Mechanisms for de-tolerance spreading of B cells in autoimmune diseases

• Project/Area Number: 18K19461
• Research Category: Grant-in-Aid for Challenging Research (Exploratory)
• Allocation Type: Multi-year Fund
• Review Section: Medium-sized Section 49:Pathology, infection/immunology, and related fields
• Research Institution: Tokyo University of Science
• Principal Investigator: Kitamura Daisuke 東京理科大学, 研究推進機構生命医科学研究所, 教授 (70204914)
• Project Period (FY): 2018-06-29 – 2020-03-31
• Project Status: Completed (Fiscal Year 2019)
• Budget Amount: ¥6,370,000 (Direct Cost: ¥4,900,000、Indirect Cost: ¥1,470,000); Fiscal Year 2019: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000); Fiscal Year 2018: ¥4,290,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥990,000)
• Keywords: 自己抗体 / 自己寛容 / 自己免疫疾患 / IgA腎症 / 自己免疫 / 免疫寛容 / 免疫記憶 / 胚中心

Outline of Final Research Achievements

The reason why autoreactive B cells are activated and produce autoantibodies in autoimmune diseases in spite of the self-tolerance principle is still unknown. Recently, a phenomenon so called de-tolerance spreading has been found, in which autoreactive germinal center B cells break tolerance of other autoreactive B cells. To understand its mechanism, we used gddY mice, a model of IgA nephropathy. We found that gddY mice produced IgA-type autoantibodies that bind to proteins of glomeruli the number of which increased with age. We also found that IgA+ plasmablasts with mutated Ig V genes accumulated in the kidneys of gddY mice with age, which was suppressed by continuous administration of antibiotics. These data suggest that continuous stimuli from commensal bacteria promote de-tolerance spreading and activation of pre-tolerized autoreactive memory B cells to produce autoantibodies.

Academic Significance and Societal Importance of the Research Achievements

SLE等の全身性自己免疫疾患では、血清自己抗体の種類が次第に拡大していく現象（epitope spreading）が知られている。これは、抗原の異なる自己反応性B細胞が次々に寛容を脱して活性化するものと解釈され、上述の脱寛容伝播という現象はこれをうまく説明できる。この脱寛容伝播現象のメカニズムの解明は自己免疫という免疫学的の中心課題の進展に繋がり、また、自己免疫疾患の進展を抑える治療法の開発にも繋がると思われる。

