Pathogenesis of ophthalmopathy in autoimmune thyroid disease.

What causes GO is still a mystery, but the disease process results from a complex interplay of genetic and environmental factors. Genes such as those for HLA genes may determine a patient's susceptibility to the disease and its severity, but environmental factors, often unknown, may determine its course. Once established, the chronic inflammatory process within the orbital tissues appears to take on a momentum of its own. Given our current state of knowledge, the following working scheme for the pathogenesis of GO can be proposed (Fig. 1): On the background of a permissive immunogenetic milieu, circulating T cells in patients with GD, directed against certain antigens on thyroid follicular cells, recognize antigenic epitopes that are shared by tissues contained in the orbital space. Of the cell types residing in these tissues, preadipocytes and fibroblasts, most likely act as target and effector cells of the orbital immune process, respectively. This includes preadipocyte fibroblasts present in the perimysium of extraocular muscles, which do not appear to be immunologically different from those located in the orbital connective tissue. Orbital preadipocyte fibroblasts may be stimulated by unknown circulating or locally produced factors to differentiate into mature adipocytes that express increased levels of TSHr. How autoreactive T cells escape deletion and control 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 still unknown. Proliferation and expansion of autoreactive T cell clones may be due to mimicry of a host antigen by a microorganism, but this remains speculative. T cell recruitment into the orbital tissues is facilitated by certain chemokines and cytokines, which help to attract T cells by stimulating the expression of certain adhesion molecules (e.g., ICAM-1, VCAM-1, CD44) in vascular endothelium and connective tissue cells. These adhesion receptors are known to also play an important costimulatory role by activating T cells and facilitating antigen recognition, which amplifies the cellular immune process. Analysis of variable region genes of T cell antigen receptors in orbital T cells of patients with active GO has revealed their restricted TcR V gene usage, suggesting that antigen-driven selection and/or expansion of specific T cells may occur early in the evolution of GO. T cells and macrophages populating the orbital space are known to synthesize and release a [figure: see text] number of cytokines (most likely a Th1-type spectrum) into the surrounding tissue. Cytokines, oxygen free radicals and fibrogenic growth factors, released both from infiltrating inflammatory and residential cells, act upon orbital preadipocytes in a paracrine and autocrine manner to stimulate adipogenesis, fibroblast proliferation, glycosaminoglycan synthesis, and the expression of immunomodulatory molecules. Smoking, a well-known aggravating factor in GO, may aggravate tissue hypoxia and exert important immunomodulatory effects. The long held hypothesis of a thyroid cross-reactive antigen within the orbital tissues has recently gained significant support by an animal model of GO, and by in vitro and ex vivo studies. If confirmed in immunological studies, these data may well explain the localized infiltration of the orbital tissues by autoreactive lymphocytes that share intriguing molecular features with intrathyroidal lymphocytes. Local release of particular cytokines, TSHr-directed antibodies, or other factors might further enhance adipogenesis, glycosaminoglycan synthesis and expression of immunomodulatory proteins within the orbit. Other factors, including inflammatory cytokines, might act as counterbalancing inhibitors of these effects. However, if the net effect of these changes is to increase the volume of the fatty connective tissues within the orbit, then proptosis, extraocular muscle dysfunction, and periorbital congestion will ensue. Whether this hypothetical sequence of events will finally explain the involvement of the orbit in GD is unknown. Future studies will be aimed at identifying factors that might modulate adipogenesis in orbital cells and clarifying the link between adipogenesis and TSHr expression in the orbit. Taken together, a number of important details in the complex pathogenesis of GO have been resolved in recent years, but many challenges are still ahead. Elucidation of the primary antigen and how it is recognized by the immune system will be key issues.