Thyrotropin receptor expression in orbital adipose/connective tissues from patients with thyroid-associated ophthalmopathy

The TSH receptor (TSHR) is the autoantigen responsible for the hyperthyroidism of Graves' disease. However, whether this receptor plays a role in the development of Graves' ophthalmopathy (GO) is unclear. Expression of TSHr is augmented in orbital tissues from patients with GO, and in newly differentiated adipocytes derived from precursor cells within the orbit. Our recent studies suggest that interleukin-6 (IL-6), a cytokine elevated in the circulation of Graves' patients, stimulates TSHr expression in vitro in orbital preadipocyte fibroblasts. This cytokine might play a role in the pathogenesis of GO by stimulating TSHr expression within the fatty connective tissues of the orbit, allowing the receptor to act there as an autoantigen. Whether IL-6 also stimulates adipogenesis in the orbit is unclear at present, but such an effect could contribute to the increased volume of orbital adipose/connective tissue characteristic of this condition. Other cytokines, including IFN-gamma and TGF-beta, inhibit TSHr expression and adipogenesis by orbital fibroblasts, effects that would seem to favor disease remission. The initiation and subsequent clinical severity of GO may therefore be influenced by competing inhibitory and stimulatory cytokine effects occurring simultaneously within the orbit. Some of these may impact the expression of TSHr, the putative orbital autoantigen in this condition.