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Comprehensive analysis of autoantigen-reactive B cell in systemic sclerosis and identification of therapeutic targets

Research Project

Project/Area Number 17H04239
Research Category

Grant-in-Aid for Scientific Research (B)

Allocation TypeSingle-year Grants
Section一般
Research Field Dermatology
Research InstitutionThe University of Tokyo

Principal Investigator

Sato Shinichi  東京大学, 医学部附属病院, 教授 (20215792)

Co-Investigator(Kenkyū-buntansha) 吉崎 歩  東京大学, 医学部附属病院, 講師 (40530415)
北森 武彦  東京大学, 大学院工学系研究科(工学部), 特任教授 (60214821)
Project Period (FY) 2017-04-01 – 2020-03-31
Project Status Completed (Fiscal Year 2019)
Budget Amount *help
¥16,770,000 (Direct Cost: ¥12,900,000、Indirect Cost: ¥3,870,000)
Fiscal Year 2019: ¥4,420,000 (Direct Cost: ¥3,400,000、Indirect Cost: ¥1,020,000)
Fiscal Year 2018: ¥6,500,000 (Direct Cost: ¥5,000,000、Indirect Cost: ¥1,500,000)
Fiscal Year 2017: ¥5,850,000 (Direct Cost: ¥4,500,000、Indirect Cost: ¥1,350,000)
Keywords強皮症 / 自己免疫疾患 / B細胞 / サイトカイン / マイクロ・ナノデバイス
Outline of Final Research Achievements

It has been suggested that B cells play an important role in systemic sclerosis (SSc), and among them, autoantigen-reactive B cells are considered to be particularly important in the development of the disease. However, the role of autoantigen-reactive B cells in the pathogenesis is unclear because they are only present in a small number and there are no direct studies to date. In this study, autoantigen-reactive B cells were analyzed at the single B cell level using a microprotein analysis system developed by a medical engineering collaboration. Furthermore, we analyzed the function of autoantigen-reactive B cells through single B cell analysis using SSc model mice.

Academic Significance and Societal Importance of the Research Achievements

自己抗原反応性B細胞の解析は単一の細胞集団ではなく、その機能は細胞ごとに異なっていると想定される。しかしながら、技術的な困難から、これまで自己抗原反応性B細胞の単一細胞解析は、タンパク質レベルでは行われていなかった。本研究は医工連携研究によって開発された分析システムを用いて、自己抗原反応性B細胞の単一細胞解析をタンパク質レベルで実現した。本研究で用いた手法は強皮症以外の自己免疫疾患にも応用可能と考えられ、その学術的意義は高いと考えた。

Report

(4 results)
  • 2019 Annual Research Report   Final Research Report ( PDF )
  • 2018 Annual Research Report
  • 2017 Annual Research Report
  • Research Products

    (29 results)

All 2020 2019 2018 2017

All Journal Article (14 results) (of which Int'l Joint Research: 11 results,  Peer Reviewed: 14 results,  Open Access: 2 results) Presentation (15 results) (of which Int'l Joint Research: 15 results)

  • [Journal Article] Combined immunosuppressive therapy provides favorable prognosis and increased risk of cytomegalovirus reactivation in anti‐melanoma differentiation‐associated gene 5 antibody‐positive dermatomyositis2020

    • Author(s)
      Matsuda Kazuki M.、Yoshizaki Ayumi、Kuzumi Ai、Fukasawa Takemichi、Ebata Satoshi、Yoshizaki‐Ogawa Asako、Sato Shinichi
    • Journal Title

      The Journal of Dermatology

      Volume: - Issue: 5 Pages: 483-489

    • DOI

      10.1111/1346-8138.15274

    • Related Report
      2019 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Fli1 deficiency induces endothelial adipsin expression, contributing to the onset of pulmonary arterial hypertension in systemic sclerosis2019

    • Author(s)
      Miyagawa Takuya、Taniguchi Takashi、Saigusa Ryosuke、Fukayama Maiko、Takahashi Takehiro、Yamashita Takashi、Hirabayashi Megumi、Miura Shunsuke、Nakamura Kouki、Yoshizaki Ayumi、Sato Shinichi、Asano Yoshihide
    • Journal Title

