Abstract
Increased iodide intake has been linked to the development of hypothyroidism and/or autoimmune thyroiditis in humans and animals, but the mechanisms involved remain poorly understood. Increased ingestion of iodide is likely to have pleiotropic effects on either metabolic or immunological processes. Within the latter domain, recent interest has been focused on two areas: a) the role of iodinated peptides in thyroglobulin (Tg) — the molecular site of biosynthesis and storage of iodotyrosines and iodothyronines — in triggering an autoimmune cascade, and b) the role of iodine-induced apoptosis/necrosis of thyrocytes in the disease process. This review presents a brief summary of recent findings in these research areas.
Article PDF
Similar content being viewed by others
Avoid common mistakes on your manuscript.
References
Markou K, Georgopoulos N, Kyriazopoulou V, Vagenakis AG, 2001 Iodine-Induced hypothyroidism. Thyroid 11: 501–510.
Bagchi N, Brown TR, Urdanivia E, Sundick RS, 1985 Induction of autoimmune thyroiditis in chickens by dietary iodine. Science 230: 325–327.
Allen EM, Appel MC, Braverman LE, 1986 The effect of iodide ingestion on the development of spontaneous lymphocytic thyroiditis in the diabetes-prone BB/W rat. Endocrinology 118: 1977–1981.
Cohen SB, Weetman AP, 1988 The effect of iodide depletion and supplementation in the Buffalo strain rat. J Endocrinol Invest 11: 625–627.
Braley-Mullen H, Sharp GC, Medling B, Tang H, 1999 Spontaneous autoimmune thyroiditis in NOD.H-2h4 mice. J Autoimmun 12: 157–165.
Rasooly L, Burek CL, Rose NR, 1996 Iodine-induced autoimmune thyroiditis in NOD-H-2h4 mice. Clin Immunol Immunopathol 81: 287–292.
Iodine 2004 In: Vitamin and mineral requirements in human nutrition: report of a joint FAO/WHO expert consultation. Bangkok, Thailand, 21–30 September 1998, pp. 305–306. Accessed at http://www.who.int/vmnis/en
Bürgi H, 2010 Iodine excess. Best Pract Res Clin Endocrinol Metab 24: 107–115.
Müssig K 2009 Iodine-induced toxic effects due to seaweed consumption. In Preedy VR, Burrow GN, & Ross Watson R (eds) Comprehensive Handbook of Iodine Amsterdam: Elsevier pp, 897–908.
Roti E, Braverman LE 1996 Iodine excess and thyroid function. In Nauman J, Glinoer D, Braverman LE & Hostalek U (eds), The Thyroid and Iodine Stuttgart: Schattauer pp, 7–17.
Zimmermann MB, Jooste PL, Pandav CS, 2008 Iodine deficiency disorders. Lancet 372: 1251–1262.
Utiger RD, 2006 Iodine nutrition — more is better. N Engl J Med 354: 2819–2821.
Camargo R, Knobel M, Medeiros-Neto G, 2007 Iodine nutrition: more is better? Arq Bras Endocrinol Metab 51: 639–640.
Pearce EN, Pino S, He X, et al, 2004 Sources of dietary iodine: bread, cow’s milk, and infant formula in the Boston area. J Clin Endocrinol Metab 89: 3421–3424.
Pedersen KM, Laurberg P, Nøhr S, et al, 1999 Iodine in drinking water varies by more than 100-fold in Denmark: importance for iodine content in infant formulas. Eur J Endocrinol 140: 400–403.
Rose NR, Witebsky E, 1956 Studies on organ specificity. V. Changes in the thyroid glands of rabbits following active immunization with rabbit thyroid extract. J Immunol 76: 417–427.
Ban Y, Greenberg DA, Concepcion E, Skrabanek L, Villanueva R, Tomer Y, 2003 Amino acid substitutions in the thyroglobulin gene are associated with susceptibility to human and murine autoimmune thyroid disease. Proc Natl Acad Sci U S A 100: 15119–15124.
Tomer Y, Greenberg DA, Concepcion E, Ban Y, Davies TF, 2002 Thyroglobulin is a thyroid specific gene for the familial autoimmune thyroid diseases. J Clin Endocrinol Metab 87: 404–407.
Tomer Y, Greenberg D, 2004 The thyroglobulin gene as the first thyroid-specific susceptibility gene for autoimmune thyroid disease. Trends Mol Med 10: 306–308.
Carayanniotis G, 2007 Recognition of thyroglobulin by T cells: the role of iodine. Thyroid 17: 963–973.
Gentile F, Conte M, Formisano S, 2004 Thyroglobulin as an autoantigen: what can we learn about immunopathogenicity from the correlation of antigenic properties with protein structure? Immunology 112: 13–25.
Champion BR, Page KR, Parish N, et al, 1991 Identification of a thyroxine-containing self-epitope of thyroglobulin which triggers thyroid autoreactive T cells 6. J Exp Med 174: 363–370.
Hutchings PR, Cooke A, Dawe K, et al, 1992 A thyroxine-containing peptide can induce murine experimental autoimmune thyroiditis. J Exp Med 175: 869–872.
Braley-Mullen H, Sharp GC, 1997 A thyroxine-containing thyroglobulin peptide induces both lymphocytic and granulomatous forms of experimental autoimmune thyroiditis. J Autoimmun 10: 531–540.
