Pathogenesis of Graves' Orbitopathy

E-ISSN： 1875-6115|11|2|72-82

ISSN： 1871-5222

Source： Immunology, Endocrine & Metabolic Agents in Medicinal Chemistry (Formerly Current Medicinal Chemistry - Immunology, Endocrine and Metabolic Agents), Vol.11, Iss.2, 2011-06, pp. : 72-82

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Abstract

About 5% of patients with Graves' disease (GD) develop Graves' orbitopathy (GO) of sufficient severity to require treatment. GD is an autoimmune condition caused by thyroid stimulating antibodies (TSAB) mimicking the action of TSH, although the mechanisms leading to loss of tolerance to the TSHR remain unknown. In GO, tissue remodeling increases the volume of the orbital contents by several mechanisms including adipogenesis and overproduction of glycosaminoglycans (GAGs). The increased volume produces proptosis, chemosis and increased intraocular pressure. GO is also an autoimmune disease and the timing of its onset (relative to GD) suggests a thyroid/orbit shared antigen. Data in favour of the antigen being the TSHR include demonstration of its increased expression during adipogenesis and the fact that the most severe GO occurs in GD patients having the highest TSAB titres. Evidence against its role are patients with euthyroid GO (devoid of TSAB) and its widespread expression. However, recent reports demonstrate a direct role for TSHR autoantibodies in GAG production, but it is likely that other antigens, such as IGF-1R, may also contribute to pathogenesis. In vitro models have demonstrated the heterogeneity of orbital fibroblasts, some destined for adipogenesis and/or secretion of GAGs in response to stimulation by inflammatory cytokines or patient immunoglobulins. GO may be exacerbated by e.g. PPARγ agonists, but PPAR&ggr; antagonists (inhibit adipogenesis) may provide novel treatment options. Of interest, B cell depletion, which does not consistently reduce TSAB levels, also shows some promise but further adds to the puzzle of the relevance of the TSHR.