T cells as regulative element during the onset of autoantibody-mediated Arthritis

抗瓜氨酸化蛋白抗体（ACPA）等自身抗体被认为是类风湿性关节炎（RA）发病机制的重要组成部分。然而，ACPA的形成可以先于临床疾病和关节炎症多年，并且ACPA水平不一定与疾病活动相关，这表明其他尚未定义的检查点控制RA中自身抗体介导的关节炎症的发作。我们从PANDORA的第一个资助期发表的数据确定了组织驻留的抗炎Cx 3cr 1+巨噬细胞，它们在滑膜关节周围形成保护屏障，并在稳态条件下防止自身抗体介导的关节炎症的发生。我们的初步数据表明，自身反应性T细胞与这种屏障形成的滑膜Cx 3cr 1+巨噬细胞相互作用之前，炎症，从而降低局部炎症阈值和“许可”的滑膜组织自身抗体诱导的关节炎通过生产粒细胞-巨噬细胞集落刺激因子（GM-CSF）。因此，在第二个资助期内，我们试图破译GM-CSF依赖的分子机制和响应滑膜细胞类型，使自身抗体诱导的关节炎发作，并计划确定人类RA的相关性的基础过程。

Autoantibodies such as anti-citrullinated protein antibodies (ACPA) are considered to essentially contribute to the pathogenesis of rheumatoid arthritis (RA). However, formation of ACPA can precede clinical disease and joint inflammation for many years and ACPA levels do not necessarily correlate with disease activity, suggesting that other yet to be defined checkpoints control onset of autoantibody-mediated joint inflammation in RA. Our published data from the first funding period of PANDORA identified tissue-resident anti-inflammatory Cx3cr1+ macrophages that form protective barriers around synovial joints and prevent onset of autoantibody-mediated joint inflammation under homeostatic conditions. Our preliminary data show that autoreactive T cells interact with such barrier-forming synovial Cx3cr1+ macrophages prior to onset of inflammation thereby lowering the local inflammatory threshold and “licensing” the synovial tissue for autoantibody-induced arthritis via production of granulocyte-macrophage colony-stimulating factor (GM-CSF). During the second funding period, we thus seek to decipher the GM-CSF-dependent molecular mechanisms and responding synovial cell types that enable onset of autoantibody-induced arthritis and additionally plan to determine the relevance of the underlying processes for human RA.