      Rheumatology

      Volume: - Issue: 8 Pages: 2005-2015

    • DOI

      10.1093/rheumatology/kez517

    • Related Report
      2019 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Rituximab therapy is more effective than cyclophosphamide therapy for Japanese patients with anti-topoisomerase I-positive systemic sclerosis-associated interstitial lung disease.2019

    • Author(s)
      Ebata S, Yoshizaki A, Fukasawa T, Miura S, Takahashi T, Sumida H, Asano Y, Sato S.
    • Journal Title

      J Dermatol

      Volume: 46 Issue: 11 Pages: 1006-1013

    • DOI

      10.1111/1346-8138.15079

    • Related Report
      2019 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Skin thickness score as a surrogate marker of organ involvements in systemic sclerosis: a retrospective observational study.2019

    • Author(s)
      Matsuda KM, Yoshizaki A, Kuzumi A, Fukasawa T, Ebata S, Miura S, Toyama T, Yoshizaki A, Sumida H, Asano Y, Oba K, Sato S.
    • Journal Title

      Arthritis Res Ther

      Volume: 21 Issue: 1 Pages: 129-129

    • DOI

      10.1186/s13075-019-1919-6

    • Related Report
      2019 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Serum levels of human β-defensin 2: possible association with fibrosis and vasculopathy in patients with systemic sclerosis.2019

    • Author(s)
      Kuzumi A, Yoshizaki A, Fukasawa T, Ebata S, Miura S, Yoshizaki A, Sumida H, Asano Y, Sato S.
    • Journal Title

      J Eur Acad Dermatol Venereol.

      Volume: In press Issue: 7

    • DOI

      10.1111/jdv.15546

    • Related Report
      2019 Annual Research Report 2018 Annual Research Report
    • Peer Reviewed / Int'l Joint Research
  • [Journal Article] A potential contribution of decreased galectin-7 expression in stratified epithelia to the development of cutaneous and esophageal manifestations in systemic sclerosis.2019

    • Author(s)
      Saigusa R, Yamashita T, Miura S, Hirabayashi M, Nakamura K, Miyagawa T, Fukui Y, Yoshizaki A, Sato S, Asano Y.
    • Journal Title

      Exp Dermatol.

      Volume: In press Issue: 5 Pages: 536-542

    • DOI

      10.1111/exd.13900

    • Related Report
      2018 Annual Research Report
    • Peer Reviewed / Int'l Joint Research
  • [Journal Article] A potential contribution of trappin-2 to the development of vasculopathy in systemic sclerosis.2019

    • Author(s)
      Miyagawa T, Asano Y, Saigusa R, Hirabayashi M, Yamashita T, Taniguchi T, Takahashi T, Nakamura K, Miura S, Yoshizaki A, Miyagaki T, Sato S.
    • Journal Title

      J Eur Acad Dermatol Venereol.

      Volume: In press Issue: 4 Pages: 753-760

    • DOI

      10.1111/jdv.15387

    • Related Report
      2018 Annual Research Report
    • Peer Reviewed / Int'l Joint Research
  • [Journal Article] Prediction of therapeutic response before and during i.v. cyclophosphamide pulse therapy for interstitial lung disease in systemic sclerosis: A longitudinal observational study2018

    • Author(s)
      Sumida Hayakazu、Asano Yoshihide、Tamaki Zenshiro、Aozasa Naohiko、Taniguchi Takashi、Toyama Tetsuo、Takahashi Takehiro、Ichimura Yohei、Noda Shinji、Akamata Kaname、Saigusa Ryosuke、Miyazaki Miki、Kuwano Yoshihiro、Yanaba Koichi、Yoshizaki Ayumi、Sato Shinichi
    • Journal Title

      The Journal of Dermatology

      Volume: 45 Issue: 12 Pages: 1425-1433

    • DOI

      10.1111/1346-8138.14669

    • Related Report
      2018 Annual Research Report
    • Peer Reviewed / Int'l Joint Research
  • [Journal Article] Rapid alteration of serum interleukin-6 levels may predict the reactivity of i.v. cyclophosphamide pulse therapy in systemic sclerosis-associated interstitial lung disease.2018

    • Author(s)
      Numajiri H, Yoshizaki A, Fukasawa T, Ebata S, Nakamura K, Yamashita T, Saigusa R, Miura S, Hirabayashi M, Yoshizaki A, Sumida H, Asano Y, Kazoe Y, Mawatari K, Kitamori T, Sato S.
    • Journal Title

      J Dermatol.

