The mechanism of autoimmune disease pathogenesis mediated by SPA-1 expressing cells

• Project/Area Number: 18K06665
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 47030:Pharmaceutical hygiene and biochemistry-related
• Research Institution: Keio University
• Principal Investigator: INOUE Joe 慶應義塾大学, 政策・メディア研究科(藤沢), 特任准教授 (00433714)
• Project Period (FY): 2018-04-01 – 2021-03-31
• Project Status: Completed (Fiscal Year 2020)
• Budget Amount: ¥4,420,000 (Direct Cost: ¥3,400,000、Indirect Cost: ¥1,020,000); Fiscal Year 2020: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000); Fiscal Year 2019: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000); Fiscal Year 2018: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000)
• Keywords: 自己免疫疾患 / SPA-1 / NKT細胞 / 辺縁帯B細胞 / Notch

Outline of Final Research Achievements

Autoimmune diseases are the general term for diseases caused by the breakdown of immune tolerance, and many of them are designated as intractable diseases because the causes of their onset are still unknown. We have previously shown that mice lacking the SPA-1 gene (SPA-1 KO mice), which regulates the activity of Rap1, one of the Small G proteins, develop autoimmune diseases. In the present study, we found that changes in NKT/MZ-B cell balance were associated with increased autoantibody titers, and that SPA-1 expression was particularly high in NKT1 and MZ-B cells. The results strongly suggest that SPA-1 is associated with Notch signaling, which is important for NKT cell and MZ-B cell differentiation.

Academic Significance and Societal Importance of the Research Achievements

自己免疫疾患の原因の一つとして、Rapシグナルの異常によるNKT/MZ-B細胞バランスの不均衡というこれまでにない知見が得られた。またNKT細胞やMZ-B細胞でSPA-1が高発現していること、分化段階から発現が上昇していることが初めて明らかとなり、今後のNKT細胞、B細胞研究において重要な分化制御因子として多くの研究の対象となり得る。自己免疫疾患に対する分子標的としても有望であり、今後さらなる研究が期待される。