Researcher Profile and Settings

Affiliation

• Faculty of Medicine　Specialized Medicine　Sensory Organ Medicine

Job Title

• Professor

URL

http://kaken.nii.ac.jp/d/r/60374435.ja.html

J-Global ID

• 201401032364760059

Research Interests

• 制御性T細胞   自己免疫疾患   疾患モデル動物   ヒト化マウス   水疱性類天疱瘡   17型コラーゲン   サイトカイン   ノックアウトマウス   Th1/Th2   補体活性化   抗体サブクラス   IgG1/IgG4   

Research Areas

• Life sciences / Dermatology

Educational Organization

•  Bachelor's degree program　Departments of Medicine, School of Medicine
•  Master's degree program　Graduate School of Medicine
•  Doctoral (PhD) degree program　Graduate School of Medicine

Academic & Professional Experience

• 2021/01 - Today Hokkaido University
• 2016/09 - 2020/12 Hokkaido University
• 2014/09 - 2016/08 Hokkaido University
• 2012/09 - 2014/08 NIH, NIAID Laboratory of Immunology Visiting fellow
• 2010/04 - 2012/08 Hokkaido University

Education

• 1996/04 - 2002/03  Hokkaido University  School of Medicine

Research Activities

Published Papers

• A familial case of extramammary Paget disease: Analysis of whole-exome sequencing

  Takuya Maeda, Teruki Yanagi, Shinya Kitamura, Hiroshi Nishihara, Yusuke Ono, Yusuke Mizukami, Shinya Tanaka, Hideyuki Ujiie

  EJC Skin Cancer 2024/03 [Refereed]
  
• Eribulin inhibits growth of cutaneous squamous cell carcinoma cell lines and a novel patient-derived xenograft

  Che Yuan Hsu, Teruki Yanagi, Takuya Maeda, Hiroshi Nishihara, Kodai Miyamoto, Shinya Kitamura, Keiko Tokuchi, Hideyuki Ujiie

  Scientific Reports 13 (1) 2023/12 

  Advanced cutaneous squamous cell carcinoma (cSCC) is treated with chemotherapy and/or radiotherapy, but these typically fail to achieve satisfactory clinical outcomes. There have been no preclinical studies to evaluate the effectiveness of eribulin against cSCC. Here, we examine the effects of eribulin using cSCC cell lines and a novel cSCC patient-derived xenograft (PDX) model. In the cSCC cell lines (A431 and DJM-1 cells), eribulin was found to inhibit tumor cell proliferation in vitro as assessed by cell ATP levels. DNA content analysis by fluorescence-activated cell sorting (FACS) showed that eribulin induced G2/M cell cycle arrest and apoptosis. In xenograft models of cSCC cell lines, the administration of eribulin suppressed tumor growth in vivo. We also developed a cSCC patient-derived xenograft (PDX) which reproduces the histological and genetic characteristics of a primary tumor. Pathogenic mutations in TP53 and ARID2 were detected in the patient’s metastatic tumor and in the PDX tumor. The cSCC-PDX responded well to the administration of eribulin and cisplatin. In conclusion, the present study shows the promising antineoplastic effects of eribulin in cSCC. Also, we established a novel cSCC-PDX model that preserves the patient’s tumor. This PDX could assist researchers who are exploring innovative therapies for cSCC.
• Development of a nutritionally balanced, melt‐in‐the‐mouth chocolate for patients with epidermolysis bullosa

  Kosei Nakamura, Shota Takashima, Takuma Nohara, Mika Watanabe, Ken Natsuga, Hideyuki Ujiie

  The Journal of Dermatology 50 (12) 1640 - 1643 0385-2407 2023/09/07 

  Abstract Epidermolysis bullosa (EB) is a group of inherited blistering disorders that primarily affect the skin and mucous membranes of the digestive tract, which can lead to poor nutritional status. Dietary supplements and nutritional support methods, such as nasogastric tubes and gastrostomy, have been employed to improve the nutritional status of patients with EB; however, few foods are suitable for enjoyable eating with family and friends. Here, we introduce a nutritionally balanced, melt‐in‐the‐mouth chocolate called andew, which was specifically designed for patients with EB. The andew chocolate is nutritionally superior and melts more easily than traditional chocolates, thus it is suitable for patients with EB, who are prone to oral erosions. Patients responded more favorably to the taste and texture of andew than to those of other dietary supplements. Not only does andew provide nutritional benefits, but it also promotes enjoyable eating with family members and friends, which could positively impact patients' mental health.
• 水疱性類天疱瘡とBullous Rheumatoid Neutrophilic Dermatosisとの鑑別を要したリウマトイド血管炎

  田中 有沙, 柳 輝希, 今福 恵輔, 渥美 達也, 氏家 英之

  皮膚科の臨床 金原出版(株) 65 (10) 1531 - 1534 0018-1404 2023/09 

  ＜文献概要＞80歳,女性。初診の2ヵ月前から両下肢に緊満性水疱が生じ,水疱性類天疱瘡の疑いで当科を紹介受診した。既往歴に関節リウマチがありトシリズマブ(アクテムラ)を投与中であった。初診の4ヵ月後にはすべての水疱が潰瘍化し拡大した。水疱辺縁部からの皮膚生検では真皮に好中球主体の血管炎像を認め,蛍光抗体直接法にて真皮深層の血管周囲にIgMとC3の沈着を認めた。リウマトイド血管炎に伴う水疱および皮膚潰瘍と診断し,プレドニゾロン30mg/日の内服とリツキシマブにて加療したところ,すべての潰瘍は上皮化した。関節リウマチの既往がある患者に水疱を認めた場合はリウマトイド血管炎の初期症状の可能性がある。
• Detection of a natural antibody targeting the shed ectodomain of BP180 in mice.

  Yosuke Mai, Kentaro Izumi, Shoko Mai, Wataru Nishie, Hideyuki Ujiie

  Journal of dermatological science 2023/08/01 

  BACKGROUND: Pemphigoid diseases are characterized by subepidermal blister formation accompanied by autoantibodies targeting skin component molecules, such as BP180. It is suggested that an epitope-phenotype correlation exists among autoantibodies recognizing BP180. However, it is unclear which regions of BP180 are likely targets for autoantibodies. OBJECTIVE: To elucidate the portions of BP180 where antibodies tend to react under the breakdown of immune tolerance. METHODS: We immunized mice with full-length mouse BP180 (mBP180) to produce anti-mBP180 antibodies. Using the immunized mice, hybridoma cells were established to produce anti-mBP180 antibodies. We analyzed the characteristics of the anti-mBP180 antibodies that were produced in terms of epitopes, immunoglobulin subclasses, and somatic hypermutations. RESULTS: Hybridoma cells derived from immunized mice with full-length mBP180 produced antibodies targeting the intracellular domain (IC) and the shed ectodomain (EC) of mBP180. Using the domain-deleted mBP180 recombinant protein, we revealed that monoclonal anti-mBP180 EC antibodies react to neoepitopes on the 13th collagenous region of cleaved mBP180, which corresponds to the epitopes of linear IgA bullous dermatosis antibodies in human BP180. Furthermore, the subclasses of these antibodies could be distinguished by epitope: The subclass of the anti-mBP180 IC monoclonal antibodies was IgG, whereas that of the anti-mBP180 EC antibodies was IgM. Of note, a clone of these IgM mBP180 EC antibodies was a germline antibody without somatic hypermutation, which is also known as a natural antibody. CONCLUSION: These data suggest that mice potentially have natural antibodies targeting the neoepitopes of cleaved mBP180 EC.
• Prognostic Analysis of Patients With Extramammary Paget Disease Treated With Conservative Excision

  Takashi Seo, Shinya Kitamura, Teruki Yanagi, Takuya Maeda, Hideyuki Ujiie

  Dermatologic surgery : official publication for American Society for Dermatologic Surgery [et al.] 49 (8) 743 - 746 2023/08/01 

  BACKGROUND: Extramammary Paget disease (EMPD) is a malignant skin tumor with a relatively good prognosis. The standard treatment is wide local resection or Mohs micrographic surgery. However, conservative excision may be a better option when radical wide local excision is difficult to perform due to the patients' mental or physical condition. There have been no studies on the prognosis of patients with EMPD who underwent conservative excision. OBJECTIVE: To compare the prognosis of conservative excision cases to wide excision cases of EMPD. MATERIALS AND METHODS: The authors retrospectively analyzed the clinical data of 69 cases of EMPD without metastases to lymph nodes or organs (11 cases treated with conservative excision, 58 cases treated with wide local excision) who underwent resection of the primary tumor from 2002 to 2022 in the Department of Dermatology at Hokkaido University Hospital. RESULTS: The log-rank test showed no significant differences in overall survival or metastasis-free survival between the wide excision group and the conservative excision group, although conservative surgery was often chosen in elderly patients or patients with lower performance status. CONCLUSION: This study suggests that conservative surgery should be considered as a treatment option for EMPD.
• 体重減少は悪性黒色腫の予後不良因子になりうる

  田中 有沙, 宮澤 元, 前田 拓哉, 北村 真也, 柳 輝希, 氏家 英之

  西日本皮膚科 日本皮膚科学会-西部支部 85 (3) 233 - 234 0386-9784 2023/06
• 姑息的切除を行った乳房外パジェット病の予後に関する検討

  瀬尾 拓志, 北村 真也, 柳 輝希, 前田 拓哉, 氏家 英之

  加齢皮膚医学セミナー 加齢皮膚医学研究会 18 (1) 42 - 42 2023/06
• Pseudotumor of the skin due to Mycobacterium genavense.

  Suguru Kurosawa, Keisuke Imafuku, Sho Nakakubo, Sumio Iwasaki, Takanori Teshima, Hideki Goto, Hideyuki Ujiie

  International journal of infectious diseases : IJID : official publication of the International Society for Infectious Diseases 2023/05/15 

  Mycobacterium genavense is a rare type of non-tuberculous mycobacterium (NTM) that has been reported to cause disseminated infections in immunocompromised patients. Because M. genavense is slow-growing and poorly able to form colonies on Ogawa's medium, genetic and molecular analyses are necessary to identify this pathogen. NTM infections present with various cutaneous manifestations. Of these, rare cases have been reported to present with mycobacterial pseudotumors. However, there are no reports of M. genavense with cutaneous pseudotumors. In this paper, we report a case of a pseudotumor due to M. genavense infection that was observed only in a cutaneous lesion. The patient was taking 5 mg of prednisolone and was aware of a tumor on the right lower leg. Biopsy samples showed diffuse spindle-shaped histiocytes and various other inflammatory cell infiltrates, and Ziehl-Neelsen staining detected mycobacterium. Since no colonies formed on Ogawa medium, genetic testing was performed, and M. genavense was identified by DNA sequence analysis. There were no other disseminated lesions beyond the skin, including in the lungs and liver. Since the patient was immunosuppressed, in accordance with previous literature, a combination therapy of clarithromycin, ethambutol, and rifampicin for 4 months was recommended. When no growth is observed on Ogawa's medium in cases of infection, it is essential to identify the infectious pathogen by genetic analysis.
• 家族性乳房外パジェット病における遺伝子変異解析結果

  前田 拓哉, 柳 輝希, 西原 広史, 小野 裕介, 水上 裕輔, 田中 伸哉, 氏家 英之

  日本皮膚科学会雑誌 (公社)日本皮膚科学会 133 (5) 1350 - 1350 0021-499X 2023/05
• 基底膜タンパク複合体を利用したELISAで診断し得た粘膜類天疱瘡の1例

  眞井 翔子, 泉 健太郎, 板本 想太, 黒澤 卓, 長田 悠里, 挽地 史織, 宮澤 元, 得地 景子, 今福 恵輔, 柳 輝希, 筒井 眞人, 氏家 英之

  日本臨床皮膚科医会雑誌 日本臨床皮膚科医会 40 (3) 477 - 477 1349-7758 2023/05
• Mycobacterium genavenseによる限局性の皮膚感染症を呈した1例

  黒澤 卓, 今福 恵輔, 宮澤 元, 中久保 祥, 岩崎 澄央, 後藤 秀樹, 豊嶋 崇徳, 氏家 英之

  日本臨床皮膚科医会雑誌 日本臨床皮膚科医会 40 (3) 470 - 470 1349-7758 2023/05
• Native Autoantigen Complex Detects Pemphigoid Autoantibodies.

  Shoko Mai, Kentaro Izumi, Yosuke Mai, Ken Natsuga, Norito Ishii, Daisuke Sawamura, Franziska Schauer, Dimitra Kiritsi, Wataru Nishie, Hideyuki Ujiie

  JID innovations : skin science from molecules to population health 3 (3) 100193 - 100193 2023/05 

  Pemphigoid diseases are a group of autoimmune disorders characterized by subepidermal blistering in the skin and mucosa. Among them, mucous membrane pemphigoid (MMP) autoantibodies are characterized by targeting multiple molecules in the hemidesmosomes, including collagen XVII, laminin-332, and integrin a6/β4. Traditionally, recombinant proteins of the autoantigens have been employed to identify circulating autoantibodies by immune assays. However, developing an efficient detection system for MMP autoantibodies has been challenging because the autoantibodies have heterogeneous profiles and the antibody titers are typically low. In this study, we introduce an ELISA that takes advantage of a native autoantigen complex rather than simple recombinant proteins. We generated HaCaT keratinocytes with a DDDDK-tag knocked in at the COL17A1 locus by CRISPR/Cas9-mediated gene editing. Immunoprecipitation using the DDDDK-tag isolated a native complex that contained full-length and processed collagen XVII and integrin α6/β4. Then, we used the complex proteins to prepare an ELISA system and enrolled 55 MMP cases to validate its diagnostic performance. The sensitivity and specificity of the ELISA for detecting MMP autoantibodies were 70.9% and 86.7%, respectively, far superior to those of conventional assays. In autoimmune diseases such as MMP, in which autoantibodies target various molecules, isolating the antigen-protein complexes can help establish a diagnostic system.
• イミキモドクリームが奏効した基底細胞母斑症候群の2例

  小川 弘記, 北村 真也, 田中 有沙, 山賀 三紗子, 平野 瑶子, 瀬尾 拓志, 葭本 倫大, 加藤 直子, 柳 輝希, 氏家 英之

  臨床皮膚科 (株)医学書院 77 (4) 347 - 352 0021-4973 2023/04 

  ＜文献概要＞症例1:基底細胞母斑症候群の70歳代,男性.顔面に黒色結節を2ヶ所認め,皮膚生検にて基底細胞癌と診断した.左前額部の病変に対してイミキモド外用療法を施行したところ,腫瘍の消退をみた.症例2:基底細胞母斑症候群の30歳代,女性.頭部に多発する褐色斑を認め,皮膚生検にて基底細胞癌と診断した.残存病変にイミキモド外用療法を施行したところ病変が消退した.同部の皮膚生検では,腫瘍細胞の残存はなかった.基底細胞母斑症候群では基底細胞癌が多発するため全病変に手術を行うことは患者に多大な負担がかかる.イミキモドクリームは欧米では表在型基底細胞癌に適応があり,基底細胞母斑症候群に対する奏効例が報告されている.自験2例の治療効果と合わせ,イミキモド外用療法は基底細胞母斑症候群に対しての治療選択肢として有用であると考えた.
• Zonula occludens‐1 distribution and barrier functions are affected by epithelial proliferation and turnover rates

  Keisuke Imafuku, Hiroaki Iwata, Ken Natsuga, Makoto Okumura, Yasuaki Kobayashi, Hiroyuki Kitahata, Akiharu Kubo, Masaharu Nagayama, Hideyuki Ujiie

  Cell Proliferation 0960-7722 2023/03/14
• ニボルマブによる術後補助療法を行った末端黒子型悪性黒色腫患者5名の治療効果の検討

  前田 拓哉, 北村 真也, 柳 輝希, 氏家 英之

  日本皮膚科学会雑誌 (公社)日本皮膚科学会 133 (3) 505 - 505 0021-499X 2023/03
• 乳房外パジェット病(EMPD)の前臨床モデルに対する抗HER2抗体薬物複合体(抗HER2ADC)の治療実験

  得地 景子, 柳 輝希, 前田 拓哉, 北村 真也, 氏家 英之

  日本皮膚科学会雑誌 (公社)日本皮膚科学会 133 (3) 539 - 539 0021-499X 2023/03
• FAM83Hの発現低下はケラチン分布の変化を介して皮膚有棘細胞癌の遊走と浸潤を促進する

  得地 景子, 北村 真也, 前田 拓哉, 氏家 英之, 柳 輝希, 渡部 昌, 畠山 鎮次, 加納 里志, 田中 伸哉

  日本皮膚科学会雑誌 (公社)日本皮膚科学会 133 (2) 265 - 265 0021-499X 2023/02
• Beneficial effects of nintedanib on cardiomyopathy in patients with systemic sclerosis: a pilot study.

  Keita Ninagawa, Masaru Kato, Satonori Tsuneta, Suguru Ishizaka, Hideyuki Ujiie, Ryo Hisada, Michihito Kono, Yuichiro Fujieda, Yoichi M Ito, Tatsuya Atsumi

  Rheumatology (Oxford, England) 2022/12/02 

  OBJECTIVES: Nintedanib is an inhibitor of tyrosine kinases that has been shown to slow the progression of interstitial lung disease (ILD), including ILD associated with systemic sclerosis (SSc). The aim of this study was to explore the effect of nintedanib on cardiomyopathy associated with SSc. METHODS: Twenty consecutively hospitalized patients with SSc-ILD were enrolled and prospectively followed. The rate of change at six months in cardiac magnetic resonance (CMR) parametric mapping, including myocardial extracellular volume, was primarily evaluated. Other endpoints included changes in CMR functional parameters, echocardiographic parameters, modified Rodnan skin score, serum biomarkers, and pulmonary function test. RESULTS: Nintedanib was administered in 10 patients, whereas the other 10 were treated without nintedanib or watched, according to ILD severity and progression. Baseline values of CMR parametric mapping were not different between the two groups. The rate of change at six months in myocardial extracellular volume was largely different, almost divergent between the nintedanib group and the control group (-1.62% vs. +2.00%, p= 0.0001). Among other endpoints, the change in right ventricular ejection fraction was significantly different between the two groups (p= 0.02), with a preferential change in the nintedanib group. CONCLUSION: Our data indicate beneficial signals of nintedanib on cardiomyopathy associated with SSc. The anti-fibrotic effect of nintedanib might not be limited to the lung.
• CDK4/6阻害剤は乳房外Paget病の腫瘍増殖を抑制する

  北村 真也, 前田 拓哉, 柳 輝希, 氏家 英之

  西日本皮膚科 日本皮膚科学会-西部支部 84 (6) 576 - 576 0386-9784 2022/12
• 陰茎リンパ浮腫上に生じたHPV52型陽性Bowen病の1例

  田中 有沙, 北村 真也, 瀬尾 拓志, 葭本 倫大, 柳 輝希, 氏家 英之

  日本皮膚科学会雑誌 (公社)日本皮膚科学会 132 (12) 2696 - 2696 0021-499X 2022/11
• 壊疽性膿皮症が疑われた壊疽性膿瘡の2例

  田中 有沙, 柳 輝希, 小川 弘記, 瀬尾 拓志, 小住 英之, 眞井 翔子, 宮澤 元, 今福 恵輔, 夏賀 健, 氏家 英之, 箱崎 茉衣

  日本皮膚科学会雑誌 (公社)日本皮膚科学会 132 (12) 2697 - 2698 0021-499X 2022/11
• 姑息的切除を行った乳房外パジェット病の予後に関する検討

  瀬尾 拓志, 北村 真也, 柳 輝希, 氏家 英之

  日本皮膚科学会雑誌 (公社)日本皮膚科学会 132 (12) 2698 - 2698 0021-499X 2022/11
• 陰嚢に生じた巨大基底細胞癌の1例

  小川 弘記, 北村 真也, 平野 瑶子, 田中 有沙, 瀬尾 拓志, 葭本 倫大, 柳 輝希, 氏家 英之, 梅本 浩平

  日本皮膚科学会雑誌 (公社)日本皮膚科学会 132 (12) 2698 - 2698 0021-499X 2022/11
• イミキモドクリームが奏効した基底細胞母斑症候群の2例

  小川 弘記, 北村 真也, 田中 有沙, 山賀 三紗子, 平野 瑶子, 瀬尾 拓志, 葭本 倫大, 柳 輝希, 氏家 英之, 加藤 直子

  日本皮膚科学会雑誌 (公社)日本皮膚科学会 132 (12) 2700 - 2700 0021-499X 2022/11
• 好塩基球活性化試験がアレルゲンの同定に有用であった自己汗アナフィラキシーの1例

  泉 健太郎, 柳 輝希, 氏家 英之, 西江 渉, 山口 泰之, 平田 悠

  日本皮膚科学会雑誌 (公社)日本皮膚科学会 132 (12) 2702 - 2702 0021-499X 2022/11
• Cutaneous epithelioid angiosarcomaの4例

  黒澤 卓, 前田 拓哉, 北村 真也, 柳 輝希, 氏家 英之, 稲村 衣美, 安藤 佐土美, 小林 仁, 安岡 厚

  日本皮膚科学会雑誌 (公社)日本皮膚科学会 132 (12) 2704 - 2704 0021-499X 2022/11
• 神経核内封入体病診断における皮膚生検の検討

  板本 想太, 柳 輝希, 氏家 英之, 矢部 一郎, 松野 吉宏

  日本皮膚科学会雑誌 (公社)日本皮膚科学会 132 (12) 2704 - 2704 0021-499X 2022/11
• Adjuvant nivolumab therapy may not improve disease-free survival in resected acral lentiginous melanoma patients: A retrospective case series

  Takuya Maeda, Teruki Yanagi, Kodai Miyamoto, Keiko Tokuchi, Shinya Kitamura, Hideyuki Ujiie

  Dermatologic Therapy 35 (11) 1396-0296 2022/11 

  Adjuvant nivolumab therapy has been reported to improve the survival of melanoma patients. Acral lentiginous melanoma (ALM) has been reported to be less likely to respond to immune checkpoint inhibitors (ICIs) than other subtypes. However, the efficacy of adjuvant nivolumab therapy for ALM patients remains uncertain due to the low number of cases. In this single-center retrospective case series, we analyzed the clinical data of patients with resected stage III/IV ALM who were referred to our department between April 1, 2004 and March 31, 2022. The analyzed clinical data included age, sex, TNM stage, treatments, adverse events and disease-free survival (DFS). Enrolled patients were divided into a nivolumab group and a non-ICI group according to the adjuvant therapy they received. In total, 27 patients were included. The nivolumab and non-ICI groups had 5 and 22 patients, respectively. There were no significant differences in patient characteristics between the two groups. There were no serious treatment-related adverse events in the non-ICI group, but one patient in the nivolumab group developed type 1 diabetes. In the survival analysis, the DFS for the nivolumab group did not exceed that of the non-ICI group in postoperative adjuvant therapy for ALM patients. Given that adjuvant nivolumab therapy sometimes results in serious adverse effects, the administration of the therapy may need to be carefully considered, especially for ALM patients.
• Rituximab therapy for intractable pemphigus: A multicenter, open-label, single-arm, prospective study of 20 Japanese patients.

  Jun Yamagami, Yuichi Kurihara, Takeru Funakoshi, Yasuko Saito, Ryo Tanaka, Hayato Takahashi, Hideyuki Ujiie, Hiroaki Iwata, Yoji Hirai, Keiji Iwatsuki, Norito Ishii, Jun Sakurai, Takayuki Abe, Ryo Takemura, Naomi Mashino, Masahiro Abe, Masayuki Amagai

  The Journal of dermatology 50 (2) 175 - 182 2022/10/04 

  This was a multicenter clinical trial of rituximab, a chimeric monoclonal IgG antibody directed against CD20, for the treatment of refractory pemphigus vulgaris and pemphigus foliaceus. In total, 20 patients were treated with two doses of rituximab (1000 mg; 2 weeks apart) on days 0 and 14. The primary end point was the proportion of patients who achieved complete or partial remission on day 168 following the first rituximab dose. Of the 20 enrolled patients, 11 (55%) and four (20%) achieved complete and partial remission, respectively; therefore, remission was achieved in a total of 15 patients (75.0% [95% confidence interval, 50.9%-91.3%]). It was demonstrated that the remission rate was greater than the prespecified threshold (5%). In addition, a significant improvement in clinical score (Pemphigus Disease Area Index) and decrease in serum anti-desmoglein antibody level were observed over time. Four serious adverse events (heart failure, pneumonia, radial fracture, and osteonecrosis) were recorded in two patients, of which only pneumonia was considered causally related with rituximab. The level of peripheral blood CD19-positive B lymphocytes was decreased on day 28 after rituximab treatment and remained low throughout the study period until day 168. Our results confirm the efficacy and safety of rituximab therapy for refractory pemphigus in Japanese patients.
• Ecthyma gangrenosum caused by Streptococcus pyogenes: Report of a case and review of the literature.

  Arisa Tanaka, Teruki Yanagi, Takashi Seo, Shoko Mai, Hajime Miyazawa, Hideyuki Ujiie

  The Journal of dermatology 49 (8) e266-e267  2022/08
• HER2-Targeted Antibody–Drug Conjugates Display Potent Antitumor Activities in Preclinical Extramammary Paget’s Disease Models: In Vivo and Immunohistochemical Analyses

  Keiko Tokuchi, Takuya Maeda, Shinya Kitamura, Teruki Yanagi, Hideyuki Ujiie

  Cancers 14 (14) 2022/07 

  Extramammary Paget’s disease (EMPD) is an adenocarcinoma that develops mainly in the genital region of older adults. The prognosis for advanced EMPD is almost always poor; thus, novel therapeutic strategies need to be developed. HER2-targeted antibody–drug conjugates (ADCs) such as trastuzumab emtansine and trastuzumab deruxtecan have proven effective against HER2-positive breast cancers; however, no studies have addressed HER2-targeted ADCs as treatments for EMPD. We examine the efficacy of ADCs against an EMPD patient-derived xenograft (PDX) model harboring pathogenic ERBB2 mutations and investigate the expression levels of HER2 using EMPD clinical samples. Trastuzumab emtansine or trastuzumab deruxtecan was administered intravenously to tumor-bearing NOD/Scid mice. Treatment with trastuzumab emtansine or trastuzumab deruxtecan was found to significantly regress EMPD-PDX tumors in only seven days, with no recurrence observed for 10 weeks. EMPD tumors extracted 48 h after drug administration revealed the TUNEL-positive ratio to be significantly higher for the HER2-targeted ADC-treated tumors than for the control tumors. EMPD patients’ clinical samples revealed a significant correlation between HER2 positivity and invasion, suggesting that HER2 status is associated with tumor progression. Our results suggest that HER2-targeted ADCs could be novel and promising treatment options for patients with EMPD, especially in ERBB2-mutant or ERBB2-overexpressed cases.
• Regression of acquired reactive perforating collagenosis after dipeptidyl peptidase-4 inhibitor cessation.

  Takuya Kawamura, Yosuke Mai, Atsushi Narahira, Yoshihiro Matsuno, Wataru Nishie, Hideyuki Ujiie

  The Journal of dermatology 49 (7) e238-e240  2022/07 [Refereed][Not invited]
  
• Human figure‐shaped contact dermatitis due to the illustration on the inner surface of compression sleeves

  Takashi Seo, Toshinari Miyauchi, Tsuyoshi Kawakami, Hideyuki Ujiie

  The Journal of Dermatology 49 (7) 0385-2407 2022/07 [Refereed][Not invited]
  
• Collagen XVII deficiency alters epidermal patterning

  Yunan Wang, Hiroyuki Kitahata, Hideyuki Kosumi, Mika Watanabe, Yu Fujimura, Shota Takashima, Shin-Ichi Osada, Tomonori Hirose, Wataru Nishie, Masaharu Nagayama, Hiroshi Shimizu, Ken Natsuga

  Laboratory Investigation 2022/06
• Wnt/β-Catenin Signaling Stabilizes Hemidesmosomes in Keratinocytes.

  Hideyuki Kosumi, Mika Watanabe, Satoru Shinkuma, Takuma Nohara, Yu Fujimura, Tadasuke Tsukiyama, Giacomo Donati, Hiroaki Iwata, Hideki Nakamura, Hideyuki Ujiie, Ken Natsuga

  The Journal of investigative dermatology 142 (6) 1576 - 1586 2022/06 [Refereed][Not invited]
   

  Hemidesmosomes (HDs) are adhesion complexes that promote epithelial-stromal attachment in stratified and complex epithelia, including the epidermis. In various biological processes, such as differentiation and migration of epidermal keratinocytes during wound healing or carcinoma invasion, quick assembly and disassembly of HDs are prerequisites. In this study, we show that inhibition of Wnt/β-catenin signaling disturbs HD organization in keratinocytes. Screening with inhibitors identified the depletion of HD components and HD-like structures through Wnt inhibition, but keratinocyte differentiation was not affected. Wnt inhibition significantly diminished plectin and type XVII collagen expression in the basal side of Wnt-inhibited cells and the dermo-epidermal junction of the Wnt-inactive murine basal epidermis. Similar to Wnt inhibition, PLEC-knockout cells or cells with plectin-type XVII collagen binding defects showed type XVII collagen reduction in the basal side of the cells, implying the possible involvement of Wnt/β-catenin signaling in HD assembly. Atypical protein kinase C inhibition ameliorated the phenotypes of Wnt-inhibited cells. These findings show that Wnt/β-catenin signaling regulates the localization of HD components in keratinocytes and that the atypical protein kinase C pathway is involved in Wnt inhibition‒induced HD disarrangement. Our study suggests that the Wnt signaling pathway could be a potential therapeutic target for treating HD-defective diseases, such as epidermolysis bullosa.
• Case Report: Hereditary Fibrosing Poikiloderma With Tendon Contractures, Myopathy, and Pulmonary Fibrosis (POIKTMP) Presenting With Liver Cirrhosis and Steroid-Responsive Interstitial Pneumonia

  Michiko Takimoto-Sato, Toshinari Miyauchi, Masaru Suzuki, Hideyuki Ujiie, Toshifumi Nomura, Tomoo Ikari, Tomohiko Nakamura, Kei Takahashi, Machiko Matsumoto-Sasaki, Hirokazu Kimura, Hiroki Kimura, Yuichiro Matsui, Takashi Kitagataya, Ren Yamada, Kazuharu Suzuki, Akihisa Nakamura, Masato Nakai, Takuya Sho, Koji Ogawa, Naoya Sakamoto, Naoko Yamaguchi, Noriyuki Otsuka, Utano Tomaru, Satoshi Konno

  Frontiers in Genetics 13 2022/05/05 [Refereed]
   

  Background: Hereditary fibrosing poikiloderma with tendon contractures, myopathy, and pulmonary fibrosis (POIKTMP) is an extremely rare disease caused by mutations in FAM111B, and only approximately 30 cases have been reported worldwide. Some patients develop interstitial pneumonia, which may lead to progressive pulmonary fibrosis and poor prognosis. However, no effective treatment for interstitial pneumonia associated with POIKTMP has been reported. Here, we report an autopsy case of POIKTMP, wherein interstitial pneumonia was improved by corticosteroids. Case Presentation: A 44-year-old Japanese man was referred to our hospital due to poikiloderma, hypotrichosis, and interstitial pneumonia. He developed progressive poikiloderma and muscle weakness since infancy. He also had tendon contractures, short stature, liver cirrhosis, and interstitial pneumonia. Mutation analysis of FAM111B revealed a novel and de novo heterozygous missense mutation, c.1886T > G (p(Phe629Cys)), through which we were able to diagnose the patient with POIKTMP. 3 years after the POIKTMP diagnosis, interstitial pneumonia had worsened. After 2 weeks of administrating 40 mg/day of prednisolone, his symptoms and lung shadows improved. However, he subsequently developed severe hepatic encephalopathy and eventually died of respiratory failure due to bacterial pneumonia and pulmonary edema. Autopsy revealed an unclassifiable pattern of interstitial pneumonia, as well as the presence of fibrosis and fatty degeneration in several organs, including the liver, kidney, skeletal muscle, heart, pancreas, and thyroid. Conclusions: We report a case of POIKTMP in which interstitial pneumonia was improved by corticosteroids, suggesting that corticosteroids could be an option for the treatment of interstitial pneumonia associated with this disease.
• 当科でパルス療法を施行した特発性後天性全身性無汗症患者の解析

  今福 恵輔, 柳 輝希, 葭本 倫大, 宮澤 元, 岩田 浩明, 氏家 英之

  日本皮膚科学会雑誌 (公社)日本皮膚科学会 132 (5) 1307 - 1307 0021-499X 2022/05
• BP180と7型コラーゲンを標的抗原とした免疫チェックポイント阻害薬関連表皮下水疱症の1例

  葭本 倫大, 平野 瑶子, 得地 景子, 泉 健太郎, 松本 隆児, 氏家 英之

  日本皮膚科学会雑誌 (公社)日本皮膚科学会 132 (5) 1310 - 1310 0021-499X 2022/05
• BP180と7型コラーゲンを標的抗原とした免疫チェックポイント阻害薬関連表皮下水疱症の1例

  葭本 倫大, 平野 瑶子, 得地 景子, 泉 健太郎, 松本 隆児, 氏家 英之

  日本皮膚科学会雑誌 (公社)日本皮膚科学会 132 (5) 1310 - 1310 0021-499X 2022/05
• Cas9-guided haplotyping of three truncation variants in autosomal recessive disease.