      Volume: 45 Issue: 10 Pages: 1221-1224

    • DOI

      10.1111/1346-8138.14580

    • Related Report
      2018 Annual Research Report
    • Peer Reviewed / Int'l Joint Research
  • [Journal Article] Fli1-haploinsufficient dermal fibroblasts promote skin-localized transdifferentiation of Th2-like regulatory T cells2018

    • Author(s)
      Saigusa Ryosuke、Asano Yoshihide、Taniguchi Takashi、Hirabayashi Megumi、Nakamura Kouki、Miura Shunsuke、Yamashita Takashi、Takahashi Takehiro、Ichimura Yohei、Toyama Tetsuo、Yoshizaki Ayumi、Trojanowska Maria、Sato Shinichi
    • Journal Title

      Arthritis Research & Therapy

      Volume: 20 Issue: 1 Pages: 23-23

    • DOI

      10.1186/s13075-018-1521-3

    • Related Report
      2017 Annual Research Report
    • Peer Reviewed / Int'l Joint Research
  • [Journal Article] Systemic sclerosis complicated with localized scleroderma-like lesions induced by Koebner phenomenon.2018

    • Author(s)
      Saigusa R, Asano Y, Yamashita T, Takahashi T, Nakamura K, Miura S, Ichimura Y, Toyama T, Taniguchi T, Sumida H, Tamaki Z, Miyazaki M, Yoshizaki A, Sato S.
    • Journal Title

      J Dermatol Sci.

      Volume: 89 Issue: 3 Pages: 282-289

    • DOI

      10.1016/j.jdermsci.2017.12.005

    • Related Report
      2017 Annual Research Report
    • Peer Reviewed / Int'l Joint Research
  • [Journal Article] Possible pro-inflammatory role of heparin-binding epidermal growth factor-like growth factor in the active phase of systemic sclerosis2017

    • Author(s)
      Hirabayashi Megumi、Asano Yoshihide、Yamashita Takashi、Miura Shunsuke、Nakamura Kouki、Taniguchi Takashi、Saigusa Ryosuke、Takahashi Takehiro、Ichimura Yohei、Miyagawa Takuya、Yoshizaki Ayumi、Miyagaki Tomomitsu、Sugaya Makoto、Sato Shinichi
    • Journal Title

      The Journal of Dermatology

      Volume: 45 Issue: 2 Pages: 182-188

    • DOI

      10.1111/1346-8138.14088

    • Related Report
      2017 Annual Research Report
    • Peer Reviewed / Int'l Joint Research
  • [Journal Article] Contribution of Soluble Forms of Programmed Death 1 and Programmed Death Ligand 2 to Disease Severity and Progression in Systemic Sclerosis2017

    • Author(s)
      Fukasawa Takemichi、Yoshizaki Ayumi、Ebata Satoshi、Nakamura Kouki、Saigusa Ryosuke、Miura Syunsuke、Yamashita Takashi、Hirabayashi Megumi、Ichimura Yohei、Taniguchi Takashi、Asano Yoshihide、Shimizu Hisashi、Kazoe Yutaka、Mawatari Kazuma、Kitamori Takehiko、Sato Shinichi
    • Journal Title

      Arthritis & Rheumatology

      Volume: 69 Issue: 9 Pages: 1879-1890

    • DOI

      10.1002/art.40164

    • Related Report
      2017 Annual Research Report
    • Peer Reviewed / Int'l Joint Research
  • [Journal Article] Fli1 Deficiency Induces CXCL6 Expression in Dermal Fibroblasts and Endothelial Cells, Contributing to the Development of Fibrosis and Vasculopathy in Systemic Sclerosis.2017

    • Author(s)
      Taniguchi T, Asano Y, Nakamura K, Yamashita T, Saigusa R, Ichimura Y, Takahashi T, Toyama T, Yoshizaki A, Sato S.
    • Journal Title

      J Rheumatol.

