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

2019 Fiscal Year Final Research Report

• 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
• Keywords: 自己抗体 / 自己寛容 / 自己免疫疾患 / IgA腎症

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.

Free Research Field

免疫学

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。