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

• Project/Area Number: 17K08878
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Immunology
• Research Institution: Tokyo 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: ¥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。

Research Products

• [Journal Article] Effective and safe treatment of a novel IL2RA deficiency with rapamycin (2020)
  • 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
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Distinct roles of BCNP1 in B-cell development and activation (2019)
  • 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
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  • 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 inflammation (2019)
  • 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
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] The B cell novel protein 1 (BCNP1) regulates BCR signaling and B cell apoptosis (2019)
  • 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
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  • 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 Proliferation (2019)
  • 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
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  • 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 cells (2019)
  • 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
  • Peer Reviewed
• [Journal Article] MZB1 promotes the secretion of J chain-containing dimeric IgA and is critical for the suppression of gut inflammation (2019)
  • 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
  • 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
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Role of the IgM Fc receptor in immunity and tolerance (2018)
  • 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
  • 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 cells (2018)
  • Author(s): Lai, N., Min, Q., Xiong, E., Liu, J., Zhang, L., Yasuda, S. and Wang, J.-Y.
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  • Peer Reviewed / Int'l Joint Research
• [Journal Article] TLR2 Promotes Glioma Immune Evasion by Downregulating MHC Class II Molecules in Microglia (2018)
  • 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
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Kelch-like protein 14 promotes B-1a but suppresses B-1b cell development (2018)
  • 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.
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  • DOI: 10.1093/intimm/dxy033
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] FcµR promotes the survival and activation of marginal zone B cells and protects mice against bacterial sepsis (2018)
  • 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
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Kelch-like protein 14 promotes B-1a but suppresses B-1b cell development (2018)
  • 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
  • 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
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] A model integrating tonic and activated BCR signals to predict the survival of primary B cells (2017)
  • 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
  • Peer Reviewed / Open Access / Int'l Joint Research