  Ken Natsuga, Yoshikazu Furuta, Shota Takashima, Takuma Nohara, Hsin-Yu Huang, Satoru Shinkuma, Hideki Nakamura, Yousuke Katsuda, Hideaki Higashi, Chao-Kai Hsu, Satoshi Fukushima, Hideyuki Ujiie

  Human mutation 43 (7) 877 - 881 2022/04/21 [Refereed]
   

  An autosomal recessive disease is caused by biallelic loss-of-function mutations. However, when more than two disease-causing variants are found in a patient's gene, it is challenging to determine which two of the variants are responsible for the disease phenotype. Here, to decipher the pathogenic variants by precise haplotyping, we applied nanopore Cas9-targeted sequencing (nCATS) to three truncation COL7A1 variants detected in a patient with recessive dystrophic epidermolysis bullosa (EB). The distance between the most 5' and 3' variants was approximately 19 kb at the level of genomic DNA. nCATS successfully demonstrated that the most 5' and 3' variants were located in one allele while the variant in between was located in the other allele. Interestingly, the proband's mother, who was phenotypically intact, was heterozygous for the allele that harbored the two truncation variants, which could otherwise be misinterpreted as those of typical recessive dystrophic EB. Our study highlights the usefulness of nCATS as a tool to determine haplotypes of complicated genetic cases. Haplotyping of multiple variants in a gene can determine which variant should be therapeutically targeted when nucleotide-specific gene therapy is applied.
• Detection of revertant mosaicism in epidermolysis bullosa through Cas9-targeted long-read sequencing.

  Ken Natsuga, Yoshikazu Furuta, Shota Takashima, Takuma Nohara, Hideyuki Kosumi, Yosuke Mai, Hideaki Higashi, Hideyuki Ujiie

  Human mutation 43 (4) 529 - 536 2022/04 [Refereed]
   

  Revertant mosaicism (RM) is a phenomenon in which inherited mutations are spontaneously corrected in somatic cells. RM occurs in some congenital skin diseases, but genetic validation of RM in clinically revertant skin has been challenging, especially when homologous recombination (HR) is responsible for RM. Here, we introduce nanopore Cas9-targeted sequencing (nCATS) for identifying HR in clinically revertant skin. We took advantage of compound heterozygous COL7A1 mutations in a patient with recessive dystrophic epidermolysis bullosa who showed revertant skin spots. Cas9-mediated enrichment of genomic DNA (gDNA) covering the two mutation sites (>8 kb) in COL7A1 and subsequent MinION sequencing successfully detected intragenic crossover in the epidermis of the clinically revertant skin. This method enables the discernment of haplotypes of up to a few tens of kilobases of gDNA. Moreover, it is devoid of polymerase chain reaction amplification, which can technically induce recombination. We, therefore, propose that nCATS is a powerful tool for understanding complicated gene modifications, including RM.
• Super-resolution imaging detects BP180 autoantigen in immunoglobulin M pemphigoid.

  Yoko Hirano, Hiroaki Iwata, Masumi Tsujuwaki, Shoko Mai, Yosuke Mai, Keisuke Imafuku, Kentaro Izumi, Hiroshi Koga, Hideyuki Ujiie

  The Journal of dermatology 49 (3) 374 - 378 2022/03 [Refereed]
   

  Bullous pemphigoid is generally caused by immunoglobulin (Ig)G autoantibodies against hemidesmosomal BP180 and/or BP230. Recently, the concept of IgM pemphigoid has been proposed. A 23-year-old Japanese woman presented with a 4-month history of severely itchy papules showing subepidermal separations with mild neutrophil infiltration. Direct immunofluorescence (DIF) revealed IgM deposits at the dermoepidermal junction, but neither IgG nor IgA deposits. Indirect immunofluorescence on 1 M NaCl-split skin demonstrated deposits on the epidermal side. The optical density (OD) value of a modified IgM enzyme-linked immunosorbent assay for full-length BP180, but not for BP180-NC16A, was increased. The patient was diagnosed with IgM pemphigoid and was treated with diphenyl sulfone at 50 mg/day without recurrence. To confirm the precise autoantigen, we tried to obtain super-resolution imaging. The deposition pattern of IgM autoantibodies seemed to be oriented parallel to that of BP180. The detailed images detect DIF deposits apart from BP180-NC16A staining, but are close to type VII collagen-NC1 staining. This result suggests that the IgM autoantibodies in the patient might target the C-terminus of BP180. IgM pemphigoid is still not a widely accepted concept, and the clinical course remains unknown. We will carefully follow-up the patient. Super-resolution images may help to detect precise autoantigens in autoimmune blistering diseases.
• IgA nephropathy preceded by erythroderma with eosinophilia.

  Mina Takatsu, Ken Natsuga, Fumihiko Hattanda, Hideyuki Ujiie

  European journal of dermatology : EJD 2022/02/15 [Refereed]
  
• Cyclin-dependent kinase 4/6 inhibitors suppress tumor growth in extramammary Paget’s disease

  Shinya Kitamura, Teruki Yanagi, Takuya Maeda, Hideyuki Ujiie

  Cancer Science 113 (2) 802 - 807 1347-9032 2022/02 

  Extramammary Paget’s disease (EMPD) is a rare adnexal neoplasm commonly seen in the genital areas among the senior population. The prognosis of advanced EMPD is not favorable; thus, the development of potential treatments has long been sought. Cyclin-dependent kinase (CDK) 4/6 inhibitors such as abemaciclib and palbociclib have been proven effective against metastatic breast cancer; however, no studies have addressed CDK4/6 inhibitors as an EMPD treatment. We herein examine the efficacy of CDK4/6 inhibitors against an EMPD patient-derived xenograft (PDX) model. Abemaciclib (50 mg/kg/day) or palbociclib (120 mg/kg/day) was given orally to tumor-bearing NOD/Scid mice over a 3-week period. We also investigated the protein expression levels of CDK4/6 and cyclin D1 through immunohistochemical staining using EMPD clinical samples. Treatment with abemaciclib or palbociclib as a single agent was found to significantly suppress tumor growth in EMPD-PDX. The Ki-67-positive ratio of the treated EMPD-PDX tumors was significantly lower than that of the nontreated tumors. Clinically, the expression levels of CDK4 and cyclin D1 were significantly higher in the EMPD tumor cells than in the normal epidermis. Our results suggest that CDK4/6 inhibitors could be novel and potent therapeutics for the treatment of EMPD.
• Case of hereditary leiomyomatosis and renal cell cancer showing multiple cutaneous leiomyomas harboring a recurrent nonsense mutation in the fumarate hydratase gene.

  Shoko Mai, Teruki Yanagi, Mayuna Shimano, Wataru Nishie, Ken Arita, Hideyuki Ujiie

  The Journal of dermatology 49 (1) e42-e43  2022/01
• The significance of preclinical anti-BP180 autoantibodies.

  Yosuke Mai, Kentaro Izumi, Shoko Mai, Hideyuki Ujiie

  Frontiers in immunology 13 963401 - 963401 2022 

  Bullous pemphigoid (BP) is the most common autoimmune subepidermal blistering disease. Although the pathomechanism of BP onset has yet to be elucidated in detail, BP autoantibodies targeting two hemidesmosomal components, BP180 and BP230, are known to play a pivotal role in BP pathogenesis. Thus, the detection and measurement of BP autoantibodies are necessary for diagnosing BP and monitoring the disease activity. Immune assays such as immunofluorescence microscopy, immunoblotting, and ELISAs using BP180 and BP230 detect BP autoantibodies in most BP cases with high specificity; however, BP autoantibodies are sometimes detected in BP patients before the onset of this disease. BP autoantibodies that are detected in patients without typical tense blisters are defined as "preclinical BP autoantibodies". These preclinical BP autoantibodies are detected even in a low percentage of normal healthy individuals. Although the importance of preclinical BP autoantibodies remains elusive, these autoantibodies might be a potential risk factor for subsequent BP development. Therefore, previous comparative epidemiological studies have focused on the prevalence of preclinical BP autoantibodies in populations susceptible to BP (e.g., the elderly) or in diseases with a higher risk of comorbid BP. This mini-review summarizes the literature on the prevalence of preclinical BP autoantibodies in patients with various conditions and diseases, and we discuss the significance of preclinical BP autoantibody detection.
• IgA nephropathy preceded by erythroderma with eosinophilia.

  Mina Takatsu, Ken Natsuga, Fumihiko Hattanda, Hideyuki Ujiie

  European journal of dermatology : EJD 32 (1) 127 - 129 2022/01/01
• The pathogeneses of pemphigus and pemphigoid diseases.

  Hideyuki Ujiie, Jun Yamagami, Hayato Takahashi, Kentaro Izumi, Hiroaki Iwata, Gang Wang, Daisuke Sawamura, Masayuki Amagai, Detlef Zillikens

  Journal of dermatological science 104 (3) 154 - 163 2021/12 

  Autoimmune bullous diseases (AIBDs) are skin disorders which are mainly induced by autoantibodies against desmosomal or hemidesmosomal structural proteins. Previous studies using patients' samples and animal disease models identified target antigens and elucidated the mechanisms of blister formation. Pemphigus has been the subject of more active clinical and basic research than any other AIBD. These efforts have revealed the pathogenesis of pemphigus, which in turn has led to optimal diagnostic methods and novel therapies, such as rituximab. In bullous pemphigoid (BP), studies with passive-transfer mouse models using rabbit anti-mouse BP180 antibodies and studies with passive-transfer or active mouse models using autoantigen-humanized mice elucidated the immune reactions to BP180 in vivo. Recently, dipeptidyl peptidase-4 inhibitors have attracted attention as a trigger for BP. For epidermolysis bullosa acquisita (EBA), investigations using mouse models are actively under way and several molecules have been identified as targets for novel therapies. In this review, we give an overview and discussion of the recent progress in our understanding of the pathogenesis of pemphigus, BP, and EBA. Further studies on the breakdown of self-tolerance and on the identification of key molecules that are relevant to blister formation may expand our understanding of the etiology of AIBDs and lead to the development of novel therapeutic strategies.
• Unilateral Naevoid Telangiectasia Associated with Oral Contraceptive.

  Takuma Nohara, Ken Natsuga, Atsushi Yasuoka, Hideyuki Ujiie

  Acta dermato-venereologica 101 (11) adv00595  2021/11/17 [Refereed]
  
• Macrolide/fluoroquinolone-resistant Campylobacter jejuni-induced cellulitis in a patient with X-linked agammaglobulinaemia successfully treated with carbapenem.

  Joohyung Youh, Keisuke Imafuku, Teruki Yanagi, Sho Nakakubo, Yosuke Mai, Hideyuki Kosumi, Takuya Kawamura, Ken Muramatsu, Chihiro Shiiya, Ayame Kimura, Sota Itamoto, Masafumi Yamada, Hideyuki Ujiie

  Dermatologic therapy 34 (6) e15176  2021/11 [Refereed]
  
• Loss of FAM83H promotes cell migration and invasion in cutaneous squamous cell carcinoma via impaired keratin distribution.

  Keiko Tokuchi, Shinya Kitamura, Takuya Maeda, Masashi Watanabe, Shigetsugu Hatakeyama, Satoshi Kano, Shinya Tanaka, Hideyuki Ujiie, Teruki Yanagi

  Journal of dermatological science 104 (2) 112 - 121 2021/11 [Refereed]
   

  BACKGROUNDS: FAM83H is essential for amelogenesis, but recent reports implicate that FAM83H is involved in the tumorigenesis. We previously clarified that TRIM29 binds to FAM83H to regulate keratin distribution and squamous cell migration. However, little is known about FAM83H in normal/malignant skin keratinocytes. OBJECTIVE: To investigate the expression of FAM83H in cutaneous squamous cell carcinoma (SCC) and its physiological function. METHODS: Immunohistochemical analysis and RT-PCR of human SCC tissues were performed. Next, we examined the effect of FAM83H knockdown/overexpression in SCC cell lines using cell proliferation, migration, and invasion assay. To investigate the molecular mechanism, immunoprecipitation of FAM83H was examined. Further, Immunofluorescence staining was performed. Finally, we examined the correlation between the expressions of FAM83H and the keratin distribution. RESULTS: FAM83H expression was lower in SCC lesions than in normal epidermis and correlated with differentiation grade. The mRNA expression levels of FAM83H in SCC tumors were also lower than in normal epidermis. The knockdown of FAM83H enhanced SCC cell migration and invasion, whereas the overexpression of FAM83H led to decreases in both. Furthermore, the knockdown of FAM83H enhanced the cancer cell metastasis in vivo. FAM83H formed a complex with TRIM29 and keratins. The knockdown of FAM83H altered keratin distribution and solubility. Clinically, the loss of FAM83H correlates with an altered keratin distribution. CONCLUSION: Our findings reveal a critical function for FAM83H in regulating keratin distribution, as well as in the migration/invasion of cutaneous SCC, suggesting that FAM83H could be a crucial molecule in the tumorigenesis of cutaneous SCC.
• Hidradenitis suppurativa successfully treated with two-stage surgery under disease control with adalimumab.

  Akihiro Orita, Shinya Kitamura, Takuya Maeda, Teruki Yanagi, Hiroaki Iwata, Keiko Shiba-Tokuchi, Toshifumi Nomura, Hideyuki Ujiie

  The Journal of dermatology 2021/09/10 [Refereed]
  
• Possible role of epiregulin from dermal fibroblasts in the keratinocyte hyperproliferation of psoriasis.

  Hiroaki Iwata, Naoya Haga, Hideyuki Ujiie

  The Journal of dermatology 48 (9) 1433 - 1438 2021/09 [Refereed]
   

  Psoriasis, an immune-mediated inflammatory disease, is characterized by keratinocyte hyperproliferation. Tumor necrosis factor (TNF)-α, interleukin (IL)-23, and IL-17A play critical roles in the pathogenesis of psoriasis. IL-17A secreted by T-helper 17 acts more directly against keratinocytes than TNF-α or IL-23 do. Regarding the receptors of cytokines, fibroblasts also express receptors against IL-17A and TNF-α, and induce the production of growth factors. Epiregulin (EREG), an epidermal growth factor receptor ligand, is produced by both keratinocytes and fibroblasts. EREG enhances keratinocyte proliferation and differentiation. We hypothesized that fibroblasts stimulated with IL-17A and/or TNF-α may play a role in epidermal hyperproliferation through the production of epidermal growth factors in psoriasis. The mRNA expression of EREG was found to be significantly upregulated by co-stimulation with IL-17A and TNF-α (mean, 49.2-fold). Furthermore, the stimulation with TNF-α alone, but not IL-17A alone, induced significant increases. Immunofluorescent staining demonstrated that the protein expression level of EREG was also increased in fibroblasts stimulated with these cytokines. Stimulation with EREG significantly enhanced keratinocyte proliferation in vitro. In human psoriatic patients' skin, immunofluorescence staining of EREG showed significantly high intensity in the dermis of lesional skin. In conclusion, cytokine stimulation with TNF-α and IL-17A induces the overexpression of EREG from dermal fibroblasts in the lesional skin of psoriasis, and plays a role in epidermal hyperproliferation.
• X連鎖無γグロブリン血症患者に発症した多剤耐性Campylobacter jejuniによる蜂窩織炎の1例

  劉 柱亨, 柳 輝希, 板本 想太, 木村 彩萌, 眞井 洋輔, 村松 憲, 今福 恵輔, 氏家 英之, 中久保 祥, 山田 雅文

  日本皮膚科学会雑誌 (公社)日本皮膚科学会 131 (9) 2072 - 2072 0021-499X 2021/08
• Pigmented eccrine poroma on the palm mimicking seborrheic keratosis: Dermoscopic findings and a review of reported cases.

  Mayuna Shimano, Shinya Kitamura, Takuya Maeda, Emi Takakuwa, Teruki Yanagi, Hideyuki Ujiie

  The Australasian journal of dermatology 62 (3) e477-e479  2021/08 [Refereed]
  
• A multicenter, open-label, uncontrolled, single-arm phase 2 study of tirabrutinib, an oral Bruton's tyrosine kinase inhibitor, in pemphigus.

  Jun Yamagami, Hideyuki Ujiie, Yumi Aoyama, Norito Ishii, Chiharu Tateishi, Akira Ishiko, Tomoki Ichijima, Shunsuke Hagihara, Koji Hashimoto, Masayuki Amagai

  Journal of dermatological science 103 (3) 135 - 142 2021/07/06 [Refereed]
   

  BACKGROUND: The treatment of pemphigus is based on systemic corticosteroid use and adjuvant therapies, but some patients are resistant to conventional therapy. Tirabrutinib is a highly selective oral Bruton's tyrosine kinase inhibitor that may be clinically effective in treating pemphigus by suppressing B-cell signaling. OBJECTIVE: We investigated the efficacy and safety of tirabrutinib in patients with refractory pemphigus. METHODS: This was a multicenter, open-label, single-arm phase 2 study of Japanese patients with refractory pemphigus receiving appropriate treatment with an oral corticosteroid and adjuvant therapies. Patients received postprandial oral tirabrutinib 80 mg once daily for 52 weeks. After 16 weeks of tirabrutinib treatment, the corticosteroid dose was tapered to ≤10 mg/day of prednisolone equivalent. RESULTS: In total, 16 patients were evaluated (mean age, 52.5 years; 50 % male). The complete remission rate after 24 weeks of treatment (primary endpoint) was 18.8 % (3/16; 95 % confidence interval, 6.6 %-43.0 %). By Week 52, eight patients (50.0 %) achieved complete remission and 10 patients (62.5 %) achieved remission. Over 52 weeks of treatment, the mean prednisolone dose decreased from 17.03 to 7.65 mg/day. Incidences of adverse events (AEs) and adverse drug reactions were 87.5 % and 43.8 %, respectively. A relationship with tirabrutinib was ruled out for all serious AEs and Grade ≥3 AEs. CONCLUSION: Treatment with tirabrutinib enabled remission and reduced oral corticosteroid exposure over time and did not result in any major safety concerns in patients with refractory pemphigus. Thus, oral tirabrutinib may be a new treatment option for patients with refractory pemphigus.
• Hair follicle stem cell progeny heal blisters while pausing skin development.

  Yu Fujimura, Mika Watanabe, Kota Ohno, Yasuaki Kobayashi, Shota Takashima, Hideki Nakamura, Hideyuki Kosumi, Yunan Wang, Yosuke Mai, Andrea Lauria, Valentina Proserpio, Hideyuki Ujiie, Hiroaki Iwata, Wataru Nishie, Masaharu Nagayama, Salvatore Oliviero, Giacomo Donati, Hiroshi Shimizu, Ken Natsuga

  EMBO reports 22 (7) e50882  2021/07/05 [Refereed]
   

  Injury in adult tissue generally reactivates developmental programs to foster regeneration, but it is not known whether this paradigm applies to growing tissue. Here, by employing blisters, we show that epidermal wounds heal at the expense of skin development. The regenerated epidermis suppresses the expression of tissue morphogenesis genes accompanied by delayed hair follicle (HF) growth. Lineage tracing experiments, cell proliferation dynamics, and mathematical modeling reveal that the progeny of HF junctional zone stem cells, which undergo a morphological transformation, repair the blisters while not promoting HF development. In contrast, the contribution of interfollicular stem cell progeny to blister healing is small. These findings demonstrate that HF development can be sacrificed for the sake of epidermal wound regeneration. Our study elucidates the key cellular mechanism of wound healing in skin blistering diseases.
• Dermoscopic features of sebaceous carcinoma of the nipple.

  Takuya Kawamura, Shinya Kitamura, Takuya Maeda, Akihiro Orita, Teruki Yanagi, Hideyuki Ujiie

  The Journal of dermatology 48 (7) e327-e328  2021/07 [Refereed]
  
• Spindle cell lipoma with a palisading pattern: A case report.

  Mayuna Shimano, Shinya Kitamura, Takuya Maeda, Teruki Yanagi, Emi Takakuwa, Hideyuki Ujiie

  The Journal of dermatology 48 (7) e351-e352  2021/07 [Refereed]
  
• A case of non-bullous pemphigoid induced by IgG4 autoantibodies targeting BP230.

  N Yoshimoto, S Takashima, T Kawamura, E Inamura, T Sugai, I Ujiie, K Izumi, K Natsuga, W Nishie, H Shimizu, H Ujiie

  Journal of the European Academy of Dermatology and Venereology : JEADV 35 (4) e282-e285  2021/04 [Refereed]
  
• Clinical characteristics and outcomes of bullous pemphigoid patients with versus without oral prednisolone treatment.

  Inkin Ujiie, Hiroaki Iwata, Norihiro Yoshimoto, Kentaro Izumi, Hiroshi Shimizu, Hideyuki Ujiie

  The Journal of dermatology 48 (4) 502 - 510 2021/04 [Refereed]
   

  Bullous pemphigoid (BP) varies in severity and stratified treatments are needed. However, there are no definitive standards for choosing appropriate treatments. To elucidate the factors involved in choosing treatments and the clinical outcomes of BP, we retrospectively reviewed the clinical records of 78 BP patients at a single center. Of the 78 patients, 49 (62.8%) were treated with oral prednisolone (PSL) and 29 (37.2%) were treated without PSL. The patients with older age, lower Bullous Pemphigoid Disease Area Index (BPDAI), and/or lower anti-BP180NC16a antibody titer at onset tended to be treated without oral PSL. Notably, only 9.1% patients without PSL experienced relapse, whereas 36.7% patients with oral PSL experienced relapse when the PSL was around 0.1 mg/kg. It suggests that the patients with mild disease severity could be well controlled without oral PSL. Receiver-operator curve analysis demonstrated that the cut-off value for the use of oral PSL was 31 for total BPDAI and was 7 for BPDAI skin urticaria/erythema, with a high (>0.9) area under the curve. Notably, none of the patients who were negative for the anti-BP180NC16a antibody at onset experienced relapse even though they were treated without PSL. In conclusion, in BP patients who were negative for anti-BP180NC16a antibody at onset, with a total BPDAI score of less than 31 or with an urticaria/erythema score of less than 7 can be treated without PSL. When the PSL is tapered to around 0.1 mg/kg, we should carefully monitor the patients to detect relapse.
• A case of mucous membrane pemphigoid with anti-BP230 autoantibodies alone.

  Norihiro Yoshimoto, Inkin Ujiie, Emi Inamura, Ken Natsuga, Wataru Nishie, Hiroshi Shimizu, Hideyuki Ujiie

  International journal of dermatology 60 (3) e92-e94  2021/03 [Refereed]
  
• Bullous pemphigoid associated with psoriasis showing marked neutrophilic infiltrates.

  Emi Inamura, Masumi Tsujiwaki, Hideyuki Ujiie, Wataru Nishie, Hiroo Hata, Hiroshi Shimizu, Hiroaki Iwata

  Journal der Deutschen Dermatologischen Gesellschaft = Journal of the German Society of Dermatology : JDDG 19 (1) 105 - 108 2021/01 [Refereed]
  
• Regulatory T cell subsets in bullous pemphigoid and dipeptidyl peptidase-4 inhibitor-associated bullous pemphigoid.

  Ken Muramatsu, Miao Zheng, Norihiro Yoshimoto, Takamasa Ito, Inkin Ujiie, Hiroaki Iwata, Hiroshi Shimizu, Hideyuki Ujiie

  Journal of dermatological science 100 (1) 23 - 30 2020/10 [Refereed][Not invited]
   

  BACKGROUND: Regulatory T (Treg) cells play an essential role in peripheral immune tolerance. Bullous pemphigoid (BP) is the most common blistering disease and is caused by autoantibodies to two BP antigens: type XVII collagen and BP230. Recently, we reported that Treg cell dysfunction may cause the production of autoantibodies to BP antigens. Several studies have suggested an association between Treg cells and BP pathogenesis. However, Treg cells are heterogeneous in humans, leading to inconsistent results in previous studies. OBJECTIVE: To assess functional Treg subsets in BP. METHODS: We examined three distinct Treg subsets in conventional BP (cBP) patients before versus after systemic corticosteroid treatment, dipeptidyl peptidase-4 inhibitor-associated BP (DPP-4i-BP) patients, younger controls and older controls. RESULTS: We found that total Treg cells and all Treg cell subsets were increased in cBP patients before treatment and decreased by systemic corticosteroid treatment. In contrast, neither total Treg cells nor all Treg subsets were increased in DPP-4i-BP. Notably, CD45RA- Foxp3hi effector Treg cells positively correlated with disease severity in cBP, whereas CD45RA+Foxp3lo naïve Treg cells positively correlated with the disease severity in DPP-4i-BP. CONCLUSION: These findings suggest that Treg cells are differently involved in the pathogeneses of cBP and DPP-4i-BP.
• Case of bullous erythema ab igne mimicking localized bullous pemphigoid.

  Naoya Haga, Hideyuki Ujiie, Takamasa Ito, Yasuyuki Yamaguchi, Takuya Mizukami, Sho Katayama, Hiroshi Shimizu

  The Journal of dermatology 47 (8) e288-e289  2020/08 [Refereed]
  
• Epitope spreading possibly from BP230 to the NC16A domain of BP180 preceding disease progression in bullous pemphigoid.

  Takashi Seo, Hideyuki Ujiie, Inkin Ujiie, Hiroaki Iwata, Hiroshi Shimizu

  The Journal of dermatology 47 (7) e255-e257  2020/07 [Refereed]
  
• Prevalence of infectious diseases in patients with autoimmune blistering diseases.

  Inkin Ujiie, Hideyuki Ujiie, Norihiro Yoshimoto, Hiroaki Iwata, Hiroshi Shimizu

  The Journal of dermatology 47 (4) 378 - 384 2020/04 [Refereed]
   

  A long-term immunosuppressive treatment can provoke latent infections. Autoimmune blistering diseases (AIBD) are mostly treated with systemic immunosuppressive agents. To prevent the reactivation or exacerbation of existing latent infections, patients must be screened for infectious diseases before immunosuppressive treatments are initiated. However, the prevalence of infectious diseases in AIBD remains to be elucidated. To evaluate the necessity of screening infectious diseases in AIBD, we retrospectively reviewed the clinical records of 215 patients at a single center with AIBD for hepatitis B virus (HBV), hepatitis C virus (HCV), Mycobacterium tuberculosis, Treponema pallidum, human T-cell leukemia virus type 1 (HTLV-1) and HIV infections. Approximately 40% of patients were infected with HBV. During systemic corticosteroid treatment, HBV DNA became positive in 3.4% of cases. Antibodies to HCV, interferon-γ release assays for M. tuberculosis and the T. pallidum latex agglutination test were positive in 0.6%, 6.6% and 1.2% cases, respectively. Neither HTLV-1 nor HIV infections were detected. In conclusion, checks for HBV and M. tuberculosis infections should be made before immunosuppressive treatments are started, because of the high prevalence of these potentially life-threatening infections. Other infections should be tested for depending on the patient's risk factors.
• Rosai-Dorfman disease: earlier spontaneous regression of skin lesions relative to nasal, pharyngeal, and bone lesions.

  Kazumasa Sato, Hideyuki Ujiie, Shinichi Nakazato, Mika Watanabe, Erika Watanabe, Teruki Yanagi, Yuji Nakamaru, Dai Takagi, Ryuta Arai, Tomohiro Onodera, Takeshi Kondo, Takanori Teshima, Hiroshi Shimizu

  European journal of dermatology : EJD 30 (2) 182 - 183 2020/04/01 [Refereed]
  
• Linear IgA/IgG bullous dermatosis with autoantibodies directing the native and processed forms of BP180.

  E Inamura, W Nishie, Y Yamaguchi, Y Fujimura, H Ujiie, K Natsuga, H Shimizu

  The British journal of dermatology 182 (4) 1061 - 1062 2020/04 [Refereed][Not invited]
  
• 水疱性類天疱瘡との鑑別を要した温熱性紅斑および低温熱傷の1例

  羽賀 直哉, 氏家 英之, 伊東 孝政, 山口 泰之, 水上 卓哉, 片山 奨, 清水 宏

  日本皮膚科学会雑誌 (公社)日本皮膚科学会 130 (3) 392 - 393 0021-499X 2020/03
• Localized bullous pemphigoid recurring at different sites: two case reports.

  Akito Hasegawa, Satoru Shinkuma, Tatsuya Katsumi, Naomi Kasahara, Kaoru Ito, Hideyuki Ujiie, Norito Ishii, Takashi Hashimoto, Riichiro Abe

  European journal of dermatology : EJD 2020/02/06 [Refereed][Not invited]
   

  BACKGROUND: Localized bullous pemphigoid is a relatively rare variant of bullous pemphigoid. Lesions develop only in localized sites including the legs or palms and soles and occasionally appear in trauma-affected body parts. In some cases, the skin lesions spread to the entire body, while in others, they remain localized and improve spontaneously or with treatment using topical corticosteroids. Rarely, the lesions recur at sites different from those of the original lesions, after the initial lesions have completely healed. OBJECTIVES: To investigate the clinical course of patients with localized bullous pemphigoid. MATERIALS AND METHODS: Two cases of localized bullous pemphigoid that recurred at sites distant from those of the initial lesions were reported. RESULTS: Case 1 involved a 62-year-old woman with mucous membrane pemphigoid. One year after the improvement of mucosal symptoms, new lesions appeared in the periumbilical area. The lesions resolved after topical corticosteroid treatment. This case is the first report of localized bullous pemphigoid occurring after an improvement of mucous membrane pemphigoid. Case 2 involved an 81-year-old man who bruised his right lower leg and developed erythematous plaques and tense bullae. The patient was diagnosed with localized bullous pemphigoid and was treated with topical corticosteroid. However, six months later, new lesions appeared on the palms and soles. The patient responded well to oral prednisolone. CONCLUSIONS: Since localized bullous pemphigoid may have a variable clinical course, clinicians should observe affected patients carefully over a long period of time.
• Japanese guidelines for the management of pemphigoid (including epidermolysis bullosa acquisita).

