Reduced hemoglobin-corrected diffusing capacity in pulmonary arterial hypertension with preserved pulmonary function and morphology.
Ayako Igarashi-Sugimoto, Ichizo Tsujino, Hideki Shima, Junichi Nakamura, Toshitaka Nakaya, Takahiro Sato, Taku Watanabe, Hiroshi Ohira, Kaoruko Shimizu, Takashi Yokota, Sari Iwasaki, Satonori Tsuneta, Isao Yokota, Satoshi Konno
Respiratory investigation, 63, 4, 600, 607, 2025年07月, ［国際誌］
英語, 研究論文（学術雑誌）, BACKGROUND: The diffusing capacity and the transfer coefficient of the lung for carbon monoxide (DLCO and KCO, respectively) are reduced in pulmonary arterial hypertension; however, the effect of pulmonary arterial hypertension alone on these parameters and their clinical impact remain unclear. We aimed to elucidate the exclusive impact of pulmonary arterial hypertension on these two parameters and examine their association with other parameters. METHODS: We retrospectively selected patients with pulmonary arterial hypertension with normal pulmonary function upon pulmonary function testing and with normal lung parenchyma upon chest computed tomography. We calculated the hemoglobin-corrected DLCO (DLCO-Hbc) and KCO (KCO-Hbc) and examined their association with established pulmonary hypertension-related parameters. An exploratory analysis of pulmonary vasculopathy was performed in an autopsy case. RESULTS: We included 50 patients with pulmonary arterial hypertension for analysis. Their median %DLCO-Hbc and %KCO-Hbc were 62 % and 70 %, respectively. The DLCO-Hbc was associated with functional class, 6-min walk distance, alveolar-arterial oxygen tension difference, cardiac output, and pulmonary arterial hypertension-related death. The DLCO-Hbc and KCO-Hbc were also correlated with the lowest minute ventilation/carbon dioxide production ratio (ρ = -0.84 and -0.49, respectively), an index that represents ventilation-perfusion mismatch. The autopsy revealed pulmonary arterial hypertension-specific arteriopathy that was heterogeneously distributed in the lungs. CONCLUSIONS: The DLCO-Hbc and KCO-Hbc were reduced to 60 %-70 % in patients with pulmonary arterial hypertension even when their pulmonary function and morphology were preserved. The decreases were associated with pulmonary hypertension-related clinical parameters and survival and may be caused by heterogeneous vasculopathy and subsequent ventilation-perfusion mismatch.

Tubulointerstitial nephritis with IgM-positive plasma cells complicated by liver failure.
Takashi Kudo, Daigo Nakazawa, Saori Nishio, Fumihiko Hattanda, Yusho Ueda, Junpei Yoshikawa, Satoka Shiratori-Aso, Sari Iwasaki, Takahiro Tsuji, Yasuni Nakanuma, Goki Suda, Koji Ogawa, Naoya Sakamoto, Tatsuya Atsumi
CEN case reports, 14, 2, 253, 260, 2025年04月, ［国内誌］
英語, 研究論文（学術雑誌）, Tubulointerstitial nephritis (TIN) is characterized by inflammation of the renal interstitium with the infiltration of immune cells, mainly consisting of T cells. Recently, patients with TIN with the predominant infiltration of immunoglobulin M (IgM)-positive plasma cells were reported, coined IgMPC-TIN. Here we report the case of a 70-year-old woman diagnosed with Fanconi syndrome and renal tubular acidosis. Renal biopsy revealed IgMPC-TIN. Her renal dysfunction and clinical findings improved after corticosteroid therapy. However, the patient died of progressive liver failure and spontaneous bacterial peritonitis. In laboratory tests, viral hepatitis was excluded, and autoantibodies associated with liver diseases were negative. Generally, IgMPC-TIN is often complicated by primary biliary cholangitis (PBC), whereas her autopsy revealed the local infiltration of IgM-positive plasma cells, obliterative portal venopathy, and nodular regenerative hyperplasia in liver. This case is the first demonstration that IgMPC-TIN is also seen in liver disease with nodular regenerative hyperplasia, although IgMPC-TIN is more common in anti-M2 antibody-positive disease.

Impaired immunoproteasomal function exacerbates renal ischemia-reperfusion injury.
Yasushi Ishii, Aya Fukui-Miyazaki, Sari Iwasaki, Takahiro Tsuji, Kiyohiko Hotta, Hajime Sasaki, Shimpei Nakagawa, Takuma Yoshida, Eri Murata, Koji Taniguchi, Nobuo Shinohara, Akihiro Ishizu, Masanori Kasahara, Utano Tomaru
Experimental and molecular pathology, 140, 104939, 104939, 2024年12月, ［国際誌］
英語, 研究論文（学術雑誌）, Oxidative stress caused by reactive oxygen species (ROS) is involved in the pathogenesis of renal ischemia-reperfusion injury (I/R injury), a major cause of acute kidney injury and delayed graft function (DGF). DGF is an early transplant complication that worsens graft prognosis and patient survival, but the underlying molecular changes are unclear. The proteasome is a multicatalytic enzyme complex that degrades both normal and damaged proteins, and recent studies have revealed that the immunoproteasome, a specific proteasome isoform whose proteolytic activity enhances the generation of antigenic peptides, plays critical roles in the cellular response against oxidative stress. In this study, we demonstrate the impact of the immunoproteasome in human DGF and in a mouse model of I/R injury. In patients with DGF, the expression of β5i, a specific immunoproteasome subunit, was decreased in vascular endothelial cells. In a mouse model, β5i knockout (KO) exacerbated renal I/R injury. KO mice showed greater inflammation, oxidative stress, and endothelial damage compared with wild-type mice. Impaired immunoproteasomal activity also caused increased cell death, ROS production, and expression of inflammatory factors in mouse renal vascular endothelial cells under conditions of hypoxia and reoxygenation. In conclusion, reduced expression of the immunoproteasomal catalytic subunit β5i exacerbates renal I/R injury in vivo, potentially increasing the risk of DGF. Further research targeting β5i expression in DGF could lead to the development of novel therapeutic strategies and biomarkers.

Transcription factor Nrf2 activation regulates NETosis, endothelial injury, and kidney disease in myeloperoxidase-positive antineutrophil cytoplasmic antibody-associated vasculitis.
Yusho Ueda, Daigo Nakazawa, Saori Nishio, Satoka Shiratori-Aso, Takashi Kudo, Atsuko Miyoshi-Harashima, Kanako Watanabe-Kusunoki, Fumihiko Hattanda, Sari Iwasaki, Takahiro Tsuji, Utano Tomaru, Yasuaki Aratani, Mamiko Yamamoto, Akihiro Ishizu, Tatsuya Atsumi
Kidney international, 105, 6, 1291, 1305, 2024年06月, ［国際誌］
英語, 研究論文（学術雑誌）, Antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) is a systemic autoimmune disease pathologically characterized by vascular necrosis with inflammation. During AAV development, activated neutrophils produce reactive oxygen species (ROS), leading to the aberrant formation of neutrophil extracellular traps (NETs) via NETosis and subsequent fibrinoid vascular necrosis. Nuclear factor-erythroid 2-related factor 2 (Nrf2) functions as an intracellular defense system to counteract oxidative stress by providing antioxidant properties. Herein, we explored the role of Nrf2 in the pathogenesis of AAV. The role and mechanism of Nrf2 in ANCA-stimulated neutrophils and subsequent endothelial injury were evaluated in vitro using Nrf2 genetic deletion and Nrf2 activator treatment. In corresponding in vivo studies, the role of Nrf2 in ANCA-transfer AAV and spontaneous AAV murine models was examined. Pharmacological activation of Nrf2 in vitro suppressed ANCA-induced NET formation via the inhibition of ROS. In contrast, NET formation was enhanced in Nrf2-deficient neutrophils. Furthermore, Nrf2 activation protected endothelial cells from ANC-induced NETs-mediated injury. In vivo, Nrf2 activation ameliorated glomerulonephritis in two AAV models by upregulating antioxidants and inhibiting ROS-mediated NETs. Furthermore, Nrf2 activation restrained the expansion of splenic immune cells, including T lymphocytes and limited the infiltration of Th17 cells into the kidney. In contrast, Nrf2 genetic deficiency exacerbated vasculitis in a spontaneous AAV model. Thus, the pathophysiological process in AAV may be downregulated by Nrf2 activation, potentially leading to a new therapeutic strategy by regulating NETosis.

