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

T 细胞作为自身抗体介导的关节炎发作期间的调节元件

• 批准号: 418295762
• 负责人: Professor Dr. Gerhard Krönke
• 金额: --
• 依托单位: Medizinische Klinik mit Schwerpunkt Rheumatologie und Klinische Immunologie (einschließlich Arbeitsbereich Physikalische Medizin)
• 依托单位国家: 德国
• 项目类别: Research Units
• 财政年份: 2019
• 资助国家: 德国
• 起止时间: 2018-12-31 至 2022-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/418295762?language=en
• 关键词: cells; regulative; element; during; onset

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.

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）发病的主要原因。然而，ACPA的形成可以先于临床疾病和关节炎症多年，并且ACPA水平与疾病活动并不一定相关，这表明其他尚未定义的检查点控制着RA中自身抗体介导的关节炎症的发生。我们在PANDORA的第一个资助期发表的数据表明，组织内驻留的抗炎Cx3cr1+巨噬细胞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。我们的初步数据显示，自身反应性T细胞在炎症发作前与这种形成屏障的滑膜Cx3cr1+巨噬细胞相互作用，从而降低局部炎症阈值，并通过产生粒细胞-巨噬细胞集落刺激因子（GM-CSF）“许可”滑膜组织发生自身抗体诱导的关节炎。因此，在第二个资助期，我们试图破解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病，并计划确定人类RA潜在过程的相关性。