Mariana J. Kaplan, MD
Our main goal is to unravel the fundamental mechanisms that lead to the development and perpetuation of systemic autoimmune disorders, particularly systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA), and their associated organ damage. SLE is a systemic syndrome of unclear etiology that affects primarily women of childbearing age. Patients with lupus also develop accelerated atherosclerosis and coronary artery disease not fully explained by traditional risk factors, which frequently lead to death in this group of patients. Patients with RA and other inflammatory joint diseases and autoimmune disorders also have increased risks for cardiovascular disease. However, the mechanisms leading to this increased vascular risk are unknown. Part of our work is focused on determining how and why premature vascular damage occurs in SLE and RA. Lupus patients show evidence of increased endothelial cell apoptosis, which correlates with tissue factor generation and vasomotor dysfunction, a predictor of future development of atherosclerosis. We have also found that patients with lupus have impaired vascular repair, and that this phenomenon is mediated by type I Interferons. Using human and murine models, we are characterizing the molecular pathways by which type I Interferons promote vascular damage and interfere with vascular repair, plaque formation and thrombotic events in lupus.. We are also studying the role of specific cytokines and immune cells in the development of vascular damage in RA. Another area of interest is how innate immunity mediates the development of organ damage in lupus and, potentially, in other autoimmune diseases. We have recently characterized an abnormal neutrophil subset that appears to be pathogenic in lupus, synthesizes type I interferons, promotes vascular damage, and interferes with vascular repair. We have found that this subset is more prone to form neutrophil extracellular traps (NETS), which are structures made of processed chromatin bound to granular and selected cytoplasmic proteins. We are determining the relevance of aberrant NET formation in the induction of autoimmune responses in SLE, RA and other autoimmune disorders, as well as their potential role in the development of vascular complications. By identifying mechanisms of tissue damage in SLE and RA, we hope to address if specific pharmacologic interventions that block identified pathways can mitigate these complications in these and other autoimmune disorders.