The risk of weekend biopsy: Impact of specimen source and fixation status on HER2 assessment in the treatment of advanced gastric cancer (The HER_WEEKEND study).
Michio Nakamura, Ayako Watanabe, Aki Yoshizawa, Sari Iwasaki, Asako Nomura, Mariko Matsumura, Taichi Murai, Kazufumi Itaya, Yuta Koike, Takaaki Izumi, Ayana Endo, Shin Kato, Yuji Ono, Takahiro Ohshima, Nanase Okazaki, Shimpei Nakagawa, Yasushi Ishii, Yuichiro Fukasawa, Isao Yokota, Takahiro Tsuji, Shuji Nishikawa
Pathology international, 73, 10, 509, 519, 2023年10月, ［国際誌］
英語, 研究論文（学術雑誌）, Accurate evaluation of human epidermal growth factor receptor type 2 (HER2) expression is crucial for determining chemotherapy regimens in gastric cancer. However, formalin fixation status has been identified as an important factor affecting HER2 assessment reliability. This retrospective cohort study aimed to investigate the correlation between sample collection day (weekday vs. weekend) and source (biopsy vs. surgical specimens) in assessing HER2 expression in patients with unresectable advanced/recurrent gastric cancer. Data were collected from gastric cancer patients who received chemotherapy at a single public hospital in Japan from 2008 to 2021. The analysis included 177 patients (109 men, 68 women) with a median age of 68.0 (21-88) years, and the primary outcome was the HER2 positivity rate. The overall HER2 positivity rate was 18.1%, with higher rates on weekdays (20.0%) compared to weekends (12.8%). Biopsies had higher positivity rates on weekdays (23.9%) but lower rates on weekends (11.1%) than surgical specimens. Significant differences were observed in formalin fixation times between weekdays and weekends for both biopsies and surgical samples. The study findings suggest that longer formalin fixation times on weekends may lead to underestimating HER2 expression, particularly in biopsies. Therefore, it is crucial to be cautious of excessive formalin fixation when collecting samples, especially during weekend biopsies.

[Inflammatory Polyp due to Peanut Aspiration, Needed to Differentiate from Malignant Tumor: Report of a Case].
Ryohei Morimoto, Taiki Takasugi, Wataru Arai, Motoki Sakuraba, Akihiko Tanaka, Toshikado Kaneda, Takuya Otsuka, Sari Iwasaki, Takahiro Tsuji
Kyobu geka. The Japanese journal of thoracic surgery, 76, 11, 973, 977, 2023年10月, ［国内誌］
日本語, 研究論文（学術雑誌）, The patient was in his 70s. He was addmitted to our hospital because of obstructive pneumonia for 3 months. Chest computed tomography( CT) showed a nodule at the base of the right B8, obstructing the basal branch, with consolidation of the peripheral lung. Bronchoscopy revealed the right basal trunk obstruction by a tumorous lesion. FDG-PET showed heterogeneous FDG uptake at the right hilum and the lower lobe suggesting malignancy, and a thoracoscopic right lower lobectomy was performed. Pathology showed a granulation-like nodule and a brown oval foreign body incarcerated in the peripheral bronchus, which was later revealed to be a peanut, and no obvious malignant findings were observed.

CD47 blockade ameliorates autoimmune vasculitis via efferocytosis of neutrophil extracellular traps.
Satoka Shiratori-Aso, Daigo Nakazawa, Takashi Kudo, Masatoshi Kanda, Yusho Ueda, Kanako Watanabe-Kusunoki, Saori Nishio, Sari Iwasaki, Takahiro Tsuji, Sakiko Masuda, Utano Tomaru, Akihiro Ishizu, Tatsuya Atsumi
JCI insight, 8, 15, 2023年08月08日, ［国際誌］
英語, 研究論文（学術雑誌）, Neutrophil extracellular trap (NET) formation contributes to immune defense and is a distinct form of cell death. Excessive NET formation is found in patients with anti-neutrophil cytoplasmic antibody-associated (ANCA-associated) vasculitis (AAV), contributing to disease progression. The clearance of dead cells by macrophages, a process known as efferocytosis, is regulated by the CD47-mediated "don't eat me" signal. Hence, we hypothesized that pathogenic NETs in AAV escape from efferocytosis via the CD47 signaling pathway, resulting in the development of necrotizing vasculitis. Immunostaining for CD47 in human renal tissues revealed high CD47 expression in crescentic glomerular lesions of patients with AAV. In ex vivo studies, ANCA-induced netting neutrophils increased the expression of CD47 with the reduction of efferocytosis. After efferocytosis, macrophages displayed proinflammatory phenotypes. The blockade of CD47 in spontaneous crescentic glomerulonephritis-forming/Kinjoh (SCG/Kj) mice ameliorated renal disease and reduced myeloperoxidase-ANCA (MPO-ANCA) titers with a reduction in NET formation. Thus, CD47 blockade would protect against developing glomerulonephritis in AAV via restored efferocytosis of ANCA-induced NETs.

Regulation of NETosis and Inflammation by Cyclophilin D in Myeloperoxidase-Positive Antineutrophil Cytoplasmic Antibody-Associated Vasculitis.
Takashi Kudo, Daigo Nakazawa, Kanako Watanabe-Kusunoki, Masatoshi Kanda, Satoka Shiratori-Aso, Nobuya Abe, Saori Nishio, Jun-Ichiro Koga, Sari Iwasaki, Takahiro Tsuji, Yuichiro Fukasawa, Miwako Yamasaki, Masahiko Watanabe, Sakiko Masuda, Utano Tomaru, Masaaki Murakami, Yasuaki Aratani, Akihiro Ishizu, Tatsuya Atsumi
Arthritis & rheumatology (Hoboken, N.J.), 75, 1, 71, 83, 2023年01月, ［国際誌］
英語, 研究論文（学術雑誌）, OBJECTIVE: Antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) is pathologically characterized by focal fibrinoid necrosis, in which ANCA-mediated neutrophil extracellular trap (NET) formation and subsequent endothelial cell necrosis occur. Cyclophilin D (CypD) plays an important role in mediation of cell necrosis and inflammation via the opening of mitochondrial permeability transition pores. This study was undertaken to examine the role of CypD in AAV pathogenesis. METHODS: We assessed the role and mechanism of CypD in ANCA-stimulated neutrophils in vitro by immunostaining and electron microscopy observation. We performed a comprehensive RNA-sequencing analysis on ANCA-treated murine neutrophils. To investigate the role of CypD in vivo, we assessed disease features in CypD-knockout mice and wild-type mice using 2 different murine AAV models: anti-myeloperoxidase IgG transfer-induced AAV and spontaneous AAV. RESULTS: In vitro experiments showed that pharmacologic and genetic inhibition of CypD suppressed ANCA-induced NET formation via the suppression of reactive oxygen species and cytochrome c release from the mitochondria. RNA-sequencing analyses in ANCA-treated murine neutrophils revealed the involvement of inflammatory responses, with CypD deficiency reducing ANCA-induced alterations in gene expression. Furthermore, analyses of upstream regulators revealed the relevance of intracellular calcium (CypD activator) and cyclosporin (CypD inhibitor) in ANCA stimulation, indicating that the CypD-dependent opening of mitochondrial permeability transition pores is associated with ANCA-induced neutrophil activation and NETosis. In both AAV mouse models, the genetic deletion of CypD ameliorated crescentic glomerulonephritis via the inhibition of CypD-dependent neutrophil and endothelial necrosis. CONCLUSION: CypD targeting is a novel and specific therapeutic strategy for AAV via the resolution of necrotizing vasculitis.

