1472: Autoantibodies Against Tripartite-Motif 72 Protein (TRIM72) in Systemic Lupus Erythematosus Patients and in a Lupus Mouse Models with Myocarditis, Can Compromise Membrane Repair in Cardiomyocytes Potentially Contributing to Cardiovascular Disease Progression

Kassidy Banford¹, hannah Bulgart¹, Shane Bruckner², Stacy Ardoin³, Noah Weisleder² and Wael Jarjour², ¹The Ohio State University Wexner Medical Center, Columbus, OH, ²The Ohio State University, Columbus, OH, ³The Ohio State College of Medicine, Columbus, OH

Background/Purpose: Systemic lupus erythematosus (SLE) is an autoimmune disease that typically manifests in multiple organs, with some of the most significant complications occurring in the heart. Much of the previous work on cardiovascular (CV) morbidity in SLE has focused on atherosclerotic mechanisms of CV disease, however, myocarditis is also emerging as a prevalent and potentially important contributor to CV morbidity in SLE. Understanding the pathophysiology and risk factors for myocardial inflammatory disease that contribute to the unacceptably high CV morbidity in SLE patients remains an important unmet need. We recently described myocarditis in the NZM2410 mouse lupus model using cardiac MRI, echocardiogram, and histology. Plasma membrane repair is a conserved mechanism necessary to restore cell membrane integrity in nearly all cell types in the body and particularly in striated muscle. Compromised membrane repair has been linked to the progression of multiple disease states, including CV disease and the inflammatory myopathies. We and others have demonstrated that tripartite-motif 72 protein (TRIM72) is necessary for plasma membrane repair in skeletal and cardiac muscle cells. Moreover, we recently published that approximately 20% of patients with dermatomyositis and polymyositis have autoantibodies against TRIM72. We showed these antibodies compromise sarcolemmal membrane repair and appear to contribute to the progression of inflammatory myopathies. As multiple previous studies from our team and others link reduced membrane repair to cardiomyopathy, we hypothesize that defects in membrane repair are critical in the pathogenesis of SLE myocarditis.

Methods: ELISA assays were used to measure TRIM72 antibodies in patient and mouse serum samples. We developed innovative confocal laser microscopy methods to injure individual cardiomyocytes in ex vivo slices of cardiac tissue and record the entry of FM4-64 fluorescent dye to measure membrane repair.

Results: We found that TRIM72 antibodies are present in the serum of the NZM2410 mouse model of SLE and that TRIM72 autoantibodies levels are elevated in many lupus patients and are further elevated in SLE patients diagnosed with myocarditis. ELISA screening of 29 lupus and 14 healthy controls samples indicated that antibodies against TRIM72 at levels higher than one standard deviation (SD) above the mean were present in 37.9% of the patients tested. We went on to test the levels of TRIM72 in SLE patients diagnosed with myocarditis (O.D. of 0.799±0.152, n=9) and found those levels to be significantly elevated over healthy control serum (O.D. of 0.576±0.117, n=14, p< 0.05 by T-test). Serum samples with high levels of TRIM72 antibodies from SLE patients or from NZM2410 mice compromise sarcolemmal membrane repair in wild type mouse cardiomyocytes from cardiac slices.

Conclusion: We demonstrate the presence of TRIM72 antibodies in SLE patients that can compromise membrane repair in cardiomyocytes in vitro. Ongoing studies will examine if these defects could lead to membrane repair protein exposure to the extracellular space causing the production of additional autoantibodies which contribute to a vicious cycle that exacerbates SLE pathology.

Disclosures: K. Banford, None; h. Bulgart, None; S. Bruckner, None; S. Ardoin, None; N. Weisleder, TRIM-edicine, Myofinity, Casma Therapeutics, Nido Biosciences; W. Jarjour, None.