The overall objectives of this project are to understand the functional importance of orbital fibroblast heterogeneity and to define the role of the CD40/CD154 fibroblast activational bridge in the pathogenesis of thyroid associated ophthalmopathy (TAO). The hypothesis to be tested is that the orbit is susceptible to tissue remodeling in TAO because of unique fibroblast phenotypes and because TAO fibroblasts, unexpectedly, express both CD40 and its cognate ligand, CD154. When CD40 on orbital fibroblasts is ligated with CD154, down-stream genes are activated, leading to the disordered production of PGE2 and hyaluronan. Orbital fibroblasts, divided into subsets on the basis of Thy-1 expression, exhibit substantially different phenotypes. Thy-1- fibroblasts, when activated, express high levels of IL-8 and represent pre-adipocytes that can differentiate in vitro into adipocytes. Thy-1+ fibroblasts, when treated with IgG from patients with Graves' disease, produce extraordinarily high levels of IL-16, a CD4+ lymphocyte specific chemoattractant, and RANTES, a c-c chemokine. This activity is apparently mediated though the IGF-1 receptor. The applicant hypothesizes that these latter inductions, limited to the Thy1+ subset, represent the basis for lymphocyte infiltration of the orbit in TAO. We now propose to 1) define the role of the CD40/CD154 bridge in the activation of orbital fibroblasts by characterizing CD40 and CD154 expression and signaling to down-stream responses; 2) compare inflammatory phenotypes exhibited by Thy-1+ and Thy-1- orbital fibroblasts by determining whether Thy-1 cross-linking results in fibroblast activation and determining the molecular basis for IGF-1 receptor involvement in the IL-16 and RANTES inductions; 3) define the inflammatory phenotype of adipocytes differentiated in vitro from Thy-1- orbital fibroblasts. We believe that the results of the proposed studies will lead to important insights concerning the pathogenesis of TAO and potentially define therapeutic targets for interrupting this disease.
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