  Hideyuki Ujiie, Hiroaki Iwata, Jun Yamagami, Takekuni Nakama, Yumi Aoyama, Shigaku Ikeda, Norito Ishii, Keiji Iwatsuki, Michiko Kurosawa, Daisuke Sawamura, Akiko Tanikawa, Daisuke Tsuruta, Wataru Nishie, Wataru Fujimoto, Masayuki Amagai, Hiroshi Shimizu

  The Journal of dermatology 46 (12) 1102 - 1135 2019/12 [Not refereed][Invited]
   

  The pemphigoid group is a category of autoimmune subepidermal blistering diseases in which autoantibodies deposit linearly at the epidermal basement membrane zone (BMZ). The main subtypes of pemphigoid mediated by immunoglobulin G autoantibodies are bullous pemphigoid (BP), mucous membrane pemphigoid (MMP) and epidermolysis bullosa acquisita (EBA). To establish the first guidelines approved by the Japanese Dermatological Association for the management of pemphigoid diseases, the Committee for Guidelines for the Management of Pemphigoid Diseases (Including EBA) was founded as part of the Study Group for Rare Intractable Skin Diseases under the Ministry of Health, Labor and Welfare Research Project on Overcoming Intractable Diseases. These guidelines aim to provide current information for the management of BP, MMP and EBA in Japan. Based on evidence, the guidelines summarize the clinical and immunological manifestations, pathophysiologies, diagnostic criteria, disease severity determination criteria, treatment algorithms and treatment recommendations. Because of the rarity of these diseases, there are few clinical studies with a high degree of evidence, so several parts of these guidelines were established based on the opinions of the Committee. To further optimize these guidelines, periodic revision in line with the new evidence is necessary.
• Disseminated Mycobacterium intracellulare infection that led to recognition of idiopathic CD4+ lymphocytopenia.

  Satoko Shimizu, Yuka Takashima, Yuka Maya, Fumihiro Kodama, Mayumi Yokozeki, Koki Tomizawa, Ken Muramatsu, Hideyuki Ujiie, Hiroshi Shimizu, Reine Moriuchi

  Journal der Deutschen Dermatologischen Gesellschaft = Journal of the German Society of Dermatology : JDDG 17 (10) 1066 - 1068 2019/10 [Refereed]
  
• 発症から診断までに10年以上が経過した粘膜類天疱瘡の1例

  鈴木 丈雄, 新熊 悟, 荻根沢 真帆子, 会沢 敦子, 高橋 奈央, 泉 健太郎, 氏家 英之, 西江 渉, 阿部 理一郎

  臨床皮膚科 (株)医学書院 73 (10) 813 - 817 0021-4973 2019/09 [Refereed][Not invited]
   

  ＜文献概要＞73歳,男性.初診の10年以上前から口腔,鼻腔および咽喉頭粘膜にびらん,潰瘍が出現した.近医耳鼻科でBehcet病を疑われ,プレドニゾロンやコルヒチンの内服などで治療されたが,難治であった.また,初診の3年前から眼球癒着を生じ,眼科で内反症解除術・眼球癒着解除術を施行されたが,術後1ヵ月で再び癒着した.口腔内の難治性潰瘍の精査・加療目的に当科を紹介され受診した.歯肉びらん部の病理組織像では粘膜上皮・固有層間に裂隙を認めた.無疹部であった口唇粘膜の生検組織を用いた蛍光抗体直接法では粘膜上皮直下に線状のIgG沈着を認め,1M食塩水剥離ヒト皮膚を用いた蛍光抗体間接法では患者血清IgGが裂隙の表皮側に沈着した.以上から,抗BP180型粘膜類天疱瘡と考えた.皮膚病変が軽症な粘膜類天疱瘡では,他科で診断が不確定なまま粘膜の難治性潰瘍として長期間治療されることがあるため,他科との密な連携が必要である.
• Clinical and immunological features of pemphigus relapse.

  I Ujiie, H Ujiie, H Iwata, H Shimizu

  The British journal of dermatology 180 (6) 1498 - 1505 2019/06 [Refereed]
   

  BACKGROUND: More than half of patients with pemphigus experience relapse during the disease course. The risk factors and clinical and immunological characteristics of relapse remain largely unclear. OBJECTIVES: To elucidate the risk factors and clinical features of pemphigus relapse. METHODS: We carried out a retrospective review of the clinical records of 42 cases of pemphigus at a single centre. RESULTS: Sixty-two per cent of patients experienced relapse, usually when oral prednisolone was tapered to around 0·1 mg kg-1 . In mucocutaneous pemphigus vulgaris (mcPV), the initial doses (mean ± SD) of prednisolone were significantly lower in patients with relapse (0·78 ± 0·24 mg kg-1 ) than in those without relapse (1·01 ± 0·01 mg kg-1 ). At relapse, mcPV shifted to mucosal dominant PV (mPV; 40%), pemphigus foliaceus (PF) (20%) or 'other' (20%). In contrast, relapsing mPV and PF had the same clinical phenotypes as the initial phenotypes. Patients with both anti-desmoglein (Dsg)1 and anti-Dsg3 antibodies at onset had recurrence with anti-Dsg3 antibodies alone (40%), with both anti-Dsg1 and anti-Dsg3 antibodies (30%), with anti-Dsg1 antibody alone (20%) or were subthreshold (10%). CONCLUSIONS: mcPV shows transitions in clinical phenotype and autoantibody profile at relapse. At least 1 mg kg-1 daily of prednisolone, especially for patients with mcPV, and prudent tapering around 0·1 mg kg-1 may lead to better outcomes.
• Case of autoimmune intraepidermal and subepidermal blistering disease in which autoantibodies to desmoglein 1 and BP230 coexist.

  Sugai T, Ujiie H, Nakamura H, Kikuchi K, Iwata H, Shimizu H

  The Journal of dermatology 46 (6) e215 - e216 0385-2407 2019/06 [Refereed][Not invited]
  
• 制御性T細胞の機能不全により類天疱瘡抗原への自己抗体産生が誘導される

  村松 憲, 氏家 英之, 西江 渉, 泉 健太郎, 伊東 孝政, 葭本 倫大, 夏賀 健, 岩田 浩明, 清水 宏, 小林 一郎

  日本皮膚科学会雑誌 (公社)日本皮膚科学会 129 (3) 353 - 353 0021-499X 2019/03
• 咽頭粘膜まで広範囲に病変を生じた粘膜型尋常性天疱瘡の1例

  野原 拓馬, 村松 憲, 眞井 翔子, 宮澤 元, 伊東 孝政, 氏家 英之, 岩田 浩明, 清水 宏, 渡辺 雅子

  日本皮膚科学会雑誌 (公社)日本皮膚科学会 129 (3) 355 - 355 0021-499X 2019/03
• H.pylori除菌療法後に生じた皮疹の機序解明

  伊東 孝政, 氏家 英之, 清水 宏, 阿部 理一郎

  日本皮膚科学会雑誌 (公社)日本皮膚科学会 129 (3) 394 - 394 0021-499X 2019/03
• Characteristics of IgG subclasses and complement deposition in BP230-type bullous pemphigoid

  M. Zheng, H. Ujiie, H. Iwata, K. Muramatsu, N. Yoshimoto, T. Ito, I. Ujiie, S. Shimizu, K. C. Sato-Matsumura, H. Shimizu

  Journal of the European Academy of Dermatology and Venereology 33 (3) 595 - 600 0926-9959 2019/03 [Refereed]
   

  Background: Bullous pemphigoid (BP) is the most common autoimmune blistering disease. BP180 is the primary autoantigen of BP, and in a portion of BP cases, BP230 is the only target of autoantibodies. Such BP is called BP230-type BP. BP230-type BP tends to show milder clinical phenotypes than conventional BP, but the reason is unclear. The pathogenic roles of autoantibodies and complement activation have been shown in conventional BP, but the distribution of IgG subclasses and the degree of complement deposition in BP230-type BP remain unclear. Objective: To compare the distribution of IgG subclasses and the degree of complement deposition in BP230-type BP with those in conventional BP with autoantibodies to BP180 and BP230 (BP180-BP230-type BP). Methods: The diagnosis of BP was confirmed by the histopathology of the lesions, the deposition of IgG and complement in the perilesional skin and the presence of circulating autoantibodies to BP180 and BP230. The disease severity was determined by bullous pemphigoid disease area index. The deposition of IgG subclasses and complement deposition were examined by direct immunofluorescence of the perilesional skin in 6 BP230-type BP cases and 11 BP180-BP230-type BP cases. Results: Sixty seven percent of BP230-type BP cases show a mild clinical phenotype. All BP230-type BP cases and 82% of BP180-BP230-type BP cases were found to demonstrate the clear deposition of IgG4 at the basement membrane zone of skin specimens. Notably, the deposition of IgG1 and IgG3 was faint or negative in all of the BP230-type BP cases, whereas they were clearly detected in 91% and 64% of the BP180-BP230-type BP cases, respectively. The deposition of complement C3 tended to be weaker in BP230-type BP than in BP180-BP230-type BP. Conclusion: The mild clinical phenotype of BP230-type BP may correlate with the weaker deposition of IgG1, IgG3 and complement in the skin lesions.
• Fc-binding proteins enhance autoantibody-induced BP180 depletion in pemphigoid.

  Iwata H, Kamaguchi M, Ujiie H, Ujiie I, Natsuga K, Nishie W, Shimizu H

  The Journal of pathology 247 (3) 371 - 380 0022-3417 2019/03 [Refereed][Not invited]
   

  Immunoglobulins (Igs) consist of two antigen-binding regions (Fab) and one constant region (Fc). Protein A and protein G are bacterial proteins used for the purification of IgG by virtue of their high affinities for the Fc fragment. Rheumatoid factors are autoantibodies against IgG Fc fragments, which are present in the body under physiological conditions. Little is known about the influence of Fc-binding proteins on the pathogenicity of antibody-induced autoimmune diseases. Pemphigoid diseases are a group of autoimmune subepidermal blistering disorders that includes bullous pemphigoid and mucous membrane pemphigoid. IgGs targeting the non-collagenous NC16A domain of the 180-kDa bullous pemphigoid antigen (BP180) are known to induce skin fragility in mice and the depletion of BP180 in keratinocytes. In this study, mAb against NC16A in combination with Fc-binding proteins was found to enhance BP180 depletion. Although mAb against the C-terminus of BP180 does not show pathogenicity in vivo or in vitro, mAb treatment with Fc-binding proteins clearly induced skin fragility in mice and BP180 depletion in keratinocytes. Anti-BP180 mAbs and Fc-binding proteins were colocalized in the cytoplasm and at the basement membrane zone. Cell adhesion strengths were decreased in parallel with BP180 amounts. Clinically, bullous pemphigoid patients had higher rheumatoid factor titers than controls. Anti-BP180 mAb in combination with high-titer rheumatoid factor serum was found to enhance BP180 depletion. Furthermore, saliva from mucous membrane pemphigoid patients contained larger quantities of bacteria and Fc-binding proteins than controls. Our results suggest that Fc-binding proteins (rheumatoid factor or protein G) may enhance the pathogenicity of autoantibodies in pemphigoid diseases. Copyright © 2018 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
• Efficient gene reframing therapy for recessive dystrophic epidermolysis bullosa using CRISPR/Cas9.

  Takashima S, Shinkuma S, Fujita Y, Nomura T, Ujiie H, Natsuga K, Iwata H, Nakamura H, Vorobyev A, Abe R, Shimizu H

  The Journal of investigative dermatology 139 (8) 1711 - 1721 0022-202X 2019/03 [Refereed][Not invited]
   

  The clustered regularly interspaced short palindromic repeats (CRISPR)/Cas9 system induces site-specific double-strand breaks, which stimulate cellular DNA repair through either the homologous recombination or non-homologous end-joining pathways. The non-homologous end-joining pathway, which is activated more frequently than homologous recombination, is prone to introducing small insertions and/or deletions at the double-strand break site, leading to changes in the reading frame. We hypothesized that the non-homologous end-joining pathway is applicable to genetic diseases caused by a frameshift mutation through restoration of the reading frame. Recessive dystrophic epidermolysis bullosa is a hereditary skin disorder caused by mutations in COL7A1. In this study, we applied gene reframing therapy to a recurrent frameshift mutation, c.5819delC, in COL7A1, which results in a premature termination codon. CRISPR/Cas9 targeting this specific mutation site was delivered to recessive dystrophic epidermolysis bullosa patient fibroblasts. After genotyping a large collection of gene-edited fibroblast clones, we identified a significant number (17/50) of clones in which the frameshift in COL7A1 was restored. The reframed COL7 was functional, as shown by triple-helix formation assay in vitro, and was correctly distributed in the basement membrane zone in mice. Our data suggest that mutation site-specific non-homologous end-joining might be a highly efficient gene therapy for inherited disorders caused by frameshift mutations.
• The direct binding of collagen XVII and collagen IV is disrupted by pemphigoid autoantibodies.

  Mayumi Kamaguchi, Hiroaki Iwata, Wataru Nishie, Ellen Toyonaga, Hideyuki Ujiie, Ken Natsuga, Yoshimasa Kitagawa, Hiroshi Shimizu

  Laboratory investigation; a journal of technical methods and pathology 99 (1) 48 - 57 0023-6837 2019/01 [Refereed][Not invited]
   

  The basement membrane zone (BMZ) is framed by hemidesmosomes and extracellular matrix (ECM) including collagen IV (COL4). Hemidesmosomes are multiprotein complexes that include collagen XVII (COL17). BMZ proteins can be targeted in autoimmune subepidermal blistering diseases, e.g., pemphigoid targeting COL17. The blistering mechanisms in pemphigoid have not been fully elucidated, especially in mucous membrane pemphigoid (MMP), which mainly affects the mucosa. In this study, we showed that oral lesions in pemphigoid may be attributed to the inhibition of protein-protein interactions by autoantibodies. Using immunoprecipitation, we revealed that COL17 directly binds to COL4 in normal human keratinocytes and normal human oral keratinocytes. In particular, the C-terminus of COL17 is binding site to COL4 in oral keratinocytes. The precise COL4-binding region on COL17 was determined by protein-protein binding assay to be from amino acid Gly1175 to Asp1340 on the C-terminus. MMP-IgG or mAb recognizing the C-terminus hindered the interaction of COL17 with COL4 in oral keratinocytes. Furthermore, keratinocyte adhesion strength to COL4-coated plates was significantly reduced by the treatment of mAb against the C-terminus. In addition, the inflammatory infiltrates around perilesions were significantly less in MMP compared to BP. These results indicate that pemphigoid IgG targeting the C-terminus plays a pathogenic role in blister formation in the oral mucosa to inhibit protein interactions with less inflammation.
• Immune Reaction to Type XVII Collagen Induces Intramolecular and Intermolecular Epitope Spreading in Experimental Bullous Pemphigoid Models.

  Hideyuki Ujiie, Norihiro Yoshimoto, Ken Natsuga, Ken Muramatsu, Hiroaki Iwata, Wataru Nishie, Hiroshi Shimizu

  Frontiers in immunology 10 1410 - 1410 2019 [Refereed][Not invited]
   

  Bullous pemphigoid (BP), the most common autoimmune blistering disease, is induced by autoantibodies to type XVII collagen (COL17). Previous studies demonstrated that COL17 harbors several epitopes targeted by autoreactive T and B cells and that the target epitopes change sequentially during the disease course. To elucidate the details of the humoral immune response to COL17, we used an active BP mouse model in which BP is induced by the adoptive transfer of spleen cells from wild-type mice immunized with human COL17-expressing skin grafting to immunodeficient COL17-humanized (Rag-2-/-, mouse Col17-/-, human COL17+) mice. By immunoblot analysis, antibodies to the NC16A domain and other extracellular domains (ECDs) of COL17 were detected earlier than antibodies to intracellular domains (ICDs) in the active BP model. Time course analysis by enzyme-linked immunosorbent assay demonstrated a delayed peak of antibodies to ICD epitopes in active BP model. The blockade of CD40-CD40 ligand interaction soon after the adoptive transfer suppressed the production of antibodies to the non-collagenous 16A (NC16A) domain but not to an ICD epitope, suggesting the sequential activation from T and B cells against the ECD epitopes including the NC16A domain to those against ICD epitopes in vivo. Both wild-type mice immunized with a fragment of the NC16A domain and the recipients of those spleen cells produced IgG antibodies to ICD and ECD epitopes, showing intramolecular epitope spreading from the NC16A domain to other epitopes of COL17. Furthermore, we found that a portion of the active BP model mice show intermolecular epitope spreading from human COL17 to murine BP230. The appearance of antibodies to ICD epitopes of COL17 or of antibodies to murine BP230 did not correlate with the skin changes in the mice, suggesting that those antibodies have low pathogenicity. These results suggest that the immune response to the ECD epitopes of COL17, especially to the NC16A domain, triggers intramolecular, and intermolecular epitope spreading to ICD epitopes of COL17 and to murine BP230. These novel findings provide insight into the mechanism of epitope spreading in organ-specific, antibody-mediated autoimmune disorders.
• Autoantibodies undetectable by chemiluminescent enzyme immunoassay require extended antigen-antibody reaction time for detection

  Mai Y, Ujiie H, Higashi T, Yamagami J, Iwata H, Shimizu H

  Br J Dermatol 180 (1) 215 - 216 0007-0963 2019/01 [Refereed][Not invited]
  
• Regulatory T-cell dysfunction induces autoantibodies to bullous pemphigoid antigens in mice and human subjects.

  Ken Muramatsu, Hideyuki Ujiie, Ichiro Kobayashi, Wataru Nishie, Kentaro Izumi, Takamasa Ito, Norihiro Yoshimoto, Ken Natsuga, Hiroaki Iwata, Hiroshi Shimizu

  The Journal of allergy and clinical immunology 142 (6) 1818 - 1830 0091-6749 2018/12 [Refereed][Not invited]
   

  BACKGROUND: Regulatory T (Treg) cells play a crucial role in peripheral immune tolerance in multiple organs, including the skin. Thus far, the effect of peripheral immune tolerance failure on autoantibody-related autoimmune reactions to the skin is unclear. OBJECTIVE: We sought to elucidate the target autoantigens in the skin under the condition of Treg cell dysfunction caused by forkhead box P3 (Foxp3) gene mutations in scurfy mice and patients with immunodysregulation, polyendocrinopathy, enteropathy, X-linked (IPEX) syndrome. METHODS: Sera and skin from scurfy mice and sera from patients with IPEX syndrome were analyzed to detect target autoantigens by using immunofluorescence studies, ELISAs, and immunoblotting. The pathogenicity of scurfy IgG was examined by using a passive transfer experiment. CD4+ T cells from scurfy mice were transferred to immunodeficient mice to examine their pathogenicity. Signal transducer and activator of transcription 6 (Stat6)-/- scurfy mice were analyzed to further clarify the molecular pathway of autoantibody production. Follicular helper T-cell counts are measured in Stat6-/- scurfy mice and scurfy mice. RESULTS: Scurfy mice spontaneously generated IgG autoantibodies to the dermal-epidermal junction, which had been class-switched from IgM within 12 days after birth. The target autoantigens were murine BP230 and type XVII collagen (COL17). The scurfy polyclonal autoantibodies did not induce skin fragility in neonatal mice. Autoantibody production was induced by CD4+ T cells from scurfy mice and was ameliorated by Stat6 gene knockout in association with a decrease of follicular helper T cells. We also identified autoantibodies to COL17 and BP230 in patients with IPEX syndrome and found an association between production of autoantibodies to COL17 and an eczematous skin phenotype. CONCLUSIONS: Dysregulation of Treg cells generates autoantibodies to COL17 and BP230 in vivo.
• The identification of autoantigens in mucous membrane pemphigoid using immortalized oral mucosal keratinocytes.

  Kamaguchi M, Iwata H, Miyauchi T, Ujiie H, Ujiie I, Nomura T, Ohga N, Shimizu H, Kitagawa Y

  Journal of oral pathology & medicine : official publication of the International Association of Oral Pathologists and the American Academy of Oral Pathology 48 (1) 60 - 67 0904-2512 2018/09 [Refereed][Not invited]
   

  BACKGROUND: Mucous membrane pemphigoid (MMP) is a rare chronic autoimmune subepithelial blistering disorder, targeting multiple basement membrane zone (BMZ) proteins including collagen XVII (COL17). Circulating autoantibodies of MMP are often undetected due to their lower titers. The oral mucosa is a valuable substrate for the detection of autoantibodies in MMP patients. However, obtaining normal human oral mucosa is more difficult than obtaining normal human skin. We established immortalized normal human oral mucosal keratinocytes (OMKs) and performed immunoblotting using immortalized OMK lysate for detecting autoantigens in MMP. METHODS: Immortalized OMKs were generated from primary OMKs using E6/E7 proteins of HPV. We compared the protein expression levels of major BMZ proteins between primary OMKs and immortalized OMKs. We performed immunoblotting to detect autoantigens using cell lysates from immortalized OMKs in 30 MMP patients. RESULTS: There were no significant differences between primary OMKs and immortalized OMKs in terms of protein expression levels of the BMZ proteins, including COL17, laminin 332, integrin α6/β4, collagen VII, and collagen IV. Cell lysates of immortalized OMKs effectively identified MMP autoantigens in 60% (18/30) of MMP sera. We found an interesting case of MMP whose autoantibodies preferentially reacted to the 120-kD protein that is an ectodomain of COL17. CONCLUSION: We demonstrated that a cell lysate of immortalized OMKs is a reliable substrate for the detection of MMP autoantigens. This newly developed immunoblotting analysis method promises to contribute to the diagnosis of MMP.
• Detection of anti-BP180 NC16A autoantibodies after the onset of dipeptidyl peptidase-IV inhibitor-associated bullous pemphigoid: a report of three patients.

  Mai Y, Nishie W, Izumi K, Yoshimoto N, Morita Y, Watanabe M, Toyonaga E, Ujiie H, Iwata H, Fujita Y, Nomura T, Sato-Matsumura KC, Shimizu S, Shimizu H

  The British journal of dermatology 179 (3) 790 - 791 0007-0963 2018/09 [Refereed][Not invited]
  
• Potential role of extracellular vesicle-mediated antigen presentation in Helicobacter pylori hypersensitivity during eradication therapy.

  Takamasa Ito, Takashi Shiromizu, Shunsuke Ohnishi, Shotaro Suzuki, Katsuhiro Mabe, Akito Hasegawa, Hideyuki Ujiie, Yasuyuki Fujita, Yuichi Sato, Shuji Terai, Mototsugu Kato, Masahiro Asaka, Takeshi Tomonaga, Hiroshi Shimizu, Riichiro Abe

  The Journal of allergy and clinical immunology 142 (2) 672 - 676 0091-6749 2018/08 [Refereed][Not invited]
  
• Mucosal substrates successfully identify the autoantigen in a case of mucous membrane pemphigoid.

  Kamaguchi M, Iwata H, Ujiie H, Ohga N, Kitagawa Y, Shimizu H

  Journal der Deutschen Dermatologischen Gesellschaft = Journal of the German Society of Dermatology : JDDG 16 (8) 1032 - 1034 1610-0379 2018/08 [Refereed][Not invited]
  
• Schleimhautsubstrate identifizieren erfolgreich das Autoantigen bei einem Schleimhautpemphigoid.

  Mayumi Kamaguchi, Hiroaki Iwata, Hideyuki Ujiie, Noritaka Ohga, Yoshimasa Kitagawa, Hiroshi Shimizu

  Journal der Deutschen Dermatologischen Gesellschaft = Journal of the German Society of Dermatology : JDDG 16 (8) 1032 - 1035 2018/08
• High Expression of Collagen XVII Compensates for its Depletion Induced by Pemphigoid IgG in the Oral Mucosa.

  Kamaguchi M, Iwata H, Ujiie H, Natsuga K, Nishie W, Kitagawa Y, Shimizu H

  The Journal of investigative dermatology 138 (8) 1707 - 1715 0022-202X 2018/08 [Refereed][Not invited]
   

  The basement membrane zone consists of multiple components, including collagen XVII (COL17), which is the target of bullous pemphigoid. To our knowledge, no research has addressed the differences in basement membrane zone components between the skin and oral mucosa; therefore, we investigated the basement membrane zone proteins, with a focus on COL17. The mRNA and protein expression levels of COL17 were significantly higher in oral keratinocytes than in skin keratinocytes. Hemidesmosomal COL17 expression was markedly higher in oral keratinocytes than in skin keratinocytes, and its level was associated with adhesion strength. Oral keratinocytes adhered to the extracellular matrix more tightly than did skin keratinocytes in vitro. Based on these results, we attempt to explain the clinical diversity of bullous pemphigoid. COL17 depletion was more prominent in skin keratinocytes than in oral keratinocytes after treatment with COL17-NC16A mAbs, which have in vivo pathogenicity. COL17 C-terminus mAbs, which are not pathogenic, facilitated COL17 depletion in combination treatment with COL17-NC16A mAbs in both types of keratinocytes. In summary, the greater amount of COL17 in oral keratinocytes than in skin keratinocytes is associated with the higher strength of oral keratinocyte hemidesmosomal adhesion at the basement membrane zone. Our results may explain why bullous pemphigoid blistering tends to be more prevalent in the skin than in the oral mucosa.
• HLA-DQB1*03:01は非炎症型DPP-4阻害薬関連水疱性類天疱瘡のバイオマーカーである

  氏家 英之, 村松 憲, 岩田 浩明, 西村 真智子, 伊東 孝政, 泉 健太郎, 西江 渉, 清水 宏, 三好 秀明, 莚田 泰誠, 大関 健志

  日本皮膚科学会雑誌 (公社)日本皮膚科学会 128 (8) 1663 - 1663 0021-499X 2018/07
• A case of red lunulae after haematopoietic stem cell transplantation.

  Yosuke Mai, Hideyuki Ujiie, Akihiro Iguchi, Hiroshi Shimizu

  European journal of dermatology : EJD 28 (3) 407 - 409 1167-1122 2018/06/01 [Refereed][Not invited]
  
• Sweet's Syndrome Mimicking Anti-Neutrophil Cytoplasmic Antibodies-Associated Vasculitis.

  Hideyuki Kosumi, Mika Watanabe, Ken Natsuga, Toshinari Miyauchi, Chihiro Shiiya, Hideyuki Ujiie, Hiroshi Shimizu

  The American journal of medicine 131 (6) e241-e242 - E242 0002-9343 2018/06 [Refereed][Not invited]
  
• Intravenous IgG Reduces Pathogenic Autoantibodies, Serum IL-6 Levels, and Disease Severity in Experimental Bullous Pemphigoid Models.

  Tetsumasa Sasaoka, Hideyuki Ujiie, Wataru Nishie, Hiroaki Iwata, Makoto Ishikawa, Hiroshi Higashino, Ken Natsuga, Satoru Shinkuma, Hiroshi Shimizu

  The Journal of investigative dermatology 138 (6) 1260 - 1267 0022-202X 2018/06 [Refereed][Not invited]
   

  Bullous pemphigoid (BP) is an autoimmune blistering disease characterized by autoantibodies to COL17. Currently, systemic corticosteroids are used as first-line treatments for BP; alternatively, intravenous administration of high-dose IgG (IVIG) has been shown to be effective for patients with steroid-resistant BP in clinical practice. However, the effect of IVIG on BP has not fully been investigated. To examine the effects and mechanisms of action of IVIG against BP, we performed IVIG experiments using two experimental BP mouse models. One is a passive-transfer BP model that reproduces subepidermal separation in neonatal mice by the passive transfer of IgGs against COL17, such as polyclonal or monoclonal mouse IgG or IgG from BP patients. The other is an active BP model that continuously develops a disease phenotype in adult mice. IVIG decreased pathogenic IgG and the disease scores in both models. Injected IVIG distributed throughout the dermis and the intercellular space of the lower epidermis. Notably, IVIG inhibited the increase of IL-6 in both models, possibly by suppressing the production of IL-6 by keratinocytes. These results suggest that the inhibitory effects of IVIG on BP are associated with the reduction of pathogenic IgG and the modulation of cytokine production.
• Case of anti-p200 pemphigoid accompanying uterine malignancy.

  Hayashi M, Okamura K, Ujiie H, Iwata H, Suzuki T

  The Journal of dermatology 45 (12) e341-e342  0385-2407 2018/05 [Refereed][Not invited]
  
• 落葉状天疱瘡合併の悪性黒色腫に免疫チェックポイント阻害薬を投与した1例

  前田 拓哉, 柳 輝希, 今福 恵輔, 北村 真也, 秦 洋郎, 泉 健太郎, 氏家 英之, 岩田 浩明, 清水 宏

  日本皮膚科学会雑誌 (公社)日本皮膚科学会 128 (5) 1232 - 1232 0021-499X 2018/05
• HLA-DQB1*03:01 as a Biomarker for Genetic Susceptibility to Bullous Pemphigoid Induced by DPP-4 Inhibitors.

  Hideyuki Ujiie, Ken Muramatsu, Taisei Mushiroda, Takeshi Ozeki, Hideaki Miyoshi, Hiroaki Iwata, Akinobu Nakamura, Hiroshi Nomoto, Kyu Yong Cho, Norihiro Sato, Machiko Nishimura, Takamasa Ito, Kentaro Izumi, Wataru Nishie, Hiroshi Shimizu

  The Journal of investigative dermatology 138 (5) 1201 - 1204 0022-202X 2018/05 [Refereed][Not invited]
  
• Maculopapular drug eruption induced by linagliptin.

  Zheng M, Yoshimoto N, Muramatsu K, Ito T, Ujiie H, Shimizu H

  The Australasian journal of dermatology 59 (4) e287-e288  0004-8380 2018/04 [Refereed][Not invited]
  
• Regulatory T cells in autoimmune skin diseases.

  Ujiie H

  Experimental dermatology 28 (6) 642 - 646 0906-6705 2018/03 [Refereed][Invited]
   

  CD4+ Foxp3+ regulatory T cells (Tregs) are suppressors of immune activation and play a crucial role in the maintenance of peripheral tolerance. Mutations of Foxp3 result in fatal autoimmunity in multiple organs, including the skin, in both humans and mice. Many studies have demonstrated the altered frequency and functions of Tregs, changes in cytokine and chemokine levels related to Tregs and the differences in genetic background regarding Tregs in autoimmune skin disorders. Recent studies have extended our knowledge of certain properties of Tregs, especially skin-resident Tregs. In addition, some novel therapies have been performed by modulating the number and the function of Tregs. This review focuses on the role of Tregs in some autoimmune skin disorders, including alopecia areata, vitiligo, pemphigoid and pemphigus, and systemic sclerosis, and discusses questions that remain to be addressed.
• Six-month history of a split thumbnail: A quiz

  Yosuke Mai, Hideyuki Ujiie, Takashi Anan, Hajime Miyazawa, Keisuke Imafuku, Kokichi Hamasaka, Hiroshi Shimizu

  Acta Dermato-Venereologica 98 (2) 297 - 298 1651-2057 2018/02/01 [Refereed][Not invited]
  
• Diagnosis and Management of Pemphigus: recommendations by an International Panel of Experts.

