IMMUNE MECHANISMS OF OCULAR INFLAMMATORY DISEASE

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The immediate goal of the candidate is to develop scientific expertise in molecular immunology and ocular biochemistry as applied to the definition of pathogenic autoantigens. This will lead to the long-term goal of an independent research program on the pathogenesis of ocular inflammatory diseases. The candidate has a strong background in clinical ophthalmology with a demonstrated interest in ocular inflammation. Past graduate school success in basic research is evidence of her scientific abilities. However, the lag time between graduate school and re-entry into basic research demands a period of mentored scientific retraining. UCLA will provide an outstanding scientific environment that will allow the candidate to develop current expertise in molecular biology and immunology. 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, which can be used as the basis for novel diagnostic tests and therapeutic interventions. 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 use new techniques iii antibody phage display cloning to isolate marker antibodies and candidate antigens for a distinctive type of uveitis that commonly occurs with ulcerative colitis (UC). The first aim is to determine whether a unique marker antibody in UC, pANCA, is associated with inflammatory uveitis. This will be tested by ELISA and immunofluorescence screening of human sera for the distinct UC form of pANCA. The correlation between disease activity and level of autoantibody will also be determined. The second aim is to identify uveal antigens that react with 5-3, a human recombinant monoclonal antibody to the pANCA antigen. If such antigens are identified, they will be characterized by protein biochemistry, or if necessary, by molecular cloning. Disease association of the antigen will be tested by characterizing the B and T cell responses to the antigen. The third aim is to develop a comprehensive library of uveal antigens reactive with the UC antibody response. Biochemical and immunologic characterization of these antigens will be performed following the experimental model of the preceding aim.