Haasken, Stefanie Sharon2013-02-202013-02-202013-01https://hdl.handle.net/11299/144805University of Minnesota Ph.D. dissertation. January 2013. Major: Microbiology, Immunology and Cancer Biology. Advisor:Bryce A. Binstadt. 1 computer file (PDF), viii, 92 pages.Immunological tolerance is achieved through multiple mechanisms, including the dominant tolerance exerted by regulatory T cells as well as the induction of anergy in potentially autoreactive lymphocytes. Here, we investigated the role of two molecules of interest, β2 integrins and the class a macrophage scavenger receptor (Msr1), in the pathogenesis of systemic autoimmune disease utilizing the K/BxN TCR transgenic mouse model of spontaneous autoimmune arthritis and endocarditis. Genetic absence of β2 integrins had no effect on the severity of arthritis and unexpectedly increased the extent of cardiovascular pathology. The exaggerated cardiac phenotype of the β2 integrin-deficient K/BxN mice was accompanied by immune hyperactivation and was linked to a defect in regulatory T cells. These findings are consistent with a model in which the development of arthritis in K/BxN mice relies primarily on autoantibodies, whereas endocarditis depends on an additional contribution of effector T cells. K/BxN mice lacking Msr1 had decreased incidence and severity of arthritis. Protection from disease was associated with undetectable levels of antibodies recognizing the key autoantigen in this model, GPI, despite the presence of a population of GPI-specific B cells. Msr1-deficient macrophages displayed impaired uptake of GPI, and Msr1-deficient mice had an elevated concentration of circulating GPI. These data suggest a model in which deficiency of Msr1 can lead to a higher concentration of a soluble autoantigen, resulting in alterations in B cell tolerance and protection from autoimmune disease. Together, these studies contribute to our understanding of the different layers of immunological tolerance responsible for protecting against spurious responses against self.en-USAutoimmunityCD18EndocarditisKRNMsr1TregsThesis or Dissertation