A study of pathogenic B-cell memory function and its regulation using an autoimmune IgA nephropathy mouse model

• Project/Area Number: 20H00510
• Research Category: Grant-in-Aid for Scientific Research (A)
• Allocation Type: Single-year Grants
• Section: 一般
• 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): 2020-04-01 – 2023-03-31
• Project Status: Completed (Fiscal Year 2022)
• Budget Amount: ¥45,240,000 (Direct Cost: ¥34,800,000、Indirect Cost: ¥10,440,000); Fiscal Year 2022: ¥14,040,000 (Direct Cost: ¥10,800,000、Indirect Cost: ¥3,240,000); Fiscal Year 2021: ¥14,820,000 (Direct Cost: ¥11,400,000、Indirect Cost: ¥3,420,000); Fiscal Year 2020: ¥16,380,000 (Direct Cost: ¥12,600,000、Indirect Cost: ¥3,780,000)
• Keywords: 自己免疫疾患 / 自己抗体 / 記憶B細胞 / IgA腎症 / 交差反応 / IgA / 常在細菌

Outline of Research at the Start

自己免疫疾患や慢性アレルギーといった免疫病の原因である自己抗体やIgE抗体の産生機序は不明である。しかい近年、B細胞除去療法の結果より、記憶B細胞の断続的な活性化が長期抗体産生に関わっていること、また、記憶B細胞の抗原提示・エフェクター機能が病因として注目されている。本研究では、このような病原性記憶B細胞に焦点を当て、自己免疫疾患の病態における記憶B細胞の役割や作用機序、制御機構を明らかにし、病原性記憶B細胞を標的とした免疫制御方法を見出すことを目的とする。その成果は、自然抗体や制御性B細胞を損なうことのない、免疫病の新たな原因療法の創出に繋がると期待される。

Outline of Final Research Achievements

We studied the mechanisms how auto-antibodies are generated in autoimmune diseases using gddY mice, a model of IgA nephropathy (IgAN). Sera of gddY mice and IgAN patients contained IgAs that bind to glomerular mesangium, and we identified βII-spectrin as a self-antigen for these IgAs. Although βII-spectrin is normally present inner plasma membrane, it was exposed on the surface of mesangial cells. IgA+ plasmablasts were accumulated in the kidneys of gddY mice and monoclonal antibodies from these cells bound to βII-spectrin and another self-antigen on the mesangial cells as well as commensal bacteria in the oral cavity of gddY mice. Administration of antibiotics mixture to gddY mice reduced the plasmablast accumulation and autoantibodies, and ameliorated the IgAN symptoms. These data suggest that particular oral bacteria primed B cells to induce immune response, generating IgA+ memory B cells that continuously provide plasmablasts producing anti-mesangial IgA autoantibodies.

Academic Significance and Societal Importance of the Research Achievements

自己免疫疾患の主な原因の1つである自己抗体の産生機序は不明である。しかし近年、B細胞除去療法の結果より、記憶B細胞の継続的な活性化が自己抗体の長期産生に関わっていること、また、記憶B細胞の抗原提示・エフェクター機能が病因として注目されている。本研究では、このような病原性記憶B細胞に焦点を当て、自己免疫疾患の病態における記憶B細胞の産生機構、その役割や作用機序を明らかにし、病原性記憶B細胞を標的とした免疫制御方法を見出すことを目的とした。この成果は、自然抗体や制御性B細胞を損なうことのない、免疫病の新たな原因療法の創出に繋がると期待される。

