The regulation of B cell tolerance by DNA demethylase, Ten-eleven translocation

2021 Fiscal Year Final Research Report

• Project/Area Number: 19K08883
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 54020:Connective tissue disease and allergy-related
• Research Institution: Kyushu University
• Principal Investigator: Tanaka Shinya 九州大学, 生体防御医学研究所, 准教授 (80462703)
• Project Period (FY): 2019-04-01 – 2022-03-31
• Keywords: 末梢寛容 / 自己免疫疾患

Outline of Final Research Achievements

It has been suggested that autoimmune diseases are induced by defect of epigenetic gene regulations which may be affected by environmental factors exposing human body during life course. However, it remains unclear how dysregulation of epigenetics causes autoimmune diseases. In this current study, B cell-specific deletion of Ten-eleven translocation (Tet), which acts as a DNA demethylase, was causative of an activation of self-reactive B cells which resulted in dysregulated T cell activation via antigen-mediated cell-cell interaction. It turned out autoimmune disease pathogenesis. These findings suggest that Tet molecules play a critical role in induction and/or maintenance of B cell peripheral tolerance. Also, this study indicates the defective epigenetic control could be a direct cause of an induction of autoimmune diseases.

Free Research Field

免疫学

Academic Significance and Societal Importance of the Research Achievements

自己免疫疾患は、ライフコース後期に頻発する炎症性疾患であり、その罹患率は、さらに上昇するものと考えられる。最近、遺伝要因だけでなく、環境要因によるエピゲノムの乱れがその発症に寄与する可能性が示唆されるようになった。しかしながら、両者の直接的関係は全く明らかではない。本研究において、DNA脱メチル化酵素の機能不全を切り口として、自己免疫疾患発症におけるエピゲノム制御の直接な役割を示したことで、今後、エピゲノム制御という観点から自己免疫疾患制御についてさらなる知見がもたらされるものと考えられ、ひいては新たは疾患治療戦略につながることが期待される。