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Mechanism of EAF2-mediated elimination of autoreactive germinal center B cells

Research Project

Project/Area Number 17K08878
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeMulti-year Fund
Section一般
Research Field Immunology
Research InstitutionTokyo Medical and Dental University

Principal Investigator

WANG JIYANG  東京医科歯科大学, 難治疾患研究所, 特任講師 (80231041)

Project Period (FY) 2017-04-01 – 2020-03-31
Project Status Completed (Fiscal Year 2019)
Budget Amount *help
¥4,810,000 (Direct Cost: ¥3,700,000、Indirect Cost: ¥1,110,000)
Fiscal Year 2019: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000)
Fiscal Year 2018: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
Fiscal Year 2017: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000)
Keywordsアポトーシス / 胚中心B細胞 / 転写伸長因子 / 転写伸張因子 / 液性免疫 / 自己抗体
Outline of Final Research Achievements

BCL-2 and FAS are known to regulate the apoptosis of the germinal center (GC) B cells. In the present study, we have identified the transcription elongation-associated factor EAF2 as a GC B-specific apoptosis inducer. EAF2-deficient mice produce elevated levels of autoantibodies and develop severe collagen-induced arthritis. RNA sequencing analysis revealed that EAF2 suppresses the transcription of the anti-apoptotic factor Bcl-2 and promotes the transcription of the pro-apoptotic molecule Bbc3/Puma. These results collectively demonstrate that EAF2 functions to suppress autoimmunity by facilitating the elimination of autoreactive GC B cells.

Academic Significance and Societal Importance of the Research Achievements

本研究により、胚中心B細胞のアポトーシスを制御する新たな因子が発見された。BCL-2やFASなどの従来知られているアポトーシス制御分子と異なり、本研究で発見されたEAF2は胚中心B細胞に特異的に発現し、自己反応性B細胞の除去と自己免疫疾患の抑制に特化した機能を有する点に独創性がある。本研究により、新たなB細胞免疫寛容機構が提示できた。また、本研究は遺伝子改変マウスを中心に進められたが、今後、ヒト胚中心B細胞のアポトーシス制御において、EAF2が同様な機能を発揮することが判明すれば、ヒト自己免疫疾患の発症、診断および治療の手掛かりとなりうるので、社会的意義が大きい。

Report

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

    (16 results)

All 2020 2019 2018 2017

All Journal Article (16 results) (of which Int'l Joint Research: 15 results,  Peer Reviewed: 16 results,  Open Access: 3 results)

  • [Journal Article] Effective and safe treatment of a novel IL2RA deficiency with rapamycin2020

    • Author(s)
      Lai Nannan、Liu Luyao、Lin Li、Cui Chaoqun、Wang Ying、Min Qing、Xiong Ermeng、Wang Wenjie、Ying Wenjing、Zhou Qinhua、Hou Jia、Sun Jinqiao、Wang Ji-Yang、Wang Xiaochuan
    • Journal Title

      The Journal of Allergy and Clinical Immunology: In Practice

      Volume: 8 Issue: 3 Pages: 1132-1135.e4

    • DOI

      10.1016/j.jaip.2019.09.027

    • Related Report
      2019 Annual Research Report
    • Peer Reviewed / Int'l Joint Research
  • [Journal Article] Distinct roles of BCNP1 in B-cell development and activation2019

    • Author(s)
      Hong Rongjian、Lai Nannan、Xiong Ermeng、Ouchida Rika、Sun Jiping、Zhou Yang、Tang Yue、Hikida Masaki、Tsubata Takeshi、Tagawa Masatoshi、Wang Yanqing、Wang Ji-Yang
    • Journal Title

      International Immunology

      Volume: 32 Issue: 1 Pages: 17-26

    • DOI

      10.1093/intimm/dxz055

    • Related Report
      2019 Annual Research Report
    • Peer Reviewed / Int'l Joint Research
  • [Journal Article] MZB1 promotes the secretion of J-chain?containing dimeric IgA and is critical for the suppression of gut inflammation2019

