Elucidation of the pathogenesis of SLE using SKG mice on C57BL/6 background

2019 Fiscal Year Final Research Report

• Project/Area Number: 16K09890
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Collagenous pathology/Allergology
• Research Institution: Kyoto University
• Principal Investigator: Hashimoto Motomu 京都大学, 医学研究科, 特定助教 (60512845)
• Project Period (FY): 2016-04-01 – 2020-03-31
• 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

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.

Free Research Field

リウマチ膠原病

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。