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

2022 Fiscal Year Final Research Report

• 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
• Keywords: 自己免疫疾患 / 自己抗体 / 記憶B細胞 / IgA腎症

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.

Free Research Field

免疫学

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。