全身性強皮症の自己抗原反応性B細胞のサイトカイン産生が他の免疫系に与える影響解析

2021 Fiscal Year Annual Research Report

• Project/Area Number: 20K22925
• Research Institution: The University of Tokyo
• Principal Investigator: 深澤 毅倫 東京大学, 医学部附属病院, 助教 (80884056)
• Project Period (FY): 2020-09-11 – 2022-03-31
• Keywords: B細胞 / 自己反応性B細胞 / 全身性強皮症 / サイトカイン / affinity

Outline of Annual Research Achievements

本研究では、マイクロ空間を用いた独自の技術と方法論を用い、全身性強皮症(systemic sclerosis; SSc)における自己反応性B細胞の機能と役割を明らかにした。まず抗Topoisomerase(topo) I抗体陽性SSc患者における末梢血中のtopoI特異的B細胞のサイトカイン産生能の解析を行い、interleukin (IL)-6やIL-23の炎症性サイトカインを産生するB細胞やIL-10やIL-35の抑制性サイトカインを産生するB細胞がtopo I特異的B細胞集団中に存在することを見出した。さらにtopoI抗原への親和性とサイトカイン産生能との関係について、high affinityなB細胞においてIL-6やIL-23を産生するB細胞の割合が多く、産生量も多かった。同様にlow affinityなB細胞においてはIL-10やIL-35の抑制性サイトカインを産生するB細胞の割合が多く、産生量も多かった。さらにtopoI抗原に対してhigh affinityなB細胞が多いほど、皮膚硬化が強く、肺機能が悪かった。
次にtopoI誘発SScモデルマウスにおいて、B細胞のaffinityの上昇とサイトカイン産生能の関係について検討した。topo I蛋白を免疫する毎にB細胞のtopo Iに対するaffinityは強められ、Low affinityなB細胞が多い、topo I1回免疫モデルでは、IL-10やIL-35といった抑制性のサイトカインを産生するB細胞の割合が多いのに対し、high affinityなB細胞が多い、topo I4回免疫モデルでは、IL-6やIL-23の炎症性サイトカインを産生する割合が多かった。
これらのhigh affinityなB細胞はTh17細胞を誘導し、low affinityなB細胞はTreg細胞を誘導することも明らかにした。

