Pathogenesis of thyroid-associated ophthalmopathy: an autoimmune disorder of the eye muscle associated with Graves' hyperthyroidism and Hashimoto's thyroiditis.

Thyroid-associated ophthalmopathy, the progressive eye disorder which occurs frequently in patients with Graves' hyperthyroidism and, occasionally, in those with Hashimoto's thyroiditis, may be a two-stage disorder of the eye muscle. In the first stage, which may occur in the great majority of patients with Graves' hyperthyroidism and in an unknown, but probably small, proportion of those with Hashimoto's thyroiditis, antibodies and CD4+ (helper) T lymphocytes reactive with eye muscle and thyroid shared antigens, of which 64-kDa membrane proteins are good candidates, may initiate a mild eye muscle inflammation, manifested as eye muscle swelling on orbital imaging. The second stage, which occurs in about 25% of patients with Graves' hyperthyroidism and in 2% of those with Hashimoto's thyroiditis, may be due to reactivity of cytotoxic antibodies against eye muscle-specific membrane antigens, one of which at approximately 35 kDa appears a likely candidate, and, possibly, cytotoxic T cells in the context of the appropriate class I MHC molecule. Orbital connective tissue inflammation, which plays an important role in the development of progressive orbital inflammation, is likely to be secondary to the eye muscle reaction. The recent cloning of a 64-kDa thyroid and eye muscle antigen which shares significant homology with the muscle protein tropomodulin and mapping of its antibody-reactive epitopes provide structural information about one candidate eye muscle autoantigen and promise for a more rational approach to the diagnosis and management of this common, progressive eye disorder.