A Case of Kidney Transplantation from a Deceased Donor with Acute Kidney Injury due to Rhabdomyolysis.
Yusuke Takada, Kiyohiko Hotta, Kimihiko Moriya, Hajime Sasaki, Daiji Takamoto, Haruka Higuchi, Tatsu Tanabe, Keita Minami, Sari Iwasaki, Takahiro Tsuji, Hiroshi Tanaka
Nephron, 147 Suppl 1, 101, 105, 2023年, ［国際誌］
英語, 研究論文（学術雑誌）, Acute kidney injury (AKI) due to rhabdomyolysis occurs because of renal ischemia or acute tubular necrosis due to the deposition of myoglobin casts in the renal tubules. Donors with AKI due to rhabdomyolysis are not contraindication for transplantation. However, the dark red kidney raises concerns about renal hypofunction or primary nonfunction after transplantation. We report the case of a 34-year-old man with a 15-year history of hemodialysis for chronic renal failure due to congenital anomalies of the kidney and urinary tract. The patient received a renal allograft from a young woman who suffered cardiac death. The serum creatinine (sCre) level of the donor at the time of transport was 0.6 mg/dL, and renal ultrasonography revealed no abnormalities in renal morphology or blood flow. Her serum creatinine kinase level increased to 57,000 IU/L 58 h after femoral artery cannulation and sCre level worsened to 1.4 mg/dL, suggesting AKI due to rhabdomyolysis. However, since the urine output of the donor was maintained, the sCre elevation was thought to be nonproblematic. The allograft had a dark red appearance at the time of procurement. The perfusion of the isolated kidney was good, but the dark red color did not improve. A 0-h biopsy showed flattening of the renal tubular epithelium and absence of the brush border and myoglobin casts in 30% of the renal tubules. Rhabdomyolysis-related tubular damage was diagnosed. Hemodialysis was discontinued on postoperative day 14. Twenty-four days after the operation, the transplanted kidney function progressed favorably (sCre 1.18 mg/dL), and the patient was discharged. Protocol biopsy 1 month after transplantation showed disappearance of myoglobin casts and improvement in renal tubular epithelial damage. The patient's sCre level was approximately 1.0 mg/dL 24 months after transplantation, and he is doing well without complications.

Exacerbation of Intimal Fibrosis and Endarteritis in a Kidney Transplant Recipient with Chronic Active Antibody-Mediated Rejection and COVID-19: A Case Report.
Takuya Otsuka, Tatsu Tanabe, Kiyohiko Hotta, Sari Iwasaki, Takahiro Tsuji, Ayumu Takahashi, Emi Takakuwa, Nobuo Shinohara, Yoshihiro Matsuno
Nephron, 147 Suppl 1, 41, 45, 2023年, ［国際誌］
英語, 研究論文（学術雑誌）, Kidney transplant recipients are immunocompromised hosts at risk for comorbidity and mortality due to infection. Currently, there are no established guidelines for the management of immunosuppressed transplant recipients with coronavirus disease 2019 (COVID-19). The impact of COVID-19 and its therapeutic management on chronic active antibody-mediated rejection (CAAMR) are still unclear. Here, we report a case of CAAMR exacerbation with endarteritis and intimal fibrosis after COVID-19. A 41-year-old female kidney transplant recipient with CAAMR was admitted to a local hospital with moderately severe COVID-19. Her doses of tacrolimus and mycophenolate mofetil were reduced, and she was administered methylprednisolone pulse and antiviral drugs. This resulted in a good clinical course and she was discharged in 15 days. During and after hospitalization, the immunosuppressants were gradually returned to the baseline levels. However, about 1.5 months after discharge, the serum creatinine level became elevated. An indication kidney biopsy showed CAAMR with intimal fibrosis and endarteritis in all interlobular arteries. An increase of immunosuppressant led to a decrease of the serum creatinine level. Factors contributing to CAAMR with intimal fibrosis and endarteritis may include (1) insufficient immunosuppression due to changes in the levels of immunosuppressive; (2) overlap with endothelial cell injury caused by COVID-19, and (3) an immune-activated state associated with COVID-19. COVID-19 is a life-threatening disease that can result in unexpected changes in immunological status. Possible allograft rejection should be carefully managed in such patients.

BK Polyomavirus-Associated Urothelial Carcinoma of the Bladder with a Background of BK Polyomavirus Nephropathy in a Kidney Transplant Recipient.
Sari Iwasaki, Kenta Takahashi, Harutaka Katano, Tadaki Suzuki, Hajime Sasaki, Hiroshi Harada, Yusuke Takada, Keishi Makita, Yuichiro Fukasawa, Takahiro Tsuji
Nephron, 147 Suppl 1, 53, 60, 2023年, ［国際誌］
英語, 研究論文（学術雑誌）, Renal transplant recipients are at increased risk for the development of a malignant neoplasm. Polyomavirus-associated urothelial carcinoma is a rare tumor that occurs in renal transplant recipients, with approximately 41 cases reported since 2002. It accounts for 27-31% of all post-transplant urothelial carcinomas and develops at an average of 8.5 years after transplantation. Histologically, it shows high-grade urothelial carcinoma (95.1%) with a high frequency of glandular differentiation and micropapillary structures (58.5%) and positive immunohistochemistry for polyomavirus large T antigen, p53 (92.9%), and p16 (100%). We encountered a case of BK polyomavirus (BKPyV)-associated urothelial carcinoma of the bladder diagnosed 54 months after kidney transplantation. Histologically, it was a high-grade urothelial carcinoma with micropapillary features, and immunohistochemically, it was diffusely positive for polyomavirus large T antigen, p16, and p53. BKPyV DNA and mRNA for BKPyV large T antigen have been identified in tissues using real-time polymerase chain reaction. The same sequence of the BKPyV VP1 genome hypervariable region was detected in both transplanted kidney tissue with polyomavirus nephropathy and urothelial carcinoma tissue, suggesting that polyomavirus-associated urothelial carcinoma developed in a background of persistent polyomavirus nephropathy. This case showed typical histological features and was detected and treated at an earlier stage than has been reported. It is important to keep in mind that polyomavirus-associated urothelial carcinoma can develop early after transplantation and might be associated with polyomavirus nephropathy. Because of its rapidly progressive nature, careful follow-up with urine cytology and cystoscopy is necessary. We report this case with a literature review.

Pseudoangiomatous stromal hyperplasia (PASH) arising in an axillary accessory breast.
Yuka Maya, Yasuyuki Fujita, Kodai Miyamoto, Machiko Nishimura, Sari Iwasaki, Satoko Shimizu
Journal der Deutschen Dermatologischen Gesellschaft = Journal of the German Society of Dermatology : JDDG, 20, 3, 353, 355, 2022年03月, ［国際誌］
英語

Pseudoangiomatöse Stromahyperplasie (PASH) in axillärer akzessorischer Brust.
Yuka Maya, Yasuyuki Fujita, Kodai Miyamoto, Machiko Nishimura, Sari Iwasaki, Satoko Shimizu
Journal der Deutschen Dermatologischen Gesellschaft = Journal of the German Society of Dermatology : JDDG, 20, 3, 354, 356, 2022年03月, ［国際誌］
英語

Soluble Interleukin-2 Receptor Predicts Treatment Outcome in Patients With Autoimmune Tubulointerstitial Nephritis. A Preliminary Study.
Satoka Shiratori-Aso, Daigo Nakazawa, Saori Nishio, Yusho Ueda, Mina Eguchi, Ai Yokoyama, Junpei Yoshikawa, Takashi Kudo, Kanako Watanabe-Kusunoki, Sayo Takeda-Otera, Junya Yamamoto, Naoko Matsuoka, Nobuharu Kaneshima, Fumihiko Hattanda, Sari Iwasaki, Takahiro Tsuji, Yuichiro Fukasawa, Tatsuya Atsumi
Frontiers in medicine, 9, 827388, 827388, 2022年, ［国際誌］
英語, 研究論文（学術雑誌）, BACKGROUND: Autoimmune tubulointerstitial nephritis (TIN) is characterized by immune-mediated tubular injury and requires immunosuppressive therapy. However, diagnosing TIN and assessing therapeutic response are challenging for clinicians due to the lack of useful biomarkers. Pathologically, CD4+ T cells infiltrate to renal tubulointerstitium, and soluble interleukin-2 receptor (sIL-2R) has been widely known as a serological marker of activated T cell. Here, we explored the usefulness of serum sIL-2R to predict the treatment outcome in patients with autoimmune TIN. METHODS: Study Design: Single-center retrospective observational study. PARTICIPANTS: 62 patients were diagnosed of TIN from 2005 to April 2018 at Hokkaido University Hospital. Among them, 30 patients were diagnosed with autoimmune TIN and treated with corticosteroids. We analyzed the association between baseline characteristics including sIL-2R and the change of estimated glomerular filtration rate (eGFR) after initiation of corticosteroids. RESULTS: The serum sIL-2R level in patients with autoimmune TIN was significantly higher than that in chronic kidney disease patients with other causes. Mean eGFR in autoimmune TIN patients treated with corticosteroids increased from 43.3 ± 20.4 mL/min/1.73 m2 (baseline) to 50.7 ± 19.9 mL/min/1.73 m2 (3 months) (ΔeGFR; 22.8 ± 26.0%). Multivariate analysis revealed that higher sIL-2R (per 100 U/mL, β = 1.102, P < 0.001) level was independently associated with the renal recovery. In ROC analysis, sIL-2R had the best area under the curve value (0.805) and the cutoff point was 1182 U/mL (sensitivity = 0.90, 1-specificity = 0.45). CONCLUSIONS: Our study showed that elevated serum sIL-2R levels might become a potential predictive marker for therapeutic response in autoimmune TIN.

