Pathogenesis of Graves' Ophthalmopathy and Autoimmune Thyroid Disease

Our laboratory is interested in the mechanisms and consequences of immune system activation of orbital preadipocyte fibroblasts, the target cells involved in Graves' ophthalmopathy (GO). We are studying the unique features of these that render them particularly susceptible to autoimmune attack in Graves' disease. Studies are underway to define retro-ocular, thyroid and pretibial cross-reactive antigens whose presence might help to explain the clinical associations between GO, pretibial dermopathy, and Graves' hyperthyroidism. We have shown that thyroid stimulating hormone receptor (TSHR), the autoimmune target in Graves' hyperthyroidism, is expressed to a greater degree in orbital connective tissue explants from patients with Graves' ophthalmopathy than in normal orbital tissue. This antigen appears to be expressed in the fat cells within the orbit. Our in vitro studies have shown that TSHR expression in orbital preadipocytes is closely associated with adipogenesis. We have shown that factors impacting adipogenesis, including interleukin-6, interferon-gamma, and the PPAR-gamma agonist rosiglitazone, appear also to have effects on TSHR expression in these cells. Other studies in our laboratory include the analysis, using gene array technology, of genes involved in the development of GO. We have identified several adipogenesis-related and immune system genes that may have novel roles in this disease process. Finally, we are developing a mouse model of GO to use in studies of novel treatments for this condition.