Abstract
The TSH receptor (TSHr) is the autoantigen responsible for the hyperthyroidism of Graves’ disease. Recent studies suggest that this receptor may also be an autoimmune target in Graves’ ophthalmopathy (GO) and pretibial dermopathy (PTD). Its involvement in the pathogenesis of these conditions would help to explain the close clinical associations between hyperthyroidism, GO and PTD. TSHr has been shown to be present in normal orbital and dermal tissues and evidence supports the conviction that expression may be increased in tissues involved in GO and PTD. In the setting of Graves’ disease, the expression of this antigen in connective tissues throughout the body may lead to systemic, subclinical connective tissue inflammation. Given this background, local or environmental factors such as circulating or local cytokines, gravitational dependency, anatomic constraint of the bony orbit, or trauma, may augment clinical disease involvement within the orbit and pretibial skin. Alternately, locally enhanced expression of this protein at the sites of clinical disease may not be directly involved in pathogenesis, but could be secondary to the ongoing process, and nonetheless important in disease progression.
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References
Werner SC, Coleman DJ, Fravzen LA. Ultrasonographic evidence of a consistent orbital involvement in Graves’ disease. N Engl J Med 1974, 290:1447–50.
Salvi M, Zhang Z-G, Haegert D, et al. Patients with endocrine ophthalmopathy not associated with overt thyroid disease have multiple thyroid immunological abnormalities. J Clin Endocrinol Metab 1990, 70: 89–94.
Suri A, Katz JD. Dissecting the role of CD4+ T cells in autoimmune diabetes through the use of TCR transgenic mice. Immunol Rev 1999, 169: 55–65.
Marcocci C, Bartalena L, Bogazzi FM, Panicucci M, Pinchera A. Studies on the occurence of ophthalmopathy in Graves’ disease. Acta Endocrinol (Copenh) 1989, 120: 473–78.
Fatourechi V, Pajouhi M, Fransway AF. Dermopathy of Graves’ disease (pretibial myxedema). Review of 150 cases. Medicine 1994, 73: 1–7.
Tomer Y, Barbesino G, Greenberg DA, Concepcion E, Davies T F. Mapping the major susceptibility loci for familial Graves’ and Hashimoto’s diseases: evidence for genetic heterogeneity and gene interactions. J Clin Endocrino Metab 1999, 84: 4656–64.
Villanueva R, Inzerillo AM, Tomer Y, et al. Davies TF.Limited genetic susceptibility to severe Graves’ ophthalmopathy: no role for CTLA-4 but evidence for an environmental etiology. Thyroid 2000, 10:791-8.
Gerding MN, van der Meer JW, Broenink M, Bakker O, Wiersinga WM, Prummel MF. Association of thyrotrophin receptor antibodies with the clinical features of Graves’ ophthalmopathy. Clin Endocrinol (Oxf) 2000, 52: 267–71.
Rodbell M. Metabolism of isolated fat cells. I. Effects of hormones on glucose metabolism and lipolysis. J Bio Chem 1964, 239: 375–80.
Davies TF, Teng CS, McLachlan SM, Rees-Smith B, Hall R. Thyrotropin receptors in adipose tissue, retro-orbital tissue and lymphocytes. Mol Cell Endocrinol 1978, 9: 303–13.
Perros P, Kendall-Taylor P. Demonstration of thyrotropin binding sites in orbital connective tissue: Possible role in the pathogenesis of thyroid-associated ophthalmoapthy. J Endocrinol Invest 1994, 17: 163–70.
Marcus C, Ehren H, Bolme P, Arner P. Regulation of lipolysis during the neonatal period: Importance of thyrotropin. J Clin Invest 1994, 82: 1793–7.
Sorisky A, Pardasani D, Gagnon A, Smith TJ. Evidence of adipocyte differentiation in human orbital fibroblasts in primary culture. J Clin Endocrinol Metab 1996, 81: 3428–31.
Haraguchi K, Shimura H, Lin L, Endo T, Onaya T. Differentiation of rat adipocytes is accompanied by expression of thyrotropin receptors. Endocrinology 1996, 137: 3200–5.
Valyasevi RW, Erickson DZ, Harteneck DA, et al. Differentiation of human orbital preadipocyte fibroblasts induces expression of functional thyrotropin receptor. J Clin Endocrinol Metab 1999, 84: 2557–62.
