EYE IN GRAVES' DISEASE--ROLE OF ORBITAL FIBROBLASTS

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DESCRIPTION: (Investigator's Abstract): The consequences of Graves' ophthalmopathy include pain, inflammation, disfigurement, diplopia and loss of vision. At present, treatment options for this debilitating condition are palliative at best. Better approaches to management and improved clinical outcome will not likely be developed until there is a better understanding of the pathogenesis. The clinical triad Graves' disease includes thyrotoxicosis, Graves' ophthalmopathy and pretibial dermopathy. The clinical signs and symptoms of the nonthyroidal manifestations of Graves' disease are the result of an accumulation of glycosaminoglycans (GAG) in the retro-ocular space, within the extra-ocular muscle bodies and in the pretibial skin of affected individuals. These hydrophilic macromolecules are produced locally by fibroblasts. The central premise of the proposed research is that disordered GAG synthesis by fibroblasts, mediated by immunologic events, results in the GAG accumulation characteristic of both Graves' ophthalmopathy and pretibial dermopathy. The investigators will examine fibroblasts from the retro-ocular connective tissue, extraocular muscles, and pretibial and abdominal skin. The investigators intend to determine (1) if the abundance of a particular retro-ocular fibroblast antigen of 23 kDa, which they have defined, is affected by the immunologic milieu; (2) whether there are differences in heat shock protein expression between fibroblasts from affected and unaffected anatomical regions; (3) whether there are differences in major histocompatibility class II (HLA-DR) or immunoglobulin binding between fibroblasts from affected and unaffected anatomical regions; and (4) if GAG synthesis by retro-ocular, extraocular perimysial and pretibial fibroblasts is stimulated by IL-1, other cytokines or conditioned media. The investigators see 600-1000 patients with Graves' ophthalmopathy annually at the Mayo Clinic, approximately 30 of whom undergo orbital decompression surgery. Thus, they have access to a very large patient population with this condition, as well as to surgical tissues from severely affected individuals. Techniques to be used include in vitro assays of GAG synthesis, immunoblot analyses of fibroblasts proteins, and immunocytochemical and immunofluorescent examinations of biopsy specimens from affected individual. The investigators believe these studies will enhance their understanding of disease pathogenesis which will translate into improve management strategies and eventually better clinical outcomes.