Comparison of administration of single- and triple-course steroid pulse therapy combined with tonsillectomy for immunoglobulin A nephropathy.
Kanako Watanabe-Kusunoki, Daigo Nakazawa, Junya Yamamoto, Naoko Matsuoka, Nobuharu Kaneshima, Tasuku Nakagaki, Rie Yamamoto, Tomochika Maoka, Sari Iwasaki, Takahiro Tsuji, Yuichiro Fukasawa, Naoki Nishimoto, Saori Nishio, Tatsuya Atsumi
Medicine, 100, 50, e27778, 2021年12月17日, ［国際誌］
英語, 研究論文（学術雑誌）, Immunoglobulin A nephropathy (IgAN) is a form of chronic glomerulonephritis that can cause end-stage renal disease. Recently, tonsillectomy combined with corticosteroid pulse (TSP) has been shown to be effective for achieving clinical remission and favorable renal outcome in patients with IgAN. However, the standard regimen of corticosteroid use in TSP has not been established. Herein, we compared the effect of single- or triple-course steroid pulse therapy combined with tonsillectomy in patients with IgAN.This retrospective, observational cohort study included 122 patients with IgAN enrolled from January 2004 to December 2018 at 2 independent institutions. We divided the patients into 2 groups; single-course (TSP1: n = 70) and triple-course (TSP3: n = 52) of corticosteroid pulse therapy (1 course comprised 3 consecutive days' infusion of 0.5 g methylprednisolone) combined with tonsillectomy. The primary outcome for renal survival was defined as the first occurrence of ≧30% decrease in estimated glomerular filtration rate from baseline. Secondary outcomes included the incidence of clinical remission and recurrence of the disease.Regarding clinical parameters and findings at baseline, there were no significant differences between the 2 groups. The 8-years renal survival in the 2 groups was not significantly different according to Kaplan-Meier curves (TSP1; 82.5% vs TSP3; 69.2%, log-rank test P = .39). The cumulative incidence rates of remission of hematuria (94.4% vs 85.4%, P = .56) and clinical remission (85.0% vs 64.8%, P = .07) were comparable in both groups, while those of proteinuria showed higher rates in TSP1 than TSP3 (88.4% vs 65.4%, P = .02). The cumulative incidence of relapse of hematuria (5.6% vs 2.3%, P = .42) and proteinuria (7.1% vs 3.3%, P = .41) showed no significant differences in the 2 groups. Cox regression analyses showed that the number of courses of corticosteroid pulse therapy was not significantly associated with renal outcome (TSP1 vs TSP3; Hazard ratios 0.69, 95% confidence intervals 0.29-1.64, P = .39).The effect of single-course corticosteroid pulse therapy is not statistically, significantly different from triple-course in TSP protocol for improving renal outcome and preventing relapse in patients with IgAN. Single-course corticosteroid pulse therapy may become a treatment option for patients with IgAN.

Infliximab-Induced Granulomatous Vasculitis With Amyloid Deposition in the Tongue of a Patient With Behçet Disease.
Sari Iwasaki, Toshiyuki Watanabe, Takahiro Tsuji, Takuya Otsuka, Keishi Makita, Yuichiro Fukasawa, Akihiro Ishizu
Journal of clinical rheumatology : practical reports on rheumatic & musculoskeletal diseases, 27, 8S, S710-S712, 2021年12月01日, ［国際誌］
英語, 研究論文（学術雑誌）

Cutaneous sarcoidosis with aggregated comedones in a young woman possibly associated with cosmetic laser treatment.
Yuka Maya, Yasuyuki Fujita, Takuya Mizukami, Sari Iwasaki, Satoko Shimizu
The Journal of dermatology, 48, 12, e589-e590, 2021年12月, ［国際誌］
英語

Expression of the immunoproteasome subunit β5i in non-small cell lung carcinomas.
Takayuki Kiuchi, Utano Tomaru, Akihiro Ishizu, Makoto Imagawa, Sari Iwasaki, Akira Suzuki, Noriyuki Otsuka, Yoshihito Ohhara, Ichiro Kinoshita, Yoshihiro Matsuno, Hirotoshi Dosaka-Akita, Masanori Kasahara
Journal of clinical pathology, 74, 5, 300, 306, 2021年05月, ［国際誌］
英語, 研究論文（学術雑誌）, AIM: The immunoproteasome is a specific proteasome isoform whose proteolytic activity enhances the generation of antigenic peptides to be presented by major histocompatibility complex class I molecules to CD8+ T cells. Physiologically, it is expressed abundantly in immune cells and is induced in somatic cells by cytokines, especially interferon-γ. Recently, variable expression of immunoproteasomes has been demonstrated in different types of cancers. However, the clinical significance of immunoproteasome expression in malignant tumours is poorly understood. In this study, we performed clinicopathological evaluation of immunoproteasome subunit β5i in non-small cell lung carcinomas (NSCLCs). METHODS: Tumour tissues were collected from 155 patients with NSCLCs, and immunohistochemical analysis for β5i was performed in relation to the prognosis of patients. RESULTS: High expression of β5i was found in about 20% of all NSCLCs and was found significantly more frequently (40%) in the adenocarcinoma subset. High expression of β5i was associated with a better 5-year relative survival rate in patients with pStage I to II adenocarcinoma and was also a significant and independent favourable prognostic factor in adenocarcinoma patients. In addition, when we performed in vitro analysis using NSCLC cell lines, combined treatment with the immunoproteasome-specific inhibitor ONX0914 and the proteasome inhibitor MG132 enhanced cell death in β5i-expressing NSCLC cell lines. CONCLUSION: The expression of immunoproteasome can be explored as both a prognostic factor and a potential therapeutic target in NSCLCs. Since immunoproteasomes have crucial role in the antigen presentation, further studies may help to provide essential knowledge for therapeutic strategies in anticancer immunotherapy.

Vitamin B12 allergy manifesting as lymphomatoid contact dermatitis.
Yasuyuki Fujita, Takuya Mizukami, Yuka Maya, Reine Moriuchi, Sari Iwasaki, Yuichiro Fukasawa, Akihiko Shibaki, Satoko Shimizu
European journal of dermatology : EJD, 30, 3, 304, 305, 2020年06月01日, ［国際誌］
英語

