Identification of Immunological Mechanisms Targeting the Myocardium in Rheumatoid Arthritis

In rheumatoid arthritis (RA), symptomatic heart failure (HF) and associated mortality rates are increased 2-3-fold even after controlling for coronary artery disease, suggesting that components of the adaptive autoimmune response intrinsic to these diseases drive this increased risk. We hypothesize that myocardial disease in RA is a consequence of the adaptive autoimmune response underlying RA and that processes leading to heart injury can be modeled at a molecular and cellular level using cardiac tissues generated from patient's iPSCs. However, the identification of potentially causative immunological mechanisms that target myocardial cells to cause left ventricular dysfunction requires direct access to autologous cardiac tissue and consequently is essentially incapable of being fully studied in patients or non-autologous conventionally cultured myocardial cell lines. Available animal models do not express human cardiac antigens and are also not suitable for this study. We will approach identification of these mechanisms using our team's recent advances in in vitro 3D models of highly differentiated and functional human cardiac tissue from iPSCs as a novel alternative in vitro platform and have obtained preliminary data demonstrating the feasibility of the techniques to demonstrate mechanisms of direct immune injury. Our goal is to address myocardial dysfunction in RA by our combined expertise in tissue engineering and the immunobiology of RA in the study of a cohort of RA patients with well-characterized particular phenotypes of myocardial dysfunction. There are two aims: first we will Identify the frequency and specificity of autoantibodies in RA sera that react with 3D micro cardiac tissues and correlate them with the patient's myocardial pathology. The lineage specificity and quantity of the auto-antibodies will be determined by gel electrophoresis and mass spectroscopy. In the second aim we will characterize and validate the effect of RA patient sera/Ig on mature engineered autologous cardiac tissue containing endothelium, and extend the assay to assess the contribution of cellular immunity, mechanism in an autologous format using iPSCs generated from candidate RA patients. Combinations of patient's serum with mononuclear cells or their subsets will be used to explore potential mechanisms of cardiac injury mediated by components of the adaptive immune system. along with the effect on autoantigen expression of stressors such as exhaustive stimulation. (AHA Program: Transformational Project Award)