  Murrell DF, Peña S, Joly P, Marinovic B, Hashimoto T, Diaz LA, Sinha AA, Payne AS, Daneshpazhooh M, Eming R, Jonkman MF, Mimouni D, Borradori L, Kim SC, Yamagami J, Lehman JS, Saleh MA, Culton DA, Czernik A, Zone JJ, Fivenson D, Ujiie H, Wozniak K, Akman-Karakaş A, Bernard P, Korman NJ, Caux F, Drenovska K, Prost-Squarcioni C, Vassileva S, Feldman RJ, Cardones AR, Bauer J, Ioannides D, Jedlickova H, Palisson F, Patsatsi A, Uzun S, Yayli S, Zillikens D, Amagai M, Hertl M, Schmidt E, Aoki V, Grando SA, Shimizu H, Baum S, Cianchini G, Feliciani C, Iranzo P, Mascaró JM Jr, Kowalewski C, Hall R, Groves R, Harman KE, Marinkovich MP, Maverakis E, Werth VP

  Journal of the American Academy of Dermatology 82 (3) 575 - 585 0190-9622 2018/02 [Refereed][Not invited]
   

  BACKGROUND: Several European countries recently developed international diagnostic and management guidelines for pemphigus, which have been instrumental in the standardization of pemphigus management. OBJECTIVE: We now present results from a subsequent Delphi consensus to broaden the generalizability of the recommendations. METHODS: A preliminary survey, based on the European Dermatology Forum and the European Academy of Dermatology and Venereology guidelines, was sent to a panel of international experts to determine the level of consensus. The results were discussed at the International Bullous Diseases Consensus Group in March 2016 during the annual American Academy of Dermatology conference. Following the meeting, a second survey was sent to more experts to achieve greater international consensus. RESULTS: The 39 experts participated in the first round of the Delphi survey, and 54 experts from 21 countries completed the second round. The number of statements in the survey was reduced from 175 topics in Delphi I to 24 topics in Delphi II on the basis of Delphi results and meeting discussion. LIMITATIONS: Each recommendation represents the majority opinion and therefore may not reflect all possible treatment options available. CONCLUSIONS: We present here the recommendations resulting from this Delphi process. This international consensus includes intravenous CD20 inhibitors as a first-line therapy option for moderate-to-severe pemphigus.
• 落葉状天疱瘡合併悪性黒色腫に免疫チェックポイント阻害薬を投与した1例

  前田 拓哉, 柳 輝希, 今福 恵輔, 北村 真也, 秦 洋郎, 泉 健太郎, 氏家 英之, 岩田 浩明, 清水 宏

  日本皮膚科学会雑誌 (公社)日本皮膚科学会 128 (1) 61 - 61 0021-499X 2018/01
• 爪線状苔癬の1例

  眞井 洋輔, 氏家 英之, 宮澤 元, 今福 恵輔, 清水 宏, 阿南 隆, 浜坂 幸吉

  日本皮膚科学会雑誌 (公社)日本皮膚科学会 128 (1) 64 - 64 0021-499X 2018/01
• 口腔粘膜基質を用いて抗原同定したBP180型粘膜類天疱瘡の1例

  鎌口 真由美, 岩田 浩明, 氏家 英之, 清水 宏, 大賀 則孝, 北川 善政

  日本皮膚科学会雑誌 (公社)日本皮膚科学会 128 (1) 64 - 64 0021-499X 2018/01
• Direct Immunofluorescence Using Non-Lesional Buccal Mucosa in Mucous Membrane Pemphigoid.

  Mayumi Kamaguchi, Hiroaki Iwata, Inkin Ujiie, Hideyuki Ujiie, Jun Sato, Yoshimasa Kitagawa, Hiroshi Shimizu

  Frontiers in medicine 5 20 - 20 2018 [Refereed][Not invited]
   

  Mucous membrane pemphigoid (MMP) is a rare organ-specific autoimmune subepithelial blistering disease with predominantly mucosal erosions, most frequently affecting the gingiva. Erosions in the oral cavity usually result in markedly decreased quality of life. The major autoantigens are BP180 and laminin332, which are components of basement membrane proteins in the skin and mucosa. Diagnosis is usually difficult due to histological destruction of the tissue and low autoantibody titers. In this study, we evaluated the diagnostic value of direct immunofluorescence (DIF) using non-lesional buccal mucosa in seven cases of MMP. In all seven patients, gingival lesions were clinically observed, and in one of the seven patients, buccal lesions were also clinically observed. First, we performed DIF to detect tissue-bound autoantibodies and complement. DIF from non-lesional buccal mucosa revealed linear deposits of IgG and C3 at the basement membrane zone in all cases. To detect autoantibodies, indirect immunofluorescence (IIF), BP180-NC16A ELISA and immunoblotting were performed. Surprisingly, circulating autoantibodies were unable to be detected in any of the cases by ELISA, IIF, or immunoblotting. Furthermore, histological separation was observed in one patient. In conclusion, DIF using non-lesional buccal mucosa was found to be superior to histological and serological tests for diagnosing mucous membrane pemphigoid. The procedure is technically easy and has high diagnostic value.
• Appearance of antidesmocollin 1 autoantibodies leading to a vegetative lesion in a patient with pemphigus vulgaris.

  Yamaguchi Y, Shinkuma S, Ishii N, Takashima S, Natsuga K, Ujiie H, Iwata H, Nomura T, Fujita Y, Hamasaka A, Hamasaka K, Hashimoto T, Shimizu H

  The British journal of dermatology 178 (1) 294 - 295 0007-0963 2018/01 [Refereed][Not invited]
  
• Autoantibodies of non-inflammatory bullous pemphigoid hardly deplete type XVII collagen of keratinocytes

  Keisuke Imafuku, Hiroaki Iwata, Mayumi Kamaguchi, Kentaro Izumi, Ken Natsuga, Hideyuki Ujiie, Wataru Nishie, Hiroshi Shimizu

  Experimental Dermatology 26 (12) 1171 - 1174 1600-0625 2017/12/01 [Refereed][Not invited]
   

  Type XVII collagen (COL17) and the non-collagenous 16A (NC16A) domain is regarded as the major pathogenic domains for bullous pemphigoid (BP). Some patients with BP have autoantibodies against parts of COL17 outside the NC16A domain (hereinafter the non-NC16A domain) and show less inflammatory manifestations. There were no significant differences in titres and IgG subclasses between NC16A-BP and non-NC16A-BP as determined by indirect immunofluorescent microscopy. The neutrophil activation capacities determined by ROS release did not differ between NC16A-BP and non-NC16A-BP. However, NC16A-BP IgG depleted COL17 in a dose-dependent manner. Treatment with NC16A-BP IgG, but not with non-NC16A-BP IgG, significantly decreased the adhesion strength. We speculate that the differences in clinical severity between NC16A-BP and non-NC16A-BP relate to the degree of COL17 depletion.
• Complement-independent blistering mechanisms in bullous pemphigoid

  Hiroaki Iwata, Hideyuki Ujiie

  Experimental Dermatology 26 (12) 1235 - 1239 1600-0625 2017/12/01 [Refereed][Not invited]
   

  Bullous pemphigoid (BP) is an autoimmune subepidermal blistering disease that clinically demonstrates tense blisters with widespread erythema, histologically demonstrates subepidermal blistering and immunologically demonstrates the presence of circulating autoantibodies against hemidesmosomal molecules. Complement activation has long been regarded as necessary for the generation of the BP. However, certain evidence has recently come to support non-complemental blistering mechanisms. The story of BP blistering mechanisms is a complicated one. This review mainly focuses on a specific blistering mechanism that highlights the role of complements in BP blistering.
• Using immune checkpoint inhibitors without exacerbation in a melanoma patient with pemphigus foliaceus

  Takuya Maeda, Teruki Yanagi, Keisuke Imafuku, Shinya Kitamura, Hiroo Hata, Kentaro Izumi, Hideyuki Ujiie, Hiroaki Iwata, Hiroshi Shimizu

  INTERNATIONAL JOURNAL OF DERMATOLOGY 56 (12) 1477 - 1479 0011-9059 2017/12 [Refereed][Not invited]
  
• C-Terminal Processing of Collagen XVII Induces Neoepitopes for Linear IgA Dermatosis Autoantibodies

  Ellen Toyonaga, Wataru Nishie, Kentaro Izumi, Ken Natsuga, Hideyuki Ujiie, Hiroaki Iwata, Jun Yamagami, Yoshiaki Hirako, Daisuke Sawamura, Wataru Fujimoto, Hiroshi Shimizu

  JOURNAL OF INVESTIGATIVE DERMATOLOGY 137 (12) 2552 - 2559 0022-202X 2017/12 [Refereed][Not invited]
   

  Transmembrane collagen XVII (COL17) is a hemidesmosomal component of basal keratinocytes that can be targeted by autoantibodies in autoimmune blistering disorders, including linear IgA dermatosis (LAD). COL17 can be physiologically cleaved within the juxtamembranous extracellular NC16A domain, and LAD autoantibodies preferentially react with the processed ectodomains, indicating that the processing induces neoepitopes. However, the details of how neoepitopes develop have not been elucidated. In this study, we show that C-terminal processing of COL17 also plays a role in inducing neoepitopes for LAD autoantibodies. First, the mAb hC17-ect15 targeting the 15th collagenous domain of COL17 was produced, which showed characteristics similar to LAD autoantibodies. The mAbs preferentially reacted with C-terminally deleted (up to 682 amino acids) recombinant COL17, suggesting that C-terminal processing shows neoepitopes on the 15th collagenous domain. The LAD autoantibodies also react with C-terminal deleted COL17. Therefore, neoepitopes for LAD autoantibodies also develop after C-terminal processing. Finally, the passive transfer of the mAb hC17-ect15 into human COL17-expressing transgenic mice failed to induce blistering disease, suggesting that neoepitope-targeting antibodies are not always pathogenic. In summary, this study shows that C-terminal processing induces dynamic structural changes and neoepitopes for LAD autoantibodies on COL17.
• Anti-idiotypic Antibodies against BP-IgG Prevent Type XVII Collagen Depletion

  Mayumi Kamaguchi, Hiroaki Iwata, Yuiko Mori, Ellen Toyonaga, Hideyuki Ujiie, Yoshimasa Kitagawa, Hiroshi Shimizu

  FRONTIERS IN IMMUNOLOGY 8 1669 - 1669 1664-3224 2017/11 [Refereed][Not invited]
   

  Bullous pemphigoid (BP) mainly targets type XVII collagen (COL17). Intravenous immunoglobulin (IVIg) is used to treat numerous autoimmune diseases, including BP. The major mechanism of action for IVIG is thought to be its immunomodulatory effect. However, little is known about the precise mechanisms of IVIg in BP. We investigate the cellular effects of IVIg, toward treatments for BP. Keratinocytes were treated with IgG from BP patients (BP-IgG) and with IVIg, and then the COL17 expression was detected by Western blotting. Cell adhesion and ex vivo dermal-epidermal separation were also investigated for the condition with BP-IgG and IVIg. BP-IgG targeting the non-collagenous 16A domain induces the depletion of COL17 in cultured keratinocytes (DJM-1 cells). The COL17 levels in DJM-1 cells were decreased by 50% after 4 h of BP-IgG stimulation as determined by Western blotting. By contrast, BP-IgG with IVIg was found to result in 70-90% increases in COL17 and to restore adhesion to the plate. Interestingly, IVIg significantly inhibited the binding of BP-IgG to the COL17-enzymelinked immunosorbent assay plate, and this was due to anti-idiotypic antibodies against BP-IgG. When anti-idiotypic antibodies against BP-IgG in 0.02% of IVIg were depleted from IVIg, those antibodies did not exhibit inhibitory effects on COL17 depletion. When cryosections of human skin were incubated with BP-IgG in the presence of leukocytes, dermal-epidermal separation was observed. BP-IgG treatment with IVIg or anti-idiotypic antibodies did not induce such separation. These findings strongly suggest the presence of anti-idiotypic antibodies against anti-COL17 IgG in IVIg. This mechanism of IVIg could be a target for therapies against BP.
• Detection of mucous membrane pemphigoid autoantibodies by full-length BP180 enzyme-linked immunosorbent assay

  Kentaro Izumi, Wataru Nishie, Yosuke Mai, Hideyuki Ujiie, Hiroaki Iwata, Ken Natsuga, Hiroshi Shimizu

  JOURNAL OF DERMATOLOGICAL SCIENCE 88 (2) 247 - 248 0923-1811 2017/11 [Refereed][Not invited]
  
• Chemiluminescent enzyme immunoassay failed to detect anti-desmoglein 3 antibodies in a case of pemphigus vulgaris

  Yosuke Mai, Hideyuki Ujiie, Machiko Nishimura, Hiroshi Koga, Yuka Maya, Keiko Shiba-Tokuchi, Yasuyuki Fujita, Hiroaki Iwata, Yohei Mikawa, Hiroshi Shimizu

  JOURNAL OF DERMATOLOGY 44 (10) E242 - E243 0385-2407 2017/10 [Refereed][Not invited]
  
• Oral mucosa is a useful substrate for detecting autoantibodies of mucous membrane pemphigoid.

  Kamaguchi M, Iwata H, Ujiie H, Izumi K, Natsuga K, Nishie W, Asaka T, Kitagawa Y, Shimizu H

  The British journal of dermatology 178 (2) e119 - e121 0007-0963 2017/09 [Refereed][Not invited]
  
• Generalized Pustular Psoriasis

  Hideyuki Kosumi, Takamasa Ito, Yasuyuki Fujita, Kentaro Izumi, Yuka Maya, Teruki Yanagi, Ken Natsuga, Hideyuki Ujiie, Satoru Shinkuma, Toshifumi Nomura, Naoya Sadanobu, Hiroshi Shimizu

  JOURNAL OF PEDIATRICS 188 305 - + 0022-3476 2017/09 [Refereed][Not invited]
  
• 複数の自己抗体を検出した自己免疫性表皮下水疱症の1例

  澤田 匡秀, 肥田 時征, 氏家 英之, 泉 健太郎, 西江 渉, 宇原 久

  日本皮膚科学会雑誌 (公社)日本皮膚科学会 127 (9) 2117 - 2117 0021-499X 2017/08
• Postherpetic abdominal pseudohernia

  Ken Muramatsu, Hideyuki Ujiie, Hiroshi Shimizu

  BMJ-BRITISH MEDICAL JOURNAL 358 1756-1833 2017/07 [Refereed][Not invited]
  
• Late-onset skin involvement on the forehead in multicentric Castleman disease

  Kazumasa Sato, Satoru Shinkuma, Hideyuki Ujiie, Toshifumi Nomura, Yasuyuki Fujita, Riichiro Abe, Hiroshi Shimizu, Katsuya Fujimoto, Kanako C. Hatanaka, Yoshihiro Matsuno

  INTERNATIONAL JOURNAL OF DERMATOLOGY 56 (7) E152 - E153 0011-9059 2017/07 [Refereed][Not invited]
  
• Type XVII collagen coordinates proliferation in the interfollicular epidermis

  Mika Watanabe, Ken Natsuga, Wataru Nishie, Yasuaki Kobayashi, Giacomo Donati, Shotaro Suzuki, Yu Fujimura, Tadasuke Tsukiyama, Hideyuki Ujiie, Satoru Shinkuma, Hideki Nakamura, Masamoto Murakami, Michitaka Ozaki, Masaharu Nagayama, Fiona M. Watt, Hiroshi Shimizu

  ELIFE 6 2050-084X 2017/07 [Refereed][Not invited]
   

  Type XVII collagen (COL17) is a transmembrane protein located at the epidermal basement membrane zone. COL17 deficiency results in premature hair aging phenotypes and in junctional epidermolysis bullosa. Here, we show that COL17 plays a central role in regulating interfollicular epidermis (IFE) proliferation. Loss of COL17 leads to transient IFE hypertrophy in neonatal mice owing to aberrant Wnt signaling. The replenishment of COL17 in the neonatal epidermis of COL17-null mice reverses the proliferative IFE phenotype and the altered Wnt signaling. Physical aging abolishes membranous COL17 in IFE basal cells because of inactive atypical protein kinase C signaling and also induces epidermal hyperproliferation. The overexpression of human COL17 in aged mouse epidermis suppresses IFE hypertrophy. These findings demonstrate that COL17 governs IFE proliferation of neonatal and aged skin in distinct ways. Our study indicates that COL17 could be an important target of anti-aging strategies in the skin.
• A case of bullous pemphigoid presenting with severe oedema of the hands during recurrence

  Shinichi Nakazato, Hideyuki Ujiie, Yuka Inamura, Machiko Nishimura, Hiroaki Iwata, Hiroshi Shimizu

  EUROPEAN JOURNAL OF DERMATOLOGY 27 (4) 421 - 422 1167-1122 2017/07 [Refereed][Not invited]
  
• Postherpetic abdominal pseudohernia.

  Muramatsu K, Ujiie H, Shimizu H

  BMJ (Clinical research ed.) 358 j2786  0959-8138 2017/07 [Refereed][Not invited]
  
• Meeting Report of the Pathogenesis of Pemphigus and Pemphigoid Meeting in Munich, September 2016

  Enno Schmidt, Volker Spindler, Ruediger Eming, Masayuki Amagai, Frank Antonicelli, John F. Baines, Meriem Belheouane, Philippe Bernard, Luca Borradori, Marzia Caproni, Giovanni Di Zenzo, Sergei Grando, Karen Harman, Marcel F. Jonkman, Hiroshi Koga, Ralf J. Ludwig, Andrew P. Kowalczyk, Eliane J. Mueller, Wataru Nishie, Hendri Pas, Aimee S. Payne, Christian D. Sadik, Allan Seppanen, Jane Setterfield, Hiroshi Shimizu, Animesh A. Sinha, Eli Sprecher, Michael Sticherling, Hideyuki Ujiie, Detlef Zillikens, Michael Hertl, Jens Waschke

  JOURNAL OF INVESTIGATIVE DERMATOLOGY 137 (6) 1199 - 1203 0022-202X 2017/06 [Refereed][Not invited]
   

  Autoimmune blistering diseases are a heterogeneous group of about a dozen complex disorders that are characterized by intraepidermal (pemphigus) and subepidermal blistering (pemphigoid diseases and dermatitis herpetiformis). The Pathogenesis of Pemphigus and Pemphigoid Meeting, organized by the Departments of Dermatology in Lubeck and Marburg and the Institute of Anatomy and Cell Biology, Munich, was held in September 2016 in Munich. The meeting brought together basic scientists and clinicians from all continents dedicating their work to autoimmune blistering diseases. Considerable advances have been made in describing incidences and prevalences of these diseases and linking comorbidities with autoantibody reactivities and clinical variants, for example, dipeptidyl peptidase-IV inhibitor-associated noninflammatory bullous pemphigoid. Although new entities are still being described, diagnosis of most autoimmune blistering diseases can now be achieved using standardized and widely available serological test systems. Various experimental mouse models of pemphigus and pemphigoid disease are increasingly being used to understand mechanisms of central and peripheral tolerance and to evaluate more specific treatment approaches for these disorders, such as molecules that target autoreactive T and B cells and anti-inflammatory mediators, that is, dimethyl fumarate, phosphodiesterase 4, and leukotriene B4 inhibitors in pemphigoid disorders, and chimeric antigen receptor T cells in pemphigus. Very recent experimental data about the immunopathology and the determinants of autoantibody formation and keratinocyte susceptibility in pemphigus were discussed. With regard to cellular mechanisms leading to the loss of cell-cell adhesion, new ideas were shared in the field of signal transduction. Major steps were taken to put the various partly contradictory and controversial findings about the effects of pemphigus autoantibodies and other inflammatory mediators into perspective and broaden our view of the complex pathophysiology of this disease. Finally, two investigator-initiated multicenter trials highlighted doxycycline and dapsone as valuable medications in the treatment of bullous pemphigoid.
• Isolated adrenocorticotropic hormone deficiency associated with nivolumab therapy

  Atsushi Narahira, Teruki Yanagi, Kyu Yong Cho, Akinobu Nakamura, Hideaki Miyoshi, Hiroo Hata, Keisuke Imafuku, Shinya Kitamura, Hiroshi Shimizu

  JOURNAL OF DERMATOLOGY 44 (4) E70 - E70 0385-2407 2017/04 [Refereed][Not invited]
  
• Linear IgA Bullous Dermatosis Associated with Immunoglobulin Light-chain Amyloidosis

  Yasuyuki Yamaguchi, Hideyuki Ujiie, Hiroyuki Ohigashi, Hiroaki Iwata, Ken Muramatsu, Tomoyuki Endou, Takanori Teshima, Hiroshi Shimizu

  ACTA DERMATO-VENEREOLOGICA 97 (4) 528 - 529 0001-5555 2017/04 [Refereed][Not invited]
  
• Hypertrophic lupus erythematosus successfully treated with hydroxychloroquine

  Norihiro Yoshimoto, Satoru Shinkuma, Hideyuki Ujiie, Toshifumi Nomura, Yasuyuki Fujita, Riichiro Abe, Hiroshi Shimizu

  JOURNAL OF DERMATOLOGY 44 (3) E48 - E49 0385-2407 2017/03 [Refereed][Not invited]
  
• Linear IgA Bullous Dermatosis in a Pregnant Woman with Autoantibodies to the Non-collagenous 16A Domain of Type XVII Collagen

  Kenshi Matsuura, Hideyuki Ujiie, Masahiro Hayashi, Ken Muramatsu, Junko Yoshizawa, Takamasa Ito, Hiroaki Iwata, Tamio Suzuki, Hiroshi Shimizu

  ACTA DERMATO-VENEREOLOGICA 97 (3) 404 - 405 0001-5555 2017/03 [Refereed][Not invited]
  
• Lichenoid drug eruption caused by clonazepam

  K. Muramatsu, H. Ujiie, K. Natsuga, W. Nishie, H. Shimizu

  JOURNAL OF THE EUROPEAN ACADEMY OF DERMATOLOGY AND VENEREOLOGY 31 (2) E117 - E118 0926-9959 2017/02 [Refereed][Not invited]
   

  Muramatsu K, Ujiie H, Natsuga K, Nishie W, Shimizu H, Journal of the European Academy of Dermatology and Venereology : JEADV, 2017, vol. 31, no. 2, pp. e117-e118, 2017
• Recurrence of juvenile dermatomyositis 8 years after remission

  Ken Muramatsu, Hideyuki Ujiie, Mayumi Yokozeki, Ichiro Tsukinaga, Mai Ito, Takaaki Shikano, Akira Suzuki, Yusuke Tozawa, Ichiro Kobayashi

  JAAD Case Reports 3 (1) 29 - 32 2352-5126 2017/01/01 [Refereed][Not invited]
  
• Plasma cell cheilitis successfully treated with topical calcineurin inhibitors.

  Yasuyuki Yamaguchi, Wataru Nishie, Takamasa Ito, Hiroshi Shimizu

  European journal of dermatology : EJD 26 (6) 609 - 610 2016/12/01
• Image Gallery: Vasculo-Behçet disease.

  Muramatsu K, Ujiie H, Ito T, Fujita Y, Inokuma D, Tsukinaga I, Abe T, Shirai S, Fukuda N, Shimizu H

  The British journal of dermatology 175 (6) e150  0007-0963 2016/12 [Refereed][Not invited]
  
• Macropinocytosis of type XVII collagen induced by bullous pemphigoid IgG is regulated via protein kinase C

  Hiroaki Iwata, Mayumi Kamaguchi, Hideyuki Ujiie, Machiko Nishimura, Kentaro Izumi, Ken Natsuga, Satoru Shinkuma, Wataru Nishie, Hiroshi Shimizu

  LABORATORY INVESTIGATION 96 (12) 1301 - 1310 0023-6837 2016/12 [Refereed][Not invited]
   

  Macropinocytosis is an endocytic pathway that is involved in the nonselective fluid uptake of extracellular fluid. Bullous pemphigoid (BP) is an autoimmune subepidermal blistering disease associated with autoantibodies to type XVII collagen (COL17), which is a component of hemidesmosome. When keratinocytes are treated with BP-IgG, COL17 internalizes into cells by way of the macropinocytosis. We investigated the mechanism of COL17 macropinocytosis using DJM-1 cells, a cutaneous squamous cell carcinoma cell line. First, non-hemidesmosomal COL17 was preferentially depleted by stimulation with the BP-IgG in the DJM-1 cells. To investigate the signaling involved in COL17-macropinocytosis, the inhibition of small GTPase family members Rac1 and Cdc42 was found to strongly repress COL17 internalization; in addition, the Rho inhibitor also partially blocked that internalization, suggesting these small GTPases are involved in signaling to mediate COL17-macropinocytosis. Western blotting using Phostag-SDS-PAGE demonstrated high levels of COL17 phosphorylation in DJM-1 cells under steady-state condition. Treatment with BP-IgG increased the intracellular calcium level within a minute, and induced the overabundant phosphorylation of COL17. The overabundant phosphorylation of COL17 was suppressed by a protein kinase C (PKC) inhibitor. In addition, PKC inhibitor repressed COL17 endocytosis using cell culture and organ culture systems. Finally, the depletion of COL17 was not observed in the HEK293 cells transfected COL17 without intracellular domain. These results suggest that COL17 internalization induced by BP-IgG may be mediated by a PKC pathway. In summary, BP-IgG initially binds to COL17 distributed on the plasma membrane, and COL17 may be internalized by means of a macropinocytic pathway related to the phosphorylation of the intracellular domain by PKC.
• Autoantibody Profile Differentiates between Inflammatory and Noninflammatory Bullous Pemphigoid

  Kentaro Izumi, Wataru Nishie, Yosuke Mai, Mayumi Wada, Ken Natsuga, Hideyuki Ujiie, Hiroaki Iwata, Jun Yamagami, Hiroshi Shimizu

  JOURNAL OF INVESTIGATIVE DERMATOLOGY 136 (11) 2201 - 2210 0022-202X 2016/11 [Refereed][Not invited]
   

  Bullous pemphigoid (BP) is a major autoimmune blistering skin disorder, in which a majority of the autoantibodies (autoAbs) target the juxtamembranous extracellular noncollagenous 16A domain (NC16A) domain of hemidesmosomal collagen XVII. BP-autoAbs may target regions of collagen XVII other than the NC16A domain; however, correlations between epitopes of BP-autoAbs and clinical features have not been fully elucidated. To address correlations between the clinical features and specific epitopes of BP-autoAbs, we evaluated the epitope profiles of BP-autoAbs in 121 patients. A total of 87 patients showed a typical inflammatory phenotype with erythema and autoAbs targeting the anti-NC16A domain, whereas 14 patients showed a distinct noninflammatory phenotype, in which autoAbs specifically targeted the midportion of collagen XVII, but not NC16A. Interestingly, this group clinically showed significantly reduced erythema associated with scant lesional infiltration of eosinophils. Surprisingly, 7 of the 14 cases (50.0%) received dipeptidyl peptidase-IV inhibitors for the treatment of diabetes. Dipeptidyl peptidase-IV inhibitors were used in 3 of 76 (3.9%) typical cases of BP with autoAbs targeting NC16A; thus, dipeptidyl peptidase-IV inhibitors are thought to be involved in the development of atypical noninflammatory BP. This study shows that the autoAb profile differentiates between inflammatory and noninflammatory BP, and that noninflammatory BP may be associated with dipeptidyl peptidase-IV inhibitors.
• Bullous pemphigoid suggestive of complement-independent blister formation with anti-BP180 IgG4 autoantibodies.

  Dainichi T, Nishie W, Yamagami Y, Sonobe H, Ujiie H, Kaku Y, Kabashima K

  The British journal of dermatology 175 (1) 187 - 190 0007-0963 2016/07 [Refereed][Not invited]
  
• Cutaneous-type pemphigus vulgaris successfully treated with topical corticosteroids

  Hideyuki Ujiie, Satoru Aoyagi, Keita Horie, Hiroshi Shimizu

  JOURNAL OF DERMATOLOGY 43 (7) 840 - 841 0385-2407 2016/07 [Refereed][Not invited]
  
• Epitope-Dependent Pathogenicity of Antibodies Targeting a Major Bullous Pemphigoid Autoantigen Collagen XVII/BP180

  Mayumi Wada, Wataru Nishie, Hideyuki Ujiie, Kentaro Izumi, Hiroaki Iwata, Ken Natsuga, Hideki Nakamura, Yoshimasa Kitagawa, Hiroshi Shimizu

  JOURNAL OF INVESTIGATIVE DERMATOLOGY 136 (5) 938 - 946 0022-202X 2016/05 [Refereed][Not invited]
   

  In bullous pemphigoid, the common autoimmune blistering disorder, IgG autoantibodies target various epitopes on hemidesmosomal transmembrane collagen XVII (COL17)/BP180. Antibodies (Abs) targeting the extracellular noncollagenous 16th A domain of COL17 may be pathogenic; however, the pathogenic roles of Abs targeting non-noncollagenous 16th A regions are poorly understood. In this study using a pathogenic and a nonpathogenic monoclonal antibody (mAb) targeting the noncollagenous 16th A domain (mAb TS39-3) and the C-terminus domain (mAb C17-C1), respectively, we show that endocytosis of immune complexes after binding of Abs to cell surface COL17 is a key phenomenon that induces skin fragility. Passive transfer of IgG1 mouse mAb TS39-3 but not mAb C17-C1 induces dermal-epidermal separation in neonatal human COL17-expressing transgenic mice. Interestingly, mAb C17-C1 strongly binds with the dermal-epidermal junction of the recipient mice skin, suggesting that binding of Abs with COL17 is insufficient to induce skin fragility. In cultured normal human epidermal keratinocytes treated with these mAbs, mAb TS39-3 but not mAb C17-C1 internalizes immune complexes after binding with cell surface COL17 via macropinocytosis, resulting in reduced COL17 expression. This study shows that pathogenicity of Abs targeting COL17 is epitope dependent, which is associated with macropinocytosis-mediated endocytosis of immune complexes and finally results in the depletion of COL17 expression in basal keratinocytes.
• gamma delta T Cells Protect the Liver and Lungs of Mice from Autoimmunity Induced by Scurfy Lymphocytes

  Hideyuki Ujiie, Ethan M. Shevach

  JOURNAL OF IMMUNOLOGY 196 (4) 1517 - 1528 0022-1767 2016/02 [Refereed][Not invited]
   

  gamma delta T cells have been shown to have immunoregulatory functions in several experimental autoimmune models. A mutation of the Foxp3 gene leads to the absence of regulatory T cells (Tregs) and a fatal systemic autoimmune disease in scurfy mice. Transfer of scurfy lymphocytes to RAG deficient (RAG(-/-)) recipients reproduces the inflammatory phenotype of the scurfy donor, including hepatitis and pneumonitis. In this study, we show that TCR alpha(-/-) recipients, which lack alpha beta T cells but have gamma delta T cells and B cells, are significantly protected from the hepatitis and pneumonitis, but not the dermatitis, induced by adoptive transfer of scurfy lymphocytes. Cotransfer of gamma delta T cells, but not B cells, prevented hepatitis and pneumonitis in RAG(-/-) recipients of scurfy lymphocytes. gamma delta T cells in the TCR alpha(-/-) recipients of scurfy cells markedly expanded and expressed a highly activated (CD62L(lo)CD44(hi)) phenotype. The activated gamma delta T cells expressed high levels of CD39 and NKG2D on their cell surface. A high frequency of scurfy T cells in TCR alpha(-/-) recipients produced IL-10, suggesting that gamma delta T cells may enhance suppressor cytokine production from scurfy T cells in TCR alpha(-/-) recipients. This study indicates that gamma delta T cells may contribute to the maintenance of immunological homeostasis by suppressing autoreactive T cells in liver and lung.
• Anti-BP180-type mucous membrane pemphigoid: report of two cases

  Mayumi Wada, Jun Sato, Masanobu Shindoh, Hideyuki Ujiie, Ken Natsuga, Wataru Nishie, Hiroshi Shimizu, Yoshimasa Kitagawa

  ODONTOLOGY 104 (1) 114 - 118 1618-1247 2016/01 [Refereed][Not invited]
   

