[Pathogenesis of Graves' ophthalmopathy]

Ophthalmopathy, the most frequent extrathyroidal manifestation of Graves' disease, results from an increased volume of the orbital tissues (connective and adipose tissue, interstitial enlargement of extraocular muscles) within the enclosed space of the bony orbits. While the primary antigen is still uncertain, the thyrotropin receptor has recently become a prime candidate because it is expressed both by thyroid epithelial cells and by orbital preadipocyte fibroblasts. Tolerance towards the thyroidal and orbital TSH receptor may be disrupted by bacterial or viral antigens through a "molecular mimicry"-type mechanism. In the context of appropriate costimulatory signals, this would prompt antigen presentation by local dendritic cells and macrophages followed by the recruitment of TSH receptor-specific T cells to the orbital space. As a result, orbital T cells, fibroblasts, adipocytes and perhaps other residential cells would release numerous cytokines, growth factors and inflammatory mediators, many of which act as potent stimulators of glycosaminoglycan accumulation and edema formation. Once initiated, the orbital immune process frequently takes on a momentum of its own, leading to non-specific but nonetheless harmful consequences such as tissue hypoxia, oxygen free radical damage and fibrogenic tissue remodeling. The clinical signs and symptoms of GO reflect the mechanical consequences of increased orbital tissue volume and pressure within the confines of the bony orbits.