Because the bony orbit lacks compliance, anterior displacement of the contained tissues may result, leading to proptosis, or protrusion of the globe. disease (GD) was named after the Irish physician Robert James Graves (1797C1853), who described the syndrome of hyperthyroidism, goiter, and exophthalmos. This autoimmune disease has an incidence of 1/1000 women per year and represents the most common form of hyperthyroidism. The overproduction of thyroid hormones by thyroid follicular cells in GD is usually mediated by autoantibodies directed against the thyroid-stimulating hormone receptor (TSHr). Graves ophthalmopathy (GO; also known as thyroid-associated ophthalmopathy or thyroid eye disease) is usually clinically evident in 25C50% of patients with GD (1). While the majority of patients experience only moderate ocular symptoms, 3C5% of patients with GO suffer from severe disease (2). The spectrum of eye manifestations ranges from lid lag and retraction to proptosis, ophthalmoplegia, conjunctivitis, chemosis, and corneal ulceration, to loss of vision. The clinical manifestations of GO stem from a combination of increased orbital fat and extraocular muscle volume within the orbital space. Because the bony orbit lacks compliance, anterior displacement of the contained tissues may result, leading Rabbit Polyclonal to Histone H2A to proptosis, or protrusion of the globe. The increased orbital pressure also causes impairment of venous and lymphatic outflow and congestive swelling of the periorbital tissues (3). Although orbital adipose tissue volume expansion predominates in some patients and increased extraocular muscle volume is usually prominent in others, most patients show a combination of both processes (Fig. 1). Open in a separate window FIG. 1 Computerized tomographic scan of the orbits of a patient with Graves ophthalmopathy showing enlargement of both the orbital fat and the extraocular muscles. The expanded orbital tissues cause forward displacement of the globe and impairment of venous and lymphatic outflow from the orbit. Histochemical examination of orbital tissues in GO reveals a lymphocytic infiltration, consisting primarily of T lymphocytes, and the presence of inflammatory cytokines (4). Fibroblasts residing within the orbital connective/adipose tissue compartment and investing the extraocular muscle cells are thought to be targets of autoimmune attack in the disease. These multipotent cells are markedly heterogeneous and may be partially characterized according to their expression of the surface glycoprotein Thy-1 (5,6). Although its function as a receptor is usually unknown, this marker appears to distinguish distinct subgroups that differ in their responses to adipogenic stimuli and in their biosynthetic properties. The minority of cells derived from the orbital connective/adipose tissue compartment are Thy-1? and thus capable of adipogenesis. In contrast, those investing the extraocular muscles (and found within dermal tissues) uniformly display Thy-1 (Thy-1+) and do not undergo adipogenesis when similarly stimulated. This phenotypic heterogeneity in fibroblasts within the orbit AG-024322 may impact the clinical presentation of the disease as regard the relative AG-024322 contributions of adipose tissue and extraocular muscle expansion (6). Fibroblast heterogeneity extends AG-024322 as well to cells derived from other anatomic sites; while orbital connective tissue fibroblasts treated with interferon-or leukoregulin synthesize high levels of hyaluronan, dermal fibroblasts produce only small quantities of this glycosaminoglycan (7,8). Furthermore, peroxisome proliferatorCactivated receptor-(PPAR-receptor being expressed at comparable levels in fibroblasts from both sites (9). Although the mechanisms at play have yet to be clarified, these and other phenotypic differences between fibroblasts may help to explain why orbital adipose tissue is usually targeted in GO while other fat depots appear not to be impacted. Involvement of Autoantibodies in GO Pathogenesis TSHr autoantibodies The close clinical association between onset of Graves hyperthyroidism and the development of GO suggests that these two conditions may share pathogenic mechanisms. Because autoantibodies directed against TSHr [TSHr autoantibodies (TRAbs)] are known to be responsible for the hyperthyroidism of GD, investigators have long sought evidence that TRAbs might be involved as well in GO pathogenesis. Clinical studies show that GO prevalence is usually increased in GD patients AG-024322 having the highest levels of TRAbs, and that euthyroid patients with GO generally have elevated TRAb levels (10,11). Furthermore, the clinical activity score, a composite based on signs of inflammation such as orbital pain, conjunctival erythema, and chemosis, is usually correlated with levels of both TSHr AG-024322 stimulatory and TSH-binding inhibitory TRAbs; a weaker, but also significant, correlation was found between levels of these antibodies and proptosis (12). In a large longitudinal study, TSH-binding inhibitory antibody levels were significantly higher in patients with severe disease than in patients with mild GO (13). A prerequisite for the involvement of TSHr and TRAbs in GO would seem to be.