| Project/Area Number |
16K09890
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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| Allocation Type | Multi-year Fund |
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| Section | 一般 |
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| Research Field |
Collagenous pathology/Allergology
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| Research Institution | Kyoto University |
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Principal Investigator |
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| Project Period (FY) |
2016-04-01 – 2020-03-31
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| Project Status |
Completed (Fiscal Year 2019)
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| Budget Amount *help |
¥4,680,000 (Direct Cost: ¥3,600,000、Indirect Cost: ¥1,080,000)
Fiscal Year 2018: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
Fiscal Year 2017: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
Fiscal Year 2016: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
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| Keywords | 全身性エリテマトーデス / T細胞シグナル伝達 / 濾胞性ヘルパーT細胞 / 補助刺激分子 / 自己抗体 / 動物モデル / follicular helper T cell / lupus nephritis / germinal center / co-stimulatory molecules / 内科 / 免疫学 |
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| Outline of Final Research Achievements |
In this study, we studied how defective T cell receptor (TCR) signaling, which is commonly observed in patients with SLE, leads to the development of SLE using an animal model. SKG mice, which develop autoimmune arthritis in a BALB/c background due to defective TCR signaling by ZAP70 mutation, developed SLE in the C57BL/6 (B6) background (B6SKG mice) with immune-complex deposition and anti-dsDNA antibody production. Follicular helper T cells (Tfh) that help germinal center formation were spontaneously expanded in B6SKG mice. Among the factors related to Tfh differentiation, the expression levels of co-stimulatory molecules (CD80/86, ICOSL) on DCs but not on B cells were specifically increased in wild-type B6 mice compared with BALB/c mice. Inhibition of co-stimulatory molecules suppressed Tfh development and lupus-like autoimmunity. Thus, defective TCR signaling leads to SLE development under the specific genetic background that facilitates Tfh development.
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| Academic Significance and Societal Importance of the Research Achievements |
TCRシグナル伝達不全は、SLEをはじめとする膠原病で観察されうる遺伝子異常だが、それがどのようにしてSLEにつながるのかは不明であった。本研究の結果、TCRシグナル伝達不全による胸腺選択の異常で出現した自己反応性T細胞が、脾臓で自己抗体の産生をヘルプするfollicular helper T細胞（Tfh）へと分化することがSLE発症のカギとなり、Tfhへの分化にやCD80/86、ICOSLなどの補助刺激分子が関与していることが見出された。SLEにおいて、補助刺激分子やそれにより誘導されるfollicular helper T細胞の分化が治療ターゲットになることが示唆された。
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