  We describe two patients with anti-BP180-type mucous membrane pemphigoid (MMP), who were correctly diagnosed and treated in early stages through the cooperation of dentists and dermatologists. Patient 1 was a 74-year-old woman who visited our dental department due to blisters over the oral mucosa and eruptions on the skin. She had also experienced bleeding of the gingiva and palate mucosa. Biopsy specimens from the oral mucosa revealed detachment of epithelial basement membrane and subepithelial lamina propria with slight chronic inflammation. Direct immunofluorescence (DIF) revealed linear IgG and IgA deposits along the basement membrane zone (BMZ). Indirect immunofluorescence (IIF) using 1 M-NaCl split normal human skin showed binding of IgG and IgA on the epidermal side. On immunoblot analysis, IgG and IgA autoantibodies reacted with the C-terminal protein of BP180. These findings indicated a diagnosis of anti-BP180-type MMP. Patient 2 was a 59-year-old woman who was referred to our dental department with a history of blisters and large erosions on the gingiva. Biopsy specimens from the oral mucosa revealed partial junctional separation at the level of the basement membrane. DIF showed linear depositions of IgG and C3 along the BMZ. IIF, using 1 M-NaCl split normal human skin, revealed circulating anti-BMZ-IgG antibodies bound to the epidermal side. These findings indicated a diagnosis of anti-BP180-type MMP. Both patients were treated successfully with systemic or topical steroids and oral health care. In conclusion, appropriate clinical examination and cooperation among medical specialists are important for the early diagnosis and treatment of patients with recurrent and chronic stomatitis and for their good prognosis.
• Kimura disease associated with severe visual dysfunction due to remarkable periorbital involvement

  Mika Watanabe, Hideyuki Ujiie, Nao Saito, Riichiro Abe, Hiroshi Shimizu

  JOURNAL OF DERMATOLOGY 42 (9) 924 - 925 0385-2407 2015/09 [Refereed][Not invited]
  
• Autoantibodies to Multiple Epitopes on the Non-Collagenous-1 Domain of Type VII Collagen Induce Blisters

  Artem Vorobyev, Hideyuki Ujiie, Andreas Recke, Jacqueline J. A. Buijsrogge, Marcel F. Jonkman, Hendri H. Pas, Hiroaki Iwata, Takashi Hashimoto, Soo-Chan Kim, Jong Hoon Kim, Richard Groves, Unni Samavedam, Yask Gupta, Enno Schmidt, Detlef Zillikens, Hiroshi Shimizu, Ralf J. Ludwig

  JOURNAL OF INVESTIGATIVE DERMATOLOGY 135 (6) 1565 - 1573 0022-202X 2015/06 [Refereed][Not invited]
   

  Epidermolysis bullosa acquisita (EBA) is an autoimmune blistering disease of the skin and mucous membranes, characterized by autoantibodies against type VII collagen (COL7), a major component of anchoring fibrils. Different clinical EBA phenotypes are described, including mechanobullous and inflammatory variants. Most EBA patients' sera react with epitopes located within the non-collagenous 1 (NC1) domain of human COL7. However, it has remained unclear whether antibody binding to these different epitopes is pathogenically relevant. To address this issue, we generated recombinant proteins covering the entire NC1 domain. IgG reactivity with these proteins was analyzed in sera of 69 EBA patients. Most recognized clusters of epitopes throughout the NC1 domain. No correlation was detected between antibody specificity and clinical phenotype. To study the pathogenicity of antibodies specific to different NC1 subdomains, rabbit antibodies were generated. All these antibodies caused dermal-epidermal separation ex vivo. Antibodies against two of these subdomains were injected into mice carrying null mutations of mouse COL7 and the human COL7 transgene and induced subepidermal blisters. We here document that autoantibodies to COL7, independent of the targeted epitopes, induce blisters both ex vivo and in vivo. In addition, using COL7-humanized mice, we provide in vivo evidence of pathogenicity of autoantibodies binding to human COL7.
• Context-Dependent Regulation of Collagen XVII Ectodomain Shedding in Skin

  Wataru Nishie, Ken Natsuga, Hiroaki Iwata, Kentaro Izumi, Hideyuki Ujiie, Ellen Toyonaga, Hiroo Hata, Hideki Nakamura, Hiroshi Shimizu

  AMERICAN JOURNAL OF PATHOLOGY 185 (5) 1361 - 1371 0002-9440 2015/05 [Refereed][Not invited]
   

  Pemphigoid is a common autoimmune blistering disorder in which autoantibodies target transmembrane collagen XVII (COL17), a component of hemidesmosomes in basal keratinocytes. The ectodomain of COL17 can be cleaved from the cell surface within the juxtamembranous extracellular NC16A domain, and, interestingly, certain autoantibodies of pemphigoid patients preferentially react with the shed ectodomain. These findings suggest that COL17 ectodomain shedding generates neoepitopes on the shed form; however, the regulatory mechanism of the shedding in in vivo skin and the pathogenicity of the neoepitope-targeting antibodies still are uncertain. To address these issues, we produced rabbit antibodies specifically reacting with N-terminal cleavage sites of the shed COL17 ectodomain. The antibodies showed that certain amounts of the human COL17 ectodomain are cleaved physiologically at Gln(525) in in vivo skin. In contrast, migrating human keratinocytes cleave COL17 at Leu(524) but not at Gln(525). The passive transfer of antibodies reacting with an N-terminal cleavage site of the mouse COL17 ectodomain into neonatal wild-type mice failed to induce blister formation, even though the antibodies bound to the dermal-epidermal junctions, indicating that cleavage site-specific antibodies have reduced or absent pathogenicity for blister formation. This study shows the ectodomain shedding of COL17 to be a physiological event in in vivo human skin that probably generates nonpathologic epitopes on the cleavage sites.
• In vivo analysis of IgE autoantibodies in bullous pemphigoid: A study of 100 cases

  Reine Moriuchi, Wataru Nishie, Hideyuki Ujiie, Ken Natsuga, Hiroshi Shimizu

  JOURNAL OF DERMATOLOGICAL SCIENCE 78 (1) 21 - 25 0923-1811 2015/04 [Refereed][Not invited]
   

  Background: Bullous pemphigoid (BP) is an acquired autoimmune blistering disease characterized by subepidermal blister formation, in vivo linear deposition of immunoglobulin G (IgG) and complements at the dermal-epidermal junction (DEJ). The circulating IgG autoantibodies are directed against two epidermal hemidesmosomal glycoproteins: BP180, also known as type XVII collagen (COL17), and BP230. In addition, recent studies have shown that IgE autoantibodies may be involved in the pathogenesis of BP, although in vivo IgE deposition in lesional skin has not been fully characterized in large numbers of BP patients. Objective: This study investigated the incidence of in vivo deposition of IgE autoantibodies at the DEJ in lesional skin from a large number of BP patients. Methods: Peri-lesional skin samples from 100 patients who met the clinical and histopathological criteria for BP were investigated by direct immunofluorescence for the deposition of autoantibodies and complement. Patients' sera were also investigated by enzyme-linked immunosorbent assay and indirect immunofluorescence. Results: 18% of BP patients were found to show IgE deposition at the DEJ. Disease severity, clinical course and outcome did not differ between IgE-positive and IgE-negative patients. In 3 IgE-positive cases, IgG was undetectable in vivo, and these cases showed atypical manifestations. Conclusion: The results of in vivo IgE deposition may not be useful in predicting the disease course of BP, although predominant IgE deposition could alter the pattern of clinical manifestations. (C) 2015 Japanese Society for Investigative Dermatology. Published by Elsevier Ireland Ltd. All rights reserved.
• IgE autoantibodies in bullous pemphigoid: Supporting role, or leading player?

  Hideyuki Ujiie

  JOURNAL OF DERMATOLOGICAL SCIENCE 78 (1) 5 - 10 0923-1811 2015/04 [Refereed][Not invited]
   

  Bullous pemphigoid (BP) is a common autoimmune blistering skin disease in which two hemidesmosomal components - the transmembrane collagen XVII (BP180 or BPAG2) and the plakin family protein BP230 (BPAG1) - are targeted by autoimmunity. Of these, collagen XVII (COL17) is thought to be a major autoantigen, and vital roles of IgG autoantibodies in blister formation have been elucidated. However, BP shows distinct features, including pruritic urticarial erythema and eosinophilic infiltration, which may be independent of IgG-mediated autoimmunity. Recently, it has been revealed that sera from certain patients with BP contain IgE autoantibodies to COL17 and that IgE autoantibodies bind to peri-lesional dermal-epidermal junctions. Mouse models have demonstrated that IgE antibodies to COL17 induce erythema and eosinophilic infiltration in skin. In addition, the successful treatment of severe BP with omalizumab, a humanized monoclonal antibody targeting IgE, has been reported. These findings suggest that both IgG and IgE autoantibodies to COL17 may be involved in the BP pathogenesis. This article summarizes IgE-mediated autoimmunity to COL17 in BP. (C) 2015 Japanese Society for Investigative Dermatology. Published by Elsevier Ireland Ltd. All rights reserved.
• Bullous Pemphigoid Autoantibodies Directly Induce Blister Formation without Complement Activation

  Hideyuki Ujiie, Tetsumasa Sasaoka, Kentaro Izumi, Wataru Nishie, Satoru Shinkuma, Ken Natsuga, Hideki Nakamura, Akihiko Shibaki, Hiroshi Shimizu

  JOURNAL OF IMMUNOLOGY 193 (9) 4415 - 4428 0022-1767 2014/11 [Refereed][Not invited]
   

  Complement activation and subsequent recruitment of inflammatory cells at the dermal/epidermal junction are thought to be essential for blister formation in bullous pemphigoid (BP), an autoimmune blistering disease induced by autoantibodies against type XVII collagen (COL17); however, this theory does not fully explain the pathological features of BP. Recently, the involvement of complement-independent pathways has been proposed. To directly address the question of the necessity of the complement activation in blister formation, we generated C3-deficient COL17-humanized mice. First, we show that passive transfer of autoantibodies from BP patients induced blister formation in neonatal C3-deficient COL17-humanized mice without complement activation. By using newly generated human and murine mAbs against the pathogenic noncollagenous 16A domain of COL17 with high (human IgG1, murine IgG2), low (murine IgG1), or no (human IgG4) complement activation abilities, we demonstrate that the deposition of Abs, and not complements, is relevant to the induction of blister formation in neonatal and adult mice. Notably, passive transfer of BP autoantibodies reduced the amount of COL17 in lesional mice skin, as observed in cultured normal human keratinocytes treated with the same Abs. Moreover, the COL17 depletion was associated with a ubiquitin/proteasome pathway. In conclusion, the COL17 depletion induced by BP autoantibodies, and not complement activation, is essential for the blister formation under our experimental system.
• Paper-Based ELISA for the Detection of Autoimmune Antibodies in Body Fluid-The Case of Bullous Pemphigoid

  Chao-Kai Hsu, Hsin-Yu Huang, Wan-Rung Chen, Wataru Nishie, Hideyuki Ujiie, Ken Natsuga, Shu-Ting Fan, Hsi-Kai Wang, Julia Yu-Yun Lee, Wei-Lun Tsai, Hiroshi Shimizu, Chao-Min Cheng

  ANALYTICAL CHEMISTRY 86 (9) 4605 - 4610 0003-2700 2014/05 [Refereed][Not invited]
   

  Bullous pemphigoid (BP), a common autoimmune blistering disease, is increasing in incidence and conveys a high mortality. Detection of autoantibodies targeting the noncollagenous 16A (NC16A) domain of type XVII collagen using enzyme-linked immunosorbent assay (ELISA) has demonstrated high sensitivity and specificity for diagnosing BP. We have developed a rapid, low-cost, and widely applicable ELISA-based system to detect the NC16A autoimmune antibody and then diagnose and monitor BP disease activity using a piece of filter paper, a wax-printer, and NC16A antigens. Both sera and/or blister fluids from 14 untreated BP patients were analyzed. The control group included healthy volunteers and patients with other blistering disorders such as pemphigus vulgaris. In our established paper-based ELISA (P-ELISA) system, only 2 mu L of serum or blister fluid and 70 min were required to detect anti-NC16A autoimmune antibodies. The relative color intensity was significantly higher in the BP group than in the control groups when using either serum (P < 0.05) or blister fluid (P < 0.001) specimens from BP patients. The results of P-ELISA were moderately correlated with the titer of the commercial ELISA kit (MBL, Japan) (rho = 0.5680, P = 0.0011). This newly developed system allows for rapid and convenient diagnosis and/or monitoring of BP disease activity.
• Novel ADAR1 mutations including a single amino acid deletion in the deaminase domain underlie dyschromatosis symmetrica hereditaria in Japanese families

  Michihiro Kono, Mutsumi Suganuma, Masashi Akiyama, Yasutomo Ito, Hideyuki Ujiie, Kenichi Morimoto

  INTERNATIONAL JOURNAL OF DERMATOLOGY 53 (3) E194 - E196 0011-9059 2014/03 [Refereed][Not invited]
  
• Tubular Spitz Naevus Mimicking Eccrine Spiradenoma

  Yasuyuki Fujita, Satoru Aoyagi, Masumi Tsujiwaki, Erina Homma, Hideyuki Ujiie, Hiromi Fujita, Kanako C. Hatanaka, Hiroshi Shimizu

  ACTA DERMATO-VENEREOLOGICA 94 (1) 114 - 115 0001-5555 2014 [Refereed][Not invited]
  
• Linear Congenital Molluscum Contagiosum on the Coccygeal Region

  Hideyuki Ujiie, Satoru Aoyagi, Yu Hirata, Rinko Osawa, Hiroshi Shimizu

  PEDIATRIC DERMATOLOGY 30 (5) E83 - E84 0736-8046 2013/09 [Refereed][Not invited]
   

  Congenital molluscum contagiosum is rare but has been reported previously. We present a unique case of linear congenital molluscum on the coccygeal region. To make a correct diagnosis, avoid unnecessary examination, and start appropriate treatment as soon as possible, it is beneficial for dermatologists to be aware that molluscum contagiosum can present at birth and can be linear.
• Coexistence case of bullous pemphigoid and pemphigus foliaceus

  Masumi Tsujiwaki, Riichiro Abe, Yukiko Nomura, Machiko Nishimura, Daichi Hoshina, Satoru Shinkuma, Ken Natsuga, Hideyuki Ujiie, Ken Arita, Hiroshi Shimizu

  EUROPEAN JOURNAL OF DERMATOLOGY 23 (4) 552 - 553 1167-1122 2013/07 [Refereed][Not invited]
  
• Confluent and reticulated papillomatosis associated with 15q tetrasomy syndrome

  Hanako Koguchi, Hideyuki Ujiie, Satoru Aoyagi, Rinko Osawa, Hiroshi Shimizu

  Acta Dermato-Venereologica 93 (2) 202 - 203 0001-5555 2013/03 [Refereed][Not invited]
  
• A Novel Keratin 5 Mutation in an African Family with Epidermolysis Bullosa Simplex Indicates the Importance of the Amino Acid Located at the Boundary Site Between the H1 and Coil 1A Domains

  Satoru Shinkuma, Wataru Nishie, Witold K. Jacyk, Ken Natsuga, Hideyuki Ujiie, Hideki Nakamura, Masashi Akiyama, Hiroshi Shimizu

  ACTA DERMATO-VENEREOLOGICA 93 (5) 585 - 587 0001-5555 2013 [Refereed][Not invited]
  
• Efficacy of N-(3,4-dimethoxycinnamoyl)-anthranilic acid (tranilast) against eruptive syringoma: Report of two cases and review of published work

  Keita Horie, Satoru Shinkuma, Yasuyuki Fujita, Hideyuki Ujiie, Satoru Aoyagi, Hiroshi Shimizu

  JOURNAL OF DERMATOLOGY 39 (12) 1044 - 1046 0385-2407 2012/12 [Refereed][Not invited]
  
• Evidence for pathogenicity of autoreactive T cells in autoimmune bullous diseases shown by animal disease models

  Hideyuki Ujiie, Hiroshi Shimizu

  EXPERIMENTAL DERMATOLOGY 21 (12) 901 - 905 0906-6705 2012/12 [Refereed][Not invited]
   

  Autoimmune bullous diseases (AIBDs) are characterized by blisters and erosions on the skin and/or mucous membranes, which are caused by autoantibodies directed to structural proteins of the epidermis and the epidermal basement membrane zone. This Viewpoint Essay discusses the contribution by autoreactive T cells to the pathogenesis of bullous pemphigoid, pemphigus and epidermolysis bullosa acquisita, with an emphasis on studies using active animal mouse models for these diseases. Previous studies have demonstrated that cytokines produced by autoreactive T cells, the interaction between antigen-specific T cells and B cells and the function of regulatory T cells are likely related to the pathogenesis of AIBDs. In interpreting the experimental results, the limitations of those animal models should be considered. Further understanding of the pathogenicity of autoreactive CD4+ T cells may lead to disease-specific treatments.
• Coexistence of pustular and vegetative pyoderma gangrenosum in a patient with myelodysplastic syndrome

  Wakana Omiya, Hideyuki Ujiie, Masashi Akiyama, Kentaro Izumi, Akio Shigematsu, Masahiro Onozawa, Hiroshi Shimizu

  EUROPEAN JOURNAL OF DERMATOLOGY 22 (5) 711 - 712 1167-1122 2012/09 [Refereed][Not invited]
  
• The beta 9 Loop Domain of PA-PLA(1)alpha Has a Crucial Role in Autosomal Recessive Woolly Hair/Hypotrichosis

  Satoru Shinkuma, Asuka Inoue, Junken Aoki, Wataru Nishie, Ken Natsuga, Hideyuki Ujiie, Toshifumi Nomura, Riichiro Abe, Masashi Akiyama, Hiroshi Shimizu

  JOURNAL OF INVESTIGATIVE DERMATOLOGY 8 132 (8) 2093 - 2095 0022-202X 2012/08 [Refereed][Not invited]
  
• Antibodies to Pathogenic Epitopes or Type XVII Collagen Cause Skin Fragility in a Complement-Dependent and -Independent Manner

  Ken Natsuga, Wataru Nishie, Satoru Shinkuma, Hideyuki Ujiie, Machiko Nishimura, Daisuke Sawamura, Hiroshi Shimizu

  JOURNAL OF IMMUNOLOGY 188 (11) 5792 - 5799 0022-1767 2012/06 [Refereed][Not invited]
   

  In bullous pemphigoid (BP), the most prevalent autoimmune blistering disease, type XVII collagen (COL17) is targeted by circulating autoantibodies. BP is thought to be an autoantibody-mediated complement-fixing blistering disease, and a juxtamembranous noncollagenous 16A (NC16A) domain spanning Glu(490) to Arg(566) was proved to be the main pathogenic region on COL17, although precise pathogenic epitopes within NC16A have not been elucidated. In this study, we showed that injection of rabbit IgG Abs targeting Asp(522) to Gln(545) induced skin fragility associated with in vivo deposition of IgG and complement in neonatal COL17-humanized mice. Notably, immunoadsorption of rabbit anti-NC16A IgG Ab with this epitope (Asp(522) to Gln(545)) or the anti-NC16A IgG administered together with the peptides of this epitope as a decoy ameliorated skin fragility in the injected neonatal COL17-humanized mice compared with the anti-NC16A IgG alone even though all of the mice showed both IgG and complement deposition. These results led us to investigate an additional, complement-independent mechanism of skin fragility in the mice injected with anti-COL17 Abs. The rabbit anti-NC16A IgG depleted the expression of COL17 in cultured normal human keratinocytes, whereas immunoadsorption of the same IgG with this epitope significantly suppressed the depletion effect. Moreover, passive transfer of F(ab')(2) fragments of the human BP or rabbit IgG Abs against COL17 demonstrated skin fragility in neonatal COL17-humanized mice. In summary, this study reveals the importance of Abs directed against distinct epitopes on COL17, which induce skin fragility in complement-dependent as well as complement-independent ways. The Journal of Immunology, 2012, 188: 5792-5799.
• Pathogenesis of Bullous Pemphigoid

  Hideyuki Ujiie, Wataru Nishie, Hiroshi Shimizu

  IMMUNOLOGY AND ALLERGY CLINICS OF NORTH AMERICA 32 (2) 207 - + 0889-8561 2012/05 [Refereed][Not invited]
   

  Bullous pemphigoid, the most common autoimmune blistering disease, is induced by autoantibodies against type XVII collagen. Passive transfer of IgG or IgE antibodies against type XVII collagen into animals has revealed not only the pathogenicity of these antibodies but also the subsequent immune responses, including complement activation, mast cell degranulation, and infiltration of neutrophils and/or eosinophils. In vitro studies on ectodomain shedding of type XVII collagen have also provided basic knowledge on the development of bullous pemphigoid. The pathogenic role of autoreactive CD4+ T lymphocytes in the development of the pathogenic autoantibodies to type XVII collagen should also be noted.
• Mucous membrane pemphigoid with generalized blisters: IgA and IgG autoantibodies target both laminin-332 and type XVII collagen.

  Hayashi I, Shinkuma S, Shimizu S, Natsuga K, Ujiie H, Yasui C, Tsuchiya K, Nishie W, Shimizu H

  The British journal of dermatology 5 166 (5) 1116 - 1120 0007-0963 2012/05 [Refereed][Not invited]
   

  Mucous membrane pemphigoid (MMP) is a mucous membrane-dominated, subepidermal autoimmune blistering disease in which autoantibodies usually react with the C-terminal domain of type XVII collagen (COL17) or with laminin-332. Only a few cases of MMP with widespread blisters have been reported. Serologically, IgA and IgG class autoantibodies directed against COL17 or IgG autoantibodies directed against laminin-332 in patients with MMP have been well documented. MMP cases in which IgA reacts with laminin-332, however, are extremely rare. We report a case of MMP in a 67-year-old man. Clinical examination revealed extensive mucosal lesions as well as generalized blisters and erosions that healed with scar formation. The disease was intractable to treatment with systemic steroids. Interestingly, in addition to IgG directed against laminin-332 and the noncollagenous 16A (NC16A) and C-terminal domains of COL17, circulating IgA reacting with laminin-332 and with the NC16A domain of COL17 was also detected. This is the first MMP case with circulating IgA and IgG autoantibodies against both laminin-332 and COL17.
• Intraepidermal neutrophilic IgA pemphigus successfully treated with dapsone

  Yu Hirata, Riichiro Abe, Kazuhiro Kikuchi, Asuka Hamasaka, Satoru Shinkuma, Toshifumi Nomura, Wataru Nishie, Ken Arita, Hiroshi Shimizu

  EUROPEAN JOURNAL OF DERMATOLOGY 22 (2) 282 - 283 1167-1122 2012/03 [Refereed][Not invited]
  
• Noncollagenous 16A domain of type XVII collagen-reactive CD4(+) T cells play a pivotal role in the development of active disease in experimental bullous pemphigoid model

  Hideyuki Ujiie, Akihiko Shibaki, Wataru Nishie, Satoru Shinkuma, Reine Moriuchi, Hongjiang Qiao, Hiroshi Shimizu

  CLINICAL IMMUNOLOGY 142 (2) 167 - 175 1521-6616 2012/02 [Refereed][Not invited]
   

  Bullous pemphigoid (BP), the most common autoimmune blistering disease, is caused by autoantibodies against type XVII collagen (COL17). We recently demonstrated that CD4(+) T cells were crucial for the production of anti-COL17 IgG and for the development of the BP phenotype by using a novel active BP mouse model by adoptively transferring immunized splenocytes into immunodeficient COL17-humanized mice. Noncollagenous 16A (NC16A) domain of COL17 is considered to contain the main pathogenic epitopes of BP, however, the pathogenicity of COL17 NC16A-reactive CD4(+) T cells has never been elucidated. To address this issue, we modulated the immune responses against COL17 in active BP model by using anti-CD4(0) ligand (CD40L) monoclonal antibody MR1, an inhibitor of the CD40-CD40L interaction, in various ways. First, we show the essential rote of CD4(+) T cells in the model by showing that CD4(+) T cells isolated from wild-type mice immunized with human COL17 enabled naive B cells to produce anti-COL17 NC16A IgG in vivo. Second, we show that the activation of anti-COL17 NC16A IgG-producing B cells via CD40-CD40L interaction was completed within 5 days after the adoptive transfer of immunized splenocytes. Notably, a single administration of MR1 at day 0 was enough to inhibit the production of anti-COL17 NC16A IgG and to diminish skin lesions despite the presence of restored anti-COL17 IgG at the later stage. In contrast, the delayed administration of MR1 failed to inhibit the production of anti-COL17 NC16A IgG and the development of the BP phenotype. These results strongly suggest that COL17 NC16A-reactive CD4(+) T cells play a pivotal role in the production of pathogenic autoantibodies and in the development of active disease in experimental BP model. (C) 2011 Elsevier Inc. All rights reserved.
• Psoriatic onycho-pachydermo-periostitis progressing to generalized pustular psoriasis.

  Watanabe M, Ujiie H, Iitani MM, Abe R, Shimizu H

  Clin Exp Dermatol 37 (6) 683 - 685 0307-6938 2012 [Refereed][Not invited]
  
• 塊状のIgA沈着を呈したDuhring疱疹状皮膚炎の1例

  LIN Hsinyu, 氏家英之, 渡邉美佳, 馬場慶子, 阿部理一郎, 清水宏

  臨床皮膚科 (株)医学書院 65 (12) 946 - 949 0021-4973 2011/11/01 [Not refereed][Not invited]
   

  49歳,日本人男性.10年前から背部にそう痒を伴う皮疹が出現し,寛解と増悪を繰り返しながら徐々に体幹全体に拡大した.近医にてステロイド外用治療を受けたが,改善しなかった.躯幹,両上腕に類円形の径30mm大までの紅斑が散在し,小水疱を伴っていた.病理組織像では,真皮乳頭の微小膿瘍と表皮下水疱を認め,蛍光抗体直接法では真皮乳頭に塊状のIgA沈着を認めた.患者血清中の抗表皮トランスグルタミナーゼ(epidermal transglutaminase:eTG)IgA抗体が陽性であった.上下部消化管内視鏡,十二指腸および回腸生検,小腸カプセル内視鏡を行ったが,特に異常所見を認めなかった.Duhring疱疹状皮膚炎(dermatitis herpetiformis Duhring:DH)と診断し,ジアフェニルスルホン50mg/日を投与したところ皮疹は速やかに改善した.本症例のような塊状のIgA沈着パターンを呈するDHはまれである.また,本邦におけるDHの診断に,抗eTG IgA抗体の測定が有用であると考えられた.(著者抄録)
• Pathogenesis of Bullous Pemphigoid

  Hideyuki Ujiie, Wataru Nishie, Hiroshi Shimizu

  DERMATOLOGIC CLINICS 29 (3) 439 - + 0733-8635 2011/07 [Refereed][Not invited]
   

  Bullous pemphigoid, the most common autoimmune blistering disease, is induced by autoantibodies against type XVII collagen. Passive transfer of IgG or IgE antibodies against type XVII collagen into animals has revealed not only the pathogenicity of these antibodies but also the subsequent immune responses, including complement activation, mast cell degranulation, and infiltration of neutrophils and/or eosinophils. In vitro studies on ectodomain shedding of type XVII collagen have also provided basic knowledge on the development of bullous pemphigoid. The pathogenic role of autoreactive CD4+ T lymphocytes in the development of the pathogenic autoantibodies to type XVII collagen should also be noted.
• Extremely severe palmoplantar hyperkeratosis in a generalized epidermolytic hyperkeratosis patient with a keratin 1 gene mutation

  Rinko Osawa, Masashi Akiyama, Kentaro Izumi, Hideyuki Ujiie, Kaori Sakai, Ikue Nemoto-Hasebe, Teruki Yanagi, Hiroko Koizumi, Hiroshi Shimizu

  JOURNAL OF THE AMERICAN ACADEMY OF DERMATOLOGY 64 (5) 991 - 993 0190-9622 2011/05 [Refereed][Not invited]
  
• Human IgG1 Monoclonal Antibody against Human Collagen 17 Noncollagenous 16A Domain Induces Blisters via Complement Activation in Experimental Bullous Pemphigoid Model

  Qiang Li, Hideyuki Ujiie, Akihiko Shibaki, Gang Wang, Reine Moriuchi, Hong-jiang Qiao, Hiroshi Morioka, Satoru Shinkuma, Ken Natsuga, Heather A. Long, Wataru Nishie, Hiroshi Shimizu

  JOURNAL OF IMMUNOLOGY 185 (12) 7746 - 7755 0022-1767 2010/12 [Refereed][Not invited]
   

  Bullous pemphigoid (BP) is an autoimmune blistering disease caused by IgG autoantibodies targeting the noncollagenous 16A (NC16A) domain of human collagen 17 (hCOL17), which triggers blister formation via complement activation. Previous in vitro analysis demonstrated that IgG1 autoantibodies showed much stronger pathogenic activity than IgG4 autoantibodies; however, the exact pathogenic role of IgG1 autoantibodies has not been fully demonstrated in vivo. We constructed a recombinant IgG1 mAb against hCOL17 NC16A from BP patients. In COL17-humanized mice, this mAb effectively reproduced a BP phenotype that included subepidermal blisters, deposition of IgG1, C1q and C3, neutrophil infiltration, and mast cell degranulation. Subsequently, alanine substitutions at various C1q binding sites were separately introduced to the Fc region of the IgG1 mAb. Among these mutated mAbs, the one that was mutated at the P331 residue completely failed to activate the complement in vitro and drastically lost pathogenic activity in COL17-humanized mice. These findings indicate that P331 is a key residue required for complement activation and that IgG1-dependent complement activation is essential for blister formation in BP. This study is, to our knowledge, the first direct evidence that IgG1 Abs to hCOL17 NC16A can induce blister formation in vivo, and it raises the possibility that IgG1 mAbs with Fc modification may be used to block pathogenic epitopes in autoimmune diseases. The Journal of Immunology, 2010, 185: 7746-7755.
• Clearance of a Thick Invasive Squamous Cell Carcinoma After Multiple Treatments with Topical Photodynamic Therapy

  Qiang Li, Tianwen Gao, Heather Ann Long, Hideyuki Ujiie

  PHOTOMEDICINE AND LASER SURGERY 28 (5) 703 - 706 1549-5418 2010/10 [Refereed][Not invited]
   

  Objective: Tumor depth is the limiting factor for topical photodynamic therapy (PDT) treating cutaneous invasive squamous cell carcinoma (SCC). The thickness of <2-3 mm below the epidermis is the currently recommended effective response depth in nonmelanoma skin cancers. We report an unusual outgrowing SCC with a tumor depth of 5.5 mm, which was successfully treated with PDT. Methods: Topical 20% (wt/wt) 5-aminolaevulinic acid emulsion was applied for 6 h before irradiation with 633-nm red light. The lesion was irradiated 7 times, 1 week apart, at a total dose of 791 J/cm(2). Results: Twelve months later, histologic and clinical examination showed a complete remission and no local or systemic metastases. No serious side effects occurred, and the cosmetic outcome was excellent. Conclusion: PDT may offer a noninvasive, well-tolerated, and effective therapy for inoperable low-risk SCC with an outgrowing pattern. It suggests that tumor depth is not an absolute predictor, but only a suggested reference.
• Prevalent LIPH Founder Mutations Lead to Loss of P2Y5 Activation Ability of PA-PLA(1)alpha in Autosomal Recessive Hypotrichosis

  Satoru Shinkuma, Masashi Akiyama, Asuka Inoue, Junken Aoki, Ken Natsuga, Toshifumi Nomura, Ken Arita, Riichiro Abe, Kei Ito, Hideki Nakamura, Hideyuki Ujiie, Akihiko Shibaki, Hiraku Suga, Yuichiro Tsunemi, Wataru Nishie, Hiroshi Shimizu

  HUMAN MUTATION 31 (5) 602 - 610 1059-7794 2010/05 [Refereed][Not invited]
   