Research Products

• [Journal Article] Decrease in MAP3Ks expression enhances the cell death caused by hyperthermia (2022)
  • Author(s): Enomoto Atsushi、Fukasawa Takemichi、Terunuma Hiroshi、Nakagawa Keiichi、Yoshizaki Ayumi、Sato Shinichi、Miyagawa Kiyoshi
  • Journal Title: International Journal of Hyperthermia Volume: 39 Pages: 200～208
  • DOI: 10.1080/02656736.2021.2024281
  • Peer Reviewed / Open Access
• [Journal Article] Predictors of rituximab effect on modified Rodnan skin score in systemic sclerosis: a machine-learning analysis of the DesiReS trial (2022)
  • Author(s): Ebata Satoshi、Oba Koji、Kashiwabara Kosuke、Ueda Keiko、Uemura Yukari、Watadani Takeyuki、Fukasawa Takemichi、Miura Shunsuke、Yoshizaki-Ogawa Asako、Yoshihide Asano、Yoshizaki Ayumi、Sato Shinichi
  • Journal Title: Rheumatology Volume: 5 Pages: 5
  • DOI: 10.1093/rheumatology/keac023
  • Peer Reviewed
• [Journal Article] Rapid decrease of serum surfactant protein‐D levels predicts the reactivity of rituximab therapy in systemic sclerosis‐associated interstitial lung disease (2021)
  • Author(s): Ebata Satoshi、Yoshizaki Ayumi、Fukasawa Takemichi、Asano Yoshihide、Oba Koji、Sato Shinichi
  • Journal Title: The Journal of Dermatology Volume: 47 Pages: 796～800
  • DOI: 10.1111/1346-8138.15379
  • Peer Reviewed
• [Journal Article] Interleukin (IL)‐17F and IL‐17E are related to fibrosis and vasculopathy in systemic sclerosis (2021)
  • Author(s): Fukayama Maiko、Yoshizaki Ayumi、Fukasawa Takemichi、Ebata Satoshi、Kuzumi Ai、Yoshizaki‐Ogawa Asako、Asano Yoshihide、Oba Koji、Sato Shinichi
  • Journal Title: The Journal of Dermatology Volume: 47 Pages: 1287～1292
  • DOI: 10.1111/1346-8138.15508
  • Peer Reviewed
• [Journal Article] COVID-19 pandemic highlighted the importance of telemedicine in the collagen disease of systemic sclerosis (2021)
  • Author(s): Y. Norimatsu, A. Yoshizaki, T. Fukasawa, S. Ebata, K. Oba, S. Sato
  • Journal Title: Clinical and Experimental Rheumatology Volume: 39 Pages: 160
  • Peer Reviewed / Open Access
• [Journal Article] Clinical Significance of Anti-U1 Ribonucleoprotein Antibody in Anti-Topoisomerase I Antibody-Positive Systemic Sclerosis Patients: A Retrospective Observational Study (2021)
  • Author(s): Kazuki M Matsuda, Ayumi Yoshizaki, Hirohito Kotani, Ai Kuzumi, Maiko Fukayama, Takemichi Fukasawa, Satoshi Ebata, Asako Yoshizaki-Ogawa, Yoshihide Asano, Koji Oba, Shinichi Sato
  • Journal Title: Archives of Clinical and Biomedical Research Volume: 5 Pages: 76-84
  • Peer Reviewed / Open Access
• [Journal Article] Serum Calponin 3 Levels in Patients with Systemic Sclerosis: Possible Association with Skin Sclerosis and Arthralgia (2021)
  • Author(s): Kotani Hirohito、Yoshizaki Ayumi、Matsuda Kazuki M.、Norimatsu Yuta、Kuzumi Ai、Fukayama Maiko、Fukasawa Takemichi、Ebata Satoshi、Yoshizaki-Ogawa Asako、Asano Yoshihide、Oba Koji、Sato Shinichi
  • Journal Title: Journal of Clinical Medicine Volume: 10 Pages: 280～280
  • DOI: 10.3390/jcm10020280
  • Peer Reviewed / Open Access
• [Journal Article] Serum heat shock protein 27 levels in patients with systemic sclerosis: a possible biomarker of skin sclerosis (2021)
  • Author(s): Matsuda K.M.、Yoshizaki A.、Kotani H.、Norimatsu Y.、Kuzumi A.、Fukayama M.、Fukasawa T.、Ebata S.、Yoshizaki‐Ogawa A.、Asano Y.、Oba K.、Sato S.
  • Journal Title: Journal of the European Academy of Dermatology and Venereology Volume: 35 Pages: 250
  • DOI: 10.1111/jdv.16885
  • Peer Reviewed
• [Journal Article] Serum TARC Levels in Patients with Systemic Sclerosis: Clinical Association with Interstitial Lung Disease (2021)
  • Author(s): Kuzumi Ai、Yoshizaki Ayumi、Ebata Satoshi、Fukasawa Takemichi、Yoshizaki-Ogawa Asako、Asano Yoshihide、Oba Koji、Sato Shinichi
  • Journal Title: Journal of Clinical Medicine Volume: 10 Pages: 660～660
  • DOI: 10.3390/jcm10040660
  • Peer Reviewed / Open Access
• [Journal Article] Cutaneous Sarcoidosis as a Predictor of Cardiac Sarcoidosis (2021)
  • Author(s): Yuta Norimatsu, Ayumi Yoshizaki, Yuki Ohno, Yuka Mizuno, Haruka Watanabe, Hirohito Kotani, Kazuki M Matsuda, Maiko Fukayama, Ai Kuzumi, Satoshi Ebata, Takemichi Fukasawa, Asako Yoshizaki-Ogawa, Shinichi Sato
  • Journal Title: Archives of Clinical and Biomedical Research Volume: 5 Pages: 368-375
  • Peer Reviewed / Open Access
• [Journal Article] Development of a prediction model of treatment response in patients with cutaneous arteritis: Insights from a cohort of 33 patients (2021)
