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

在全身性自身免疫性风湿性疾病（包括类风湿性关节炎（RA））患者中，动脉粥样硬化已越来越多地被认识到。RA患者的心血管并发症在很大程度上导致死亡率增加。然而，动脉粥样硬化的发生机制仍不清楚，本研究的目的是探讨适应性免疫如何促进RA动脉粥样硬化的发生。血管内皮功能障碍是动脉粥样硬化发病过程中的第一步，也是动脉粥样硬化的一个致病标志。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细胞是否具有增加的亲和力与EC相互作用。第二个目标是鉴定使EC和T细胞之间的通信成为可能的分子，并测量通过这种EC/T细胞信号传导调节哪些效应器功能。作为第三个目标，我们想比较已建立的适应性免疫和内皮功能障碍的RA模型与非自身免疫性条件，导致动脉粥样硬化。最终目的是研究可能的干预措施，以防止加速动脉粥样硬化RA。不同的CD 4 + T细胞亚群RA患者和非自身免疫性疾病将共同培养EC。内皮功能障碍和EC/T细胞信号传导的诱导将通过使用流式细胞术和免疫染色的两种细胞类型上的表面蛋白的表达来评估。此外，细胞因子和内皮应激标记物的产生也将被确定。除了目前的知识，即加速动脉粥样硬化是由与慢性炎症沿着的条件驱动的，在细胞水平上深入了解免疫发病机制是必要的。T细胞和EC是动脉粥样硬化起始过程以及维持动脉粥样硬化的关键参与者。我们的模型能够比较动脉粥样硬化的自身免疫性和非自身免疫性疾病，并确定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.