The orbital fibroblasts are widely viewed as the target cells of the autoimmune attack in GO. During the early stages of the disease, macrophages, highly specialized T cells, mast cells, and occasional plasma cells infiltrate the orbital connective, adipose, and muscle tissues [4, 5]. Activation of T cells directed against a thyroid follicular cell antigen(s) that then recognizes and binds to a similar antigen(s) in orbital tissue is a probable but yet unproven theory .
Alternatively, macrophages and dendritic cells may nonspecifically initiate the orbital immune response, which is then propagated by recruitment of sensitized T cells. Several cytokines have been associated with the evolution of the orbital tissue changes in TED [6, 7]. These include interferon-7 , tumor necrosis factor-a, interleukin-1 (IL-1), and transforming growth factor-^  as well as other growth factors such as insulin-like growth factor-I (IGF-I) [10, 11] and platelet-derived growth factor [12, 13]. These compounds are now known to be produced both by infiltrating immunocompetent cells and by residential fibroblasts, adipocytes, myocytes, and microvascular endothelial cells. These cytokines and growth factors stimulate cell proliferation, glycosaminoglycan (GAG) synthesis, and expression of immunomodulatory molecules in orbital fibroblasts and microvascular endothelial cells [13-15]. An increase in connective tissue and extraocular muscle volume within the bony orbits caused by accumulating hydrophilic compounds (predominantly GAG, the hydrophilic nature of which can attract water by osmosis) leads to the clinical manifestations of TED and causes proptosis, extraocular muscle dysfunction, and periorbital edema [1, 2].
The orbital fibroblasts do express functional TSH receptors (TSH-R). This recent finding has led to the currently favored view that the TSH-R is the long sought after shared antigen between the thyroid and the orbit and that the TSH-R is the autoantigen involved in GO. Indeed, cytokine-induced differentiation of a particular subset of orbital fibroblasts into adipocytes is associated with increased TSH-R expression and adipogenesis .
Furthermore, TSH-R immunization of experimental animals results in histological changes in orbital tissues resembling GO .
A causative role of stimulating TSH-R antibodies (TSI) in the development of GO is very attractive as it allows a unifying hypothesis for the various clinical manifestations of GD: Graves' hyperthyroidism (GH), GO and thyroid dermopathy. Arguments against such a hypothesis cannot, however, be dismissed. TSI, in contrast to T cells, cross the placenta and may cause fetal and neonatal hyperthyroidism. GO, however, has never been observed in neonatal thyrotoxicosis TSI are almost always present in GH, but clinically apparent GO develops only in a subset of the patients. Lastly, serum TSI are only slightly related to the severity of GO, although more so to the activity of the eye disease . Whereas TSI might contribute to further progression of GO, it remains doubtful if TSI act as the primary mediator in the immunopathogene-sis of GO.
Consequently, the search for other antigens and antibodies involved in GO continues. Graves' IgG added to a culture of human skin fibroblasts increased the synthesis of collagen. The effect was not mimicked by TSH and rather specific for GO as IgG of Graves' hyperthyroid patients without GO were not active in this respect . Another study demonstrated that Graves' IgG was able to induce the release of T-cell chemoattractants from cultured orbital fibrobasts, notably IL-16 (a CD+ ligand that activates T cells) and RANTES (a C-C type chemokine) . The authors postulated IgG binding to a surface receptor of the fibroblasts distinct from the TSH-R, because TSH had no effect and there was no relation with TSH-R antibodies. The induction of IL-16 and RANTES could be blocked by rapamycin and the authors speculated the surface receptor could be the IGF-I receptor as IGF-I post-receptor signaling is also blocked by rapamycin.
Several antibody markers of immune-mediated damage to eye muscle have also been identified and the great majority of patients with active ophthalmopathy have antibodies against one or more eye muscle antigens. However, none of the target antigens are localized exclusively in the eye muscle and all are intra-cellular, indicating that their exposure to the immune system would be a consequence of eye muscle fiber damage rather than its cause .
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