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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Type
Clinical Investigator Award (CIA) (K08)
Project #
5K08AR054317-05
Application #
8101818
Study Section
Arthritis and Musculoskeletal and Skin Diseases Special Grants Review Committee (AMS)
Program Officer
Mancini, Marie
Project Start
2007-07-01
Project End
2012-06-30
Budget Start
2011-07-01
Budget End
2012-06-30
Support Year
5
Fiscal Year
2011
Total Cost
$128,844
Indirect Cost
Name
University of Minnesota Twin Cities
Department
Type
Other Domestic Higher Education
DUNS #
555917996
City
Minneapolis
State
MN
Country
United States
Zip Code
55455
Hobday, Patricia M; Auger, Jennifer L; Schuneman, Gregory R et al. (2014) Fc? receptor III and Fc? receptor IV on macrophages drive autoimmune valvular carditis in mice. Arthritis Rheumatol 66:852-62
Hobday, Patricia M; Auger, Jennifer L; Schuneman, Gregory R et al. (2013) FcýýRIII and IV on macrophages drive autoimmune valvular carditis. Arthritis Rheum :
Haasken, Stefanie; Auger, Jennifer L; Taylor, Justin J et al. (2013) Macrophage scavenger receptor 1 (Msr1, SR-A) influences B cell autoimmunity by regulating soluble autoantigen concentration. J Immunol 191:1055-62
Auger, Jennifer L; Haasken, Stefanie; Binstadt, Bryce A (2012) Autoantibody-mediated arthritis in the absence of C3 and activating Fc? receptors: C5 is activated by the coagulation cascade. Arthritis Res Ther 14:R269
Rao, Sindhuja M; Auger, Jennifer L; Gaillard, Philippe et al. (2012) The neuropeptide neuromedin U promotes autoantibody-mediated arthritis. Arthritis Res Ther 14:R29
Auger, Jennifer L; Haasken, Stefanie; Steinert, Elizabeth M et al. (2012) Incomplete TCR-? allelic exclusion accelerates spontaneous autoimmune arthritis in K/BxN TCR transgenic mice. Eur J Immunol 42:2354-62
Haasken, Stefanie; Auger, Jennifer L; Binstadt, Bryce A (2011) Absence of ?2 integrins impairs regulatory T cells and exacerbates CD4+ T cell-dependent autoimmune carditis. J Immunol 187:2702-10
Stingl, Cory; Moller, James H; Binstadt, Bryce A (2010) Cardiac operations for North American children with rheumatic diseases: 1985-2005. Pediatr Cardiol 31:66-73
Binstadt, Bryce A; Hebert, Jennifer L; Ortiz-Lopez, Adriana et al. (2009) The same systemic autoimmune disease provokes arthritis and endocarditis via distinct mechanisms. Proc Natl Acad Sci U S A 106:16758-63
Zhang, Kejian; Biroschak, Jennifer; Glass, David N et al. (2008) Macrophage activation syndrome in patients with systemic juvenile idiopathic arthritis is associated with MUNC13-4 polymorphisms. Arthritis Rheum 58:2892-6