Preceding T-Cell-Mediated Rejection Is Associated with the Development of Chronic Active Antibody-Mediated Rejection by de Novo Donor-Specific Antibody.
Takahiro Tsuji, Sari Iwasaki, Keishi Makita, Teppei Imamoto, Naomichi Ishidate, Akihiko Mitsuke, Nobuyuki Fukuzawa, Hiroshi Harada, Yuichiro Fukazawa
Nephron, 144 Suppl 1, 13, 17, 2020年, ［国際誌］
英語, 研究論文（学術雑誌）, AIM: Chronic active antibody-mediated rejection (CAABMR) is an important cause of late-stage renal allograft loss. Early inflammatory events such as acute rejection and infection after transplantation are considered to be the risk factors of de novo donor-specific antibody (dnDSA) production. In this study, we investigated the relationship between pre-disposing T-cell-mediated rejection and dnDSA-positive CAABMR. METHODS: We recruited 365 patients who underwent ABO-compatible renal transplantation at our hospital. Among them, 16 patients diagnosed as having dnDSA-positive CAABMR were designated as a CAABMR group, and 38 randomly selected patients were designated as a control group. All biopsies from 1 month after transplantation were included in the study. The presence or absence of borderline changes (BLCs), acute T-cell-mediated rejection (ATMR), microvascular inflammation (MVI), and C4d positive on peritubular capillaries (C4d-P) was examined. RESULTS: In the CAABMR group, BLC/ATMR was found in 12 cases (75%), and the mean duration until appearance of BLC/ATMR was 282.7 ± 328.7 days. C4d-P was found in 11 cases (68.8%), and the mean duration until its appearance was 1,432 ± 1,307 days. MVI was found in all cases, and the mean duration until its appearance was 1,333 ± 1,126 days. The mean duration until diagnosis of CAABMR was 2,268 ± 1,191 days. In the control group, BLC/ATMR was found in 13 cases (34.2%), and the mean duration until the appearance of BLC/ATMR was 173.1 ± 170.4 days. C4d-P was found in 2 cases (5.3%), and the durations until its appearance were 748 and 1,881 days. No cases of MVI were found in the control group. The frequency of BLC/ATMR was significantly higher in the CAABMR group (p < 0.01). CONCLUSION: Preceding BLC/ATMR is associated with the development of CAABMR with dnDSA.

Novel Detection of CALR-Mutated Cells in Myeloproliferative Neoplasm-Related Glomerulopathy With Interstitial Extramedullary Hematopoiesis: A Case Report.
Keisuke Maruyama, Naoki Nakagawa, Ayana Suzuki, Maki Kabara, Motoki Matsuki, Motohiro Shindo, Sari Iwasaki, Yayoi Ogawa, Naoyuki Hasebe
American journal of kidney diseases : the official journal of the National Kidney Foundation, 74, 6, 844, 848, 2019年12月, ［国際誌］
英語, 研究論文（学術雑誌）, Myeloproliferative neoplasms (MPNs) are associated with somatic mutations of genes including JAK2, CALR, or MPL in hematopoietic stem cells. Various glomerular lesions are known to be involved in MPN-related glomerulopathy, including mesangial hypercellularity, segmental sclerosis, features of chronic thrombotic microangiopathy, and intracapillary hematopoietic cell infiltration. Renal extramedullary hematopoiesis (EMH) is uncommon, but it is reported to occur in the setting of MPN; however, to our knowledge, there have been no reports of renal EMH with pathologically verified mutations. We report the case of a 65-year-old woman with MPN who had a CALR mutation and developed nephrotic syndrome. Kidney biopsy showed the typical findings of MPN-related glomerulopathy. CALR mutation-specific immunostaining of the kidney revealed immunopositive cells in the EMH lesion of the interstitium, indicating that renal EMH was caused by CALR-mutated cells. Based on these findings, we diagnosed nephrotic syndrome caused by MPN-related glomerulopathy. After initiation of steroid therapy, the patient's proteinuria gradually decreased and she achieved an incomplete remission. Additionally, the patient was prescribed the JAK inhibitor ruxolitinib and maintained incomplete remission. There is no established treatment for MPN-related glomerulopathy; therefore, further studies are needed to elucidate its pathophysiology.

Formation and Disordered Degradation of Neutrophil Extracellular Traps in Necrotizing Lesions of Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis.
Sakiko Masuda, Mayu Nonokawa, Emika Futamata, Yuka Nishibata, Sari Iwasaki, Takahiro Tsuji, Yutaka Hatanaka, Daigo Nakazawa, Satoshi Tanaka, Utano Tomaru, Tamihiro Kawakami, Tatsuya Atsumi, Akihiro Ishizu
The American journal of pathology, 189, 4, 839, 846, 2019年04月, ［国際誌］
英語, 研究論文（学術雑誌）, Antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) is characterized by the production of ANCAs and systemic necrotizing vasculitis in small vessels. Disordered regulation of neutrophil extracellular traps (NETs) is critically involved in the pathogenesis of AAV. NETs are web-like DNA decorated with antimicrobial proteins; they are extruded from activated neutrophils. The principal degradation factor of NETs in vivo is DNase I; however, NETs resistant to DNase I can persist in tissues and can lead to the production of ANCAs. Deposition of NETs has been demonstrated in glomerular crescents and necrotizing vasculitis in AAV. Here, the amount of NETs in formalin-fixed, paraffin-embedded tissue sections was examined, and the results for AAV were compared with the results for diseases that should be distinguished from AAV. NETs were more abundant in necrotizing vasculitis of AAV than in non-ANCA-associated vasculitis, or in granulomatous angiitis. Pulmonary granulomas in AAV and non-ANCA-associated diseases were further studied. The amount of NETs was significantly greater in necrotizing granulomas of AAV than in granulomas of sarcoidosis without necrosis. Although NETs were formed in necrotizing granulomas of tuberculosis equivalently to those formed in AAV, they were more susceptible to degradation by DNase I than were NETs in AAV. The formation and disordered degradation of NETs in necrotizing lesions are characteristics of AAV and are possibly related to its pathogenesis.

Expression of cathepsins V and S in thymic epithelial tumors.
Shizuka Kiuchi, Utano Tomaru, Akihiro Ishizu, Makoto Imagawa, Takayuki Kiuchi, Sari Iwasaki, Akira Suzuki, Noriyuki Otsuka, Takahiro Deguchi, Tomohiro Shimizu, Katsuji Marukawa, Yoshihiro Matsuno, Masanori Kasahara
Human pathology, 60, 66, 74, 2017年02月, ［国際誌］
英語, 研究論文（学術雑誌）, Cathepsins are a group of proteolytic enzymes of the endosomal/lysosomal pathway involved in the thymic development of T cells restricted by major histocompatibility complex class II molecules. In the normal thymus, cathepsin V (CTV) and cathepsin S (CTS) are expressed in cortical and medullary epithelial cells, respectively. To investigate whether cathepsins could serve as a diagnostic marker, we performed immunohistochemical analysis for CTV and CTS in 77 cases of thymic epithelial tumors. Almost all cases (59/60) of thymoma expressed CTV, whereas 28 of 60 cases of thymoma expressed CTS. Notably, CTS was expressed in most cases of type A and type AB thymomas, but not in type B thymoma. The expression of cathepsins in type AB thymoma showed a clear correlation with histologic features; CTV was found predominantly in the type B component, and CTS was frequently expressed in the type A component. In thymic carcinoma, CTV was expressed in less than half cases (7/17), and the ratio of CTS-positive cases was equivalent to that of thymoma (8/17). Cases of CTV-negative thymic carcinoma tended to have a higher incidence of recurrence than did CTV-positive cases. Although further studies with a larger number of cases are required to confirm the utility of cathepsin immunostaining, CTV and CTS appear to serve as auxiliary diagnostic and/or prognostic markers in thymic epithelial tumors.

An unusual case of uterine cotyledonoid dissecting leiomyoma with adenomyosis.
Ai Shimizu, Hoshihito Tanaka, Sari Iwasaki, Yukio Wakui, Hitoshi Ikeda, Akira Suzuki
Diagnostic pathology, 11, 1, 69, 69, 2016年08月04日, ［国際誌］
英語, 研究論文（学術雑誌）, BACKGROUND: Cotyledonoid dissecting leiomyoma is a rare variant of uterine smooth muscle tumor with an unusual growth pattern that shows intramural dissection within uterine myometrium and often a placenta-like appearance in its extrauterine components. CASE PRESENTATION: We present a unique case of cotyledonoid dissecting leiomyoma with adenomyosis. A 40-year-old Japanese female presented with prolonged menorrhagia and severe anemia. She had a pelvic mass followed-up for 6 years with a diagnosis of leiomyoma. However, increase in tumor size and cystic changes with hemorrhage were found by magnetic resonance imaging, and total abdominal hysterectomy with bilateral salpingectomy was performed. Macroscopically, the placenta-like exophytic mass protruding from the posterior uterine wall was composed of multiple nodules containing numerous hemorrhagic cysts. The mass showed continuity as a white multinodular dissecting mass infiltrating the posterolateral myometrium. Microscopically, both extra-and intrauterine portions of the mass were composed of nodules that contained swirled neoplastic smooth muscle cells with marked hyalinized degeneration, as observed in cotyledonoid dissecting leiomyomas of conventional type. In addition, numerous non-neoplastic glands of endometrial type surrounded by abundant endometrium-like stromal cells and non-neoplastic smooth muscle cells were found in the tumor, suggesting that it involved a part of concomitant adenomyosis originating from the nontumoral myometrium. CONCLUSIONS: Thus far, over 30 cases of cotyledonoid dissecting leiomyoma have been reported, none of which have described the presence of adenomyosis within the tumor. The present case suggested that cotyledonoid dissecting leiomyoma might have a unique clinical presentation involving concomitant uterine adenomyosis. It is critical for pathologists, gynecologists, and radiologists to be cognizant of cotyledonoid dissecting leiomyoma variants for timely and appropriate diagnosis and treatment.

