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

• Applicant: Dr. Markus Christopher Zeisbrich
• Subject Area: Rheumatology
• Term: from 2015 to 2019
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 285965097

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.

• DFG Programme: Research Fellowships
• International Connection: USA
• Host: Professorin Dr. Cornelia M. Weyand, Ph.D.