Elucidation of the mechanism of breakdown of cutaneous immune tolerance using an innovative mouse model

2022 Fiscal Year Final Research Report

• Project/Area Number: 20K21590
• Research Category: Grant-in-Aid for Challenging Research (Exploratory)
• Allocation Type: Multi-year Fund
• Review Section: Medium-sized Section 53:Organ-based internal medicine and related fields
• Research Institution: Hokkaido University
• Principal Investigator: Ujiie Hideyuki 北海道大学, 医学研究院, 教授 (60374435)
• Co-Investigator(Kenkyū-buntansha): 鄭 ビョウ 北海道大学, 医学研究院, 客員研究員 (50833802)
• Project Period (FY): 2020-07-30 – 2023-03-31
• Keywords: 免疫寛容 / 水疱性類天疱瘡 / 胸腺 / mTEC / 制御性T細胞

Outline of Final Research Achievements

To elucidate the mechanism by which BP180, a bullous pemphigoid antigen, is a likely target of autoimmunity, we focused our analysis on central immune tolerance. Since the mRNA expression of BP180 in thymic medullary epithelial cells (mTECs) was not lower than that of other proteins, a loss of central immune tolerance of T cells was considered less likely to be involved as a mechanism of BP180 immune tolerance failure. In addition, Treg-deficient/K14-BP180-humanized mice, in which human BP180 was forced to be expressed in the basement membrane and mTECs by the K14 promoter and the Foxp3 gene was deleted, did not produce anti-human BP180 antibodies, suggesting that forced self-antigen expression in mTECs may rescue the breakdown of peripheral immune tolerance. The results suggest that forced expression of autoantigen in mTECs may be able to rescue the disruption of peripheral immune tolerance.

Free Research Field

皮膚科学、自己免疫性水疱症

Academic Significance and Societal Importance of the Research Achievements

マウスのmTECにおける皮膚構造タンパクのmRNA発現解析結果からは、ヒトでBP180が自己免疫のターゲットとなりやすい機序の解明には至らなかった。しかし、本研究ではmTECにおけるタンパクレベルの自己抗原発現解析は行っておらず、今後更なる検討が必要である。一方、mTECにおける自己抗原の強制発現によって自己抗体産生を抑制できている可能性が示されたため、今後、中枢性免疫寛容の強化が新規治療戦略となる可能性が示唆された。