがヒト以外の動物細胞で効率よく増殖できないのは、ウイルス粒子の形成に必要なRexの働きを支持する細胞性因子CRM1のうち、ヒト型のもののみHTLV-Iに有効に作用するためであると考えられる。本研究では、ヒトcrm1遺伝子導入ラットを作製した。本ラットではHTLV-Iに対する高い感染感受性が期待される。2.腫瘍性疾患を発症するHTLV-I pX遺伝子導入ラットの解析乳癌や胸腺腫を発症するHTLV-I pX遺伝子導入ラットから、腫瘍化前組織、腫瘍、およびこれらから単離した培養細胞についてDNAアレイを用いた包括的遺伝子発現の解析ならびにリアルタイムRT-PCR法による定量的遺伝子発現解析を行った。その結果、pX遺伝子を発現する細胞では細胞周期やアポトーシスに関わる分子群に発現異常が認められた。3.自己免疫疾患を発症するHTLV-I env-pX遺伝子導入ラットの解析種々の自己免疫疾患を発症するHTLV-I env-pX遺伝子導入ラットの解析では、標的となる臓器により発症機序が異なることが明らかとなり、中でも壊死性血管炎の発症には、env-pX...
• 自己免疫疾患の病因としてのヒト内在性レトロウイルスに関する研究

  文部科学省：科学研究費補助金(基盤研究(C))

  研究期間 : 2000年 -2001年 

  代表者 : 池田 仁, 石津 明洋, 柴田 雅彦, 吉木 敬

   

  ヒト内在性レトロウイルスの自己免疫疾患への病因論的関与の可能性について研究を進めるべく、トランスジェニックラットを樹立し、それをモデルとしてヒト内在性レトロウイルスに対する免疫反応性や発現と疾患発症の関連性を検討した。また、血管内皮細胞や慢性関節リウマチ患者の滑膜組織など自己免疫疾患標的組織から新しい内在性レトロウイルスをクローニングを試みた。その結果、当該研究計画期間中に以下の成果を得た。1.HERV-Rトランスジェニックラット 2系統の1コピー型ヒト内在性レトロウイルスHERV-R遺伝子のトランスジェニックラットを樹立した。導入遺伝子はHarderian腺と唾液腺を主体に組織特異的に高発現を示し、Harderian腺の腺房細胞での特異的発現や導入遺伝子から想定される約23kDaの糖質を含む約85kDaのEnv糖蛋白を同定した。また、妊娠12日頃から胎盤でも発現することや胎生18日胎児での発現を明らかにした。一方、正常同系ラットへの皮膚移植により、このEnv糖蛋白は免疫反応の標的となり得ることを明らかにした。したがって、本トランスジェニックラットのEnv糖蛋白に対する免疫学的自己寛容が破綻すれば、このEnv糖蛋白を標的にした免疫疾患の誘導が可能であると考えられた。2.新しいヒト内在性レトロウイルスを分離 胎盤や自己免疫疾患の標的となる培養血管内皮細胞あるいは慢性リウマチ関節...
• モデル動物を用いたHTLV-I発がんおよび関連疾患発症機構の解析

  文部科学省：科学研究費補助金(特定領域研究(C))

  研究期間 : 2000年 -2000年 

  代表者 : 吉木 敬, 柴田 雅彦, 池田 仁, 志田 壽利, 石津 明洋

   

  HTIV-I発がんおよび関連疾患発症機構について動物モデルを用いて解析した。下肢痙性麻痺を発症するHTLV-I持続感染ラット(HAMラット)の脊髄オリゴデンドロサイトでは、麻痺の出現に先行してpXおよびTNF-αの発現亢進とbcl-2の発現抑制が認められた。pXの発現亢進とそれにより誘導されるTNF-αの発現亢進およびbcl-2の発現抑制を介したオリゴデンドロサイトのアポトーシスが脱髄に関与する主要な分子細胞病態と考えられる。lck-pXラット胸腺腫細胞では、Fas ligand、TRADD、FADDの発現が正常胸腺上皮細胞に比し低下していた。これらアポトーシス関連分子の発現低下は胸腺腫細胞の増殖性維持に関与している可能性がある。一方、lck-pXラット胸腺腫は初期病変が髄質に存在し、UEA-1陽性を示すので、髄質の上皮細胞が腫瘍化したものと考えられる。骨髄移植実験により、lck-pXラット胸腺腫の起原となる細胞は骨髄浮遊系分画中に存在することが明かとなった。このことは胸腺髄質の上皮細胞が骨髄浮遊系細胞由来である可能性を示している。また、種々の自己免疫疾患を発症するLTR-env-pXラットの解析では、標的となる臓器により発症機序が異なることが明らかとなり、中でも血管炎の発症には、env-pX遺伝子を発現する胸腺におけるリンパ球の分化異常が主要な病因となっている可能性が示唆さ...

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