  • Author(s): Matsuda Kazuki Mitsuru、Yoshizaki Ayumi、Kotani Hirohito、Kuzumi Ai、Fukayama Maiko、Ebata Satoshi、Fukasawa Takemichi、Yoshizaki‐Ogawa Asako、Sato Shinichi
  • Journal Title: The Journal of Dermatology Volume: 5 Pages: 5
  • DOI: 10.1111/1346-8138.15868
  • Peer Reviewed
• [Journal Article] Expert-Level Distinction of Systemic Sclerosis from Hand Photographs Using Deep Convolutional Neural Networks (2021)
  • Author(s): Norimatsu Yuta、Yoshizaki Ayumi、Kabeya Yoshinori、Fukasawa Takemichi、Omatsu Jun、Fukayama Maiko、Kuzumi Ai、Ebata Satoshi、Yoshizaki-Ogawa Asako、Asano Yoshihide、Ichimura Haruka、Yonezawa Sho、Nakano Hiroki、Sato Shinichi
  • Journal Title: Journal of Investigative Dermatology Volume: 141 Pages: 2536～2539
  • DOI: 10.1016/j.jid.2021.03.020
  • Peer Reviewed / Open Access
• [Journal Article] Single-cell-level protein analysis revealing the roles of autoantigen-reactive B lymphocytes in autoimmune disease and the murine model (2021)
  • Author(s): Fukasawa Takemichi、Yoshizaki Ayumi、Ebata Satoshi、Yoshizaki-Ogawa Asako、Asano Yoshihide、Enomoto Atsushi、Miyagawa Kiyoshi、Kazoe Yutaka、Mawatari Kazuma、Kitamori Takehiko、Sato Shinichi
  • Journal Title: eLife Volume: 10 Pages: 5
  • DOI: 10.7554/eLife.67209
  • Peer Reviewed / Open Access
• [Journal Article] B Cell Depletion Inhibits Fibrosis via Suppression of Profibrotic Macrophage Differentiation in a Mouse Model of Systemic Sclerosis (2021)
  • Author(s): Numajiri Hiroko、Kuzumi Ai、Fukasawa Takemichi、Ebata Satoshi、Yoshizaki‐Ogawa Asako、Asano Yoshihide、Kazoe Yutaka、Mawatari Kazuma、Kitamori Takehiko、Yoshizaki Ayumi、Sato Shinichi
  • Journal Title: Arthritis & Rheumatology Volume: 73 Pages: 2086～2095
  • DOI: 10.1002/art.41798
  • Peer Reviewed
• [Journal Article] Safety and efficacy of rituximab in systemic sclerosis (DESIRES): a double-blind, investigator-initiated, randomised, placebo-controlled trial. (2021)
  • Author(s): Ebata, S., Yoshizaki, A., Oba, K., Kashiwabara, K., Ueda, K., Uemura, Y., Watadani, T., Fukasawa, T., Miura, S., Yoshizaki-Ogawa, A., Asano, Y., Okiyama, N., Kodera, M., Hasegawa, M., & Sato, S.
  • Journal Title: Lancet Rheumatology Volume: 3 Pages: 489-497
  • Peer Reviewed
• [Journal Article] Interleukin-31 promotes fibrosis and T helper 2 polarization in systemic sclerosis (2021)
  • Author(s): Kuzumi Ai、Yoshizaki Ayumi、Matsuda Kazuki M.、Kotani Hirohito、Norimatsu Yuta、Fukayama Maiko、Ebata Satoshi、Fukasawa Takemichi、Yoshizaki-Ogawa Asako、Asano Yoshihide、Morikawa Kyojiro、Kazoe Yutaka、Mawatari Kazuma、Kitamori Takehiko、Sato Shinichi
  • Journal Title: Nature Communications Volume: 12 Pages: 5
  • DOI: 10.1038/s41467-021-26099-w
  • Peer Reviewed / Open Access
• [Journal Article] Percentage of residual B cells after 2 weeks of rituximab treatment predicts the improvement of systemic sclerosis‐associated interstitial lung disease (2021)
  • Author(s): Ebata Satoshi、Yoshizaki Ayumi、Fukasawa Takemichi、Yoshizaki‐Ogawa Asako、Asano Yoshihide、Kashiwabara Kosuke、Oba Koji、Sato Shinichi
  • Journal Title: The Journal of Dermatology Volume: 49 Pages: 179～183
  • DOI: 10.1111/1346-8138.16206
  • Peer Reviewed
• [Journal Article] Increased Red Blood Cell Distribution Width in the First Year after Diagnosis Predicts Worsening of Systemic Sclerosis-Associated Interstitial Lung Disease at 5 Years: A Pilot Study (2021)
  • Author(s): Ebata Satoshi、Yoshizaki Ayumi、Fukasawa Takemichi、Yoshizaki-Ogawa Asako、Asano Yoshihide、Kashiwabara Kosuke、Oba Koji、Sato Shinichi
  • Journal Title: Diagnostics Volume: 11 Pages: 2274～2274
  • DOI: 10.3390/diagnostics11122274
  • Peer Reviewed / Open Access
• [Presentation] Safety and Efficacy of Rituximab for Systemic Sclerosis: A Double-Blind, Parallel-Group Comparison, Investigators Initiated Confirmatory Randomized Clinical Trial (DESIRES Study) (2021)
  • Author(s): Satoshi Ebata, Ayumi Yoshizaki, Koji Oba, Kosuke Kashiwabara, Keiko Ueda, Yukari Umemura, Takeyuki Watadani, Takemichi Fukasawa, Shunsuke Miura, Asako Yoshizaki-Ogawa, Yoshihide Asano, Naoko Okiyama, Masanari Kodera, Minoru Hasegawa and Shinichi Sato
  • Organizer: American college of rheumatology 2021
  • Int'l Joint Research
• [Book] 「臨床と研究」 (2022)
  • Author(s): 深澤毅倫、吉崎歩、佐藤伸一
  • Total Pages: 5
  • Publisher: 大道学館出版部
• [Book] 皮膚科 膠原病 皮疹から全身を診る (2021)
  • Author(s): 深澤毅倫
  • Total Pages: 5
  • Publisher: 中山書店