Thrombocytopenia and Anemia with Anti-c-Mpl antibodies Effectively Treated with Cyclosporine in a Patient with Rheumatoid Arthritis and Chronic Renal Failure.
Akari Hashimoto, Yuji Kanisawa, Akihito Fujimi, Chisa Nakajima, Naotaka Hayasaka, Shota Yamada, Toshinori Okuda, Shinya Minami, Natsumi Yamauchi, Sari Iwasaki, Akira Suzuki, Junji Kato
Internal medicine (Tokyo, Japan), 55, 6, 683, 7, 2016年, ［国内誌］
英語, 研究論文（学術雑誌）, A 61-year-old woman with rheumatoid arthritis who was undergoing hemodialysis for end-stage renal failure was transferred to our hospital due to severe thrombocytopenia and anemia. A bone marrow biopsy showed the complete absence of megakaryocytes and erythroblasts. Cyclosporine treatment resulted in the improvement of her megakaryocyte and erythroblast levels, and a decrease in her serum level of anti-c-Mpl (thrombopoietin receptor) antibodies. After this initial improvement, her anemia progressively worsened, despite the continuous administration of immunosuppressive therapy with cyclosporine. Her platelet and leukocyte counts remained stable. This is the first report of a probable case of anti-c-Mpl antibody-associated pure red cell aplasia and acquired amegakaryocytic thrombocytopenic purpura.

[Successful treatment with dose-adjusted EPOCH-R for triple-hit lymphoma having BCL2, BCL6 and MYC translocations].
Akari Hashimoto, Akihito Fujimi, Yuji Kanisawa, Chisa Nakajima, Naotaka Hayasaka, Shota Yamada, Toshinori Okuda, Shinya Minami, Tomoaki Matsumoto, Takanori Shibata, Kota Hamaguchi, Yusuke Kamihara, Sari Iwasaki, Junji Kato
[Rinsho ketsueki] The Japanese journal of clinical hematology, 56, 7, 905, 10, 2015年07月, ［国内誌］
日本語, 研究論文（学術雑誌）, Double- and triple-hit lymphomas (DHL/THL), high-grade B-cell lymphomas with an extremely poor prognosis, are defined by a chromosomal breakpoint affecting the MYC/8q24 locus in combination with another recurrent breakpoint. The successful use of dose-adjusted (DA) EPOCH-R in patients with MYC-positive lymphoma and Burkitt lymphoma (BL) was recently reported. A 74-year-old man with acute renal dysfunction and hyperkalemia was transferred to our emergency center by ambulance. PET-CT revealed a left renal hilar mass enveloping the abdominal para-aortic domain and bladder and hydronephrosis. High (18)F-FDG uptake revealed lymph node, peritoneum, and multiple bone metastases. Analysis of the bone marrow aspirate revealed abnormal lymphoid cells with deeply basophilic cytoplasm and numerous vacuoles resembling Burkitt cells. Chromosomal analysis revealed a complex chromosomal karyotype, including t(14;18)(q32;q21), and FISH analysis confirmed split BCL2, BCL6, and MYC signals. Bone marrow biopsy revealed diffusely infiltrating large abnormal lymphoid cells with a CD10⁺, CD20⁺, BCL2⁺, BCL6⁺, c-MYC⁺ and MUM1(-) immunophenotype. B-cell lymphoma, unclassifiable with features intermediate between diffuse large B-cell lymphoma and BL, was diagnosed. The patient achieved a partial response after eight courses of DA-EPOCH-R chemotherapy. Our experience suggests that DA-EPOCH-R may be an effective treatment for DHL/THL.

Establishment of a vascular endothelial cell-reactive type II NKT cell clone from a rat model of autoimmune vasculitis.
Chihiro Iinuma, Masashi Waki, Ai Kawakami, Madoka Yamaguchi, Utano Tomaru, Naomi Sasaki, Sakiko Masuda, Yuki Matsui, Sari Iwasaki, Tomohisa Baba, Masanori Kasahara, Takashi Yoshiki, Daniel Paletta, Thomas Herrmann, Akihiro Ishizu
International immunology, 27, 2, 105, 14, 2015年02月, ［国際誌］
英語, 研究論文（学術雑誌）, We previously generated a rat model that spontaneously developed small vessel vasculitis (SVV). In this study, a T cell clone reactive with rat vascular endothelial cells (REC) was established and named VASC-1. Intravenous injection of VASC-1 induced SVV in normal recipients. VASC-1 was a TCRαβ/CD3-positive CD4/CD8 double-negative T cell clone with expression of NKG2D. The cytokine mRNA profile under unstimulated condition was positive for IL-4 and IFN-γ but negative for IL-2 and IL-10. After interaction with REC, the mRNA expression of IL-2, IL-5 and IL-6 was induced in VASC-1, which was inhibited by blocking of CD1d on the REC surface. Although the protein levels of these cytokines seemed to be lower than the detection limit in the culture medium, IFN-γ was detectable. The production of IFN-γ from the VASC-1 stimulated with LPS-pre-treated REC was inhibited by the CD1d blockade on the REC. These findings indicated VASC-1 as an NKT cell clone. The NKT cell pool includes two major subsets, namely types I and II. Type I NKT cells are characterized by expression of semi-invariant TCRs and the potential to bind to marine sponge-derived α-galactosylceramide (α-GalCer) loaded on CD1d; whereas, type II NKT cells do not manifest these characteristics. VASC-1 exhibited a usage of TCR other than the type I invariant TCR α chain and did not bind to α-GalCer-loaded CD1d; therefore, it was determined as a type II NKT cell clone. The collective evidence suggested that REC-reactive type II NKT cells could be involved in the pathogenesis of SVV in rats.

Fatal cardiac small-vessel involvement in ANCA-associated vasculitis: an autopsy case report.
Sari Iwasaki, Akira Suzuki, Takashi Fujisawa, Taiju Sato, Shinya Shirai, Mitsunori Kamigaki, Noriyuki Otsuka, Utano Tomaru, Akihiro Ishizu
Cardiovascular pathology : the official journal of the Society for Cardiovascular Pathology, 24, 6, 408, 10, 2015年, ［国際誌］
英語, 研究論文（学術雑誌）, An 80-year-old Japanese man, who had fever and generalized fatigue not improved by antibiotics, was admitted to our hospital. Laboratory data indicative of renal dysfunction and antineutrophil cytoplasmic antibody (ANCA) in the serum led to the consideration of ANCA-associated vasculitis as a differential diagnosis. However, before the diagnostic confirmation, he was found dead on the bed. Autopsy revealed necrotizing crescentic glomerulonephritis in the kidneys. In addition, necrotizing granulomatous vasculitis with infiltration of multinucleated giant cells and neutrophils but not eosinophils was present in multiple organs. The direct cause of death was presumed as cardiac arrest by lethal arrhythmia because vasculitic lesions were distributed widely in the cardiac walls, acute congestion was observed in the systemic organs, and other causes of death were ruled out. This report presents the unusual manifestation of cardiac small-vessel involvement in ANCA-associated vasculitis related to sudden death.

