Pathogenesis of Graves ophthalmopathy: the role of orbital thyroid-stimulating hormone receptor expression

Abstract

The thyroid-stimulating hormone, or thyrotropin, receptor (TSHr) is the autoantigen against which the autoimmune response is directed in Graves hyperthyroidism. The close clinical associations between hyperthyroidism, Graves ophthalmopathy (GO), and pretibial dermopathy (PTD) led to the hypothesis that these conditions represent different manifestations of the same autoimmune disease. This paper reviews recent literature concerning the potential role of TSHr as an autoantigen in the pathogenesis of the extrathyroidal manifestations of Graves disease. Recent studies from several laboratories suggested that low-abundance TSHr messenger RNA and protein are present in normal connective and adipose tissues from many anatomic sites. In addition, increased expression of this receptor has been demonstrated in orbital and dermal tissues from patients with GO and PTD. In normal individuals, low-abundance TSHr expression in connective tissues throughout the body may have little physiologic relevance. However, in the setting of Graves disease with circulating antibodies and T cells directed against this antigen, a generalized, subclinical, connective tissue inflammation may develop. On this background, local environmental factors affecting the orbit and pretibial skin may contribute to the development of clinical disease at these sites. Alternately, locally enhanced expression of TSHr at the sites of clinical disease may not be directly involved in pathogenesis but could be secondary to the ongoing disease process and important in disease progression.