Endothelial activation occurs in many of the systemic autoimmune rheumatologic disorders, including rheumatoid arthritis, systemic lupus erythematosus, the antiphospholipid antibody syndrome, and rheumatic fever. This endothelial activation may lead to coronary artery disease, thrombosis, or cardiac valve inflammation, all of which contribute to the increased mortality risk these patients incur. Understanding the basic mechanisms by which autoimmune diseases lead to endothelial pathology is therefore essential to reduce the burden of such diseases. The K/BxN murine model of arthritis provides a novel system in which to study the interplay between systemic autoimmunity and endothelial pathology. The mechanisms of arthritogenesis in this model are well understood, and include autoantibody formation against a ubiquitously expressed antigen, immune complex formation and deposition on synovial surfaces, recruitment of inflammatory cells and complement activation. Although the inflammatory attack in this model was thought to be restricted to the joints, preliminary data presented herein show that the cardiac valves of K/BxN mice are also inflamed and thickened. This is the first animal model of spontaneous cardiac valve inflammation. The fact that the valve disease occurs in an established murine model of arthritis affords a unique opportunity to dissect the mechanisms by which systemic autoimmunity provokes endothelial injury in the heart. This new model of autoimmune carditis will be characterized via three specific aims, including (1) describing the histopathologic and immunopathologic features of the inflammatory valvular carditis in the K/BxN model, (2) determining the role that B cells and immunoglobulins play in generation of the valve pathology and (3) determining the mechanism(s) by which the complement system regulates the valve pathology, based on the preliminary observation that genetic deficiency of complement component C1q exacerbates carditis severity. It is expected that the knowledge gained by studying this new animal model of autoimmune cardiac valve disease will open further avenues for investigating the mechanisms of endothelial pathology in systemic autoimmune conditions and also lead to innovative therapeutic approaches for patients with such disorders.

National Institute of Health (NIH)
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Clinical Investigator Award (CIA) (K08)
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Arthritis and Musculoskeletal and Skin Diseases Special Grants Review Committee (AMS)
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Mancini, Marie
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University of Minnesota Twin Cities
Other Domestic Higher Education
United States
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