Beta-B1 Crystallin - a New Candidate Uveitis Autoantigen

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DESCRIPTION: (Applicant?s Abstract) The long-term objectives of this work are to enhance the understanding of the pathogenic mechanisms of anterior uveitis, an important clinical disease that affects more than one million individuals and causes vision loss in up to 11%. The health-relatedness of the project is that it specifically attempts to define candidate antigens that drive certain endogenous human inflammatory diseases of the eye, resulting in improved diagnostic testing, novel therapeutic interventions, or identification of patient subsets at high risk for secondary disease. Although many immune-mediated inflammatory diseases are thought to result from activated CD4 T cells, B cell activation and clonal expansion is expected to occur in tandem. These selected B cells have the same antigenic specificity of the pathogenic T cell, and their antibodies offer an important tool to characterize the target antigen driving the immune response. The subject of this proposal is to evaluate an exciting candidate uveitis antigen, betaB1 crystallin, identified by reactivity with a uveitis marker antibody, Fab 5-3 ANCA, for its relevance in anterior uveitis and for its extra-lenticular expression. A strength of this proposal is the enthusiastic support and cooperation of a group of collaborators have who are leaders in lens crystallin research, studies of betaB1 crystallin, and in human uveitis clinical research to help with the acquisition of experimental materials and reagents. The first specific aim characterizes betaB1 crystallin expression in ocular and non-ocular tissues using immunohistochemical studies and molecular biology tools. These studies will confirm the preliminary findings and enhance our knowledge about this protein, which has not previously been demonstrated outside of the lens. The second specific aim is designed to explore the relationship between seroreactivity against betaB1 crystallin and the development of intraocular inflammation or cataract. In the third specific aim, betaB1 crystallin is used as an antigen to develop a rodent model of human anterior uveitis. The classic animal uveitis models mimic posterior, not anterior uveitis; therefore development of an anterior uveitis animal model would significantly expand our ability to study the pathogenesis of this important cause of visual morbidity. This proposal thus addresses two novel and important predictions: that betaB1 crystallin is present in an extralenticular distribution, and that specific immune reactivity against this protein is relevant in uveitis or uveitis-associated cataract.