[A case of complete response to multiple liver metastasis of gastric cancer after discontinuation of S-1 administration].
Masahiko Koike, Kazuhiro Mino, Hirotaka Shoji, Yuji Konishi, Tomonari Katayama, Hiroaki Kuwahara, Hirofumi Kon, Motoshi Tamura, Sari Iwasaki, Akira Suzuki, Yoshinobu Akasaka
Gan to kagaku ryoho. Cancer & chemotherapy, 41, 7, 893, 6, 2014年07月, ［国内誌］
日本語, 研究論文（学術雑誌）, An 80-year-old man was diagnosed with advanced gastric cancer and underwent distal gastrectomy. Although the pathological Stage of the cancer was III A, he refused adjuvant chemotherapy. One year later, CT revealed multiple liver metastases. Therefore, he was started with S-1 administration and a complete response was obtained at 10 months after starting S-1 administration. He has maintained a complete response for 22 months after S-1 discontinuation.

Focal 18F-FDG uptake in bone marrow on PET/CT in a patient with JAK2 mutation without overt myeloproliferative neoplasm.
Akihito Fujimi, Yuji Kanisawa, Shinya Minami, Yusuke Kamihara, Sari Iwasaki
International journal of hematology, 99, 1, 1, 3, 2014年01月, ［国内誌］
英語, 研究論文（学術雑誌）

Possible implication of Fc γ receptor-mediated trogocytosis in susceptibility to systemic autoimmune disease.
Sakiko Masuda, Sari Iwasaki, Utano Tomaru, Tomohisa Baba, Kazuaki Katsumata, Akihiro Ishizu
Clinical & developmental immunology, 2013, 345745, 345745, 2013年, ［国際誌］
英語, 研究論文（学術雑誌）, Leukocytes can "gnaw away" the plasma membrane of other cells. This phenomenon, called trogocytosis, occurs subsequent to cell-to-cell adhesion. Currently, two mechanisms of trogocytosis, adhesion molecule-mediated trogocytosis and Fc γ receptor-(Fc γ R-) mediated trogocytosis, have been identified. In our earlier study, we established an in vitro model of Fc γ R-mediated trogocytosis, namely, CD8 translocation model from T cells to neutrophils. By using this model, we demonstrated that the molecules transferred to neutrophils via Fc γ R-mediated trogocytosis were taken into the cytoplasm immediately. This result suggests that the chance of molecules transferred via Fc γ R-mediated trogocytosis to play a role on the cell surface could be time-limited. Thus, we consider the physiological role of Fc γ R-mediated trogocytosis as a means to remove antibodies (Abs) that bind with self-molecules rather than to extract molecules from other cells. This concept means that Fc γ R-mediated trogocytosis can be a defense mechanism to Ab-mediated autoimmune response. Moreover, the activity of Fc γ R-mediated trogocytosis was revealed to be parallel to the endocytotic activity of neutrophils, which was critically related to the susceptibility to systemic autoimmune diseases. The collective findings suggest that Fc γ R-mediated trogocytosis could physiologically play a role in removal of Abs bound to self-antigens and prevent autoimmune diseases.

Mechanism of Fcγ receptor-mediated trogocytosis-based false-positive results in flow cytometry.
Sakiko Masuda, Sari Iwasaki, Utano Tomaru, Juri Sato, Ai Kawakami, Kana Ichijo, Sayuri Sogo, Tomohisa Baba, Kazuaki Katsumata, Masanori Kasahara, Akihiro Ishizu
PloS one, 7, 12, e52918, 2012年, ［国際誌］
英語, 研究論文（学術雑誌）, The whole blood erythrocyte lysis method is the most common protocol of sample preparation for flow cytometry (FCM). Although this method has many virtues, our recent study has demonstrated false-positive results when surface markers of monocytes were examined by this method due to the phenomenon called Fcγ receptor (FcγR)-mediated trogocytosis. In the present study, similar FcγR-mediated trogocytosis-based false-positive results have been demonstrated when granulocytes were focused on instead of monocytes. These findings indicated that not only monocytes but also granulocytes, the largest population with FcγR expression in peripheral blood, could perform FcγR-mediated trogocytosis. Since the capacity of FcγR-mediated trogocytosis was different among blood samples, identification of factors that could regulate the occurrence of FcγR-mediated trogocytosis should be important for the quality control of FCM. Our studies have suggested that such factors are present in the serum. In order to identify the serum factors, we employed the in vitro model of FcγR-mediated trogocytosis using granulocytes. Investigation with this model determined the serum factors as heat-labile molecules with molecular weight of more than 100 kDa. Complements in the classical pathway were initially assumed as candidates; however, the C1 inhibitor did not yield an obvious influence on FcγR-mediated trogocytosis. On the other hand, although immunoglobulin ought to be resistant to heat inactivation, the inhibitor of human anti-mouse antibodies (HAMA) effectively blocked FcγR-mediated trogocytosis. Moreover, the inhibition rates were significantly higher in HAMA(high) serum than HAMA(low) serum. The collective findings suggested the involvement of heterophilic antibodies such as HAMA in the mechanism of false-positive results in FCM due to FcγR-mediated trogocytosis.

Plasma-dependent, antibody- and Fcγ receptor-mediated translocation of CD8 molecules from T cells to monocytes.
Sari Iwasaki, Sakiko Masuda, Tomohisa Baba, Utano Tomaru, Kazuaki Katsumata, Masanori Kasahara, Akihiro Ishizu
Cytometry. Part A : the journal of the International Society for Analytical Cytology, 79, 1, 46, 56, 2011年01月, ［国際誌］
英語, 研究論文（学術雑誌）, CD8αβ heterodimers are mainly expressed on cytotoxic T lymphocytes. This study demonstrated the detection of CD8αβ heterodimers on human monocytes by whole blood erythrocyte lysis method in flow cytometry. Results revealed that CD8αβ heterodimers were not produced by monocytes themselves, but were transferred from T cells to monocytes when these cells were coincubated in plasma and with anti-CD8 monoclonal antibody (mAb). For completion of CD8 translocation from T cells to monocytes, cell-to-cell contact between T cells and monocytes, as well as binding of the Fc portion of the anti-CD8 mAb and Fcγ receptor II (FcγRII) on monocytes were required. Furthermore, the dynamism of cell membrane and cytoskeleton were involved in the mechanism of CD8 translocation. Interestingly, CD3 and αβT cell receptor (TCR) were also transferred from T cells to monocytes accompanied by CD8. These phenomena are consistent with Ab-dependent and FcγR-mediated trogocytosis, which is recently recognized as one of the intercellular communication processes of the immune system. Trogocytosis means exchange of plasma membrane including cell surface molecules in conjugates formed between immune cells. Results of this study could provide another model of trogocytosis and clearly indicated that putative plasma factors were critically implicated in the mechanism of Ab-dependent and FcγR-mediated trogocytosis.

Exclusive expression of proteasome subunit {beta}5t in the human thymic cortex.
Utano Tomaru, Akihiro Ishizu, Shigeo Murata, Yukiko Miyatake, Sayuri Suzuki, Satomi Takahashi, Taku Kazamaki, Jiro Ohara, Tomohisa Baba, Sari Iwasaki, Kazunori Fugo, Noriyuki Otsuka, Keiji Tanaka, Masanori Kasahara
Blood, 113, 21, 5186, 91, 2009年05月21日, ［国際誌］
英語, 研究論文（学術雑誌）, The ubiquitin-proteasome pathway, which degrades intracellular proteins, is involved in numerous cellular processes, including the supply of immunocompetent peptides to the antigen presenting machinery. Proteolysis by proteasomes is conducted by three beta subunits, beta1, beta2, and beta5, of the 20S proteasome. Recently, a novel beta subunit expressed exclusively in cortical thymic epithelial cells was discovered in mice. This subunit, designated beta5t, is a component of the thymoproteasome, a specialized type of proteasomes implicated in thymic positive selection. In this study, we show that, like its mouse counterpart, human beta5t is expressed exclusively in the thymic cortex. Human beta5t was expressed in approximately 80% of cortical thymic epithelial cells and some cortical dendritic cells. Human beta5t was incorporated into proteasomes with two other catalytically active beta subunits beta1i and beta2i, forming 20S proteasomes with subunit compositions characteristic of thymoproteasomes. The present study demonstrates, for the first time, the existence of thymoproteasomes in the human thymic cortex, indicating that thymoproteasome function is likely conserved between humans and mice.

