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

Research Project

Project/Area Number 20K21590
Research Category

Grant-in-Aid for Challenging Research (Exploratory)

Allocation TypeMulti-year Fund
Review Section Medium-sized Section 53:Organ-based internal medicine and related fields
Research InstitutionHokkaido 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
Project Status Completed (Fiscal Year 2022)
Budget Amount *help
¥6,500,000 (Direct Cost: ¥5,000,000、Indirect Cost: ¥1,500,000)
Fiscal Year 2021: ¥2,600,000 (Direct Cost: ¥2,000,000、Indirect Cost: ¥600,000)
Fiscal Year 2020: ¥3,900,000 (Direct Cost: ¥3,000,000、Indirect Cost: ¥900,000)
Keywords免疫寛容 / 水疱性類天疱瘡 / 胸腺 / mTEC / 制御性T細胞 / 尋常性天疱瘡
Outline of Research at the Start

自己免疫疾患は全身臓器に生じるが、生体内に存在する無数のタンパクのなかで一部のタンパクが自己免疫の標的になりやすい理由は大部分が不明である。本研究では特定のタンパクが免疫自己の標的となる機序を解明し、それを回避する方法を創出する。皮膚の代表的な自己免疫疾患である「水疱性類天疱瘡」と「尋常性天疱瘡」を対象として、新規マウスモデルの胸腺を解析することで「中枢性免疫寛容の強化は末梢性免疫寛容の機能不全を補完できるかどうか」を検証する。

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.

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。

Report

(4 results)
  • 2022 Annual Research Report   Final Research Report ( PDF )
  • 2021 Research-status Report
  • 2020 Research-status Report
  • Research Products

    (2 results)

All 2022

All Journal Article (1 results) (of which Peer Reviewed: 1 results) Presentation (1 results)

  • [Journal Article] What's new in the pathogeneses and triggering factors of bullous pemphigoid2022

    • Author(s)
      Ujiie Hideyuki
    • Journal Title

      The Journal of Dermatology

      Volume: 50 Issue: 2 Pages: 140-149

    • DOI

      10.1111/1346-8138.16654

    • Related Report
      2022 Annual Research Report
    • Peer Reviewed
  • [Presentation] 中枢性免疫寛容に着目した 自己免疫性水疱症の発症機序の解明2022

    • Author(s)
      氏家 英之
    • Organizer
      第121回日本皮膚科学会総会
    • Related Report
      2022 Annual Research Report

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Published: 2020-08-03   Modified: 2024-01-30  

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