  Autosomal recessive hypotrichosis (ARH) is characterized by sparse hair on the scalp without other abnormalities. Three genes, DSG4, LIPH, and LPAR6 (P2RY5), have been reported to underlie ARH. We performed a mutation search for the three candidate genes in five independent Japanese ARH families and identified two LIPH mutations: c.736T > A (p.Cys246Ser) in all five families, and c.742C > A (p.His248Asn) in four of the five families. Out of 200 unrelated control alleles, we detected c.736T > A in three alleles and c.742C > A in one allele. Haplotype analysis revealed each of the two mutant alleles is derived from a respective founder. These results suggest the LIPH mutations are prevalent founder mutations for ARH in the Japanese population. LIPH encodes PA-PLA(1)alpha (LIPH), a membrane-associated phosphatidic acid-preferring phospholipase A(1)alpha. Two residues, altered by these mutations, are conserved among PA-PLA(1)alpha of diverse species. Cys(246) forms intramolecular disulfide bonds on the lid domain, a crucial structure for substrate recognition, and His(248) is one amino acid of the catalytic triad. Both p.Cys246Ser- and p.His248Asn-PA-PLA(1)alpha mutants showed complete abolition of hydrolytic activity and had no P2Y5 activation ability. These results suggest defective activation of P2Y5 due to reduced 2-acyl lysophosphatidic acid production by the mutant PA-PLA(1)alpha is involved in the pathogenesis of ARH. Hum Mutat 31:602-610, 2010. (C) 2010 Wiley-Liss, Inc.
• What's new in bullous pemphigoid

  Hideyuki Ujiie, Akihiko Shibaki, Wataru Nishie, Hiroshi Shimizu

  JOURNAL OF DERMATOLOGY 37 (3) 194 - 204 0385-2407 2010/03 [Refereed][Not invited]
   

  Bullous pemphigoid (BP) is the most common autoimmune blistering disease. BP patients have autoantibodies against type XVII collagen (COL17, also called BP180 or BPAG2), a type II transmembrane protein that spans the lamina lucida and projects into the lamina densa of the epidermal basement membrane. The non-collagenous 16A domain of COL17 is considered to contain pathogenic epitopes of BP. The transfer of immunoglobulin (Ig)G from BP patients fails to cause blisters on mouse skin probably due to differences between humans and mice in the amino acid sequence of NC16A pathogenic epitope of COL17. Passive transfer of rabbit IgG antibodies against the murine homolog of human COL17 NC16A triggers immune reactions to COL17 in mice, including complement activation, mast cell degranulation and neutrophilic infiltration, resulting in dermal-epidermal separation. Recent studies using COL17-humanized mice that express human COL17 but lack murine COL17 were the first to demonstrate the pathogenicity of anti-COL17 human BP IgG autoantibodies in vivo. These new findings provide a greater understanding of BP pathomechanisms and facilitate the development of novel specific and efficient therapeutic strategies for BP.
• Blockade of Autoantibody-Initiated Tissue Damage by Using Recombinant Fab Antibody Fragments against Pathogenic Autoantigen

  Gang Wang, Hideyuki Ujiie, Akihiko Shibaki, Wataru Nishie, Yasuki Tateishi, Kazuhiro Kikuchi, Qiang Li, James R. McMillan, Hiroshi Morioka, Daisuke Sawamura, Hideki Nakamura, Hiroshi Shimizu

  AMERICAN JOURNAL OF PATHOLOGY 176 (2) 914 - 925 0002-9440 2010/02 [Refereed][Not invited]
   

  Activation of the complement cascade via the classical pathway is required for the development of tissue injury in many autoantibody-mediated diseases. It therefore makes sense to block the pathological action of autoantibodies by preventing complement activation through inhibition of autoantibody binding to the corresponding pathogenic autoantigen using targeted Fab antibody fragments. To achieve this, we use bullous pemphigoid (BP) as an example of a typical autoimmune disease. Recombinant Fabs against the non-collagenous 16th-A domain of type XVII collagen, the main pathogenic epitope for autoantibodies in BP, were generated from antibody repertoires of BP patients by phage display. Two Fabs, Fab-B4 and Fab-19, showed marked ability to inhibit the binding of BP autoantibodies and subsequent complement activation in vitro. In the in vivo experiments using type XVII collagen humanized BP model mice, these Fabs protected mice against BP autoantibody-induced blistering disease. Thus, the blocking of pathogenic epitopes using engineered Fabs appears to demonstrate efficacy and may lead to disease-specific treatments for antibody-mediated autoimmune diseases. (Am J Pathol 2010, 176:914-925; DOI: 10.2353/ajpath.2010.090744)
• A Novel Active Mouse Model for Bullous Pemphigoid Targeting Humanized Pathogenic Antigen

  Hideyuki Ujiie, Akihiko Shibaki, Wataru Nishie, Daisuke Sawamura, Gang Wang, Yasuki Tateishi, Qiang Li, Reine Moriuchi, Hongjiang Qiao, Hideki Nakamura, Masashi Akiyama, Hiroshi Shimizu

  JOURNAL OF IMMUNOLOGY 184 (4) 2166 - 2174 0022-1767 2010/02 [Refereed][Not invited]
   

  Bullous pemphigoid (BP), the most common autoimmune blistering disease, is caused by autoantibodies against type XVII collagen (COL17). To establish an active stable BP animal model that demonstrates the persistent inflammatory skin lesions initiated by the anti-human COL17 Abs, we used COL17-humanized (COL17(m-/-,h+)) mice that we recently produced. First, we generated immunodeficient Rag-2(-/-)/COL17-humanized mice by crossing Rag-2(-/-) mice with COL17-humanized mice. Then, splenocytes from wild-type mice that had been immunized by grafting of human COL17-transgenic mouse skin were transferred into Rag-2(-/-)/COL17-humanized mice. The recipient mice continuously produced anti-human COL17 IgG Abs in vivo and developed blisters and erosions corresponding to clinical, histological, and immunopathological features of BP, although eosinophil infiltration, one of the characteristic histological findings observed in BP patients, was not detected in the recipients. Although the depletion of CD8(+) T cells from the immunized splenocytes was found to produce no effects in the recipients, the depletion of CD4(+) T cells as well as CD45R(+) B cells was found to inhibit the production of anti-human COL17 IgG Abs in the recipients, resulting in no apparent clinical phenotype. Furthermore, we demonstrated that cyclosporin A significantly suppressed the production of anti-human COL17 IgG Abs and prevented the development of the BP phenotype in the treated recipients. Although this model in an immunodeficient mouse does not exactly reproduce the induction mechanism of BP in human patients, this unique experimental system targeting humanized pathogenic Ag allows us to investigate ongoing autoimmune responses to human molecules in experimental animal models. The Journal of Immunology, 2010, 184: 2166-2174.
• Hereditary Benign Telangiectasia: Two Families With Punctate Telangiectasias Surrounded by Anemic Halos

  Hideyuki Ujiie, Kazuo Kodama, Masashi Akiyama, Hiroshi Shimizu

  ARCHIVES OF DERMATOLOGY 146 (1) 98 - 99 0003-987X 2010/01 [Refereed][Not invited]
  
• Successful Treatment of Nail Lichen Planus with Topical Tacrolimus

  Hideyuki Ujiie, Akihiko Shibaki, Masashi Akiyama, Hiroshi Shimizu

  ACTA DERMATO-VENEREOLOGICA 90 (2) 218 - 219 0001-5555 2010 [Refereed][Not invited]
  
• Squamous Cell Carcinoma in a Chronic Genital Ulcer in Behcet's Disease

  Hiroo Hata, Satoru Aoyagi, Maria Maroto Iitani, Erina Homma, Hiroshi Shimizu

  ACTA DERMATO-VENEREOLOGICA 5 90 (5) 539 - 540 0001-5555 2010 [Refereed][Not invited]
  
• A Novel Humanized Neonatal Autoimmune Blistering Skin Disease Model Induced by Maternally Transferred Antibodies

  Wataru Nishie, Daisuke Sawamura, Ken Natsuga, Satoru Shinkuma, Maki Goto, Akihiko Shibaki, Hideyuki Ujiie, Edit Olasz, Kim B. Yancey, Hiroshi Shimizu

  JOURNAL OF IMMUNOLOGY 183 (6) 4088 - 4093 0022-1767 2009/09 [Refereed][Not invited]
   

  All mammal neonates receive maternal Abs for protection against pathogenic organisms in the postnatal environment. However, neonates can experience serious adverse reactions if the Abs transferred from the mother recognize self-molecules as autoAgs. In this study, we describe a novel model for autoimmune disease induced by transferred maternal Abs in genetically transformed Ag-humanized mice progeny. Bullous pemphigoid is the most common life-threatening autoimmune blistering skin disease that affects the elderly, in which circulating IgG autoAbs are directed against epidermal type XVII collagen (COL17). We have established a genetically manipulated experimental mouse model in which maternal Abs against human COL17 are transferred to pups whose skin expresses only human and not mouse COL17, resulting in blistering similar to that seen in patients with bullous pemphigoid. Maternal transfer of pathogenic Abs to humanized neonatal mice is a unique and potential experimental system to establish a novel autoimmune disease model. The Journal of Immunology, 2009, 183: 4088-4093.
• Bloody Nipple Discharge in an Infant

  Hideyuki Ujiie, Masashi Akiyama, Rinko Osawa, Satoru Shida, Satoru Aoyagi, Hiroshi Shimizu

  ARCHIVES OF DERMATOLOGY 145 (9) 1068 - 1069 0003-987X 2009/09 [Refereed][Not invited]
  
• Conradi-Hunermann-Happle syndrome with abnormal lamellar granule contents.

  Akiyama M, Sakai K, Hayasaka K, Tabata N, Yamada M, Ujiie H, Shibaki A, Shimizu H

  Br J Dermatol 160 1335 - 1337 2009 [Refereed][Not invited]
  
• A novel PTPN11 missense mutation in a patient with LEOPARD syndrome.

  Osawa R, Akiyama M, Yamanaka Y, Ujiie H, Nemoto-Hasebe I, Takeda A, Yanagi T, Shimizu H

  Br J Dermatol 161 1202 - 1204 2009 [Refereed][Not invited]
  
• Leukaemic dissemination of Merkel cell carcinoma in a patient with systemic lupus erythematosus.

  Nemoto I, Sato-Matsumura KC, Fujita Y, Natsuga K, Ujiie H, Tomita Y, Kato N, Kondo M, Ohnishi K

  Clinical and experimental dermatology 3 33 (3) 270 - 272 0307-6938 2008/05 [Refereed][Not invited]
   

  Nemoto I, Sato-Matsumura KC, Fujita Y, Natsuga K, Ujiie H, Tomita Y, Kato N, Kondo M, Ohnishi K, Clinical and experimental dermatology, 2008, vol. 33, no. 3, pp. 270-272
• Large subcutaneous abscesses caused by Mycobacterium fortuitum infection

  Reine Moriuchi, Ken Arita, Hideyuki Ujiie, Kazuo Kodama, Tadamichi Shimizu, Hiroshi Shimizu

  ACTA DERMATO-VENEREOLOGICA 88 (3) 313 - 314 0001-5555 2008 [Refereed][Not invited]
  
• Novel ABCA12 mutations identified in two cases of non-bullous congenital ichthyosiform erythroderma associated with multiple skin malignant neoplasia

  Ken Natsuga, Masashi Akiyama, Naoko Kato, Kaori Sakai, Yoriko Sugiyama-Nakagiri, Machiko Nishimura, Hiroo Hata, Masataka Abe, Ken Arita, Yukiko Tsuji-Abe, Takashi Onozuka, Satoru Aoyagi, Kazuo Kodama, Hideyuki Ujiie, Yuki Tomita, Hiroshi Shimizu

  JOURNAL OF INVESTIGATIVE DERMATOLOGY 127 (11) 2669 - 2673 0022-202X 2007/11 [Refereed][Not invited]
  
• Non-Hodgkin lymphoma preceded by recalcitrant eczema

  Ken Natsuga, Riichiro Abe, Hideyuki Ujiie, Akihiko Shibaki, Daisuke Sawamura, Mitsufumi Nishio, Katsuya Fujimoto, Takao Koike, Hiroshi Shimizu

  EUROPEAN JOURNAL OF HAEMATOLOGY 79 (4) 369 - 370 0902-4441 2007/10 [Refereed][Not invited]
  
• Unilateral periorbital oedema due to sarcoid infiltration of the eyelid: an unusual presentation of sarcoidosis with facial nerve palsy and parotid gland enlargement.

  Yaosaka M, Abe R, Ujiie H, Abe Y, Shimizu H

  Br J Dermatol 157 (1) 200 - 202 0007-0963 2007/07 [Refereed][Not invited]
  
• Keratoacanthoma developing on nevus sebaceous in a child

  Hideyuki Ujiie, Naoko Kato, Ken Natsuga, Yuki Tomita

  JOURNAL OF THE AMERICAN ACADEMY OF DERMATOLOGY 56 (2) S57 - S58 0190-9622 2007/02 [Refereed][Not invited]
  
• Severe cholinergic urticaria successfully treated with scopolamine butylbromide in addition to antihistamines.

  Ujiie H, Shimizu T, Natsuga K, Arita K, Tomizawa K, Shimizu H

  Clinical and experimental dermatology 2006/07 [Refereed][Not invited]
  
• Peginterferon alfa-2b for mycosis fungoides

  T Yanagi, T Shimizu, H Ujiie, M Ito, R Abe, Y Tsuji-Abe, S Hige, H Shimizu

  ARCHIVES OF DERMATOLOGY 142 (5) 649 - 651 0003-987X 2006/05 [Refereed][Not invited]
  
• Development of lichen planus and psoriasis on lesions of vitiligo vulgaris.

  Ujiie H, Sawamura D, Shimizu H

  Clinical and experimental dermatology 3 31 375 - 377 0307-6938 2006/05 [Refereed][Not invited]
  
• Lupus erythematosus profundus successfully treated with dapsone: Review of the literature

  H Ujiie, T Shimizu, M Ito, K Arita, H Shimizu

  ARCHIVES OF DERMATOLOGY 142 (3) 399 - 401 0003-987X 2006/03 [Refereed][Not invited]
  
• Cutaneous reactions to imatinib mesylate treated by topical steroid

  H Ujiie, T Shimizu, H Shimizu

  AMERICAN JOURNAL OF HEMATOLOGY 78 (3) 246 - 246 0361-8609 2005/03 [Refereed][Not invited]
  
• Prolonged dermatitis distant to the site of squaric acid dibutyl ester applications and recovery of alopecia areata.

  Ujiie H, Sawamura D, Shibaki A, Shimizu H

  Clin Exp Dermatol 30 579 - 580 2005 [Refereed][Not invited]
  
• Intractable erythema nodosum associated with severe breast abscesses: reports of two cases.

  Ujiie H, Sawamura D, Yokota K, Tateishi Y, Inokuma D, Shimizu H

  Clin Exp Dermatol 30 584 - 585 2005 [Refereed][Not invited]
  
• Pyoderma gangrenosum associated with Takayasu's arteritis.

  Ujiie H, Sawamura D, Yokota K, Nishie W, Shichinohe R, Shimizu H

  Clin Exp Dermatol 29 (4) 357 - 359 0307-6938 2004 [Refereed][Not invited]
   

  Pyoderma gangrenosum (PG) is a neutrophilic dermatosis characterized by destructive, necrotizing and noninfective ulceration of the skin mostly on lower extremities. PG is well known as a complication of Takayasu's arteritis in Japan. However, this association is not commonly observed in North American and European patients. We describe a case of PG that was associated with Takayasu's arteritis who was successfully treated with systemic cyclosporin. We have reviewed 35 well-documented PG cases with Takayasu's arteritis in comparison to 106 PG cases without Takayasu's arteritis. The results demonstrate that this association occurs predominantly in young females and that these cases exhibit more widespread PG lesions.
• Generalized pustular psoriasis and Hepatitis C virus infection.

  Ujiie H, Shimizu T, Shimizu H

  Acta virologica 2004/01 [Refereed][Not invited]
  

MISC

• 体重減少は悪性黒色腫の予後不良因子になりうる

  田中有沙, 田中有沙, 宮澤元, 前田拓哉, 北村真也, 柳輝希, 氏家英之  西日本皮膚科  85-  (3)  2023
• 姑息的切除を行った乳房外パジェット病の予後に関する検討

  瀬尾拓志, 北村真也, 柳輝希, 前田拓哉, 氏家英之  加齢皮膚医学セミナー  18-  (1)  2023
• 水疱性類天疱瘡とBullous Rheumatoid Neutrophilic Dermatosisとの鑑別を要したリウマトイド血管炎

  田中有沙, 田中有沙, 柳輝希, 今福恵輔, 渥美達也, 氏家英之  皮膚科の臨床  65-  (10)  2023
• Diagnosis and Management of Porocarcinoma

  Kodai Miyamoto, Teruki Yanagi, Takuya Maeda, Hideyuki Ujiie  Cancers  14-  (21)  2022/11  

  Eccrine porocarcinoma, also known as porocarcinoma (PC) and malignant eccrine poroma, is very rare and is known to arise from the cutaneous intraepidermal ducts of the sweat glands. Its etiology is not well understood; however, some studies suggest that PC tumors originate from benign eccrine poroma. Recently, several gene alterations have been reported in PC that can reveal mechanisms of the oncogenic process. Since the clinical and histopathological findings of PC are variable, PC is difficult to diagnose precisely, especially when the histology resembles that of cutaneous squamous cell carcinoma or poroma. Immunohistochemical staining with carcinoembryonic antigen and epithelial membrane antigen may help to distinguish PC from other tumors. The standard treatment for local PC is wide local excision. The prognosis of patients with metastatic PC is poor, with mortality rates of approximately 60–70%. The efficacy of radiation and chemotherapy for metastatic PC is limited; however, immunotherapy with pembrolizumab, a programmed cell death protein 1 inhibitor, could be a promising treatment. This review focuses on the history, pathogenesis, pathological features, diagnosis, and treatment of eccrine porocarcinoma.
• 肺病変にステロイドが奏功したPOIKTMPの1例(アンコール演題)

  佐藤 理子, 鈴木 雅, 猪狩 智生, 中村 友彦, 高橋 桂, 佐々木 真知子, 木村 孔一, 木村 裕樹, 宮内 俊成, 乃村 俊史, 氏家 英之, 山口 直子, 大塚 紀幸, 外丸 詩野, 今野 哲  日本呼吸器学会誌  11-  (増刊)  272  -272  2022/04
• 【皮膚科医もいまさらしっかり総復習!糖尿病の今!】(Part2)糖尿病の皮膚!いま改めて総復習!(Atlas 9) DPP-4阻害薬を投薬中に発症した水疱性類天疱瘡

  氏家 英之  Visual Dermatology  20-  (8)  822  -822  2021/07
• Serpiginous erythema on the trunk

  Takamasa Ito, Hideyuki Ujiie  The BMJ  372-  2021/01/21
• 類天疱瘡update

  氏家 英之  日本皮膚科学会雑誌  131-  (1)  121  -122  2021/01
• Familial chilblain lupus with TREX1 mutation and cerebrovascular disease

  Takuma Nohara, Teruki Yanagi, Ichiro Yabe, Nakao Ota, Nobuo Kanazawa, Hideyuki Ujiie, Hideyuki Kosumi, Yosuke Mai, Hiroshi Shimizu  LANCET RHEUMATOLOGY  2-  (11)  E724  -E724  2020/11
• 治療法の再整理とアップデートのために 専門家による 私の治療 類天疱瘡

  氏家 英之  日本医事新報  (5018)  43  -43  2020/06
• DPP-4阻害薬服用中の糖尿病患者に生じた水疱性類天疱瘡

  氏家 英之, 岩田 浩明, 葭本 倫大, 氏家 韻欣, 中村 昭伸, 三好 秀明, 清水 宏  糖尿病  63-  (5)  355  -355  2020/05
• 【検査値を読む2020】(19章)自己免疫検査 抗デスモグレイン抗体

  氏家 英之  内科  125-  (4)  850  -850  2020/04
• 【検査値を読む2020】(19章)自己免疫検査 抗BP180NC16a抗体

  氏家 英之  内科  125-  (4)  851  -851  2020/04
• 【水疱をどう診る?どう治す?】水疱性類天疱瘡と粘膜類天疱瘡

  氏家 英之  Derma.  (292)  29  -37  2020/02  

  水疱性類天疱瘡と粘膜類天疱瘡は、いずれも表皮基底膜部に対する自己抗体によって生じる自己免疫性表皮下水疱症である。診断は臨床像、病理組織学的所見、および免疫学的検査所見に基づいて決定する。典型例では診断は比較的容易であるが、非典型的な臨床像や検査所見を呈する症例も多く、しばしば診断に難渋する。治療は重症度に応じて選択するが、個々の症例の背景や合併症なども勘案し総合的に判断する。いずれも軽症例ではステロイド全身投与を用いずに寛解に至る症例が多いため、早期診断と適切な重症度判定が重要である。ステロイド全身投与にあたっては、特に高齢者では血圧や血糖の上昇、筋力低下、骨粗鬆症などが顕在化しやすいため、注意深く経過観察するとともに他科と連携しながら診療にあたる必要がある。(著者抄録)
• 自己免疫性水疱症の診断の最前線

  氏家 英之  検査と技術  48-  (1)  10  -13  2020/01  

  ＜文献概要＞はじめに 自己免疫性水疱症は,表皮角化細胞(ケラチノサイト)の細胞膜や表皮基底膜部に存在する蛋白に対する自己抗体によって,皮膚や粘膜に水疱やびらんなどの皮膚症状を呈する疾患群です.角化細胞の細胞膜に存在する蛋白に対する自己抗体によって表皮内に水疱が形成される"天疱瘡群"と,表皮基底膜部に存在する蛋白に対する自己抗体によって表皮下に水疱が形成される"類天疱瘡群"の2群に分けられます(表1).また,IgG自己抗体が検出される疾患と,IgA自己抗体が検出される疾患があります(表1).頻度として,水疱性類天疱瘡が最も高く,次いで尋常性天疱瘡や落葉状天疱瘡が高いとされています.天疱瘡群のほとんどの亜型と,水疱性類天疱瘡,粘膜類天疱瘡,後天性表皮水疱症は,中等症以上の場合は厚生労働省の指定難病に含まれます.診断には,臨床症状に加え,病理組織学的検査と自己抗体の検出が必要です.典型的な症例では診断が容易ですが,非典型的な症例では一般的な検査で自己抗体が検出されないことがあり,しばしば診断が困難です.そこで本稿では,自己免疫性水疱症の診断のために行われる検査法について解説します.
• 【日常診療で接する薬剤性皮膚障害】(Part1.)糖尿病治療薬による薬疹(総説1) DPP-4阻害薬内服に伴う水疱性類天疱瘡

  氏家 英之  Visual Dermatology  19-  (2)  134  -139  2020/01  

  DPP-4阻害薬関連水疱性類天疱瘡(BP)の特徴として、高齢の男性が多く、薬剤によってバラツキがあるものの約1000人に1人が発症し、内服開始から発症までの期間が数ヵ月〜数年と長く、紅斑に乏しい非炎症型が比較的多い。抗BP180NC16A抗体が低値あるいは陰性の症例が多く、診断には全長BP180ELISA法が有用である。日本人の非炎症型症例ではHLA-DQB1*03:01の保有率が高い。
• 【日常診療で接する薬剤性皮膚障害】(Part1.)糖尿病治療薬による薬疹(case1) DPP-4阻害薬内服患者に生じた水疱性類天疱瘡の1例

  葭本 倫大, 氏家 英之  Visual Dermatology  19-  (2)  140  -142  2020/01
• 眼粘膜症状を呈した後天性表皮水疱症の1例

  村田 真美, 浅野 伸幸, 氏家 英之, 山田 隆弘, 下村 裕  西日本皮膚科  81-  (6)  478  -482  2019/12  

  58歳,男性。初診の2週間前より,体幹・四肢に散在する紅斑・緊満性水疱と眼・口腔粘膜症状が出現した。体幹の紅斑部からの皮膚生検組織を用いた蛍光抗体直接法では,表皮真皮境界部にIgG,IgAおよびC3の線状沈着を認めた。また,健常人の1M食塩水処理皮膚と患者血清を用いた蛍光抗体間接法では,真皮側にIgGが沈着した。さらに,健常人の真皮抽出液を用いた免疫ブロット法で,患者血清中のIgGがVII型コラーゲンの分子量に相当する290kDaの蛋白と反応したため,後天性表皮水疱症と確定診断した。プレドニゾロンとアザチオプリンを併用したが,病勢を完全には抑えきれなかった。免疫グロブリン静注療法とシクロフォスファミドパルス療法を追加したところ,徐々に症状の改善を認めた。眼粘膜症状を呈する後天性表皮水疱症は稀であり,自験例では,IgG型の抗VII型コラーゲン抗体だけでなく,IgA型の自己抗体も病態に関与している可能性が示唆された。(著者抄録)
• Epitope spreading現象によって抗BP180 NC16a抗体が陽転化したdipeptidyl peptidase-IV阻害薬関連水疱性類天疱瘡の3例

  眞井 洋輔, 西江 渉, 泉 健太郎, 葭本 倫大, 森田 裕介, 渡邉 美佳, 豊永 愛恋, 氏家 英之, 岩田 浩明, 藤田 靖幸, 乃村 俊史, 松村 和子, 清水 聡子, 清水 宏  加齢皮膚医学セミナー  14-  (2)  67  -67  2019/12
• 糖尿病をめぐる診療科リレー 皮膚科 糖尿病と皮膚疾患、特にDPP-4阻害薬と水疱性類天疱瘡の関連

  氏家 英之  DM Ensemble  8-  (3)  42  -45  2019/11  

  糖尿病患者さんには、糖尿病性壊疽をはじめとした様々な皮膚疾患が生じます。近年、DPP-4阻害薬を服用中の2型糖尿病患者さんに、自己免疫性水疱症である水疱性類天疱瘡が生じた報告が国内外で増加しています。水疱性類天疱瘡(bullous pemphigoid;BP)は、表皮基底膜部にあるヘミデスモソームという細胞接着装置の構成蛋白であるBP180に対する自己抗体によって、表皮真皮間の結合が低下するために、皮膚および粘膜に表皮下水疱が生じる自己免疫性水疱症です。水疱性類天疱瘡は本邦で最も頻度の高い自己免疫性水疱症で、70歳代以上の高齢者に好発し、中等症以上は厚生労働省指定難病に含まれます。最近の研究により、DPP-4阻害薬関連水疱性類天疱瘡は高齢者に好発することや、通常の水疱性類天疱瘡と比べて紅斑が乏しい「非炎症型」が多いこと、HLA-DQB1*03:01陽性例が多いことなどが明らかとなってきました。DPP-4阻害薬服用患者さんの約0.09%に水疱性類天疱瘡が生じるという報告もあります。本症はまれな疾患ですが、見逃されやすく、重症化することもあるため、糖尿病治療に関わる内科医や医療スタッフに広く周知されるべき疾患です。DPP-4阻害薬服用中の患者さんに複数のびらんや水疱が見られた場合には、本疾患を想起して速やかに対応する必要があります。(著者抄録)
• 発症から診断までに10年以上が経過した粘膜類天疱瘡の1例

  鈴木 丈雄, 新熊 悟, 荻根沢 真帆子, 会沢 敦子, 高橋 奈央, 泉 健太郎, 氏家 英之, 西江 渉, 阿部 理一郎  臨床皮膚科  73-  (10)  813  -817  2019/09  

  ＜文献概要＞73歳,男性.初診の10年以上前から口腔,鼻腔および咽喉頭粘膜にびらん,潰瘍が出現した.近医耳鼻科でBehcet病を疑われ,プレドニゾロンやコルヒチンの内服などで治療されたが,難治であった.また,初診の3年前から眼球癒着を生じ,眼科で内反症解除術・眼球癒着解除術を施行されたが,術後1ヵ月で再び癒着した.口腔内の難治性潰瘍の精査・加療目的に当科を紹介され受診した.歯肉びらん部の病理組織像では粘膜上皮・固有層間に裂隙を認めた.無疹部であった口唇粘膜の生検組織を用いた蛍光抗体直接法では粘膜上皮直下に線状のIgG沈着を認め,1M食塩水剥離ヒト皮膚を用いた蛍光抗体間接法では患者血清IgGが裂隙の表皮側に沈着した.以上から,抗BP180型粘膜類天疱瘡と考えた.皮膚病変が軽症な粘膜類天疱瘡では,他科で診断が不確定なまま粘膜の難治性潰瘍として長期間治療されることがあるため,他科との密な連携が必要である.
• 眼粘膜症状を呈した後天性表皮水疱症の1例

  村田 真美, 浅野 伸幸, 下村 裕, 氏家 英之  西日本皮膚科  81-  (3)  235  -235  2019/06
• Epitope spreading現象によって抗BP180 NC16a抗体が陽転化したdipeptidyl peptidase-IV阻害薬関連水疱性類天疱瘡の3例

  眞井 洋輔, 西江 渉, 泉 健太郎, 葭本 倫大, 森田 裕介, 渡邉 美佳, 豊永 愛恋, 氏家 英之, 岩田 浩明, 藤田 靖幸, 乃村 俊史, 松村 和子, 清水 聡子, 清水 宏  加齢皮膚医学セミナー  14-  (1)  65  -65  2019/06
• Linear immunoglobulin A/immunoglobulin G bullous dermatosis with autoantibodies to LAD-1 and laminin-γ1

  Y. Matsudate, K. Yamasaki, H. Ujiie, H. Iwata, Y. Kubo  Clinical and Experimental Dermatology  44-  (3)  e44  -e46  2019/04
• 尋常性乾癬に合併した組織学的に好中球浸潤が著しい類天疱瘡の1例

  稲村 衣美, 岩田 浩明, 野原 拓馬, 水上 卓哉, 羽賀 直哉, 中山 ちひろ, 村松 憲, 辻脇 真澄, 秦 洋郎, 氏家 英之, 清水 宏  日本皮膚科学会雑誌  129-  (1)  47  -47  2019/01
• 重篤な喉頭粘膜疹により気管切開を要した水疱性類天疱瘡の1例

  鬼頭 由紀子, 浦野 聖子, 望月 大極, 関 敦郎, 氏家 英之, 西江 渉  皮膚科の臨床  60-  (11)  1757  -1761  2018/10  

  ＜文献概要＞67歳,男性。全身の浮腫性紅斑,緊満性水疱,軟口蓋のびらんを認め入院した。ステロイド全身投与と免疫グロブリン大量静注療法を併用するも,咽頭痛と唾液の飲み込みにくさが出現した。喉頭鏡にて喉頭浮腫を認め,緊急気管切開を要した。抗BP180抗体(ELISA)は2310U/mlと高値であった。病理組織学的所見では表皮下水疱を認め,1M食塩水で処理したsplit skinによる蛍光抗体間接法ではIgGが表皮側に陽性であった。表皮抽出液を用いた免疫ブロット法ではIgGが230kDaの蛋白(BP230)に陽性であった。BP180のC末端のリコンビナント蛋白を用いた免疫ブロット法ではIgGがごく弱く陽性であった。口腔粘膜疹がみられる例では,自験例のような重篤な喉頭粘膜疹を合併する可能性があることを念頭に置き,診療にあたる必要がある。
• A case of subepidermal autoimmune bullous disease with autoantibodies against 200 and 290-kDa antigens

  M. Sawada, T. Hida, H. Ujiie, H. Iwata, H. Uhara  Journal of the European Academy of Dermatology and Venereology  32-  (9)  e354  -e355  2018/09
• Bullous pemphigoid with the deposition of IgG2 but not IgG1, IgG3 nor IgG4 autoantibodies at the basement membrane zone

