Abstract
The thyrotropin (TSH) receptor is implicated in the pathogenesis of thyroid-associated ophthalmopathy, but its presence has not been demonstrated in orbital tissues. Binding of 125|-TSH to porcine orbital connective tissue and thyroid membranes was studied. At pH 7.4 125|-TSH bound to thyroid membranes with high affinity, but not to orbital connective tissue membranes. At pH 5.2, binding of 125|-TSH was evident on thyroid and orbital connective tissue membranes, although of low affinity. Low affinity binding at pH 5.2, could also be demonstrated on orbital fibroblasts; binding to membranes prepared from extraocular muscle, or from abdominal adipose tissue was not detected. Immunoglobulin G from healthy subjects (n=17) and patients with ophthalmopathy (n=19) were tested for inhibition of 125|-TSH binding to membranes. As anticipated patients’ IgG exhibited greater inhibition than normal controls with thyroid membranes at pH 7.4 (p<0.001). Similar results were obtained with thyroid membranes (p< 0.05), and orbital connective tissue membranes at pH 5.2 (p<0.001). Significant correlations were found when percentage inhibition by IgG was compared between: thyroid membranes at pH 7.4 and thyroid membranes at pH 5.2, orbital connective tissue membranes at pH 5.2 and thyroid membranes at pH 7.4, and orbital connective tissue membranes at pH 5.2 and thyroid membranes at pH 5.2. A low affinity TSH-binding site is present in orbital connective tissue, and is recognized by IgG’s from patients with ophthalmopathy which suggests that TSH receptor antibodies may target the orbit.
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Perros P., Kendall-Taylor P. Pathogenetic mechanisms in thyroid-associated ophthalmopathy. J. Intern. Med. 231: 205, 1992.
Kroll A.J., Kuwabara T. Dysthyroid ocular myopathy. Arch. Ophthalmol. 76: 244, 1966.
Hufnagel T.J., Hichey W.F., Cobbs N.H., Jacobiec F.A., Iwamoto T., Eagle R.C. Immunohistochemical and ultrastructural studies on the exenterated orbital tissues of a patient with Graves’ disease. Ophthalmology 91: 1411, 1984.
Tallstedt L, Norberg R. Immunohistochemical staining of normal and Graves’ extraocular muscle. Invest. Ophthalmol. Vis. Sci. 29: 175, 1988.
Bahn R.S., Heufelder A.E. Role of connective tissue autoimmunity in Graves’ ophthalmopathy. Autoimmunity 13: 75, 1992.
Kodama K., Bandy-Dafoe P., Sikorsa H., Bayly R., Wall J.R. Demonstration of a circulating autoantibody against a soluble eye muscle antigen in Graves’ ophthalmopathy. Lancet ii: 1353, 1982.
Kendall-Taylor P., Atkinson S., Holcombe M. A specific IgG in Graves’ ophthalmopathy and its relation to retroorbital and thyroid autoimmunity. Br. Med. J. 288: 1183, 1984.
Bahn R.S., Gorman C.A., Woloschak G.E., David C.S., Johnson P.M. Johnson C.M. Human retroocular fibroblast in vitro. A model for the study of Graves’ ophthalmopathy. J. Clin. Endocrinol. Metab. 65: 665, 1987.
Salvi M., Miller A., Wall J.R. Human orbital tissue and thyroid membranes express a 64kDa protein which is recognized by autoantibodies in the serum of patients with thyroid-associated ophthalmopathy. FEBS Lett. 232: 135, 1988.
Rotella C.M., Zonefrati R., Toccafondi R., Valente W.A., Kohn L.D. Ability of monoclonal antibodies to the thyrotropin receptor to increase collagen synthesis in human fibroblast. An assay which appears to measure exophthalmogenic immunoglobulins in Graves’ sera. J. Clin. Endocrinol. Metab. 62: 357, 1986.
Tao T.-W., Leu S.-L., Kriss J.P. Biological activity of autoantibodies associated with Graves’ dermopathy. J. Clin. Endocrinol. Metab. 69: 90, 1989.
Davies T.F., Teng C.S., Mc.Lachlan S.M., Rees Smith B., Hall R. Thyrotropin receptors in adipose tissue, retro-orbital tissue and lymphocytes. Mol. Cell. Endocrinol. 9: 301, 1978.
Weetman A.P. Thyroid-associated eye disease: pathophysiology. Lancet 338: 25, 1991.