Research Products

• [Journal Article] Ubiquitination of IgG1 cytoplasmic tail modulates B-cell signalling and activation (2020)
  • Author(s): Kodama Tadahiro、Hasegawa Mika、Sakamoto Yui、Haniuda Kei、Kitamura Daisuke
  • Journal Title: International Immunology Volume: - Issue: 6 Pages: 385-395
  • DOI: 10.1093/intimm/dxaa009
  • Peer Reviewed
• [Journal Article] Cross-reactivity to kynureninase tolerizes B cells that express the HIV-1 broadly neutralizing antibody 2F5. (2019)
  • Author(s): Finney, J., Yang, G., Kuraoka, M., Song, S., Nojima, T., Verkoczy, L., Kitamura, D., Haynes, B.F., Kelsoe, G.
  • Journal Title: The Journal of Immunology Volume: 203 Issue: 12 Pages: 3268-3281
  • DOI: 10.4049/jimmunol.1900069
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] The quantity of CD40 signaling determines the differentiation of B cells into functionally distinct memory cell subsets. (2019)
  • Author(s): Koike, T., Harada, K., Horiuchi, S., Kitamura, D.
  • Journal Title: eLife Volume: 8
  • DOI: 10.7554/elife.44245
  • Peer Reviewed / Open Access
• [Journal Article] Induced Germinal Center B Cell Culture System (2019)
  • Author(s): Haniuda Kei、Kitamura Daisuke
  • Journal Title: BIO-PROTOCOL Volume: 9 Issue: 4 Pages: 3163-3163
  • DOI: 10.21769/bioprotoc.3163
  • Peer Reviewed / Open Access
• [Journal Article] PRMT5 is essential for B cell development and germinal center dynamics. (2019)
  • Author(s): Litzler, L.C., Zahn, A., Meli, A.P., Hebert, S., Patenaude, A., Methot, S.P., Sprumont, A., Bois, T., Kitamura, D., Costantino, S., King, I.L., Kleinman, C.L., Richard, S., Di Noia, J.M.
  • Journal Title: Nature Communications Volume: 10 Issue: 1 Pages: 22-22
  • DOI: 10.1038/s41467-018-07884-6
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Transcription Factor STAT3 Serves as a negative regulator controlling IgE class switching in mice. (2018)
  • Author(s): Dascani, P., Ding, C., Kong, K., Tieri, D., Hu, X., Zhang, H., Kitamura, D., Bolli, R., Rouchka, E.C., Yan, J.
  • Journal Title: ImmunoHorizens Volume: 2 Issue: 11 Pages: 349-362
  • DOI: 10.4049/immunohorizons.1800069
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] IL-9 receptor signaling in memory B cells regulates humoral recall responses. (2018)
  • Author(s): Takatsuka, S., Yamada, H., Haniuda, K., Saruwatari, H., Ichihashi, M., Renauld, J.-C. and Kitamura, D.
  • Journal Title: Nature Immunology Volume: 19 Issue: 9 Pages: 1025-1034
  • DOI: 10.1038/s41590-018-0177-0
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] A splenic IgM memory subset with antibacterial specificities is sustained from persistent mucosal responses. (2018)
  • Author(s): Le Gallou, S., Zhou, Z., Thai, L.H., Fritzen, R., de Los Aires, A.V., Megret, J., Yu, P., Kitamura, D., Bille, E., Tros, F., Nassif, X., Charbit, A., Weller, S., Weill, J.C. and Reynaud, C.A.
  • Journal Title: Journal of Experimental Medicine Volume: 215 Issue: 8 Pages: 2035-2053
  • DOI: 10.1084/jem.20180977
  • Peer Reviewed / Int'l Joint Research
• [Presentation] Memory B cell generation and response. (2019)
  • Author(s): 北村大介
  • Organizer: The 30th Anniversary International Symposium of Research Institute for Biomedical Sciences, Tokyo University of Science
  • Int'l Joint Research
• [Presentation] ベーシックシンポジウム２：B細胞 (2019)
  • Author(s): 北村大介
  • Organizer: 第47回日本臨床免疫学会総会
  • Invited
• [Presentation] Commensal bacteria-dependent IgA+ Plasmablasts secrete autoantibodies against glomerular antigens in a mouse model for IgAN. (2019)
  • Author(s): Shohei Asami, Yoshihito Nihei, Kei Haniuda, Mizuki Higashiyama, Yusuke Suzuki, Daisuke Kitamura
  • Organizer: 第48回日本免疫学会学術集会
• [Presentation] Characteristics of B cells in IgA Nephropathy model mice. (2019)
  • Author(s): Yoshihito Nihei, Kei Haniuda, Hitoshi Suzuki, Toshiki Kano, Yusuke Fukao, Daisuke Kitamura, Yusuke Suzuki
  • Organizer: Kidney week 2019
  • Int'l Joint Research
• [Presentation] Characteristics of naive and germinal center B cells in murine IgA nephropathy. (2019)
  • Author(s): Yoshihito Nihei, Kei Haniuda, Hitoshi Suzuki, Toshiki Kano, Yusuke Fukao, Daisuke Kitamura, Yusuke Suzuki
  • Organizer: International Society of Nephrology World Congress of Nephrology 2019
  • Int'l Joint Research
• [Presentation] Mechanisms for Memory B-Cell Formation and Function: Possible Implications for Vaccination. (2019)
  • Author(s): Daisuke Kitamura
  • Organizer: The 3rd Annual Chiba University-UCSD Symposium on Mucosal Immunology, Allergy and Vaccines.
  • Int'l Joint Research
• [Presentation] Regulatory Mechanisms for Memory B Cell Development and Function. (2018)
  • Author(s): Daisuke Kitamura
  • Organizer: KEYSTONE SYMPOSIA, B Cells: Mechanisms in Immunity and Autoimmunity.
  • Int'l Joint Research / Invited
• [Presentation] IL-9 receptor signaling in memory B cells regulates humoral recall responses. (2018)
  • Author(s): Daisuke Kitamura
  • Organizer: 2nd International Innovation Dialogue on Genome Engineering Animal Models and Biomedical Research Symposium.
  • Int'l Joint Research / Invited
• [Presentation] B細胞による獲得免疫応答とその制御メカニズム (2018)
  • Author(s): 北村大介
  • Organizer: 第4回川島カンファレンス
  • Invited
• [Presentation] Characteristics of naive B cells in murine IgA nephropathy. (2018)
  • Author(s): Yoshihito Nihei, Kei Haniuda, Mizuki Higashiyama, Yusuke Suzuki and Daisuke Kitamura
  • Organizer: 第47回日本免疫学会学術集会