Patients with systemic lupus erythematosus (SLE) have accelerated atherosclerosis that is not predicted by classical risk factors. Most affected are women, who make up 90% of the SLE patient population. It is estimated that premenopausal women with lupus are at 50 times greater risk of suffering from myocardial infarction. The underlying mechanisms for increased risk are poorly understood, and investigations have been hampered by the absence of animal models reflecting the human equivalent of accelerated atherosclerosis and lupus. We addressed this by transferring lupus-susceptible, B6.Sle1.2.3 congenic or C57Bl/6 control bone marrow to LDLr-/- mice (LDLr.Sle and LDLr.B6, respectively). When fed high fat diet, LDLr.Sle mice had increased mortality and atherosclerotic lesions without enhances in serum cholesterol or triglycerides or direct correlation with serum creatinine or urea levels. The LDLr.Sle mice did, however, have increased activation and apoptosis of CD4+ T cells and increased B cell proliferation and antibody production against oxidized LDL and cardiolipin. LDLr.Sle mice also had a three-fold increase in lesional CD4+ T cells and increased expression of inflammatory markers. Therefore, the long-term objective of this proposal is to elucidate the genetic, cellular and immunoregulatory components of SLE that mediate accelerated atherosclerosis. To test the hypothesis that immune dysfunction accelerates atherosclerosis we will use our novel animal model to determine (1) the immune regulatory factors involved in accelerated atherosclerosis by studying LDLr-/- mice biocongenic for lupus-susceptibility gene intervals; 2) the cellular components necessary for accelerated atherosclerosis by transferring lymphocyte populations from B6.Sle mice to lymphocyte-deficient Rag-/-LDLr-/- mice; 3) whether dysregulated T cell apoptosis and/or deficient clearance of apoptotic cells by macrophages is a mechanism to exacerbate early atherosclerotic lesions and 4) if correction of autoimmunity by nonmyeloablative cell transfer can cease or regress atherogenesis. The relevance of this research to public health, especially to women, is steeped in its pursuit of underlying mechanisms for premature, often fatal, cardiovascular events in SLE. The completion of these studies will ultimately lead to improved therapeutics to treat both lupus and cardiovascular disease. ? ? ?
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