Many systemic autoimmune diseases affect both the synovial joints and the cardiovascular system. For example, patients with rheumatoid arthritis or systemic lupus erythematosus (SLE) are at increased risk for developing coronary artery disease. In particular, inflammation of the cardiac valves occurs in rheumatic fever (rheumatic carditis) and in SLE and the related antiphospholipid syndrome (Libman-Sacks endocarditis). The immune mechanisms that provoke concomitant inflammation of synovial joints and cardiac valves in these human systemic autoimmune disorders remain poorly defined. We have recently discovered spontaneous cardiac valve inflammation (endocarditis) in a well-studied model of autoantibody-associated arthritis. This model affords the unique opportunity to dissect the immune mechanisms mediating autoimmune attack on the joints versus the heart valves. The preliminary data presented herein demonstrate that endocarditis and arthritis depend on the same adaptive immune system elements for the initial breach of immunologic tolerance leading to autoantibody production. In contrast, the key innate immune system effector pathways differ between the two target tissues. Arthritis in this mouse model depends primarily on complement C5 and not Fc receptors;conversely, endocarditis depends essentially on Fc receptors and not C5. In contrast to the neutrophil-predominated joint infiltrate, the cardiac valve infiltrate in these mice comprises T cells and macrophages bearing 22 integrin adhesion receptors, as well as up-regulation of the endothelial ligands for these receptors. The current proposal investigates how two families of innate immune receptors, Fc receptors and 22 integrins, contribute to the development of autoimmune endocarditis. We will determine what cell types must express Fc receptors and which particular Fc receptor is critical for the development of endocarditis. In addition, we will investigate the possibility that members of the 22 integrin receptor family contribute differentially to the development of arthritis and endocarditis by studying the effects that deficiencies of specific 22 integrins have on the progression of disease in both tissues. It is hoped that these studies will provide important groundwork for additional research into the mechanisms by which a single systemic, autoantibody-associated autoimmune disease differentially engages the innate immune system to provoke damage in discrete target tissues. Understanding these differences may allow the development of more targeted therapies for systemic autoimmune diseases, based on which organ systems are involved in an individual patient.
The valves of the heart can be damaged by the immune system in diseases such as rheumatic fever and systemic lupus erythematosus. Our research program uses a mouse model to study in depth the mechanisms by which the immune system damages the heart valves. We expect that our findings will lead eventually to the development of new therapies for patients with rheumatic fever, lupus, and related autoimmune diseases.
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