INVOLVEMENT OF THE ORBITAL FIBROBLAST AND TSH RECEPTOR IN THE PATHOGENESIS OF GRAVES OPHTHALMOPATHY

Our concepts and understanding of the etiology, evolution, and propagation of Graves' ophthalmopathy have become much more sophisticated than they were 10 years ago. Given our current state of knowledge, the following scheme for the pathogenesis of Graves' ophthalmopathy can be proposed. Circulating T cells in patients with Graves' disease, directed against an antigen on thyroid follicular cells, recognize antigenic epitopes that are shared by tissues contained in the retroorbital space. Of the cell types residing in these tissues, fibroblasts are most likely to act as both target and effector cells of the retroorbital immune process. This includes those fibroblasts present in the perimysium of extraocular muscles, which do not appear to be immunologically different from fibroblasts located in the retroorbital connective tissue. By contrast, convincing evidence implicating the human extraocular myocyte itself (rather than the tissue conglomerate of extraocular muscle) as a primary target in GO remains to be demonstrated. Together with adipocytes, fibroblasts may also serve as target and effector cells in pretibial myxedema. How autoreactive T cells escape deletion by the immune system and come to be directed against a self-antigen presented by cells residing in the thyroid gland and extrathyroidal locations is unknown. T cells are recruited to and infiltrate the orbit via certain adhesion receptors, which may also play a costimulatory role in T cell activation and facilitate antigen recognition. Analysis of variable region gene usage of the T cell antigen receptors in retroorbital T cells of patients with active GO reveals limited variability, suggesting that antigen-driven selection and/or expansion of specific T cells may occur early in the evolution of GO. Although the relative contributions of cellular and humoral immunity to the pathogenesis of GO are still uncertain, it is likely that both are important for full clinical expression and propagation of the autoimmune process within the orbit. T cells and macrophages populating the retroorbital space are now known to release certain cytokines (most likely a Th1-type spectrum) into the surrounding tissue. Cytokines and growth factors released both from infiltrating inflammatory and residential cells act upon fibroblasts in a paracrine and autocrine manner to stimulate the expression of immunomodulatory molecules, glycosaminoglycan synthesis, and cell proliferation in retroorbital fibroblasts. The existence of a thyroid cross-reactive antigen within the retroorbital tissues has long been postulated to explain the localized infiltration of autoreactive lymphocytes into the orbit. The recent detection, in fibroblasts and possibly other cellular components of the retroorbital space, of mRNA transcripts encoding the human TSH receptor, together with evidence of TSHr immunoreactivity in these cells, further highlight this intriguing possibility. However, presence of functionally active and/or immunogenic TSH receptor protein within the retroorbital tissues remains to be further substantiated. Taken together, a number of important steps in the complex pathogenesis of GO have been elucidated in recent years. Nevertheless, before the enigma of GO will be resolved, many important problems remain to be tackled, of which the nature of the primary antigen is only one.