  N. Yoshimoto, H. Ujiie, M. Zheng, H. Iwata, H. Kosumi, H. Hata, H. Shimizu  Journal of the European Academy of Dermatology and Venereology  32-  (9)  e344  -e346  2018/09
• 糖尿病の療養指導 DPP-4阻害薬と類天疱瘡の関係 糖尿病治療薬であるDPP-4阻害薬と類天疱瘡の関係について教えてください。また、薬剤を使用中に類天疱瘡を発症した際の対処法について教えてください

  氏家 英之  プラクティス  35-  (5)  577  -578  2018/09
• 【妊娠と皮膚】(Part2)妊娠に伴って出現、増悪する皮膚疾患(case 2) 線状IgA水疱性皮膚症

  氏家 英之, 林 昌浩  Visual Dermatology  17-  (10)  936  -938  2018/09
• 眼粘膜症状を呈した後天性表皮水疱症の1例

  村田 真美, 浅野 伸幸, 下村 裕, 氏家 英之  日本皮膚科学会雑誌  128-  (10)  2122  -2122  2018/09
• DPP-4阻害薬による類天疱瘡のリスク因子

  氏家 英之  内分泌・糖尿病・代謝内科  47-  (3)  210  -214  2018/09
• エリテマトーデスに対するヒドロキシクロロキンの使い方 CLEとSLEで投与方法などに違いはあるが、注意点は同様となる

  谷川 瑛子, 氏家 英之  日本医事新報  (4913)  57  -58  2018/06
• 抗デスモグレイン3抗体がCLEIAで陰性、ELISAで陽性となった尋常性天疱瘡の1例

  眞井 洋輔, 氏家 英之, 西村 真智子, 古賀 浩嗣, 真屋 由佳, 得地 景子, 藤田 靖幸, 三河 洋平, 清水 宏  西日本皮膚科  80-  (3)  289  -290  2018/06
• A possible association between BP230-type bullous pemphigoid and dementia: a report of two cases in elderly patients

  M. Zheng, H. Ujiie, K. Muramatsu, K. C. Sato-Matsumura, T. Maeda, I. Ujiie, H. Iwata, K. Izumi, W. Nishie, H. Shimizu  British Journal of Dermatology  178-  (6)  1449  -1450  2018/06/01  [Not refereed][Not invited]
  
• CLEIAで検出されない抗デスモグレイン3抗体は抗原との結合速度が遅い

  眞井 洋輔, 氏家 英之, 東 恒仁, 岩田 浩明, 清水 宏  日本皮膚科学会雑誌  128-  (4)  607  -607  2018/04
• 【最近のトピックス2018】皮膚疾患治療のポイント 類天疱瘡診療ガイドラインについて

  氏家 英之  臨床皮膚科  72-  (5)  121  -124  2018/04  

  ＜文献概要＞類天疱瘡は,水疱性類天疱瘡,粘膜類天疱瘡および後天性表皮水疱症を一連の疾患群として2015年に厚生労働省指定難病に追加された.それを受け,それら3疾患を含む形で類天疱瘡診療ガイドラインが策定され,2017年に公表された.診断の確定には臨床症状のほか,皮膚あるいは粘膜生検が必須である.国際基準であるBPDAI(Bullous Pemphigoid Disease Area Index)に準じた重症度分類を行い,水疱性類天疱瘡と後天性表皮水疱症では軽症と中等症以上に分け治療方針を決定する.粘膜類天疱瘡では,低リスク群(口腔粘膜と皮膚に限局)と高リスク群(広範囲または進行性の口腔粘膜病変,あるいは口腔粘膜以外の粘膜病変あり)に分類し,治療方針を立てる.本疾患群は稀少であるため,現時点で治療に関するエビデンスは十分とは言えず,今後も新たなエビデンスに即した継続的なガイドラインの改訂が求められる.
• 17型コラーゲンは加齢による表皮の過増殖を抑制する

  渡邉 美佳, 夏賀 健, 西江 渉, 藤村 悠, 氏家 英之, 尾崎 倫孝, 清水 宏  日本皮膚科学会雑誌  128-  (4)  607  -607  2018/04  [Not refereed][Not invited]
  
• DPP-4阻害薬による類天疱瘡の発症 通常の薬疹とは異なる発症機序が推定される。HLA-DQB1*03:01がリスク因子

  氏家 英之, 大塚 篤司  日本医事新報  (4901)  56  -56  2018/03
• 【内科医が知っておくべき皮膚疾患】DPP-4阻害薬と類天疱瘡

  氏家 英之  Mebio  34-  (10)  92  -98  2017/10  

  ＜Point＞水疱性類天疱瘡はわが国で最も頻度が高い自己免疫性水疱症で、緊満性水疱と痒みを伴う紅斑が特徴的である。DPP-4阻害薬内服開始から数ヵ月以上経過した後に、水疱性類天疱瘡が生じることがある。DPP-4阻害薬関連水疱性類天疱瘡は、紅斑に乏しい「非炎症型」の臨床像を呈することが多い。通常の水疱性類天疱瘡では抗BP180NC16a抗体が陽性となるが、DPP-4阻害薬関連水疱性類天疱瘡ではそれが陰性となることがあるため注意する。(著者抄録)
• 乳癌を合併した後天性表皮水疱症の1例

  緋田 哲也, 廣瀬 憲志, 村尾 和俊, 武知 浩和, 氏家 英之, 久保 宜明  西日本皮膚科  79-  (5)  514  -514  2017/10
• Type XVII collagen suppresses interfollicular epidermal proliferation in neonatal and aged skin, and helps rejuvenate epidermis

  M. Watanabe, K. Natsuga, W. Nishie, G. Donati, Y. Fujimura, T. Tsukiyama, H. Ujiie, M. Ozaki, F. M. Watt, H. Shimizu  JOURNAL OF INVESTIGATIVE DERMATOLOGY  137-  (10)  S207  -S207  2017/10  [Not refereed][Not invited]
  
• Treg dysfunction leads to spontaneous production of autoantibodies to bullous pemphigoid antigens in mice

  K. Muramatsu, H. Ujiie, W. Nishie, K. Izumi, T. Ito, H. Iwata, H. Shimizu  JOURNAL OF INVESTIGATIVE DERMATOLOGY  137-  (10)  S254  -S254  2017/10  [Not refereed][Not invited]
  
• High-dose immunoglobulin contains anti-idiotypic antibodies against BP-IgG

  M. Kamaguchi, H. Iwata, Y. Mori, H. Ujiie, Y. Kitagawa, H. Shimizu  JOURNAL OF INVESTIGATIVE DERMATOLOGY  137-  (10)  S243  -S243  2017/10  [Not refereed][Not invited]
  
• IgA型ALアミロイドーシスに線状IgA皮膚症を併発した1例

  山口 泰之, 氏家 英之, 大東 寛幸, 岩田 浩明, 村松 憲, 清水 宏, 遠藤 知之, 豊嶋 崇徳  日本皮膚科学会雑誌  127-  (9)  2111  -2111  2017/08  [Not refereed][Not invited]
  
• 皮膚粘膜移行部と手掌に限局した抗ラミニンγ1類天疱瘡

  大日 輝記, 椛島 健治, 本田 由貴, 服部 ゆかり, 宮地 良樹, 西江 渉, 氏家 英之  日本皮膚科学会雑誌  127-  (7)  1562  -1562  2017/06
• 【診断基準を満たさないとき、どうする?】(Part2)非典型例をどう考えるか(case8) 類天疱瘡

  氏家 英之  Visual Dermatology  16-  (7)  670  -674  2017/06
• 日本皮膚科学会ガイドライン 類天疱瘡(後天性表皮水疱症を含む)診療ガイドライン

  氏家 英之, 岩田 浩明, 山上 淳, 名嘉眞 武国, 青山 裕美, 池田 志斈, 石井 文人, 岩月 啓氏, 黒沢 美智子, 澤村 大輔, 谷川 瑛子, 鶴田 大輔, 西江 渉, 藤本 亘, 天谷 雅行, 清水 宏, 類天疱瘡(後天性表皮水疱症を含む)診療ガイドライン作成委員会  日本皮膚科学会雑誌  127-  (7)  1483  -1521  2017/06
• 【押さえておきたい新しい指定難病】類天疱瘡(後天性表皮水疱症を含む)(疾病番号162)

  氏家 英之  Derma.  (257)  41  -47  2017/05  

  類天疱瘡は、水疱性類天疱瘡、粘膜類天疱瘡および後天性表皮水疱症を一連の疾患群として2015年に厚生労働省指定難病に追加された。診断基準は臨床症状と検査所見、鑑別診断からなり、基準を満たすためには皮膚あるいは粘膜生検が必須である。重症度分類は、国際基準であるBPDAI(bullous pemphigoid disease area index)に準じてなされ、(1)皮膚のびらん・水疱、(2)皮膚の膨疹・紅斑、(3)粘膜のびらん・水疱の3項目に分けてそれぞれ計算し、(1)〜(3)のいずれかが中等症以上の場合に認定対象となる。現在、類天疱瘡診療ガイドラインの作成が進行中である。本稿では、類天疱瘡の指定難病診断基準と重症度分類について解説し、類天疱瘡診療ガイドライン(案)の概要につき紹介する。(著者抄録)
• Gene-edition targeting mutation site recovers null-expression of type VII collagen caused by frameshift mutation via non-homologous end joining in Recessive Dystrophic Epidermolysis Bullosa

  S. Takashima, S. Shinkukma, Y. Fujita, T. Nomura, H. Ujiie, R. Abe, H. Shimizu  JOURNAL OF INVESTIGATIVE DERMATOLOGY  137-  (5)  S83  -S83  2017/05  [Not refereed][Not invited]
  
• ENPP1に新規ミスセンス変異を同定したCole病の1家系

  宮内 俊成, 乃村 俊史, 鈴木 翔多朗, 竹田 真依, 新熊 悟, 氏家 英之, 藤田 靖幸, 阿部 理一郎, 清水 宏  日本皮膚科学会雑誌  127-  (5)  1170  -1170  2017/05  [Not refereed][Not invited]
  
• Bullous pemphigoid developed in a patient with prurigo nodularis

  N. Yoshimoto, H. Ujiie, Y. Hirata, K. Izumi, W. Nishie, H. Shimizu  JOURNAL OF THE EUROPEAN ACADEMY OF DERMATOLOGY AND VENEREOLOGY  31-  (4)  E187  -E189  2017/04  [Not refereed][Not invited]
  
• 色素異常を伴う掌蹠角化症の1家系

  宮内 俊成, 乃村 俊史, 鈴木 翔多朗, 竹田 真依, 新熊 悟, 氏家 英之, 藤田 靖幸, 清水 宏, 阿部 理一郎  角化症研究会記録集  31-  114  -117  2017/03  [Not refereed][Not invited]
  
• Linagliptin-associated bullous pemphigoid that was most likely caused by IgG autoantibodies against the midportion of BP180

  A. Sakai, Y. Shimomura, O. Ansai, Y. Saito, K. Tomii, Y. Tsuchida, H. Iwata, H. Ujiie, H. Shimizu, R. Abe  British Journal of Dermatology  176-  (2)  541  -543  2017/02/01  [Not refereed][Not invited]
  
• IgE autoantibodies in bullous pemphigoid

  H. Ujiie  British Journal of Dermatology  177-  (6)  1481  -1482  2017  [Not refereed][Not invited]
  
• IgEが関与する皮膚疾患 アトピー性皮膚炎と水疱性類天疱瘡の病態

  氏家 英之  北海道医学雑誌  91-  (2)  99  -99  2016/11
• Subepidermal autoimmune bullous disease affecting predominantly mucocutaneous junctions and the palms with autoantibodies to BP230 and laminin γ1

  Y. Honda, T. Dainichi, W. Nishie, H. Ujiie, Y. Hattori, Y. Miyachi, K. Kabashima  British Journal of Dermatology  175-  (3)  619  -621  2016/09/01  [Not refereed][Not invited]
  
• Macropinocytosis of type XVII collagen induced by bullous pemphigoid IgG is regulated by protein kinase C

  H. Iwata, H. Ujiie, K. Izumi, K. Natsuga, S. Shinkuma, W. Nishie, H. Shimizu  JOURNAL OF INVESTIGATIVE DERMATOLOGY  136-  (9)  S172  -S172  2016/09  [Not refereed][Not invited]
  
• Not only ectodomain shedding but also C-terminal cleavage induces neoepitopes on proteolyzed collagen XVII

  E. Toyonaga, W. Nishie, K. Izumi, H. Ujiie, H. Shimizu  JOURNAL OF INVESTIGATIVE DERMATOLOGY  136-  (9)  S178  -S178  2016/09  [Not refereed][Not invited]
  
• A novel mechanism of skin reaction related to Helicobacter pylori treatment

  T. Ito, H. Ujiie, Y. Fujita, H. Shimizu, R. Abe  JOURNAL OF INVESTIGATIVE DERMATOLOGY  136-  (9)  S165  -S165  2016/09  [Not refereed][Not invited]
  
• Collagen XVII is the major autoantigen in mucous membrane pemphigoid

  K. Izumi, W. Nishie, M. Nishimura, H. Ujiie, H. Iwata, H. Shimizu  JOURNAL OF INVESTIGATIVE DERMATOLOGY  136-  (9)  S213  -S213  2016/09  [Not refereed][Not invited]
  
• 【リンフォーマ・白血病】 顔面の巨大な腫瘤に対して電子線照射療法が著効した菌状息肉症の1例

  葭本 倫大, 藤田 靖幸, 平田 悠, 保科 大地, 守内 玲寧, 氏家 英之, 井上 哲也, 清水 宏  皮膚科の臨床  58-  (10)  1483  -1487  2016/09  [Not refereed][Not invited]
   

  62歳女。左下腿の疼痛・腫脹、全身の紅斑を主訴とした。54歳時に紅斑期菌状息肉症(MF)と診断されたが通院を自己中断していた。顔面に出現した紅斑が急速に隆起して右上眼瞼に75mm大、眉間に55mm大、上口唇に50mm大の腫瘤を形成して右眼は開眼不能であり、腫瘤期MFと診断した。左下腿の疼痛・腫脹は蜂窩織炎と診断してセフェピムおよびクリンダマイシン連日投与を行い、1週間で全身状態改善後、エトレチナート内服を併用しつつ週5回のメトキサレン内服による内服PUVA療法に加え、顔面の腫瘤に対して40Gy/20Frの電子線照射を施行した。腫瘤は瘢痕を残して速やかに消退し、4年経過時点で顔面病変は寛解を維持している。
• 【肥満細胞は今】自己免疫性水疱症と肥満細胞

  氏家 英之  皮膚アレルギーフロンティア  14-  (2)  77  -80  2016/07  

  自己免疫性水疱症である水疱性類天疱瘡では、かゆみを伴う浮腫性紅斑が臨床的特徴であり、組織学的にも肥満細胞の脱顆粒が観察されることから、肥満細胞がその病態に大きく関与していると考えられている。肥満細胞欠損マウスや類天疱瘡抗原(XVII型コラーゲン)特異的IgE抗体を用いた研究により、肥満細胞が発症早期の炎症惹起および浮腫性紅斑の形成に重要な役割を果たしていることが明らかになりつつある。肥満細胞の脱顆粒を促す要素として、類天疱瘡抗原と類天疱瘡抗原特異的IgEによるIgE受容体の架橋や、補体活性化に伴って生じる補体成分C3aやC5aの受容体への結合が考えられている。(著者抄録)
• Complement-independent blister formation in IgG4-dominant bullous pemphigoid

  T. Dainichi, W. Nishie, Y. Yamagami, H. Sonobe, H. Ujiie, Y. Kaku, K. Kabashima  JOURNAL OF INVESTIGATIVE DERMATOLOGY  136-  (5)  S7  -S7  2016/05  [Not refereed][Not invited]
  
• 水疱性類天疱瘡におけるIgE自己抗体の解析

  守内 玲寧, 西江 渉, 氏家 英之, 夏賀 健, 清水 宏  日本皮膚科学会雑誌  125-  (12)  2301  -2301  2015/11  [Not refereed][Not invited]
  
• Mycosis fungoides associated with splenic infarction and muscle involvement

  M. Watanabe, H. Ujiie, K. Nishimura, T. Kamiyama, R. Abe, H. Shimizu  BRITISH JOURNAL OF DERMATOLOGY  173-  (4)  1100  -1102  2015/10  [Not refereed][Not invited]
  
• Autoantibodies to parts of type XVII collagen outside of the non-collageneous 16A domain lead to mild bullous pemphigoid due to the non-depletion of autoantigen

  H. Iwata, K. Imafuku, K. Izumi, M. Wada, K. Natsuga, H. Ujiie, W. Nishie, H. Shimizu  JOURNAL OF INVESTIGATIVE DERMATOLOGY  135-  S4  -S4  2015/09  [Not refereed][Not invited]
  
• 【アレルギー性皮膚疾患の今がわかる!-動物モデルから見えてきたこと】(Part2.)アレルギー性皮膚疾患における動物モデルと臨床の繋がり(case11) 水疱性類天疱瘡

  氏家 英之  Visual Dermatology  14-  (9)  1080  -1083  2015/08
• 抗NC16A抗体を有さない軽症の水疱性類天疱瘡の1例

  今福 恵輔, 岩田 浩明, 泉 健太郎, 夏賀 健, 氏家 英之, 西江 渉, 清水 宏  日本皮膚科学会雑誌  125-  (4)  915  -915  2015/04  [Not refereed][Not invited]
  
• 水疱性類天疱瘡自己抗原である17型コラーゲンの異なるエピトープに対する抗体の病原性解析

  和田 麻友美, 西江 渉, 氏家 英之, 泉 健太郎, 岩田 浩明, 夏賀 健, 清水 宏, 北川 善政  北海道歯学雑誌  35-  (2)  188  -188  2015/03  [Not refereed][Not invited]
  
• ヒト17型コラーゲン全長リコンビナントタンパクを用いた新規ELISAの確立

  泉 健太郎, 西江 渉, 氏家 英之, 清水 宏  日本皮膚科学会雑誌  124-  (10)  1928  -1929  2014/09
• gamma delta T cells protect TCR alpha deficient mice from the autoimmunity induced by scurfy lymphocytes

  Hideyuki Ujiie, Ethan Shevach  JOURNAL OF IMMUNOLOGY  192-  2014/05  [Not refereed][Not invited]
  
• Alternaria alternata感染による深在性皮膚真菌症の1例

  柴 景子, 大口 由香, 青柳 哲, 氏家 英之, 西谷 道子, 鎗田 響子, 亀井 克彦, 清水 宏  臨床皮膚科  68-  (4)  355  -359  2014/04  

  79歳,男性.約15年前より両上肢,手背にそう痒を伴う紅斑,乳頭状結節が出現した.ステロイド剤を外用したが改善しないため,紹介され受診した.右手背から前腕伸側に表面凹凸,虫食い状の硬い紅色局面を認め,乳頭状に隆起した小結節が多発していた.左前腕伸側に落屑を付着する紅斑を認めた.血中β-Dグルカンは,546.6pg/mlと高値であった.右手背の乳頭状結節および右前腕の局面の2ヶ所から生検し,真皮内に肉芽腫および多数の細胞浸潤を認め,Grocott染色陽性の菌糸を多数認めた.同部位の真菌培養では,灰黒色のコロニーを形成し,スライド培養では洋梨状で石垣状の多細胞からなる分生子が確認された.菌学的性状および遺伝子解析によりAlternaria alternataと同定し,深在性皮膚アルテルナリア症と診断した.イトラコナゾール200mg/日の内服を開始し,約半年で皮疹はほぼ平坦化した.自験例では,免疫不全を引き起こす合併症はないが,不適切なステロイド剤の長期外用により深在性皮膚真菌症の症状が遷延,増悪したと考えられた.(著者抄録)
• 成人型肥満細胞症の2例

  中里 信一, 藤田 靖幸, 氏家 英之, 西江 渉, 阿部 理一郎, 近藤 健, 清水 宏  皮膚科の臨床  56-  (4)  595  -599  2014/04  

  症例1は50歳女性で、30年前よりそう痒を伴う皮疹を自覚し、3ヵ月前に頭痛があり、1ヵ月前から全身のそう痒が強くなり、腹痛、嘔気、下痢を繰り返すようになり、当科紹介となった。症例2は56歳男性で、全身のそう痒を伴う皮疹を主訴に当科を受診した。臨床像と病理組織像から、いずれの症例も肥満細胞症と診断した。症例1はフェキソフェナジン塩酸塩、レボセチリジン塩酸塩、ベポタスチンベシル酸塩の内服にて全身のそう痒は一時軽快したが、膝痛に対するフェルビナク貼布剤を追加後、頭痛や消化器症状、顔面の発赤、呼吸苦などを生じ、発作に対してはプレドニゾロン内服が有効であった。症例2は皮疹以外に症状は認めず、無治療にて7年間著変なく経過している。
• 著明な粘液を伴ったグロムス腫瘍の1例

  柴 景子, 本間 英里奈, 青柳 哲, 堀江 啓太, 秦 洋郎, 大澤 倫子, 氏家 英之, 高橋 祥公, 清水 宏  皮膚科の臨床  56-  (1)  111  -114  2014/01  

  症例は41歳女性で、20年前より右小指爪甲の菲薄化を自覚していた。8年前に爪甲下に有痛性小結節が出現した。その後徐々に結節が増大し爪甲が変形し、圧痛も増強してきた。右小指後爪郭に、14×13×6mmの比較的境界明瞭な半円錐状の紅色結節が認められた。病理組織学的所見にて爪床〜爪母下に結合性の被膜を有する二房性の腫瘍細胞巣が認められた。腫瘍巣には血管腔があり、その周囲に腫瘍細胞が増殖していた。グリムス腫瘍と診断し、結節を一塊にして全摘出術を施行した。病理組織を確認した後、植皮術にて二期的に再建した結果、術後6ヵ月経過時点で、局所再発は認められなかった。
• Characteristic findings of handprint and dermoscopy in reticulate acropigmentation of Kitamura

  H. Koguchi, H. Ujiie, S. Aoyagi, R. Osawa, H. Shimizu  CLINICAL AND EXPERIMENTAL DERMATOLOGY  39-  (1)  85  -87  2014/01  [Not refereed][Not invited]
  
• 水疱性類天疱瘡と落葉状天疱瘡が合併した1例

  辻脇 真澄, 阿部 理一郎, 野村 友希子, 保科 大地, 山根 尚子, 新熊 悟, 氏家 英之, 有田 賢, 清水 宏  日本皮膚科学会雑誌  123-  (8)  1543  -1543  2013/07  [Not refereed][Not invited]
  
• Bullous pemphigoid autoantibodies induce skin fragility in neonatal mice in a complement independent manner

  T. Sasaoka, H. Ujiie, W. Nishie, A. Shibaki, H. Nakamura, H. Shimizu  JOURNAL OF INVESTIGATIVE DERMATOLOGY  133-  S29  -S29  2013/05  [Not refereed][Not invited]
  
• Detection of pathological cleavage sites and neoepitopes on collagen XVII, a major autoantigen for bullous pemphigoid

  W. Nishie, H. Ujiie, K. Izumi, H. Shimizu  JOURNAL OF INVESTIGATIVE DERMATOLOGY  133-  S20  -S20  2013/05  [Not refereed][Not invited]
  
• Establishment of novel ELISA using full-length recombinant human collagen XVII

  K. Izumi, W. Nishie, H. Ujiie, H. Shimizu  JOURNAL OF INVESTIGATIVE DERMATOLOGY  133-  S33  -S33  2013/05  [Not refereed][Not invited]
  
• Human type VII collagen harbors multiple pathogenically relevant epitopes

  A. Vorobyev, H. Ujiie, A. Recke, J. A. Buijsrogge, M. F. Jonkman, T. Hashimoto, S. C. Kim, J. H. Kim, R. Groves, E. Schmidt, D. Zillikens, H. Shimizu, R. J. Ludwig  JOURNAL OF INVESTIGATIVE DERMATOLOGY  133-  S45  -S45  2013/05  [Not refereed][Not invited]
  
• Recombinant anti-collagen VII Fab fragments which compete against autoantibodies in patients with epidermolysis bullosa acquisita

  H. Qiao, H. Ujiie, R. Abe, Q. Li, R. Moriuchi, J. R. McMillan, H. Shimizu, G. Wang  JOURNAL OF INVESTIGATIVE DERMATOLOGY  133-  S26  -S26  2013/05  [Not refereed][Not invited]
  
• 水疱性類天疱瘡と落葉状天疱瘡の合併例-表皮間・基底膜自己抗体におけるIgG subclassの検討

  辻脇 真澄, 野村 友希子, 保科 大地, 山根 尚子, 新熊 悟, 氏家 英之, 清水 宏, 有田 賢  日本皮膚科学会雑誌  123-  (6)  1084  -1084  2013/05  [Not refereed][Not invited]
  
• ケラチン5のコイル1A領域N末端部にミスセンス変異を生じた単純型表皮水疱症

  新熊 悟, 西江 渉, 夏賀 健, 氏家 英之, 中村 秀樹, 清水 宏, Jacyk Witold, 秋山 真志  日本皮膚科学会雑誌  123-  (4)  461  -461  2013/04  [Not refereed][Not invited]
  
• 右鎖骨上窩リンパ節腫脹を契機に発見された食道原発悪性黒色腫の1例

  堀江 啓太, 秦 洋郎, 馬場 慶子, 泉 健太郎, 本間 英里奈, 氏家 英之, 青柳 哲, 細川 正夫, 清水 宏  臨床皮膚科  67-  (3)  249  -253  2013/03  

  70歳,男性.初診の約2週間前から右鎖骨上窩の皮下腫瘤を自覚していた.近医で施行された穿刺吸引細胞診で悪性黒色腫のリンパ節転移と診断され,全身精査・加療目的に当科紹介受診となった.初診時,原発を疑わせる皮疹はなく,PET/CTでも右鎖骨上窩の皮下腫瘤のみにしかFDGの集積を認めなかった.上部消化管内視鏡検査を施行したところ,食道内に20×15mmの隆起性黒色病変があり,生検にて食道原発の悪性黒色腫と診断した.食道亜全摘,噴門側胃切除,3領域リンパ節郭清施行し,食道原発悪性黒色腫Stage IIと診断し,術後DAV-フェロン療法5コースを追加した.食道原発悪性黒色腫は非常に稀で,通常のより予後不良である.頸部あるいは鎖骨上窩リンパ節の転移性病変を見た際には,原発となりうる咽頭,喉頭,および消化管の内視鏡検査などによる直視下での病変検索を怠ってはいけないことを留意すべきであると考えた.(著者抄録)
• Human type VII collagen harbors multiple pathogenically relevant epitopes

  A. Vorobyev, H. Ujiie, A. Recke, J. Buijsrogge, M. Jonkman, T. Hashimoto, S. Kim, J. Kim, R. Groves, E. Schmidt, D. Zillikens, H. Shimizu, R. J. Ludwig  EXPERIMENTAL DERMATOLOGY  22-  (3)  E33  -E33  2013/03  [Not refereed][Not invited]
  
• Antibodies to pathogenic epitopes on type X VII collagen cause skin fragility in a complement-dependent and -independent manner

  夏賀 健, 西江 渉, 新熊 悟, 氏家 英之, 西村 真知子, 澤村 大輔, 清水 宏  北海道醫學雜誌 = Acta medica Hokkaidonensia  87-  (6)  262  -262  2012/11/01  [Not refereed][Not invited]
  
• Neoepitopes on the modified amino-terminus of the shed ectodomain of collagen XVII

  W. Nishie, H. Ujiie, S. Shinkuma, L. Bruckner-Tuderman, H. Shimizu  JOURNAL OF INVESTIGATIVE DERMATOLOGY  132-  S22  -S22  2012/09  [Not refereed][Not invited]
  
• Generation of recombinant anti-collagen VII Fab fragments which compete against autoantibodies in patients with epidermolysis bullosa acquisita

  Qiao Hong-jiang, Hideyuki Ujiie, Riichiro Abe, Li Qiang, Reine Moriuchi, James R. McMillan, Wang Gang, Hiroshi Shimizu  JOURNAL OF DERMATOLOGY  39-  29  -29  2012/06  [Not refereed][Not invited]
  
• Intraepidermal neutrophilic IgA pemphigus successfully treated with dapson (vol 22, pg 282, 2012)

  Yu Hirata, Riichiro Abe, Kazuhiro Kikuchi, Asuka Hamasaka, Satoru Shinkuma, Hideyuki Ujiie, Toshifumi Nomura, Wataru Nishie, Ken Arita, Hiroshi Shimizu  EUROPEAN JOURNAL OF DERMATOLOGY  22-  (3)  429  -429  2012/05  [Not refereed][Not invited]
  
• 抗BP230抗体陽性pemphigoid nodularisの1例

  新熊 悟, 猪熊 大輔, 夏賀 健, 氏家 英之, 西江 渉, 清水 宏  日本皮膚科学会雑誌  122-  (3)  625  -625  2012/03  [Not refereed][Not invited]
  
• 日本人に生じたDuhring疱疹状皮膚炎における表皮トランスグルタミナーゼ(eTG)抗体価の検討

  新熊 悟, 阿部 理一郎, 林 欣宇, 夏賀 健, 氏家 英之, 西江 渉, 清水 宏, 大田 光仁, 土屋 喜久夫, 福本 隆也, 浅田 秀夫  日本皮膚科学会雑誌  122-  (2)  383  -383  2012/02  [Not refereed][Not invited]
  
• 筋肉内浸潤および脾梗塞を呈した進行期菌状息肉症の1例

  渡邉 美佳, 氏家 英之, 馬場 慶子, 芝木 晃彦, 阿部 理一郎, 清水 宏, 山田 洋介, 山口 圭介, 神山 俊哉  日本皮膚科学会雑誌  122-  (1)  64  -64  2012/01  [Not refereed][Not invited]
  
• 皮膚結節性アミロイドーシスの2例

  泉 健太郎, 猪熊 大輔, 笠井 麻希, 藤田 靖幸, 氏家 英之, 山中 快子, 伊藤 圭, 清水 宏  日本皮膚科学会雑誌  122-  (1)  51  -51  2012/01
• 塊状のIgA沈着を呈したDuhring疱疹状皮膚炎の1例

  林 欣宇, 氏家 英之, 渡邉 美佳, 馬場 慶子, 新熊 悟, 阿部 理一郎, 清水 宏  日本皮膚科学会雑誌  122-  (1)  64  -64  2012/01  [Not refereed][Not invited]
  
• 自己免疫性水疱症の最新知見 自己免疫性水疱症発症機序解明のための最新研究

  氏家 英之  日本皮膚科学会雑誌  121-  (13)  2971  -2973  2011/12
• 水疱性類天疱瘡 病態と治療update

  守内 玲寧, 氏家 英之, 西江 渉, 清水 宏  BIO Clinica  26-  (10)  957  -961  2011/09  

  水疱性類天疱瘡は、抗表皮基底膜部に対する自己抗体により表皮下水疱を形成する、代表的な自己免疫性水疱症である。最も頻度の高い自己免疫性水疱症で、日本では近年の高度の高齢化に伴い患者数は増加傾向にある。主な標的抗原は180kDa水疱性類天疱瘡抗原であり、この分子を中心とした免疫反応の解析が進められている。近年では副腎皮質ホルモンに加え、IVIG療法や分子標的薬を用いた治療が試みられるようになり、良好な成績を収めている。(著者抄録)
• タクロリムス軟膏外用が奏効した爪扁平苔癬

  氏家 英之, 芝木 晃彦, 秋山 真志, 清水 宏  皮膚病診療  33-  (3)  299  -302  2011/03
• 【自己免疫性水疱症 今日の進歩】水疱性類天疱瘡の病態解明 動物モデルを用いた最新研究