Research Products

• [Journal Article] Identification of IgA autoantibodies targeting mesangial cells redefines the pathogenesis of IgA nep (2023)
  • Author(s): Nihei, Y., Haniuda, K., Higashiyama, M., Asami, S., Iwasaki, H., Fukao, Y., Nakayama, M., Suzuki, H., Kikkawa, M., Kazuno, S., Miura, Y., Suzuki, Y., Kitamura, D.
  • Journal Title: Science Advances Volume: 9 Issue: 12
  • DOI: 10.1126/sciadv.add6734
  • Peer Reviewed / Open Access
• [Journal Article] Integrin CD11b provides a new marker of pre-germinal center IgA+ B cells in murine Peyer's patches. (2022)
  • Author(s): Gao P, Adachi T, Okai S, Morita N, Kitamura D, Shinkura R.
  • Journal Title: International Immunology Volume: 34 Issue: 5 Pages: 249-262
  • DOI: 10.1093/intimm/dxab113
  • Peer Reviewed / Open Access
• [Journal Article] An IL-9-pulmonary macrophage axis defines the allergic lung inflammatory environment. (2022)
  • Author(s): Fu, Y., Wang, J., Zhou, B., Pajulas, A., Gao, H., Ramdas, B., Koh, B., Ulrich, B.J., Yang, S., Kapur, R., Renauld, J.-C., Paczesny, S., Liu, Y., Tighe, R.M., Licona-Limon, P., Flavell, R.A., Takatsuka, S., Kitamura, D., Tepper, R.S., Sun, J., and Kaplan, M.H.
  • Journal Title: Science Immunology Volume: 7 Issue: 68
  • DOI: 10.1126/sciimmunol.abi9768
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Protein kinase Cδ is essential for the IgG response against T-cell-independent type 2 antigens and commensal bacteria. (2021)
  • Author(s): Fukao, S., Haniuda, K., Tamaki, H. and Kitamura, D.
  • Journal Title: eLife Volume: 10
  • DOI: 10.7554/elife.72116
  • Peer Reviewed / Open Access
• [Journal Article] C/EBPβ induces B‐cell acute lymphoblastic leukemia and cooperates with <i>BLNK</i> mutations (2021)
  • Author(s): Kurata Morito、Onishi Iichiro、Takahara Tomoko、Yamazaki Yukari、Ishibashi Sachiko、Goitsuka Ryo、Kitamura Daisuke、Takita Junko、Hayashi Yasuhide、Largaesapda David A、Kitagawa Masanobu、Nakamura Takuro
  • Journal Title: Cancer Science Volume: 112 Issue: 12 Pages: 4920-4930
  • DOI: 10.1111/cas.15164
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] MicroRNA-directed pathway discovery elucidates an miR-221/222-mediated regulatory circuit in class switch recombination. (2021)
  • Author(s): Wigton, E.J., Mikami, Y., McMonigle, R.J., Castellanos, C.A., Wade-Vallance, A.K., Zhou, S.K., Kageyama, R., Litterman, A., Roy, S., Kitamura, D., Dykhuizen, E.C., Allen, C.D.C., Hu, H., O'Shea, J.J., Ansel, K.M.
  • Journal Title: Journal of Experimental Medicine Volume: 218 Issue: 11
  • DOI: 10.1084/jem.20201422
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Mechanisms for the regulation of memory B-cell recall responses in mice. (2021)
  • Author(s): Kitamura, D.
  • Journal Title: International Immunology Volume: 33 Issue: 12 Pages: 791-796
  • DOI: 10.1093/intimm/dxab042
  • Peer Reviewed / Open Access
• [Journal Article] Multi-faceted regulation of IgE production and humoral memory formation (2021)
  • Author(s): Haniuda, K. and Kitamura, D.
  • Journal Title: Allergology International Volume: 70 Issue: 2 Pages: 163-168
  • DOI: 10.1016/j.alit.2020.11.002
  • NAID: 130008024333
  • ISSN: 1323-8930, 1440-1592
  • Peer Reviewed / Open Access
• [Journal Article] A novel cancer immunotherapy using tumor-infiltrating B cells in the APCmin/+ mouse model. (2021)
  • Author(s): Wang X., Asami, S. and Kitamura D.
  • Journal Title: PLoS ONE Volume: 16 Issue: 1 Pages: e0245608-e0245608
  • DOI: 10.1371/journal.pone.0245608
  • Peer Reviewed / Open Access
• [Journal Article] Metabolic reprogramming induces germinal center B cell differentiation through Bcl6 locus remodeling. (2020)
  • Author(s): Haniuda, K., Fukao, S. and Kitamura, D.
  • Journal Title: Cell Reports Volume: 33 Issue: 5 Pages: 108333-108333
  • DOI: 10.1016/j.celrep.2020.108333
  • Peer Reviewed / Open Access
• [Journal Article] Tracing self-reactive B cells in normal mice. (2020)
  • Author(s): Nojima, T., Reynolds, A.E., Kitamura, D., Kelsoe, G. and Kuraoka, M.
  • Journal Title: The Journal of Immunology Volume: 205 Issue: 1 Pages: 90-101
  • DOI: 10.4049/jimmunol.1901015
  • Peer Reviewed / Int'l Joint Research
• [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
• [Presentation] Identification of IgA autoantibodies against glomerular mesangial cells and the target autoantigen using an IgA nephropathy mouse model (2022)
  • Author(s): Yoshihito Nihei, Kei Haniuda, Mizuki Higashiyama, Hiroyuki Iwasaki, Shohei Asami, Yusuke Suzuki, Daisuke Kitamura
  • Organizer: 第51回日本免疫学会学術集会
• [Presentation] A mechanism for anti-mesangium IgA production in an IgA nephropathy mouse model (2022)
  • Author(s): Mizuki Higashiyama, Kei Haniuda, Yoshihito Nihei, Riku Hisato, Daisuke Kitamura
  • Organizer: 第51回日本免疫学会学術集会
• [Presentation] Pathogenic antibody production by microbiota in an IgA nephropathy mouse model. (2021)
  • Author(s): 北村大介
  • Organizer: 5th Symposium of the International Immunological Memory and Vaccine Forum
  • Int'l Joint Research / Invited
• [Presentation] IgA腎症におけるIgA自己抗体産生 (2021)
  • Author(s): 北村大介、二瓶義人、東山瑞希、岩崎裕幸、久斗陸、羽生田圭、鈴木祐介
  • Organizer: 第85回日本インターフェロン・サイトカイン学会学術集会
  • Invited
• [Presentation] B細胞におけるIgE産生制御 (2021)
  • Author(s): 北村大介
  • Organizer: 第7回総合アレルギー講習会
  • Invited
• [Patent(Industrial Property Rights)] IgA腎症に関連する自己抗体 (2021)
  • Inventor(s): 北村大介，鈴木祐介，二瓶義人
  • Industrial Property Rights Holder: 北村大介，鈴木祐介，二瓶義人
  • Industrial Property Rights Type: 特許
  • Filing Date: 2021
  • Overseas