Studies on the mechanisms underlying autoimmune ambivalence

2019 Fiscal Year Final Research Report

• Project/Area Number: 18K19564
• Research Category: Grant-in-Aid for Challenging Research (Exploratory)
• Allocation Type: Multi-year Fund
• Review Section: Medium-sized Section 54:Internal medicine of the bio-information integration and related fields
• Research Institution: The University of Tokushima
• Principal Investigator: MATSUMOTO Mitsuru 徳島大学, 先端酵素学研究所(次世代), 教授 (60221595)
• Co-Investigator(Kenkyū-buntansha): 森本 純子 徳島大学, 先端酵素学研究所(次世代), 助教 (20451396) ; 西嶋 仁 徳島大学, 先端酵素学研究所(次世代), 助教 (60425410)
• Project Period (FY): 2018-06-29 – 2020-03-31
• Keywords: 自己免疫疾患 / Aire / 多発性筋炎 / I型糖尿病 / 抗原提示細胞

Outline of Final Research Achievements

Roles of Aire in the pathogenesis of tissue-specific autoimmune diseases remain elusive. In order to elucidate the function of Aire, we have established transgenic mice expressing Aire. Aire-Tg which express Aire under the control of MHC-II promoter showed an ambivalent phenotype with polymyositis-like autoimmunity and resistance to type I diabetes (T1D). We have revealed that polymyositis-like autoimmunity was caused by the combination of mTECs and BM-APCs with the use of BM transfer. In contrast, T1D resistance was mediated by BM-APCs. Finally, we have discovered that over-expression of Aire in DCs resulted in the reduced numbers of Xcr1-positive DCs, that play a critical role in the development of T1D. Thus, our studies for the first time uncovered a dual role of Aire in the induction (polymyositis-like autoimmunity) and suppression of autoimmunity (development of T1D).

Free Research Field

免疫学

Academic Significance and Societal Importance of the Research Achievements

多発性内分泌疾患I型（APSI）の原因遺伝子Aireは自己寛容の成立機構に必須の役割を担う。本研究ではmTECやBM-APCなどの抗原提示細胞におけるAireの過剰発現が、どのようなメカニズムによって自己免疫病態の発生と修復（両価性）をもたらすかを明らかにし、それによってAireの本質的な機能解明を図った。Aireの過剰発現によるI型糖尿病抵抗性の獲得機構のメカニズムについてはXcr1陽性DCの減少がその原因であることを突き止めた。さらに、Aireの過剰発現によって多発性筋炎様病態が観察された事実から、ヒトの多発性筋炎においてもAireの過剰発現が病気の原因であるという大胆な仮説を検証した。