T cell-induced autoinflammatory diseases

• Project/Area Number: 18K15118
• Research Category: Grant-in-Aid for Early-Career Scientists
• Allocation Type: Multi-year Fund
• Review Section: Basic Section 49030:Experimental pathology-related
• Research Institution: Kyoto University
• Principal Investigator: Sasaki Katsuhiro 京都大学, 医学研究科, 講師 (70739862)
• Project Period (FY): 2018-04-01 – 2021-03-31
• Project Status: Completed (Fiscal Year 2020)
• Budget Amount: ¥4,160,000 (Direct Cost: ¥3,200,000、Indirect Cost: ¥960,000); Fiscal Year 2019: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000); Fiscal Year 2018: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000)
• Keywords: 自己炎症 / 自己免疫 / 細胞死誘導 / T細胞 / LUBAC / ユビキチンリガーゼ / Treg / 制御性T細胞 / 細胞死 / 炎症 / TNF / Ｔ細胞 / 免疫

Outline of Final Research Achievements

Autoimmunity and autoinflammation are immune-mediated systemic inflammaotry diseases. The two types are contrasting on etiology; autoimmunity is induced by breakdown of immune tolerance and hyper-activation of self-reactive lymphocytes, whereas autoinflammtion is contributed by innate immune-secreting inflammatory cytokines. This study has discovered the following two points in detail. 1. The LUBAC is recognized as a causative factor for both autoimmune and autoinflammaotry diseases. 2. Self-reactive T cells can trigger autoinflammatory-like pathogenesis that may be a therapeutic target for atypical types of T cell-unrelated inflammatory diseases.

Academic Significance and Societal Importance of the Research Achievements

本研究によって作製された複数のLUBACを標的とした疾患マウスは、典型的自己免疫疾患から典型的自己炎症疾患まで多彩な炎症を引き起こすことから、炎症分野の研究における解析ツールとして今後利用されることが大いに期待できる。また本研究から自己炎症の誘導におけるT細胞細胞障害機能が新たに示されたことから、自己免疫と自己炎症の概念の垣根を越えた、炎症誘導に寄与する未だ明らかにされていない多様な炎症細胞の特性や細胞間相互応答の理解の重要性を改めて示した。自己炎症疾患における病因・増悪化因子としてT細胞を提唱した本研究は、ヒト疾患の治療改善に繋がる可能性もある。

Research Products

• [Journal Article] LUBAC, the E3 ligase complex generating linear polyubiquitin chains (2020)
  • Author(s): 佐々木克博、岩井一宏
  • Journal Title: 生化学 Volume: 92 Issue: 1 Pages: 20-27
  • DOI: 10.14952/SEIKAGAKU.2020.920020
  • ISSN: 0037-1017
  • Year and Date: 2020-02-25
  • Peer Reviewed / Open Access
• [Journal Article] Modulation of autoimmune pathogenesis by T cell-triggered inflammatory cell death. (2019)
  • Author(s): Sasaki, K., Himeno, A., Nakagawa, T., Sasaki, Y., Kiyonari, H. and Iwai, K.
  • Journal Title: Nature Communications Volume: 10 Issue: 1 Pages: 3878-3878
  • DOI: 10.1038/s41467-019-11858-7
  • NAID: 120006716601
  • Peer Reviewed / Open Access
• [Presentation] An autoinflammatory mechanism by TNF-expressing T cells (2019)
  • Author(s): Katsuhiro Sasaki and Kazuhiro Iwai
  • Organizer: 17th TNF conference 2019
  • Int'l Joint Research
• [Remarks] 自己免疫疾患の新たな病態発症メカニズムを解明 －炎症性疾患におけるT細胞の新たな役割－
  • URL: http://www.kyoto-u.ac.jp/ja/research/research_results/2019/190828_2.html