Systemic lupus erythematosus (SLE) is a prototypical autoimmune disease characterized by the production of autoantibodies recognizing self-antigens. Clinical manifestation of lupus includes nephritis, pericarditis. Recent studies have implicated that lupus accelerates atherosclerosis, and accounts for premature mortality. Autoantibodies contribute to the pathology of lupus by recruiting and activating innate-immune effector cells. Interaction between Fc? receptors (Fc?R) expressed on inflammatory cells and B-lymphocytes to autoantibody-autoantigen immune complexes (IC) promote inflammatory responses associated with lupus and atherosclerosis. Fc?Rs are classified into activating and inhibitory receptors. Activating Fc?Rs are involved in innate immune cellular functions and inflammatory responses. The inhibitory Fc?RIIb regulates the inflammatory response initiated by the activating Fc?Rs and control antibody production by regulating B lymphocyte activation. Autoantibodies in lupus and oxidized low-density lipoprotein immune complexes (oxLDL-IC) generated during hyperlipidemia could bind to the activating and/or inhibitory Fc?Rs and contribute to the inflammatory processes. Interestingly, Fc?RIIb polymorphisms have been implicated as a risk factor for lupus and coronary artery disease. Furthermore, Fc?RIIb deficiency has been shown to regulate type I interferon response, implicated in the pathogenesis of lupus and atherosclerosis. These studies suggest that crosstalk between inhibitory Fc?RIIb and type I interferon response could contribute to the pathogenesis of lupus-induced atherosclerosis. Although the presence of autoantibodies has been reported in lupus patients and animal models, the contribution of Fc?Rs to the initiation and/or progression of lupus-induced atherosclerosis has not been studied. The central hypothesis of this proposal is that Fc?Rs play an important role in the progression of lupus-induced premature atherosclerosis. To test this hypothesis, we will complete the following aims:
Aim 1. To determine molecular mechanism(s) by which Fc?RIIb signaling modulate lupus-induced atherosclerosis, Aim 2. To determine crosstalk between inhibitory Fc?RIIb and type I IFN signaling contributing to lupus-induced atherosclerosis, and Aim 3. Investigate the role of human Fc?R in promoting inflammatory responses associated with lupus-induced atherosclerosis. The proposed studies will be significant because they will provide novel information supporting the contention that Fc?R signaling pathways may represent a novel therapeutic target for interventions aimed at ameliorating the vascular complications of autoimmune diseases, an area that is in dire need for development.
Lupus is an autoimmune disease involving several organ systems. Early onset of cardiovascular disease (CVD) is one of the major causes of lupus-associated mortality. In patients with lupus, antibodies against autoantigen correlate with carotid atherosclerosis. Autoantigen-autoantibody complexes (also known as immune complexes) to Fc? receptors expressed by inflammatory cells resulting in uncontrolled inflammation. The inflammatory responses can feed into promoting atherosclerosis. Interestingly, Fc? receptor polymorphism has been implicated with lupus as well as cardiovascular disease independently. Combination of lupus, Fc? receptor polymorphism and elevated cholesterol levels could cause more damage to blood vessels. In this application we will investigate the causal link between lupus, Fc? receptors and atherosclerosis. We expect to understand mechanism contributing to increased morbidity associated with patients with lupus. We believe that findings from this study will identify potential biomarkers, and therapeutic targets to treat autoimmune disease patients developing premature atherosclerosis.