Werner S.C. Modification of the classification of the eye changes in Graves’ Disease; Recommendations of the ad hoc committee of the American Thyroid Association. J. Clin. Endocrinol. Metab. 44: 203, 1977.
Atkinson S., Hardwick M., Kendall-Taylor P. Thyrotropin-blocking antibodies in goitrous primary hypothyroidism: detection by a highly sensitive bioassay and determination of site of action. J. Endocrinol. 118: 141, 1988.
Weightman D.R., Shale D.J., Tomlinson W.R. A rapid radioassay for human IgG produced in lymphocytes in vitro culture systems. J. Immunol. Methods 46: 307, 1981.
Rees Smith B., Pyle G.A., Petersen V.B., Hall R. Interaction of thyrotropin with the human thyrotrophin receptor. J. Endocrinol. 75: 391, 1977.
Pekonen F., Weintraub B.D. Thyrotropin binding to cultured lymphocytes and thyroid cells. Endocrinology 103: 1668, 1978.
Winand R.J., Kohn LD. The binding of [3H] thyrotropin and an 3H-labeled exophthalmogenic factor by plasma membranes of retro-orbital tissue. Proc. Natl. Acad. Sci. USA 69: 1711, 1972.
Gill D.L., Marshall N.J., Ekins R.P. Binding of thyrotropin to receptors in fat tissue. Mol. Cell. Endocrinol. 87: 33, 1978.
Trokoudes K.M., Michelson H., Kidd A., Row V.V., Volpe R. Properties of human thyroidal and extrathyroidal TSH receptors. Acta Endocrinol. (Copenh.) 97: 473, 1981.
Meek J.C., Kobayashi M., Waxman J.E. Radioreceptor assay for human thyrotropin (hTSH). Clin. Res. 22: 634A, 1974.
Pekonen F., Weintraub B.D. Thyrotropin receptors on bovine thyroid membranes: two types with different affinities and specificities. Endocrinology 105: 352, 1979.
Rees Smith B., McLachlan S.M., Furmaniak J. Autoantibodies to the thyrotropin receptor. Endocr. Rev. 9: 106, 1988.
Shewring G., Rees Smith B. An improved radioreceptor assay for TSH receptor antibodies. Clin. Endocrinol. (Oxf.) 17: 409, 1982.
Yamamoto M., Rapaport B. Studies on the binding of radiolabeled thyrotropin to cultured human thyroid cells. Endocrinology 103: 2011, 1978.
Akamizu T., Saji M., Kohn L.D. A microsequencing approach to identify proteins which appear to interact with thyrotropin in rat FRTL-5 thyroid cels. Biochem. Biophys. Res. Commun. 170: 351, 1990.
Libert F., Lefort A., Gerand D., Parmantier M., Perret J., Ludgate M., Dumont J.E., Vassart G. Cloning, sequencing and expression of the human thyrotropin (TSH) receptor: evidence for binding of autoantibodies. Biochem. Biophys. Res. Commun. 165: 1250, 1989.
Nagayama Y., Kaufman K.D., Seto P., Rappaport B. Molecular cloning, sequence and functional expression of the cDNA for the human thyrotropin receptor. Biochem. Biophys. Res. Commun. 165: 1184; 1989.
Permantier M., Libert F., Maenhaut C., Lefort A., Gerard C., Perret. G.J., van Sande J., Dumond J.E., Vassart G. Molecular cloning of the thyrotropin receptor. Science 246: 1620, 1989.
Feliciello A., Porcellini A., Ciullo I., Bonavolontà G., Avvedimento V.E., Fenzi G.F. Expression of thyrotropin-receptor mRNA in healthy and Graves’ disease retro-orbital tissue. Lancet 342: 337, 1993.
Francis T., Burch H.B., Cai W.-Y., Lukes Y., Peele M., Carr F.E., Wartofski L, Burman K.D. Lymphocytes express thyrotropin receptor-specific mRNA as detected by the PCR technique. Thyroid 1: 223, 1991.
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Perros, P., Kendall-Taylor, P. Demonstration of thyrotropin binding sites in orbital connective tissue: Possible role in the pathogenesis of thyroid-associated ophthalmopathy. J Endocrinol Invest 17, 163–170 (1994). https://doi.org/10.1007/BF03347708
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DOI: https://doi.org/10.1007/BF03347708