Pathological analysis of the mechanism underlying resistance to diabetes controlled by AIRE

2020 Fiscal Year Final Research Report

• Project/Area Number: 19K16613
• Research Category: Grant-in-Aid for Early-Career Scientists
• Allocation Type: Multi-year Fund
• Review Section: Basic Section 49030:Experimental pathology-related
• Research Institution: The University of Tokushima
• Principal Investigator: MATSUMOTO Minoru 徳島大学, 大学院医歯薬学研究部(医学域), 助教 (30836250)
• Project Period (FY): 2019-04-01 – 2021-03-31
• Keywords: AIRE / I型糖尿病 / Xcr1陽性樹状細胞 / NOD

Outline of Final Research Achievements

The number of patients with type I diabetes mellitus is increasing worldwide, but its pathogenesis is still unclear. On the other hand, AIRE is expressed in the medullary epithelial cells of the thymus, and its loss of function results in hereditary autoimmune diseases that target various endocrine organs. Interestingly, additional expression of human AIRE in NOD mice, a mouse model of human type I diabetes, showed complete resistance to the development of diabetes. Experiments utilizing bone marrow transplantation revealed that this diabetic resistance was acquired by bone marrow-derived antigen presenting cells that additionally express AIRE. Furthermore, Xcr1 positive dendritic cells, which play an important role in the presentation of pancreatic beta cell-associated antigens, were revealed to be reduced in response to the level of AIRE expression.

Free Research Field

実験病理学

Academic Significance and Societal Importance of the Research Achievements

I型糖尿病の原因究明は、近年の患者数の増加をふまえると、緊急性の高い重要研究課題である。さらに、AIREは単一遺伝子の異常により遺伝性の自己免疫を発症するが、AIREの詳細な機能は未だ完全に解明されたとは言い難い。本研究では、ヒトAIREの付加的な発現に伴って、特定のモデルにおいて糖尿病抵抗性を示すメカニズムを明らかにした。本研究はI型糖尿病の発症およびAIREによる自己寛容成立のメカニズムの双方に焦点を当てた、非常に独自性をもった内容である。さらに、AIREの機能異常に基づく疾患病態の解明は、AIRE欠損症のみならず、他の自己免疫疾患の原因究明にもつながると期待される。