      Volume: 44 Issue: 8 Pages: 1198-1205

    • DOI

      10.3899/jrheum.161092

    • Related Report
      2017 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Presentation] Tissue microenvironment maintains tissue-resident B cells during B cell depletion therapy in systemic sclerosis2019

    • Author(s)
      Ayumi Yoshizaki, Ai Kuzumi, Takemichi Fukasawa, Satoshi Ebata, Shinichi Sato
    • Organizer
      14th Annual Meeting of the Taiwanese Society for Investigative Dermatology
    • Related Report
      2019 Annual Research Report
    • Int'l Joint Research
  • [Presentation] Responses to therapy are determined by effector B cells in systemic sclerosis-associated interstitial lung disease2019

    • Author(s)
      Satoshi Ebata, Ayumi Yoshizaki, Takemichi Fukasawa, Kazuma Mawatari, Takehiko Kitamori, Shinichi Sato
    • Organizer
      14th Annual Meeting of the Taiwanese Society for Investigative Dermatology
    • Related Report
      2019 Annual Research Report
    • Int'l Joint Research
  • [Presentation] Microenvironment in systemic sclerosis provides a protective niche for tissue-resident B cells during B cell depletion therapy with anti-CD20 antibody2019

    • Author(s)
      Ai Kuzumi, Ayumi Yoshizaki, Takemichi Fukasawa, Satoshi Ebata, Yoshihide Asano, Shinichi Sato
    • Organizer
      2019 ACR (83th)/ARHP (53th) Annual Meeting
    • Related Report
      2019 Annual Research Report
    • Int'l Joint Research
  • [Presentation] 全身性強皮症の組織微小環境は、抗CD20交代によるB細胞除去療法において、組織中B細胞のprotective nicheとしてはたらく2019

    • Author(s)
      久住藍、吉崎歩、深澤毅倫、江畑慧、佐藤伸一
    • Organizer
      第47回日本臨床免疫学会総会
    • Related Report
      2019 Annual Research Report
    • Int'l Joint Research
  • [Presentation] Tissue microenvironment provides a protective niche for tissue-resident B cells during B cell depletion therapy with anti-CD20 antibody in systemic sclerosis2019

    • Author(s)
      Kuzumi A, Yoshizaki A, Fukasawa T, Ebata S, Asano Y, Sato S
    • Organizer
      16th International Workshop on SCLERODERMA RESEARCH
    • Related Report
      2019 Annual Research Report
    • Int'l Joint Research
  • [Presentation] Elevated Serum Interleukin-34 Levels Are Correlated with Interstitial Lung isease in Systemic Sclerosis.2018

    • Author(s)
      Suga H, Kuzumi A, Asano Y, Yoshizaki A, Sato S
    • Organizer
      2018 ACR (82th)/ARHP (53th) Annual Meeting
    • Related Report
      2018 Annual Research Report
    • Int'l Joint Research
  • [Presentation] Direct Interaction between Autoreactive B Cells and Endothelial Colony Forming Cells Induces Cytokine Production from B cells through B Cell Receptor and IL-6-JAK2-STAT3 Signaling Pathway, Suppressing Proliferation of Endothelial Colony Forming Cells in Systemic Scleosis.2018

    • Author(s)
      Fukasawa T, Yoshizaki A, Ebata S, Nakamura K, Asano Y, Kazoe Y, Mawatari K, Kitamori T, Sato S
    • Organizer
      2018 ACR (82th)/ARHP (53th) Annual Meeting
    • Related Report
      2018 Annual Research Report
    • Int'l Joint Research
  • [Presentation] Heterozygote deficiency of the keratinocyte proline-rich protein enhances the skin barrier by increasing lysophosphatidic acid receptor expression.2018