Valyasevi RW, Harteneck DA, Dutton CM, Bahn RS. Stimuation of adipogenesis, peroxisome proliferator-activated receptor-γ (PPAR-γ), and thyrotropin receptor by PPAR-γ agonist in human orbital preadipocyte fibroblasts. J Clin Endocrinol Metab 2002, 87: 2352–8.
Jyonouchi S, Valyasevi R, Harteneck DA, Dutton CM, Bahn RS. Interleukin-6 stimulates thyrotropin receptor expression in human orbital preadipocyte fibroblasts from patients with Graves’ ophthalmopathy. Thyroid 2001, 11: 929–34.
Watson PF, Pickerill AP, Davies R, Weetman AP Semi-quantitative analysis of interleukin-1 alpha, interleukin-6 and interleukin-8 mRNA expression by human thyrocytes. J Mol Endocrinol 1995, 15: 11–21.
Salvi M, Pedrazzoni M, Girasole G, et al. Serum Concentrations of proinflammatory cytokines in Graves’ disease: effect of treatment, thyroid function, ophthalmopathy and cigarette smoking. Eur J Endocrinol 2000, 143: 197–202.
Valyasevi RW, Jyonouchi SC, Dutton CM, Munsakul N, Bahn RS. Effect of TNF-α, IFN-γ, TGF-β on adipogenesis and expression of TSH receptor in human orbital preadipocyte fibroblasts. J Clin Endocrinol Metab 2001, 86: 903–8.
Heufelder AE, Dutton CM, Sarkar G, Donovan KA, Bahn RS. Detection of TSH receptor RNA in cultured fibroblasts from patients with Graves’ ophthalmopathy and pretibial dermopathy. Thyroid 1993, 3: 297–300.
Feliciello A, Porcellini A, Ciullo, Bonavolonta G, Avvedimento E V, Fenzi G. Expression of thyrotropin-receptor mRNA in healthy and Graves’ retro-orbital tissue. Lancet 1993, 342: 337–8.
Mengistu M, Lukes YG, Nagy EV, et al. TSH receptor gene expression in retroocular fibroblasts. J Endocrinol Invest 1994, 7: 437–41.
Bahn RS, Dutton CM, Natt N, Joba W, Spitzweg C, Heufelder AE. Thyrotropin receptor expression in Graves’ orbital adipose/connective tissues: potential autoantigen in Graves’ ophthalmopathy. J Clin Endocrinol Metab 1998, 83: 998–1002.
Crisp MS, Lane C, Halliwell M, Wynford Thomas D, Ludgate M. Thyrotropin receptor transcripts in human adipose tissue. J Clin Endocrinol Metab 1997, 82: 2003–5.
Rapoport B, Alsabeth R, Aftergood D, McLachlan SM. Elephantiasic pretibial myxedema: insight into and a hypothesis regarding the pathogenesis of the extrathyroidal manifestations of Graves’ disease. Thyroid 2000, 10: 685–92.
Dutton CM, Joba W, Spitzweg C, Heufelder AE, Bahn RS. Thyrotropin receptor expression in adrenal, kidney, and thymus. Thyroid 1997, 7: 879–84.
Davies TF. Editorial: The thyrotropin receptors spread themselves around. J Clin Endocrinol Metab 1994, 79: 1232–3.
Grubeck-Loebenstein B, Trieb K, Sztankay A, Holter W, Anderl H, Wick G. Retrobulbar T cells from patients with Graves’ ophthalmopathy are CD8+ and specifically recognize autologous fibroblasts. J Clin Invest 1994, 3: 2738–43.
Otto EA, Ochs K, Hansen C, Wall JR, Kahaly GJ. Orbital tissue-derived T lymphocytes from patients with Graves’ ophthalmopathy recognize autologous orbital antigens. J Clin Endocrinol Metab 1996,1: 3045–50.
Many MC, Costagliola S, Detrait M, Denef JF, Vassart G, Ludgate M. Development of an animal model of autoimmune thyroid eye disease. J Immunol 1999, 162: 4966–74.
Bahn RS. Pathophysiology of Graves’ ophthalmopathy: The cycle of disease. J Clin Endocrinol Metab 2003 (in press).
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Bahn, R.S. TSH receptor expression in orbital tissue and its role in the pathogenesis of Graves’ ophthalmopathy. J Endocrinol Invest 27, 216–220 (2004). https://doi.org/10.1007/BF03345269
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DOI: https://doi.org/10.1007/BF03345269