Atherosclerosis is a disease defined as the accumulation of lipids with the arterial intima. Systemic lupus erythematosus (SLE), an autoimmune disorder, is characterized by the production of anti-nuclear antibodies. Patients suffering from SLE also have an increased risk for premature atherosclerosis. Most disturbing are studies showing that premenopausal women are 50 times more likely to develop fatal myocardial infarction compared to normal premenopausal women. The link between the two diseases has not been extensively studied, however it is thought that immune dysregulation plays a role in the acceleration of atherosclerosis in SLE. The long term goal of this project is to understand the mechanism of autoimmune-mediated accelerated atherosclerosis, specifically the role of T cells in mediating disease. In the first aim, we will determine the immune components necessary to accelerate atherosclerosis. In order to accomplish this, we will use a mouse model of lupus-accelerated atherosclerosis to determine the lupus susceptibility loci necessary to accelerate atherosclerosis. We will also adoptive transfer and immune cell depletion techniques to determine the cellular types needed to mediate changes in vascular disease in the presence of SLE. The goal of the second aim is to determine if T cells bias toward a pathogenic T helper 17 response in SLE leads to enhanced vascular disease. In this aim we will investigate the molecular mechanism of T helper 17 and induced regulatory T cell differentiation in the B6.Sle1.2.3 mouse model. Ultimately, these studies will enhance our knowledge of both vascular disease and lupus.
Patients with SLE, especially premenopausal women, have an increased risk for developing cardiovascular disease. Additionally, many treatments for SLE disease are thought to exacerbate vascular complications. Therefore understanding the mechanism autoimmune-accelerated atherosclerosis is necessary for the development of new therapeutic targets to treat both autoimmune and vascular disease.
|Wilhelm, Ashley J; Rhoads, Jillian P; Wade, Nekeithia S et al. (2015) Dysregulated CD4+ T cells from SLE-susceptible mice are sufficient to accelerate atherosclerosis in LDLr-/- mice. Ann Rheum Dis 74:778-85|