[Spontaneous pneumothorax, an unusual manifestation of imatinib-resistant chronic eosinophilic leukemia: an autopsy study].
Akihito Fujimi, Yuji Kanisawa, Shingo Tanaka, Toshinori Okuda, Yasuhiro Sato, Tadashi Doi, Hidetoshi Ohta, Sari Iwasaki, Akihiro Ishizu, Yongze Huang
Nihon Naika Gakkai zasshi. The Journal of the Japanese Society of Internal Medicine, 98, 4, 862, 5, 2009年04月10日, ［国内誌］
日本語, 研究論文（学術雑誌）

Rat CD4+CD8+ macrophages kill tumor cells through an NKG2D- and granzyme/perforin-dependent mechanism.
Tomohisa Baba, Sari Iwasaki, Takako Maruoka, Akira Suzuki, Utano Tomaru, Hitoshi Ikeda, Takashi Yoshiki, Masanori Kasahara, Akihiro Ishizu
Journal of immunology (Baltimore, Md. : 1950), 180, 5, 2999, 3006, 2008年03月01日, ［国際誌］
英語, 研究論文（学術雑誌）, We previously identified a subpopulation of monocyte/macrophage lineage cells expressing both CD4 and CD8. This subpopulation was expanded in rat peripheral blood and spleen after immunization with adjuvants containing killed tuberculosis germs. CD4+CD8+ monocytes/macrophages obtained from preimmunized rats exhibited a Th1-type cytokine/chemokine profile, expressed high levels of Fas ligand, perforin, granzyme B, and NKR-P2 (rat ortholog of human NKG2D), and killed certain tumor cells. In the present study, we confirmed that CD4+CD8+ monocytes/macrophages are distinct from splenic dendritic cells (DCs) or IFN-producing killer DCs. In vitro cytotoxic assays revealed that CD4+CD8+ macrophages killed tumor cells in a cell-cell contact-dependent manner and that expression of the retinoic acid early transcript 1 (a ligand for NKG2D) made tumor cells susceptible to killing by CD4+CD8+ macrophages. Furthermore, inhibitors of granzyme and perforin significantly decreased cytotoxic activities of CD4+CD8+ macrophages. Consistent with these in vitro findings, preimmunization with adjuvants containing killed tuberculosis germs elevated the expression of granzyme B in tumor-infiltrating CD4+CD8+ macrophages and significantly inhibited the growth of inoculated tumor cells. Our current work demonstrates that CD4+CD8+ macrophages are a unique subpopulation of monocyte/macrophage lineage cells that kill tumor cells in an NKG2D- and granzyme/perforin-dependent mechanism.

CD4+/CD8+ macrophages infiltrating at inflammatory sites: a population of monocytes/macrophages with a cytotoxic phenotype.
Tomohisa Baba, Akihiro Ishizu, Sari Iwasaki, Akira Suzuki, Utano Tomaru, Hitoshi Ikeda, Takashi Yoshiki, Masanori Kasahara
Blood, 107, 5, 2004, 12, 2006年03月01日, ［国際誌］
英語, 研究論文（学術雑誌）, We found a population of nonlymphoid cells expressing both CD4 and CD8 in peripheral blood mononuclear cells (PBMCs) of human T-cell leukemia virus type-I pX transgenic rats with autoimmune diseases. These cells, which showed a monocytic phenotype, were also found in wild-type rats, and their number increased by adjuvant-assisted immunization. GM-CSF increased the number of these double-positive (DP) monocytes in PBMCs. Consistent with the idea that DP monocytes differentiate into DP macrophages at sites of inflammation, we found infiltration of DP macrophages at the site of myosin-induced myocarditis in wild-type rats; these cells exhibited a T-helper 1 (Th1)-type cytokine/chemokine profile and expressed high levels of Fas ligand, perforin, granzyme B, and NKR-P2 (rat orthologue of human NKG2D). Adoptive transfer of GFP-positive spleen cells confirmed hematogenous origin of DP macrophages. DP monocytes had a cytotoxic phenotype similar to DP macrophages, indicating that this phenotypic specialization occurred before entry into a tissue. In line with this, DP monocytes killed tumor cells in vitro. Combined evidence indicates that certain inflammatory stimuli that induce GM-CSF trigger the expansion of a population of DP monocytes with a cytotoxic phenotype and that these cells differentiate into macrophages at inflammatory sites. Interestingly, human PBMCs also contain DP monocytes.

Cadaveric domino liver transplantation: the first case in Japan.
Kenji Wakayama, Maeng Bong Jin, Hiroyuki Furukawa, Satoru Todo, Tsuyoshi Shimamura, Tomomi Suzuki, Masahiro Hattori, Ryouji Yokoyama, Sari Iwasaki, Masanori Sato, Takahito Nakagawa, Noriaki Kurauchi, Hirohumi Kamachi, Toshiya Kamiyama, Michiaki Matsushita
Journal of hepato-biliary-pancreatic surgery, 11, 6, 445, 8, 2004年, ［国内誌］
英語, 研究論文（学術雑誌）, The first case of domino liver transplantation from a brain-dead donor in Japan is described. A 49-year-old man with familial amyloidotic polyneuropathy received a cadaver liver, and his native liver was transplanted into a 53-year-old man with polycystic liver and kidney disease. The cadaveric liver allograft was transplanted by the conventional technique. The graft taken from the first recipient had four outflow orifices (the left, middle, and right hepatic veins, and upper vena cava), for which a single orifice was created at the back table. This graft was transplanted in piggy-back fashion. The first recipient developed acute rejection on day 13 and hepatic artery stenosis on day 36. These were treated by steroid recycle therapy and percutaneous transarterial angioplasty. He was discharged on day 57 with normal liver function. The second recipient underwent re-operation for bleeding from the right adrenal gland and left thoracic cavity. He was diagnosed with acute rejection on day 7, which was treated by steroid pulse therapy. He was discharged uneventfully on day 39 with normal liver function.

血栓性微小血管症の病因診断の試みー腎生検組織の空間的トランスクリプトーム解析ー
科学研究費助成事業
2022年08月31日 - 2024年03月31日
岩崎 沙理
本研究では、様々な病因で発症する血栓性微小血管症（TMA）の症例について、腎生検組織を用いて、空間的トランスクリプトーム解析を行った。
まず、予備実験用に11検体を抽出した。腎生検組織を載せた専用スライドを蛍光染色し、糸球体を関心領域として設定した。関心領域ごとに得られた遺伝子発現データについて、品質確認、正規化し、2群に分けてクラスター解析等を行い、解析可能なことを確認した。次に、病理学的TMAのうち①造血幹細胞移植後TMA、②薬剤性TMA、③膠原病関連TMA、④陰性コントロール を2-3例ずつ抽出し、GeoMxの検討を行った。得られた遺伝子発現データについて、解析を行っている最中である。
日本学術振興会, 研究活動スタート支援, 北海道大学, 22K20908

血管炎発症機序の解明と新しい分子標的治療法および病態診断法の開発
科学研究費助成事業
2008年 - 2010年
石津 明洋, 外丸 詩野, 岩崎 沙理
中・小型血管炎を発症するenv-pXラットから自己血管内皮細胞反応性血管炎惹起性T 細胞を単離した。このT細胞の標的分子や血管傷害機構を明らかにすることにより、血管炎の新しい分子標的治療法の開発が可能となる。また、顕微鏡的多発血管炎患者の治療前および治療開始1週間後の末梢血を用いて、網羅的遺伝子発現解析を行った。治療前後の末梢血における16個の遺伝子の発現変化を調べることにより、患者予後を治療開始後の早期に予測できる可能性が示された。
日本学術振興会, 基盤研究(C), 北海道大学, 20590390

ヒト末梢血に検出されるCD8陽性単球に関する研究
科学研究費助成事業
2008年 - 2009年
岩崎 沙理
全血溶血法を用いたヒト末梢血のフローサイトメトリーにおいて,CD14陽性の単球上にCD8分子が検出される現象を見出した.必要な血清因子の存在下において,Tリンパ球上のCD8分子に抗CD8抗体が結合することにより,抗体のFc部分と単球上のFcγRII(CD32)が結合してTリンパ球と単球を架橋し,細胞膜の流動性や細胞骨格の変動を伴って,CD8やCD3,TCRといったTリンパ球上の機能分子が単球へと移動すると考えられた.
日本学術振興会, 若手研究(B), 北海道大学, 20790409