The central role of the fibroblast in the pathogenesis of extrathyroidal manifestations of Graves' disease

Ophthalmopathy and pretibial dermopathy, nonthyroidal manifestations of Graves' disease, are characterized histologically by an accumulation of glycosaminoglycans. These hydrophilic macromolecules are elaborated by fibroblasts, principle cellular components of connective tissue. Regulation of this accumulation is incompletely understood. We, and others, have postulated that antibodies directed against fibroblasts, capable of influencing glycosaminoglycan synthesis, may be present in the sera of patients with the extrathyroidal manifestations of Graves' disease. Using immunoblotting techniques, we have demonstrated that antibodies directed against a 23 kD antigen found in fibroblasts were present in the majority (55%) of sera from patients with Graves' ophthalmopathy. These antibodies were rarely present in sera from control subjects or patients with other autoimmune or thyroid diseases. The abundance of this fibroblast protein, present in cultures derived from all anatomic sites studied, was uninfluenced by T₃, dexamethasone, or n-butyrate, all known to inhibit the synthesis of hyaluronate in human dermal fibroblasts. In studies examining the response of fibroblasts from different sites, n-butyrate inhibited markedly [³H]glycosaminoglycan accumulation in cultures of retro-ocular, abdominal and pretibial cells, unlike T₃ and dexamethasone which failed to influence macromolecular synthesis in retro-ocular cultures. These results suggest that retro-ocular fibroblasts share certain phenotypic features with their counterparts derived from dermal sites, but differ in that the rate of [³H]glycosaminoglycan synthesis is apparently uninfluenced by thyroid hormone or glucocorticoids. The sera from the majority of patients with Graves' disease, irrespective of the presence of extrathyroidal manifestations of that process, contain antibodies which recognize a 23 kD protein expressed in fibroblasts derived from all anatomic sites tested. The pathogenic significance of these findings is uncertain.