Genetic Susceptibility to Graves’ Ophthalmopathy

Abstract

Graves’ disease (GD) is an autoimmune thyroid disorder (AITD) with aberrant antibody production resulting in hyperthyroidism [1]. It is characterized by T cell and B cell reactivity to the thyrotropin (thyroid stimulating hormone; TSH) receptor (TSHR) located on the endothelial surface of thyroid follicular cells, and the presence of abundant serum antibodies against TSHR (TRAb) is used as a specific marker of GD. Follicular hyperplasia, intracellular colloid droplets, cell thinning and patchy T cell-predominant lymphocytic infiltrations can be observed in thyroid gland histology of GD patients. GD is considered primarily a T helper-2 (Th2) autoimmune disease, as TRAb stimulates TSHR as an agonist, resulting in the excessive production of thyroid hormones. The pathogenesis of GD has been studied for decades and several risk factors have been identified. Similar to other autoimmune diseases, GD is believed to develop because of a combination of genetic susceptibility and environmental triggers. Often there is a familial history of disease and it is prevalent in women [2]. These facts support a role for genetic susceptibility in the pathogenesis of GD. Environmental factors are also considered important for the susceptibility and onset of disease. Infections have been predicted to have a pivotal role in triggering autoimmune reactions and the breakdown of tolerance leading to GD, although evidence is scarce. Patients with GD frequently have a history of some type of psychological and/or physiological stress [3]. Recently, epigenetic factors have also been demonstrated to be involved in autoimmune pathogenesis [4]. Classical GD was descri‐ bed as a syndrome consisting of tachycardia, goiter and orbitopathy, called “Merseburg triad”. Most GD patients develop tachycardia and goiter; however, GD patients with orbitopathy, named Graves’ ophthalmopathy (GO), occur in up to 60% of all GD patients [5]. In particular, GO worsens the patients quality of life because of its intractable symptoms, including diplopia, proptosis, chemosis and retro-orbital pain. With severe GO patients may risk visual loss. Moreover, GO is also experienced in patients with Hashimoto’s thyroiditis (HT) across ethnic backgrounds [6, 7]. HT is another common AITD, which is thought to develop from a combi‐