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

Our concepts and understanding of the etiology, evolution, and propaga tion of Graves' ophthalmopathy have become much more sophisticated tha n they were 10 years ago. Given our current state of knowledge, the fo llowing scheme for the pathogenesis of Graves' ophthalmopathy can be p roposed. Circulating T cells in patients with Graves' disease, directe d against an antigen on thyroid follicular cells, recognize antigenic epitopes that are shared by tissues contained in the retroorbital spac e. Of the cell types residing in these tissues, fibroblasts are most l ikely to act as both target and effector cells of the retroorbital imm une process. This includes those fibroblasts present in the perimysium of extraocular muscles, which do not appear to be immunologically dif ferent from fibroblasts located in the retroorbital connective tissue. By contrast, convincing evidence implicating the human extraocular my ocyte itself (rather than the tissue conglomerate of extraocular muscl e) as a primary target in GO remains to be demonstrated. Together with adipocytes, fibroblasts may also serve as target and effector cells i n 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 i s unknown. T cells are recruited to and infiltrate the orbit via certa in adhesion receptors, which may also play a costimulatory role in T c ell activation and facilitate antigen recognition. Analysis of variabl e region gene usage of the T cell antigen receptors in retroorbital T cells of patients with active GO reveals limited variability, suggesti ng that antigen-driven selection and/or expansion of specific T cells may occur early in the evolution of GO. Although the relative contribu tions of cellular and humoral immunity to the pathogenesis of GO are s till 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 kn own to release certain cytokines (most likely a Th1-type spectrum) int o the surrounding tissue. Cytokines and growth factors released both f rom infiltrating inflammatory and residential cells act upon fibroblas ts in a paracrine and autocrine manner to stimulate the expression of immunomodulatory molecules, glycosaminoglycan synthesis, and cell prol iferation in retroorbital fibroblasts. The existence of a thyroid cros s-reactive antigen within the retroorbital tissues has long been postu lated to explain the localized infiltration of autoreactive lymphocyte s into the orbit. The recent detection, in fibroblasts and possibly ot her cellular components of the retroorbital space, of mRNA transcripts encoding the human TSH receptor, together with evidence of TSHr immun oreactivity in these cells, further highlight this intriguing possibil ity. However, presence of functionally active and/or immunogenic TSH r eceptor protein within the retroorbital tissues remains to be further substantiated. Taken together, a number of important steps in the comp lex pathogenesis of GO have been elucidated in recent years. Neverthel ess, before the enigma of GO will be resolved, many important problems remain to be tackled, of which the nature of the primary antigen is o nly one.