Pathogenesis of Graves' Ophthalmopathy: The Role of Autoantibodies

Abstract

The clinical manifestations of Graves' ophthalmopathy (GO) stem from a combination of increased orbital fat and extraocular muscle volume within the orbital space. Fibroblasts residing within these tissues are thought to be targets of autoimmune attack in the disease. Thyrotropin receptor (TSHr) mRNA and functional protein have been demonstrated in orbital fibroblasts from both normal individuals and GO patients, with higher levels present in the latter. Autoantibodies directed against TSHr or the insulin-like growth factor-1 (IGF-1) receptor have been implicated in GO pathogenesis. Evidence from our laboratory suggests that monoclonal TSHr autoantibodies (TRAbs) are potent stimulators of adipogenesis in GO orbital cells. Therefore, it is possible that circulating TRAbs in Graves' patients both stimulate overproduction of thyroid hormones and increase orbital adipose tissue volume. Antibodies to the IGF-1 receptor appear to impact GO pathogenesis through recruitment and activation of T-cells and stimulation of hyaluronan production, processes that play key roles in the development of inflammation and increased orbital tissue swelling. Although originally thought to represent another causative agent, antibodies to extraocular muscles are now generally thought to be secondary to extraocular muscle inflammation and damage.

Relevance of TSH-receptor antibody levels in predicting disease course in Graves’ orbitopathy: comparison of the third-generation TBII assay and Mc4-TSI bioassay

“…The GO ocular manifestations include eyelid retraction, proptosis, chemosis, periorbital edema, altered ocular motility, and loss of vision with significant functional, social, and cosmetic consequences. [1][2][3][4] As there are few clues currently available to assist clinicians in estimating GO prognosis, it is very difficult to predict which patients will suffer from such severe sequelae. Recently, Eckstein et al 5 reported that persistently high TSH-receptor antibody (TRAb) levels were associated with a severe course of GO by demonstrating that TRAb levels at 12-24 months after diagnosis were significantly higher in patients with a severe course of GO than in those with a mild outcome.…”

Genetic Profiling in Graves' Disease: Further Evidence for Lack of a Distinct Genetic Contribution to Graves' Ophthalmopathy

“…TSHR antibodies act as TSH agonists and induce thyroid overactivity. It has been estimated that 25%-50% of GD patients have clinical signs of Graves' ophthalmopathy or orbitopathy (GO), with the vast majority having relatively mild disease (3,4). As with all autoimmune disorders, it is thought that GD is caused by the interaction of genetic, epigenetic, and environmental factors in a stochastic manner.…”

Increased oxidative DNA damage, lipid peroxidation, and reactive oxygen species in cultured orbital fibroblasts from patients with Graves’ ophthalmopathy: evidence that oxidative stress has a role in this disorder

“…[1][2][3] Despite recent progress in the understanding of its pathogenesis, clear and indisputable mechanisms have not been established and treatment is often not satisfactory. [4][5][6][7][8][9] It may represent a complex interplay among orbital fibroblasts, immune cells, cytokines, autoantibodies, genetics, and environmental factors. [9][10][11][12][13] Recently, there is growing evidence that a change of reactive oxygen species (ROS) metabolism has been implicated in the aetiopathogenesis of several autoimmune disorders including Graves' disease and GO.…”

“…[4][5][6][7][8][9] It may represent a complex interplay among orbital fibroblasts, immune cells, cytokines, autoantibodies, genetics, and environmental factors. [9][10][11][12][13] Recently, there is growing evidence that a change of reactive oxygen species (ROS) metabolism has been implicated in the aetiopathogenesis of several autoimmune disorders including Graves' disease and GO. [14][15][16] Bednarek et al 17,18 reported that the ROS and antioxidant enzymes were increased in peripheral blood of hyperthyroid patients and euthyroid patients with infiltrative ophthalmopathy.…”