Analysis of the effect of cytokine production by autoantigen-reactive B cells in systemic sclerosis on other immune systems.

• Project/Area Number: 20K22925
• Research Category: Grant-in-Aid for Research Activity Start-up
• Allocation Type: Multi-year Fund
• Review Section: 0903:Organ-based internal medicine and related fields
• Research Institution: The University of Tokyo
• Principal Investigator: Fukasawa Takemichi 東京大学, 医学部附属病院, 助教 (80884056)
• Project Period (FY): 2020-09-11 – 2022-03-31
• Project Status: Completed (Fiscal Year 2021)
• Budget Amount: ¥2,860,000 (Direct Cost: ¥2,200,000、Indirect Cost: ¥660,000); Fiscal Year 2021: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2020: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
• Keywords: 自己反応性B細胞 / サイトカイン / 全身性強皮症 / T細胞 / microfluidics / 単一細胞解析 / B細胞 / affinity / 医工連携

Outline of Research at the Start

全身性強皮症は全身性自己免疫疾患で、本邦における指定難病であり、有効な治療法はない。近年、この病態形成には免疫系の主要構成因子であるB細胞、中でも自己抗体産生の担い手である自己抗原反応性B細胞が全身性強皮症の病態に重要な役割を果たすことが想定されるが、数は少なく、直接的な病原性の解析法が十分に確立していない。今回の研究では、医工連携研究によって開発された少数細胞のタンパク質レベルでの解析システムを用い、全身性強皮症における自己抗原反応性B細胞の役割を検討し、広く自己免疫疾患における自己抗原反応性B細胞の役割の理解を深め、新たな治療ターゲットの同定と治療法開発へとつなげることを目指す。

Outline of Final Research Achievements

In this study, we used original microspace-based techniques and methodologies to elucidate the function and role of autoreactive B cells in systemic sclerosis (SSc). Regarding the relationship between affinity to topoI antigen and cytokine production capacity, the proportion of B cells producing inflammatory cytokines such as IL-6 and IL-23 was higher in high affinity B cells, and the amount produced was also higher. Similarly, low affinity B cells produced a higher percentage of B cells that produced IL-10 and IL-35 inhibitory cytokines, and the amount produced was also higher. The former was also shown to induce Th17 cells and the latter Treg cells.

Academic Significance and Societal Importance of the Research Achievements

本研究は、自己抗原反応性B細胞の機能を明らかとすることで、数あるB細胞集団中から、病原性を有するB細胞集団を明らかとする。さらに我々の技術では、少数の自己抗原反応性B細胞のタンパク分析を可能としており、表面抗原の分析によって新たな治療ターゲットの同定につながることが期待される。このような研究は他に類が無く、他の自己免疫疾患においても応用可能であることから、革新的かつ創造的な研究となることが期待される。

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 Issue: 1 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 Issue: 11 Pages: 5-5
  • 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 Issue: 7 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 Issue: 11 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: 160-160
  • 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 Issue: 2 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 Issue: 2 Pages: 250-250
  • 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 Issue: 4 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 Issue: 7 Pages: 5-5
  • 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 Issue: 10 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 T, Yoshizaki A, Ebata S, Yoshizaki-Ogawa A, Asano Y, Enomoto A, Miyagawa K, Kazoe Y, Mawatari K, Kitamori T, Sato S.
  • Journal Title: Elife Volume: 10 Pages: 5-5
  • 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 Issue: 11 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 Issue: 1 Pages: 5-5
  • 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 Issue: 1 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 Issue: 12 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