Abnormal adaptive immunity, endothelial dysfunction and accelerated atherosclerosis in Rheumatoid Arthritis

包括类风湿关节炎(RA)在内的全身性自身免疫性风湿病患者日益认识到加速的动脉粥样硬化。类风湿关节炎患者的心血管并发症在很大程度上增加了死亡率。然而，导致动脉粥样硬化的潜在机制仍不清楚。本研究的目的是探讨获得性免疫在RA加速动脉粥样硬化中的作用。血管内皮细胞功能障碍是疾病进程的初始步骤，也是动脉粥样硬化的致病标志。第一个目标是确定内皮细胞(EC)与T细胞相互作用的先决条件，并研究RA患者的T细胞是否具有更高的亲和力与EC相互作用。第二个目标是确定使EC和T细胞之间能够通信的分子，并测量哪些效应器功能是通过EC/T细胞信号调节的。作为第三个目标，我们希望将已建立的RA适应性免疫和内皮功能障碍模型与导致动脉粥样硬化的非自身免疫性疾病进行比较。最后的目标是研究可能的干预措施来预防RA加速的动脉粥样硬化。来自RA患者和非自身免疫性疾病的不同的CD4+T细胞亚群将与EC共同培养。内皮功能障碍的诱导和EC/T细胞信号转导将通过流式细胞术和免疫染色检测两种细胞表面蛋白的表达来评估。此外，还将测定细胞因子和内皮应激标志物的产生。除了目前的知识，加速的动脉粥样硬化是由伴随慢性炎症的条件驱动的，必须在细胞水平上对免疫发病机制有深入的了解。T细胞和EC在动脉粥样硬化的启动过程和维持过程中起着关键作用。我们的模型能够比较动脉粥样硬化的自身免疫和非自身免疫状况，并识别共享和非共享的异常。

Accelarated atherosclerosis has become increasingly recognized in patients with systemic autoimmune rheumatic diseases, including rheumatoid arthritis (RA). Cardiovascular complications in RA patients substantially contribute to an increased mortality. However, the underlying mechanisms causing atherosclerosis remain poorly understood.The aim of this study is to investigate how adaptive immunity contributes to accelerated atherosclerosis in RA. The initial step in the disease process and a pathogenic hallmark of atherosclerosis is endothelial dysfunction. The first objective is to determine the prerequisites for the interaction of endothelial cells (EC) with T cells and to investigate whether T cells from RA patients have an increased affinity to interact with EC. The second objective is to identify the molecules that enable the communication between EC and T cells, and to measure which effector functions are regulated through this EC/T cell signaling. As a third objective we want to compare the established model of adaptive immunity and endothelial dysfunction in RA with a non-autoimmune condition that causes atherosclerosis. The final objective is to investigate possible interventions to prevent accelerated atherosclerosis in RA.Different CD4+ T cell subsets from RA patients and from a non-autoimmune condition will be co-cultured together with EC. The induction of endothelial dysfunction and the EC/T cell signaling will be assessed by the expression of surface proteins on both cell types using flow cytometry and immunostaining. Additionally, the production of cytokines and endothelial stress markers will be determined.Besides the current knowledge that accelerated atherosclerosis is driven by conditions that go along with chronic inflammation it is mandatory to acquire an in-depth insight into the immunopathogenesis on a cellular level. T cells and EC are key players in the initiation process as well as in the maintenance of atherosclerosis. Our model enables to compare autoimmune and non-autoimmune conditions of athersclerosis and to identify shared and non-shared abnormalities.