Immune Activation of Fibroblasts

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DESCRIPTION (provided by applicant): Fibroblast activation plays an important role in initiating the inflammatory response. Phenotypic attributes of fibroblasts from specific anatomic regions are thought to underlie the peculiar pattern of manifestations associated with certain disease. Other fibroblast characteristics appear global, such as the expression of chemoattractants including IL-16, a CD4-specific ligand and RANTES, a C-C chemokine. We have found that fibroblasts from patients with Graves' disease (GD), when treated with their IgGs (GD-IgG), become activated and express high levels of IL-16 and RANTES. Control fibroblasts from donors without autoimmune disease fail to respond to these IgGs. GD-IgG which are disease specific, appear to be binding to the insulin-like growth factor 1 receptor (IGF-1R) displayed on fibroblasts. We hypothesize that IGF-1R represents an important activational self-antigen. We now propose the following studies to test our central hypothesis. 1) To define the mechanism(s) involved in the GD-specific anti IGF-1R IgG upregulation of IL-16 and RANTES expression by fibroblasts; 2) To determine the serum levels of GD-IgG, IL-16 and RANTES in autoimmune graves disease patients and normal controls and determine the clinical utility of these parameters; 3) To test in vivo the hypothesis that IGF-1R is a critical self-antigen in GD that when ligated with GD-IgG, activates IL-16 and RANTES expression and T cell infiltration. The candidate and mentor have worked closely together for the last year in a productive relationship. The research career development award, continued mentoring and the availability of the General Clinical Research Center, will allow the candidate to further investigate and answer these clinically relevant questions. The candidate will develop the scientific knowledge base, problem solving abilities and technical skills to develop into an independent researcher.