  氏家 英之  医学のあゆみ  236-  (11)  1027  -1032  2011/03  

  水疱性類天疱瘡(BP)はもっとも頻度の高い自己免疫性水疱症であり、多発性のかゆみを伴う蕁麻疹様紅斑と緊満性水疱(表皮下水疱)を臨床的特徴とする。患者血清中には表皮基底膜部の構成蛋白であるXVII型コラーゲン(COL17)に対する自己抗体が存在し、その病原性は疾患動物モデルを用いた最近の研究によって証明された。BPでは、自己抗体が抗原に結合することによって引き起こされる複雑な免疫応答の結果、表皮下水疱が形成されると考えられているが、その病態はいまだ十分に解明されていない。近年、さまざまなBPマウスモデルが樹立され、抗COL17 IgG抗体のみならず、抗COL17 IgE抗体やCOL17反応性ヘルパーT細胞に関する研究も盛んに行われるようになってきており、さらなる病態解明が期待される。(著者抄録)
• トラニラストの内服が有効であったeruptive syringomaの2例

  堀江 啓太, 新熊 悟, 藤田 靖幸, 氏家 英之, 剱持 靖子, 青柳 哲, 清水 宏  日本皮膚科学会雑誌  121-  (3)  605  -605  2011/03  [Not refereed][Not invited]
  
• Psoriatic onycho-pachydermo periostitis that progressed to generalized pustular psoriasis

  Mika Watanabe, Hideyuki Ujiie, Maria Iitani Maroto, Riichiro Abe, Hiroshi Shimizu  JOURNAL OF DERMATOLOGY  37-  120  -121  2010/09  [Not refereed][Not invited]
  
• Erratum: Bone marrow transplantation restores epidermal basement membrane protein expression and rescues epidermolysis bullosa model mice (Proceedings of the National Academy of Sciences of the United States of America (2010) 107, (14345-14350) DOI: 10.10

  Yasuyuki Fujita, Riichiro Abe, Daisuke Inokuma, Mikako Sasaki, Daichi Hoshina, Ken Natsuga, Wataru Nishie, James R. McMillan, Hideki Nakamura, Tadamichi Shimizu, Masashi Akiyama, Daisuke Sawamura, Hiroshi Shimizu  Proceedings of the National Academy of Sciences of the United States of America  107-  14514  2010/08/10  [Not refereed][Not invited]
  
• Mohs氏軟膏療法を試みた原発性および転移性皮膚悪性腫瘍の6例

  渡邊 英里香, 加藤 直子, 村田 純子, 斎藤 奈央, 氏家 英之, 田中 寛之  臨床皮膚科  64-  (8)  605  -608  2010/07  

  原発性皮膚癌1例,他癌の皮膚浸潤2例,転移性皮膚癌3例に対し,Mohs氏軟膏療法を施行した.治療の施行回数,固定時間,有効性の程度などは症例によりさまざまであり,個体ごとの状況に応じた治療を行う必要があった.結果として根治的な治療にはならなかったものの,いずれも重篤な副作用なしに腫瘍局所の臨床症状の緩和,患者および家族のQOLの改善を得ることができた.(著者抄録)
• Human IgG1 mAb against human COL17 NC16A developed from BP patients induces blisters in experimental bullous pemphigoid model

  A. Shibaki, Q. Li, H. Ujiie, G. Wang, R. Moriuchi, H. Qiao, H. Morioka, S. Shinkuma, K. Natsuga, H. A. Long, W. Nishie, H. Shimizu  JOURNAL OF INVESTIGATIVE DERMATOLOGY  130-  S11  -S11  2010/04  [Not refereed][Not invited]
  
• 筋肉内浸潤および脾梗塞を呈した進行期菌状息肉症の1例

  渡邉 美佳, 氏家 英之, 馬場 慶子, 阿部 理一郎, 芝木 晃彦, 山田 洋介, 山口 圭介, 神山 俊哉, 清水 宏  日本皮膚科学会雑誌  120-  (3)  743  -743  2010/03  [Not refereed][Not invited]
  
• 塊状のIgA沈着を呈したDuhring疱疹状皮膚炎の1例

  林 欣宇, 氏家 英之, 渡邉 美佳, 馬場 慶子, 新熊 悟, 阿部 理一郎, 清水 宏  日本皮膚科学会雑誌  120-  (3)  696  -696  2010/03  [Not refereed][Not invited]
  
• 骨浸潤を伴ったエクリン汗孔癌の2例

  山根 尚子, 加藤 直子, 柳 輝希, 大澤 倫子, 皆川 英彦, 合田 猛俊, 井須 和男, 氏家 英之  日本皮膚科学会雑誌  119-  (1)  61  -61  2009/01
• 複数の皮膚悪性腫瘍に罹患し、ABCA12遺伝子の新規変異が同定された非水疱型先天性魚鱗癬様紅皮症の2例

  夏賀 健, 秋山 真志, 坂井 香織, 中桐 頼子, 西村 真智子, 安倍 将隆, 有田 賢, 阿部 由紀子, 小野塚 貴, 青柳 哲, 秦 洋郎, 小玉 和郎, 清水 宏, 加藤 直子, 氏家 英之, 冨田 幸希  日本皮膚科学会雑誌  119-  (1)  71  -71  2009/01  [Not refereed][Not invited]
  
• Anaplastic large cell lymphoma(ALCL)の1例

  山根 尚子, 加藤 直子, 柳 輝希, 大澤 倫子, 夏賀 健, 氏家 英之, 富田 幸希  日本皮膚科学会雑誌  119-  (1)  73  -73  2009/01  [Not refereed][Not invited]
  
• 【ケブネル現象をめぐって】比較的皮膚に限局した疾患 乾癬+扁平苔癬+尋常性白斑

  氏家 英之, 澤村 大輔, 清水 宏  Visual Dermatology  8-  (1)  26  -27  2008/12
• 【汗から探る皮膚病 汗は善玉か、悪玉か?】病変の深さによる整理 汗疱(IVIG治療中に生じたもの)

  氏家 英之, 澤村 大輔, 清水 宏  Visual Dermatology  7-  (9)  974  -975  2008/08
• 非水疱型先天性魚鱗癬様紅皮症(NBCIE)患者に生じた悪性黒色腫と末梢T細胞性リンパ腫(PTCL)

  夏賀 健, 加藤 直子, 氏家 英之, 冨田 幸希  日本皮膚科学会雑誌  118-  (7)  1278  -1279  2008/06  [Not refereed][Not invited]
  
• A Case of Bullous Pemphigoid Successfully Treated with Intravenous Immunoglobulin

  SHINKUMA Satoru, TSUJI ABE Yukiko, TOMITA Yuki, NATSUGA Ken, UJIIE Hideyuki, ABE Riichiro, AKIYAMA Masashi, SHIMIZU Hiroshi  Japanese journal of dermatology  118-  (5)  933  -937  2008/04/20  [Not refereed][Not invited]
   

  83歳女性。略全身の浮腫性紅斑と水疱、びらんを主訴に来院した。臨床、病理組織、免疫組織学的所見およびBP180ELISA値から水疱性類天疱瘡と診断した。ステロイドの全身投与(prednisolone,0.75mg/kg/日)を開始したが、内服開始後4週間の時点でも紅斑、水疱の新生を認めた。肺癌を併発しており全身状態が不良であることから、免疫抑制剤の併用や血漿交換療法はリスクが高いと考え、免疫グロブリン大量静注療法(400mg/kg/日、5日間)を施行した。投与直後より皮疹の著明な改善とBP180ELISA値の著明な低下を認め、その後ステロイドの減量を行うも皮疹の再燃は認めなかった。(著者抄録)
• Development of an active disease model for bullous pemphigoid

  H. Ujiie, A. Shibaki, W. Nishie, G. Wang, Y. Tateishi, H. Nakamura, M. Akiyama, H. Shimizu  JOURNAL OF INVESTIGATIVE DERMATOLOGY  128-  S10  -S10  2008/04  [Not refereed][Not invited]
  
• Novel therapeutic strategy for bullous pemphigoid using recombinant monoclonal fab antibody against NC16A domain of collagen XVII

  G. Wang, A. Shibaki, H. Ujiie, W. Nishie, Y. Tateishi, K. Kikuchi, Q. Li, J. R. McMilan, H. Morioka, D. Sawamura, H. Nakamura, H. Shimizu  JOURNAL OF INVESTIGATIVE DERMATOLOGY  128-  S12  -S12  2008/04  [Not refereed][Not invited]
  
• 頭皮に生じた脂腺癌の1例

  冨田 幸希, 加藤 直子, 夏賀 健, 氏家 英之  皮膚科の臨床  50-  (4)  539  -541  2008/04  [Not refereed][Not invited]
   

  42歳男。左頭頂部に非対称性で2.8×1.5×1.5cmの淡紅色から黄色調の弾性硬で表面平滑な広茎性の腫瘤が発現し、徐々に増大して一部潰瘍を伴っていた。病理所見では真皮から皮下脂肪織に細胞塊が存在し、基底細胞様細胞と脂腺細胞への分化を示す細胞が混在し、胞巣中心部に塊状壊死を認めた。また免疫組織染色では抗ヒトMLH1抗体と抗ヒトMSH2抗体ともに陰性でMTS(Muir-Torre症候群)の可能性は低いと考えた。以上より脂腺癌で病期は皮膚有棘細胞癌の病期分類のT2 N0M0、Stage IIと診断した。治療は辺縁2cmマージンで下方は帽状腱膜上で腫瘍を切除し、分層植皮術を施行した。術後7ヵ月経過して再発転移は認めていない。
• Genomic ABCA12 mutations in ichthyosis patients with multiple skin malignant neoplasia

  K. Natsuga, M. Akiyama, N. Kato, K. Sakai, Y. Sugiyama-Nakagiri, M. Nishimura, H. Hata, M. Abe, K. Arita, Y. Tsuji-Abe, T. Onozuka, S. Aoyagi, K. Kodama, H. Ujiie, Y. Tomita, H. Shimizu  JOURNAL OF INVESTIGATIVE DERMATOLOGY  127-  S81  -S81  2007/10  [Not refereed][Not invited]
  
• 免疫グロブリン大量静注療法が著効した水疱性類天疱瘡の1例

  新熊 悟, 阿部 由紀子, 冨田 幸希, 夏賀 健, 氏家 英之, 阿部 理一郎, 秋山 真志, 清水 宏  皮膚の科学  6-  (3)  319  -319  2007/06  [Not refereed][Not invited]
  
• タクロリムスが有効であったsclerodermatous chronic GVHDの1例

  冨田 幸希, 加藤 直子, 夏賀 健, 氏家 英之, 笠井 正晴  臨床皮膚科  61-  (4)  318  -321  2007/04  

  41歳女。35歳時に急性骨髄白血病(AML)を発症し化学療法施行後に非血縁者間同種骨髄移植(allo-BMT)を受けた。肝障害、皮膚の紅斑を発症したが完全寛解し、移植後2年半後から両肘窩に萎縮硬化性局面が出現し当科受診となった。抗潰瘍薬外用で上皮化するも間擦部に拡大し、頸部から体幹、上腕にかけて皮膚硬化、肩関節と肘関節の可動制限を認めた。病理組織より真皮全層に膠原線維の増生と付属器の減少を認め、表皮は個細胞壊死の散見と軽度の液状変性を認め、表皮直下にはメラノファージを伴っておりSclerodermatous chronic GVHD(scl cGVHD)と診断した。シクロスポリンとプレドニゾロンを投与するも改善はみられず、エトレチナートによる落屑や脱毛が激しいため漸減中止してミコフェノール酸モフェチルを投与し、さらにタクロリムスを追加した。1ヵ月後には皮膚の硬化進行は停止し、関節可動制限も改善がみられ、現在はタクロリムスを増量して治療中である。
• 巨大皮膚腫瘤より発見された後腹膜腔原発びまん性大細胞型B細胞リンパ腫の1例

  飯塚 さとし, 氏家 英之, 夏賀 健, 冨田 幸希, 加藤 直子, 鈴木 宏明, 山城 勝重  臨床皮膚科  60-  (13)  1258  -1261  2006/12  

  86歳男、多発する紅色の皮膚腫瘤を主訴とした。高血圧、慢性気管支炎、膀胱癌、脳梗塞の既往があり、咽頭麻痺のため胃瘻が造設されていた。初診時、体幹部に1〜2cm大から7cm大までの弾性硬、境界明瞭な皮膚および皮下腫瘤約20個を認めた。CTにて左腎背側の後腹膜腔に9×6cm大の腫瘤を認め、Gaシンチグラフィでは皮膚腫瘤部と後腹膜腔の腫瘤部に一致して集積を認めた。臨床検査にてHb 10g/dl、CRP 1.03mg/dl、β2MG 4.2μg/ml、sIL-2R 3560U/ml、LDH 499IU/l、BUN 23.8mg/dlを呈した。生検の病理組織像では真皮上層から皮下脂肪織にかけてcentroblast様細胞が増殖し、免疫組織化学的にCD20、CD79a、Bcl-2陽性であった。遺伝子解析にて免疫グロブリン遺伝子重鎖JH領域の再構成、T細胞受容体遺伝子β鎖Cβ領域の再構成を認めた。後腹膜腔原発のびまん性大細胞型B細胞リンパ腫(DLBCL)が皮膚転移をきたしたと診断した。誤嚥性肺炎を繰り返していたため化学療法は断念し、放射線療法を行った。腫瘍は縮小したが肺炎と胸水貯留を生じ、徐々に呼吸状態は悪化して初診1ヵ月半後に死亡した。剖検所見では肝門部、心膜、右副腎周囲、腸間膜リンパ節などにもDLBCLを認めた。
• CD10が陽性を示したatypical fibroxanthomaの1例

  氏家 英之, 加藤 直子, 夏賀 健, 冨田 幸希, 皆川 英彦, 舟山 恵美, 國分 一郎  臨床皮膚科  60-  (13)  1262  -1264  2006/12  

  79歳男、数か月前より右耳前部に無症候性で小豆大の紅色丘疹を自覚し、表面のびらん化、痂皮の付着を繰り返した。前立腺癌、高血圧症の既往があった。初診時、右耳前部にびらんを伴う暗赤色ドーム状隆起性腫瘍(径10mm)を認めた。毛細血管拡張性肉芽腫などの疑いで全摘出術を施行した。病理組織学的に真皮内に比較的境界明瞭な腫瘍塊を認め、腫瘍細胞は核に多形性を有する紡錘形の線維芽細胞様細胞が主体で、不規則な錯綜配列を呈した。免疫組織化学的にほとんど全ての腫瘍細胞の細胞質でvimentin、CD10陽性であった。atypical fibroxanthomaと診断し、拡大切除を行った。根治術後4か月の現在まで再発や転移は認めなかった。
• 組織球系マーカーが陽性であったCellular Neurothekeomaの1例

  氏家 英之, 加藤 直子, 夏賀 健, 冨田 幸希, 柳 輝希  皮膚科の臨床  48-  (12)  1707  -1710  2006/11  

  19歳男。1ヵ月前より出現した紅色の紅色丘疹の精査を主訴とした。丘疹は急速に増大したため、全切除生検を行った。免疫組織染色所見ではS-100蛋白、CD68、microphthalmia transcription factorは陽性で、病理組織学的所見にて境界明瞭な結節性病変を認め、腫瘍細胞が類上皮細胞様細胞、紡錘形細胞が大小の胞巣を形成し、核異型や核分裂像を認めた。粘液様基質は認めなかった。以上より、cellular neurothekeoma(CNT)と診断した。
• 25年後に脳転移をきたした悪性黒色腫の1例

  夏賀 健, 加藤 直子, 氏家 英之, 冨田 幸希  臨床皮膚科  60-  (11)  1052  -1054  2006/10  

  55歳女。右脛骨痛、多発性の皮膚腫瘤を主訴とした。29歳時、左下腿内側の黒色皮疹に気付き、その後増大した。黒褐色の有茎性の結節を呈していた。Thicknessが5.5mmの悪性黒色腫と診断された。5cmマージンで拡大切除術、中間層植皮術が施行された。術後の補助化学療法を受けた。再発なく経過していたが、55歳時に記銘力の低下を自覚した。左前頭葉の腫瘍が発見され、摘出された腫瘍は悪性黒色腫と診断された。その後、定位脳照射を受けたが5ヵ月後に右下腿に疼痛が出現した。同時期から多発性の皮膚腫瘤が出現した。右脛骨の針生検より組織学的に悪性黒色腫が確認された。右脛骨転移部に放射線両方を施行した。化学療法を施行中であり、皮下の結節にはIFN-βの局注も併用している。現在のところ、stable diseaseである。
• 免疫グロブリン大量静注療法による薬疹として生じた汗疱

  氏家 英之, 澤村 大輔, 立石 八寿貴, 芝木 晃彦, 清水 宏  皮膚科の臨床  46-  (1)  89  -91  2004/01  

  症例1は56歳男性で,慢性炎症性脱髄性多発神経炎に対し免疫グロブリン大量静療法(IVIG)施行後,翌日から両足底に掻痒を伴う小水疱が多発した.その後,両手掌,顔面にも同様の皮疹が出現した.症例2は31歳女性で,過去4回の自然流産歴があった.習慣性流産に対し妊娠4週5日目からIVIG施行し,治療終了2日目から臀部と両手掌に掻痒感を伴う皮疹が出現した.両例とも手掌の生検像は海綿状態を伴う表皮水疱であり,汗疱と診断した.症例1は手掌・足底に吉草酸ジフルコルトロン軟膏外用,顔面に酪酸ヒドロコルチゾン軟膏を外用した順調に軽快せず,酪酸プロピオン酸ベタメタゾン軟膏に変更し,マレイン酸クロルフェニラミン内服を開始した結果,顔面の皮疹は速やかに改善した.手掌・足底の小水疱は再発を繰返し,初診後約5ヵ月で鱗屑を残して治癒した.症例2は吉草酸ジフルコルトロン軟膏外用2週間で皮疹は徐々に消失した.IVIGに伴う薬疹としての汗疱の報告は少なく,本邦では神経内科領域に1例,皮膚科領域に5例あるのみである
• 免疫グロブリン大量静注療法後に生じた汗疱の2例

  氏家 英之, 澤村 大輔, 立石 八寿貴, 芝木 晃彦, 清水 宏  日本皮膚科学会雑誌  113-  (10)  1577  -1578  2003/09

Research Grants & Projects

• Development of a novel therapeutic strategy for angiosarcoma through drug screening

  Japan Society for the Promotion of Science：Grants-in-Aid for Scientific Research

  Date (from‐to) : 2023/04 -2026/03 

  Author : 中村 秀樹, 柳 輝希, 氏家 英之
• 水疱性類天疱瘡におけるIgE自己抗体特異的皮膚炎症増幅機構の解明

  日本学術振興会：科学研究費助成事業

  Date (from‐to) : 2022/04 -2025/03 

  Author : 泉 健太郎, 氏家 英之
• 加齢に着目した皮膚の免疫自己寛容破綻機序の解明

  日本学術振興会：科学研究費助成事業 基盤研究(B)

  Date (from‐to) : 2021/04 -2024/03 

  Author : 氏家 英之, 岩田 浩明, 泉 健太郎, 夏賀 健, 柳 輝希

   

  免疫系の老化、すなわち免疫老化によって自己免疫疾患のリスクが増加することが知られているが、詳細な機序の大部分は不明である。水疱性類天疱瘡（BP）は表皮基底膜部に存在するBP180やBP230に対する自己抗体によって生じる自己免疫性水疱症で、高齢者に好発する。我々は最近、一部の高齢マウスは表皮基底膜部に対する自己抗体を自然産生していることを発見した。本研究の目的は、BPをモデル疾患として“加齢に伴う免疫自己寛容の破綻機序を解明する”ことである。 まず、高齢マウスが産生する抗基底膜部自己抗体の標的抗原を同定するため、BP180、ラミニンγ1、ラミニンγ2、ラミニンβ3、ラミニンα3の各リコンビナントタンパクを作成した。高齢マウス（70週齢以上）の血清を採取し、作成したリコンビナントタンパクを基質としてウエスタンブロットを施行した。BP180リコンビナントタンパクを基質としたウエスタンブロット法で、約半数の高齢マウス血清中に抗BP180 IgM抗体が検出された。ラミニンγ1、ラミニンγ2、ラミニンβ3、ラミニンα3を基質としたウエスタンブロット法は陰性だった。 次に、加齢に伴いB細胞が抗基底膜部自己抗体を産生する機序を、制御性T細胞(Treg)とAge-associate B cells（ABCs）に着目して検討した。Treg欠損マウスでは野生型マウスに比較して、脾臓におけるABCsが増加していた。 また、薬剤投与により高齢マウスに病原性自己抗体を誘導できるかどうかを、近年BPの発症誘因として注目されているDPP-4阻害薬と抗PD-1抗体に着目して検討している。現在、高齢マウスにこれらの薬剤を投与中だが、今のところBP自己抗体の有意な誘導は見られていない。
• エピトープスプレディング現象に着目した水疱性類天疱瘡の病態解明

  日本学術振興会：科学研究費助成事業 基盤研究(B)

  Date (from‐to) : 2020/04 -2023/03 

  Author : 西江 渉, 岩田 浩明, 泉 健太郎, 氏家 英之, 夏賀 健

   

  2020年度は、18名の水疱性類天疱瘡患者（DPP4阻害薬内服中の症例を含む）末梢血単核球中のB細胞をEBウイルスを用い形質転換した。樹立したLymphoblastoid cell lineの培養上清を用い、水疱性類天疱瘡抗原であるBP180タンパクへの自己抗体の反応性をELISA法で確認したところ、全ての患者さん由来細胞でIgGクラス自己抗体の反応性は確認できなかった。しかし、6名のLymphoblastoid cell line培養上清に坑BP180 IgMクラス自己抗体を確認したため、形質転換した細胞群から単一あるいはポリクローナルな状態での、坑BP180自己抗体産生細胞の採取をFACSソーティングで試みた。その結果、坑BP180自己抗体産生細胞数が極めて少なかったことと、蛍光標識BP180タンパクが細胞表面に結合した後のエンドサイトーシスに伴う蛍光の減弱のため、細胞の単離は上手くいかなかった。そこで、pH耐性緑色蛍光タンパクであるGamillusを融合したBP180タンパクを作製し、再度FACSソーティングを行うこととした。細胞を単離したのち、次世代シークエンサーによる自己抗体可変領域のアミノ酸配列の解読と、リコンビナント坑BP180自己抗体の作製、そしてマウスへ投与し病原性の確認を計画しそれぞれの予備実験を開始していたが、今後の研究を遂行できなくなったため、2021年以降の交付申請は辞退することにした。
• 画期的マウスモデルを用いた皮膚免疫寛容の破綻機序の解明

  日本学術振興会：科学研究費助成事業 挑戦的研究(萌芽)

  Date (from‐to) : 2020/07 -2022/03 

  Author : 氏家 英之, 鄭 ビョウ

   

  自己免疫疾患は全身臓器に生じるが、生体内に存在する無数のタンパクのなかで一部のタンパクが自己免疫の標的になりやすい理由は大部分が不明である。本研究の目的は、特定のタンパクが免疫自己の標的となる機序を解明し、それを回避する方法を創出することである。本研究では皮膚の代表的な自己免疫疾患である「水疱性類天疱瘡（BP）」と「尋常性天疱瘡（PV）」を対象とする。発症頻度はPVよりBPが圧倒的に高いことが知られている。本研究ではこれらの疾患に着目してマウスの胸腺を解析し、なぜBPはPVより頻度が高いかを明らかにする。また、新規マウスモデルを作製して胸腺での自己抗原の発現を増加させることで「中枢性免疫寛容の強化は末梢性免疫寛容の機能不全を補完できるかどうか」を検証する。 マウス胸腺の皮膚構造タンパクの発現の網羅的解析のため、マウスの胸腺髄質上皮細胞をソーティングしRNAを回収する方法を確立した。RNA-sequenceでmTECにおけるmRNA発現を網羅的に解析したところ、BP180若年マウス胸腺のmTECではBP180（Col17a1）のmRNAが十分に発現していることが明らかとなった。 胸腺にBP180を過剰発現させ免疫寛容の破綻を回避できるかどうか検証するため、マウス胸腺のmTECにBP180を過剰発現させ、BP180に対する中枢性免疫寛容が回復するかどうかを解析する。現在、ケラチン14（K14）プロモーター下にヒトBP180タンパクを発現し、マウスBP180は欠損している「K14-BP180ヒト化マウス」とTreg欠損マウスを交配して「Treg欠損／K14-BP180ヒト化マウス」を作製している。
• The impact of complement in blistering formation of pemphigoid

  Japan Society for the Promotion of Science：Grants-in-Aid for Scientific Research

  Date (from‐to) : 2019/04 -2022/03 

  Author : Iwata Hiroaki

   

  The inflammation caused by complement is thought to be essential for the blistering mechanism of bullous pemphigoid. However, we have previously shown the complement independent blstering mechanism. At this study, we found that C1q which is a component of comlement systems enhaces the endocytosis of BP180 after binding BP-IgG to BP180 using cell culture system. In additon, keratinocytes stimulated with BP-IgG produced C1q from from keratinocytes and enhaced the endocytosis of BP180. Based on these results, we think that the complement may directly modulate the pathogenicity of BP-IgG autoantibody. In addition, complement ennhance the severity of buloous pemphigid though the inflammation.
• Generation of bullous pemphigoid antigen specific T cell clones

  Japan Society for the Promotion of Science：Grants-in-Aid for Scientific Research Grant-in-Aid for Scientific Research (B)

  Date (from‐to) : 2017/04 -2020/03 

  Author : UJIIE Hideyuki

   

  Bullous pemphigoid (BP) is a most common autoimmune blistering disorder, which preferentially affects elderly people. It is caused by autoantibodies to type XVII collagen (COL17, BP180) at the dermal-epidermal junction of the skin. Although autoreactive T cells is important to produce autoantibody, the pathogenicity of COL17-reactive T cells is still largely unclear. In this study, we have successfully established human COL17-reactive T cell lines by stimulating and culturing lymphocytes obtained from human COL17-immunized mice. Those T cell lines are CD4+ effector T cells which produce IFN-gamma and showed weak pathogenicity in a mouse model.
• Novel bullous pemphigoid models induced by breaking tolerance to autoantigens.

  Japan Society for the Promotion of Science：Grants-in-Aid for Scientific Research Grant-in-Aid for Scientific Research (B)

  Date (from‐to) : 2016/04 -2019/03 

  Author : Nishie Wataru, IZUMI kentaro, TOYONAGA ellen

   

  The aim of this study is to develop bullous pemphigoid models for elucidating the pathomechanisms and producing novel therapies. We have established several novel bullous pemphigoid models by immunizing recombinant collagen XVII (COL17) proteins. Notably, monoclonal antibodies derived from the immunized mice disclosed that epitopes and subclasses of the monoclonal antibodies were associated with phenotypes of skin disease.
• The role of Th17 cells in the pathogenesis of autoimmune blistering disease

  Japan Society for the Promotion of Science：Grants-in-Aid for Scientific Research Grant-in-Aid for Scientific Research (C)

  Date (from‐to) : 2016/04 -2019/03 

  Author : Iwata Hiroaki

   

  We tried the establishment of the autoimmune blistering disease mouse model induced by epicutaneous immunization instead of subctaneous injection. In this process, imiquimod cream was applied onto the mouse back skin, and then antigen protein was applied on the inflamed skin. Imiquimod cream is known to activate dendritic cell in the skin and induce Th17 cells. Compared to conventional subctaneous immunization with adjuvant, epicutaneous immunization induced the autoaintibodies less frequently and also less titier levels. However, epicutaneous immunization without adjuvant could induce autoantibodies in several mice.
• Analysis of regulatory T cells and application for cell therapy in bullous pemphigoid

  Japan Society for the Promotion of Science：Grants-in-Aid for Scientific Research Grant-in-Aid for Young Scientists (B)

  Date (from‐to) : 2015/04 -2017/03 

  Author : Ujiie Hideyuki, MURAMATSU KEN

   

  Regulatory T cells (Treg) are a T cell subset which play an important role on the self-tolerance. The master transcription factor of Treg is Foxp3, and its gene mutations induce severe systemic autoimmunity in mice (scurfy mice) and humans (IPEX syndrome). This study demonstrates that the absence of Tregs induce autoantibodies to epidermal basement membrane zone. We further revealed that the autoantibodies in scurfy mice and IPEX patients target bullous pemphigoid antigens, BP230 and type XVII collagen. These results suggest that a dysfunction of Tregs may trigger the development of bullous pemphigoid.
• Production of a novel blistering disease model by regulating expression of collagen XVII

  Japan Society for the Promotion of Science：Grants-in-Aid for Scientific Research Grant-in-Aid for Scientific Research (B)

  Date (from‐to) : 2012/04 -2016/03 

  Author : Nishie Wataru, UJIIE HIDEYUKI, SHINKUMA SATORU, NATSUGA KEN

   

  Collagen XVII (COL17) is a hemidesmosomal molecule which keeps adhesion between the epidermis and dermis. Loss of CO17 expression due to mutation in the COL17A1 leads to blistering disease, epidermolysis bullosa (EB); in addition, autoimmunity to COL17 results in autoimmune blistering disorder bullous pemphigoid (BP). The purpose of this study is to produce a novel blistering model by regulating COL17 expression based on Tet-on system. Transgenic mice carrying human COL17 cDNA driven under the CMV promoter with Tet response element and Tet transactivator sequences driven under the K14 promoter were produced. Upon oral administration of doxycycline (DOX), the Tg mice started to express human COL17 in basal keratinocytes, following by production of IgG autoantibodies directing human COL17. The Tg mice must be useful tool for elucidating pathogenesis of EB and BP, as well as for establishing therapies for these orphan diseases.
• Development of novel treatment targeting complement for bullous pemphigoid

  Japan Society for the Promotion of Science：Grants-in-Aid for Scientific Research Grant-in-Aid for Scientific Research (C)

  Date (from‐to) : 2011 -2013 

  Author : SHIBAKI Akihiko, SHIMIZU Hiroshi, UJIIE Hideyuki

   

  Complement activation and subsequent recruitment of inflammatory cells at the dermal-epidermal junction are believed to be essential for blister formation in bullous pemphigoid (BP), an autoimmune blistering disease induced by autoantibodies against COL17; however, the involvement of complement-independent pathways has recently been proposed. To directly examine the necessity of the complement activation in blister formation, we generated C3-deficient COL17-humanized mice and monoclonal antibodies against COL17 with different ability of complement activation. By using them, we demonstrate that the deposition of antibodies, and not complements, is relevant to the induction of blister formation. BP autoantibodies reduced the amount of COL17 in cultured normal human keratinocytes, and the COL17-depletion was associated with a ubiquitin-proteasome pathway. In conclusion, the COL17-depletion induced by BP autoantibodies, and not complement activation, is essential for the blister formation.
• Analysis of the role of T cell subsets and the development of novel treatment for bullous pemphigoid

  Japan Society for the Promotion of Science：Grants-in-Aid for Scientific Research Grant-in-Aid for Young Scientists (B)

  Date (from‐to) : 2011 -2012 

  Author : UJIIE Hideyuki

   

  We analyzed the role of T cell subsets in bullous pemphigoid (BP) by using active BP mouse model and cytokine knockout (KO) mice. We generated active BP mouse model by using IL-12KO mice and IL-4KO mice. BP model mice that received IL-12KO splenocytes showed strong deposition of IgG1 (Th2-type reaction) and BP model mice that received IL-4KO splenocytes showed strong deposition of IgG2 (Th1-type reaction), while the deposition of complement and skin disease were almost same in both models. These results indicate that cytokine KO induce the difference in IgG subclass but fail to induce the difference in the amount of IgG-production, disease severity or complement activation in BP model.

Educational Activities

Teaching Experience