    • Author(s)
      Xiong Ermeng、Li Yingqian、Min Qing、Cui Chaoqun、Liu Jun、Hong Rongjian、Lai Nannan、Wang Ying、Sun Jiping、Matsumoto Ryohtaroh、Takahashi Daisuke、Hase Koji、Shinkura Reiko、Tsubata Takeshi、Wang Ji-Yang
    • Journal Title

      Proceedings of the National Academy of Sciences

      Volume: 116 Issue: 27 Pages: 13480-13489

    • DOI

      10.1073/pnas.1904204116

    • Related Report
      2019 Annual Research Report
    • Peer Reviewed / Int'l Joint Research
  • [Journal Article] The B cell novel protein 1 (BCNP1) regulates BCR signaling and B cell apoptosis2019

    • Author(s)
      Hong Rongjian、Lai Nannan、Ouchida Rika、Xiong Ermeng、Zhou Yang、Min Qing、Liu Jun、Tang Yue、Hikida Masaki、Tsubata Takeshi、Wang Yanqing、Wang Ji‐Yang
    • Journal Title

      European Journal of Immunology

      Volume: 49 Issue: 6 Pages: 911-917

    • DOI

      10.1002/eji.201847985

    • Related Report
      2019 Annual Research Report
    • Peer Reviewed / Int'l Joint Research
  • [Journal Article] Essential Role of NADPH Oxidase?Dependent Production of Reactive Oxygen Species in Maintenance of Sustained B Cell Receptor Signaling and B Cell Proliferation2019

    • Author(s)
      Feng Yang-Yang、Tang Miao、Suzuki Mitsuhiro、Gunasekara Chinthika、Anbe Yuki、Hiraoka Yuichi、Liu Jun、Grasberger Helmut、Ohkita Mamoru、Matsumura Yasuo、Wang Ji-Yang、Tsubata Takeshi
    • Journal Title

      The Journal of Immunology

      Volume: 202 Issue: 9 Pages: 2546-2557

    • DOI

      10.4049/jimmunol.1800443

    • Related Report
      2019 Annual Research Report
    • Peer Reviewed / Int'l Joint Research
  • [Journal Article] A tetrameric form of CD40 ligand with potent biological activities in both mouse and human primary B cells2019

    • Author(s)
      Lai Nannan、Min Qing、Xiong Ermeng、Liu Jun、Zhang Lumin、Yasuda Shoya、Wang Ji-Yang
    • Journal Title

      Molecular Immunology

      Volume: 105 Pages: 173-180

    • DOI

      10.1016/j.molimm.2018.11.018

    • Related Report
      2019 Annual Research Report
    • Peer Reviewed
  • [Journal Article] MZB1 promotes the secretion of J chain-containing dimeric IgA and is critical for the suppression of gut inflammation2019

    • Author(s)
      Xiong, E., Li, Y., Min, Q., Cui, C., Liu, J., Hong, R., Lai, N., Wang, Y., Sun, J., Matsumoto, R., Takahashi, D., Hase, K., Shinkura, R., Tsubata, T. and Wang, J.-Y.
    • Journal Title

      Proc. Natl. Acad. Sci. USA

      Volume: 印刷中

    • Related Report
      2018 Research-status Report
    • Peer Reviewed / Int'l Joint Research
  • [Journal Article] The B cell novel protein 1 regulates BCR signaling and B cell apoptosis.2019

    • Author(s)
      Hong, R., Lai, N., Ouchida, R., Xiong, E., Zhou, Y., Hikida, M., Tsubata, T., Wang Y.Q. and Wang, J.-Y.
    • Journal Title

      Eur. J. Immunol.

      Volume: 印刷中

    • Related Report
      2018 Research-status Report
    • Peer Reviewed / Int'l Joint Research
  • [Journal Article] Role of the IgM Fc receptor in immunity and tolerance2018

    • Author(s)
      Liu, J., Wang, Y., Xiong, E., Hong, R., Ohno, H. and Wang, J.-Y.
    • Journal Title

      Front. Immunol.

