Thyroid eye disease is an immunological disorder that affects the orbital muscles and fat. Hyperthyroidism is observed with orbitopathy at some point in most patients, although the two are commonly synchronous. Histological examination of the retroocular connective tissues in thyroid eye disease reveals lymphocytic infiltration and accumulation of glycosaminoglycans produced locally by fibro-blasts, which contribute to the pathogenesis of ophthalmopathy.
Effective parameters involving glycosaminoglycans to indicate the activity of thyroid eye disease have been reported. The concentrations of glycosaminoglycans were determined in patients with thyroid eye disease and control subjects (68). The orbital extracellular matrix glycosaminoglycans exhibited a significant increase in the tissue fractions containing chondroitin sulfate A and hyaluronan in patients with thyroid eye disease in comparison to those from control subjects. Patients with increased glycosaminoglycan concentrations responded well to steroids and/or orbital irradiation. Therefore, glycosaminoglycans are candidates for activity markers in patients with thyroid eye disease.
Transmission electron microscopy analysis revealed a marked expansion of the endomysial space in thyroid eye disease extraocular muscle biopsies compared with that in control biopsies (69). An increased number of collagen fibers with hya-luronan were detected by immunogold staining, although the serum levels of hya-luronan and urinary glycosaminoglycans were not found to be sensitive indicators for the presence of these molecules within the extraocular muscles (69). Imai et al. further confirmed that the local accumulation of glycosaminoglycans in thyroid eye disease was not associated with the serum hyaluronan concentration (70).
On the other hand, Kahaly et al. reported that urinary glycosaminoglycan excretion is an effective parameter for the activity of thyroid eye disease (71). Urinary glycosaminoglycan excretion was quantified in patients with thyroid eye disease and control subjects. In comparison with the control subjects, a significant elevation of urinary glycosaminoglycan excretion was found in patients with ophthalmopathy, whereas patients with thyroid eye disease and no ophthalmopa-thy and patients with toxic nodular goiter exhibited no markedly increased values. In particular, patients with active untreated ophthalmopathy showed a twofold increase in urinary glycosaminoglycan excretion on average. In contrast, high values were not detected in patients with inactive ophthalmopathy and the elevated values decreased after treatment, consistent with the clinical findings.
Humoral and cell-mediated immunity responses are related to glycosaminogly-can synthesis by retrobulbar fibroblasts in patients with thyroid eye disease. Previous studies have produced the following results. First, an ELISA using hyaluronan as the antigen detected isotype IgG antibodies in the sera of thyroid eye disease patients and healthy control subjects. In comparison with the control subjects, significantly higher hyaluronan antibody levels were found in the thyroid eye disease patients. Furthermore, when hyaluronan synthesis was measured in retrobulbar fibroblasts from the control subjects and patients after coculture with lymphocytes, the patient lymphocytes showed a marked ability to increase the hyaluronan concentration compared to the control lymphocytes (72,73). The hyaluronan concentration after incubation of patient retrobulbar fibroblasts with autologous lymphocytes was markedly more elevated than the intrinsic hyaluronan production of control retrobulbar fibroblasts. Second, thyroid eye disease is characterized by infiltration of mast cells into the orbit (74). The effects of mast cell coculture on human orbital fibroblasts have been determined. HMC-1, an established human mast cell line, activated human orbital fibroblasts to produce increased levels of hyaluronan, as was evidenced by a twofold increase in [3H]-glucosamine incorporation into macromolecules upon coculture. Some molecules stimulated the accumulation of glycosaminoglycans in cultured human retroocular fibroblasts. Thus, these molecules released from lymphocytes, macrophages, or other cells infiltrating the retroocular space may play roles in the pathogenesis of thyroid eye disease.
Some of the released molecules have been identified. Interleukin (IL)-1, which is produced by macrophages and fibroblasts within the thyroid eye disease orbit, stimulated glycosaminoglycan synthesis by normal orbital fibroblasts (75). IL-1 and TGF-p significantly stimulated glycosaminoglycan accumulation by retroocular connective tissue in a dose- and time-dependent fashion (76,77). Although retroocular tissue fibroblasts synthesized hyaluronan, as well as large and small chondroitin sulfate proteoglycans, both insulin-like growth factor (IGF)-I and platelet-derived growth factor (PDGF) increased the synthesis of hyaluronan and proteoglycans in a dose-dependent manner (78). Furthermore, IGF-1 predominantly stimulated the secretion of small chondroitin sulfate proteoglycans, while PDGF increased that of large chondroitin sulfate proteoglycans. Recombinant interferon-g stimulated glycosaminoglycan accumulation in retroocular fibroblast cultures (79). In contrast, interferon-g had no consistent effect on macromolecular accumulation in dermal fibroblast cultures derived from the pretibium or areas ordinarily noninvolved in thyroid eye disease. Therefore, retroocular fibroblasts may be uniquely targeted for one action of interferon-g.
Cyclic AMP (cAMP) stimulates glycosaminoglycan synthesis by retroocular tissue fibroblasts (80). Antithyrotropin (TSH)-receptor antibodies are involved in the pathogenesis of thyroid eye disease, and TSH-receptor antibodies increase cAMP as a second messenger in thyroid cells. The effects of dibutyryl cAMP on glycosaminoglycan synthesis by retroocular tissue fibroblasts have been examined. Retroocular tissue fibroblasts mainly synthesized hyaluronan, large chondroitin sulfate proteoglycans, and small chondroitin sulfate proteoglycans as glycosamino-glycans in cell culture. Dibutyryl cAMP increased hyaluronan and proteoglycan syntheses by retroocular tissue fibroblasts, and particularly stimulated the secretion of the large proteoglycans.
On the other hand, some molecules inhibit glycosaminoglycan synthesis. Pen-toxifylline, an analogue of methylxanthine theobromine, inhibits the proliferation and biosynthetic activities of fibroblasts (81). Fibroblasts from the extraocular muscles of patients with thyroid eye disease and normal extraocular muscles were cultured in vitro in the presence or absence of pentoxifylline. In these fibroblast cultures, exposure to pentoxifylline resulted in a dose-dependent inhibition of gly-cosaminoglycan synthesis in all the fibroblasts. Therefore, pentoxifylline may be useful for the treatment of thyroid eye disease. In addition, treatment of fibroblasts with an IL-1-receptor antagonist or soluble IL-1 receptor significantly inhibited IL-1-stimulated glycosaminoglycan synthesis, indicating that such treatments may be useful for the prevention of thyroid eye disease (75).
Interestingly, fibroblasts derived from retroocular connective tissue and skin in thyroid eye disease exhibited different hormonal regulation. Specifically, skin fibroblasts responded to T3 (100 nmol/liter) and dexamethasone (100 nmol/liter) with 27% and 55% inhibition of glycosaminoglycan accumulation, respectively, whereas retroocular fibroblasts responded to the two hormones with 12% and 8% inhibition, respectively (82).
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