    • Author(s)
      Matsumoto A, Yoshizaki A, Nakanishi H, Ishikawa S, Fukayama M, Sato S
    • Organizer
      The 5th Eastern Asia Dermatology Congress
    • Related Report
      2018 Annual Research Report
    • Int'l Joint Research
  • [Presentation] Serum levels of soluble PD-1 and PD-L2 associate with abnormal immune activation and disease severity in patients with systemic sclerosis.2018

    • Author(s)
      Yoshizaki A, Fukasawa T, Ebata S, Yoshizaki A, Kazoe Y, Mawatari K, Kitamori T, Sato S.
    • Organizer
      The 5th Eastern Asia Dermatology Congress
    • Related Report
      2018 Annual Research Report
    • Int'l Joint Research
  • [Presentation] B cell depletion ameliorates tissue fibrosis through regulating macrophage differentiation in a bleomycin-induced systemic sclerosis model mouse.2018

    • Author(s)
      Numajiri H, Yoshizaki A, Fukasawa T, Ebata S, Asano Y, Sato S
    • Organizer
      2018 The 19th Annual European Congress of Rheumatology
    • Related Report
      2018 Annual Research Report
    • Int'l Joint Research
  • [Presentation] The cytokine profile revealed with the high sensitive microfluidic-ELISA system associates with the efficacy of antibody drugs in psoriasis2018

    • Author(s)
      Fukasawa T, Yoshizaki A, Ebata S, Asano Y, Kazoe Y, Mawatari K, Kitamori T, Sato S
    • Organizer
      11th Asian Dermatological Congress held in conjunction with the 18th Dubai World Dermatology & Laser Conference and Exhibition-Dubai Derma
    • Related Report
      2017 Annual Research Report
    • Int'l Joint Research
  • [Presentation] Fli1-deficient B cells induce scleroderma-like vascular disorganization via activating pro-angiogenic gene program in dermal microvascular endothelial cells - A possible role in scleroderma vasculopathy2017

    • Author(s)
      Ryosuke Saigusa, Yoshihide Asano, Ayumi Yoshizaki, Maria Trojanowska, Shinichi Sato
    • Organizer
      2017 SID (76th) Annual Meeting
    • Related Report
      2017 Annual Research Report
    • Int'l Joint Research
  • [Presentation] B10 cells suppress contact dermatitis in an antigen specific manner2017

    • Author(s)
      M Kamata, KM Candando, E Kountikov, A Yoshizaki, T Miyagaki, JM Lykken, JC Poe, S Sato, T Tedder
    • Organizer
      2017 SID (76th) Annual Meeting
    • Related Report
      2017 Annual Research Report
    • Int'l Joint Research
  • [Presentation] Distinct B cell cytokine production is determined by B cell autoantigen affinity and is related to its pathogenic role in systemic sclerosis2017

    • Author(s)
      Takemichi Fukasawa, Ayumi Yoshizaki, Satoshi Ebata, Kouki Nakamura, Ryosuke Saigusa, Takashi Yamashita, Yoshihide Asano, Yutaka Kazoe, Kazuma Mawatari, Takehiko Kitamori, Shinichi Sato
    • Organizer
      The 42nd Annual Meeting of the Japanese Society for Investigative Dermatology
    • Related Report
      2017 Annual Research Report
    • Int'l Joint Research
  • [Presentation] The novel micro-fluidic system reveals the pathogenic roles of vascular endothelium-specific B cells in cutaneous arteritis2017

    • Author(s)
      Ayumi Yoshizaki, Kouki Nakamura, Satoshi Ebata, Takemichi Fukasawa, Yoshihide Asano, Yutaka Kazoe, Kazuma Mawatari, Takehiko Kitamori, Shinichi Sato
    • Organizer
      The 42nd Annual Meeting of the Japanese Society for Investigative Dermatology
    • Related Report
      2017 Annual Research Report
    • Int'l Joint Research

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Published: 2017-04-28   Modified: 2021-02-19  

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