      Volume: 10 Pages: 529-529

    • DOI

      10.3389/fimmu.2019.00529

    • Related Report
      2019 Annual Research Report 2018 Research-status Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] A tetrameric form of CD40 ligand with potent biological activities in both mouse and human primary B cells2018

    • Author(s)
      Lai, N., Min, Q., Xiong, E., Liu, J., Zhang, L., Yasuda, S. and Wang, J.-Y.
    • Journal Title

      Mol. Immunol.

      Volume: 105 Pages: 173-180

    • Related Report
      2018 Research-status Report
    • Peer Reviewed / Int'l Joint Research
  • [Journal Article] TLR2 Promotes Glioma Immune Evasion by Downregulating MHC Class II Molecules in Microglia2018

    • Author(s)
      Qian, J., Luo, F., Yang, J., Liu, J., Liu, R., Wang, L., Wang, C., Deng, Y., Lu, Z., Wang, Y., Lu, M., Wang, J.-Y. and Chu, Y.
    • Journal Title

      Cancer Immunol. Res.

      Volume: 6 Issue: 10 Pages: 1220-1233

    • DOI

      10.1158/2326-6066.cir-18-0020

    • Related Report
      2018 Research-status Report
    • Peer Reviewed / Int'l Joint Research
  • [Journal Article] Kelch-like protein 14 promotes B-1a but suppresses B-1b cell development2018

    • Author(s)
      Li, S., Liu, J., Min, Q., Ikawa, T., Yasuda, S., Yang, Y., Wang, Y.-Q., Tsubata, T., Zhao, Y. and Wang, J.-Y.
    • Journal Title

      Int. Immunol.

      Volume: 30 Issue: 7 Pages: 311-318

    • DOI

      10.1093/intimm/dxy033

    • Related Report
      2018 Research-status Report
    • Peer Reviewed / Int'l Joint Research
  • [Journal Article] FcµR promotes the survival and activation of marginal zone B cells and protects mice against bacterial sepsis2018

    • Author(s)
      Liu, J., Zhu, H., Qian, J., Xiong, E., Zhang, L., Chu, Y., Kubagawa, H., Tsubata, T. and Wang, J.-Y.
    • Journal Title

      Frontiers in Immunology

      Volume: 9 Pages: 160-160

    • DOI

      10.3389/fimmu.2018.00160

    • Related Report
      2018 Research-status Report 2017 Research-status Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Kelch-like protein 14 promotes B-1a but suppresses B-1b cell development2018

    • Author(s)
      Li, S., Liu, J., Min, Q., Ikawa, T., Yasuda, S., Yang, Y., Wang, Y., Tsubata, T., Zhao, Y. and Wang, J.-Y.
    • Journal Title

      International Immunology

      Volume: in press

    • Related Report
      2017 Research-status Report
    • Peer Reviewed / Int'l Joint Research
  • [Journal Article] Efficient induction of Ig gene hypermutation in ex vivo-activated primary B cells.2017

    • Author(s)
      Liu, J., Xiong, E., Zhu, H., Mori, H., Yasuda, S., Kinoshita, K., Tsubata, T. and Wang, J.-Y.
    • Journal Title

      Journal of Immunology

      Volume: 199 Issue: 9 Pages: 3023-3030

    • DOI

      10.4049/jimmunol.1700868

    • Related Report
      2017 Research-status Report
    • Peer Reviewed / Int'l Joint Research
  • [Journal Article] A model integrating tonic and activated BCR signals to predict the survival of primary B cells2017

    • Author(s)
      Yasuda, S., Zhou, Y., Wang, Y., Yamamura, M. and Wang, J.-Y.
    • Journal Title

      Scientific Reports

      Volume: 7 Issue: 1 Pages: 14888-14888

    • DOI

      10.1038/s41598-017-13993-x

    • Related Report
      2017 Research-status Report
    • Peer Reviewed / Open Access / Int'l Joint Research

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

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