Wan Q, McCormick DJ, David CS, Kong YC, 1998 Thyroglobulin peptides of specific primary hormonogenic sites can generate cytotoxic T cells and serve as target autoantigens in experimental autoimmune thyroiditis. Clin Immunol Immunopathol 86: 110–114.
Dunn JT, Anderson PC, Fox JW, et al, 1987 The sites of thyroid hormone formation in rabbit thyroglobulin. J Biol Chem 262: 16948–16952.
Marriq C, Lejeune PJ, Malthiery Y, Rolland M, Lissitzky S, 1984 Precursor-product relationship between the 26-kDa and 18-kDa fragments formed by iodination of human thyroglobulin. FEBS Lett 175: 140–146.
Kong YC, McCormick DJ, Wan Q, et al, 1995 Primary hormonogenic sites as conserved autoepitopes on thyroglobulin in murine autoimmune thyroiditis. Secondary role of iodination. J Immunol 155: 5847–5854.
Flynn JC, McCormick DJ, Brusic V, et al, 2004 Pathogenic human thyroglobulin peptides in HLA-DR3 transgenic mouse model of autoimmune thyroiditis. Cell Immunol 229: 79–85.
Muixi L, Alvarez I, Jaraquemada D, 2008 Peptides presented in vivo by HLA-DR in thyroid autoimmunity. Adv Immunol 99: 165–209.
Muixi L, Carrascal M, Alvarez I, et al, 2008 Thyroglobulin peptides associate in vivo to HLA-DR in autoimmune thyroid glands. J Immunol 181: 795–807.
Wan Q, Motte RW, McCormick DJ, et al, 1997 Primary hormonogenic sites as conserved autoepitopes on thyroglobulin in murine autoimmune thyroiditis: role of MHC class II. Clin Immunol Immunopathol 85: 187–194.
Leonardi A, Acquaviva R, Marinaccio M, et al, 1994 Presence of dityrosine bridges in thyroglobulin and their relationship with iodination. Biochem Biophys Res Commun 202: 38–43
Li HS, Carayanniotis G, 2006 Iodination of tyrosyls in thyroglobulin generates neoantigenic determinants that cause thyroiditis. J Immunol 176: 4479–4483.
Li HS, Jiang HY, Carayanniotis G, 2007 Modifying effects of iodine on the immunogenicity of thyroglobulin peptides. J Autoimmun 28: 171–176.
Jiang HY, Li HS, Carayanniotis K, Carayanniotis G, 2007 Variable influences of iodine on the T-cell recognition of a single thyroglobulin epitope. Immunology 121: 370–376.
Saboori AM, Rose NR, Bresler HS, Vladut-Talor M, Burek CL, 1998 Iodination of human thyroglobulin (Tg) alters its immunoreactivity. I. Iodination alters multiple epitopes of human Tg. Clin Exp Immunol 113: 297–302.
Saboori AM, Rose NR, Burek CL, 1998 Iodination of human thyroglobulin (Tg) alters its immunoreactivity. II. Fine specificity of a monoclonal antibody that recognizes iodinated Tg. Clin Exp Immunol 113: 303–308.
Edelhoch H, Carlomagno MS, Salvatore G, 1969 Iodine and the structure of thyroglobulin. Arch Biochem Biophys 134: 264–260.
Fouchier F, Mego JL, Dang J, Simon C, 1983 Intralysosomal hydrolysis of thyroglobulin. II. Different fates of poorly and fully iodinated Tg and specific activation by TSH of the degradation of fully iodinated Tg. Acta Endocrinol (Copenh) 103: 62–67.
Lamas L, Ingbar SH, 1978 The effect of varying iodine content on the susceptibility of thyroglobulin to hydrolysis by thyroid acid protease. Endocrinology 102: 188–197.
Dai YD, Rao VP, Carayanniotis G, 2002 Enhanced iodination of thyroglobulin facilitates processing and presentation of a cryptic pathogenic peptide. J Immunol 168: 5907–5911.
Duthoit C, Estienne V, Delom F, et al, 2000 Production of immunoreactive thyroglobulin C-terminal fragments during thyroid hormone synthesis. Endocrinology 141: 2518–2525.
Lehmann PV, Sercarz EE, Forsthuber T, Dayan CM, Gammon G, 1993 Determinant spreading and the dynamics of the autoimmune T-cell repertoire. Immunol Today 14: 203–208.
Gentile F, Salvatore G, 1993 Preferential sites of proteolytic cleavage of bovine, human and rat thyroglobulin. Eur J Ciochem 218: 603–621.
Benvenga S, Trimarchi F, Robbins J, 1987 Circulating thyroid hormone autoantibodies. J Endocrinol Invest 10: 605–619.
Sakata S, 1994 Autoimmunity against thyroid hormones. Crit Rev Immunol 14: 157–191.
Dai YD, Eliades P, Carayanniotis KA, et al, 2005 Thyroxine-binding antibodies inhibit T cell recognition of a pathogenic thyroglobulin epitope. J Immunol 174: 3105–3110.
Dai Y, Carayanniotis KA, Eliades P, et al, 1999 Enhancing or suppressive effects of antibodies on processing of a pathogenic T cell epitope in thyroglobulin. J Immunol 162: 6987–6992.
Barin JG, Talor MV, Sharma RB, Rose NR, Burek CL, 2005 Iodination of murine thyroglobulin enhances autoimmune reactivity in the NOD.H2 mouse. Clin Exp Immunol 142: 251–259.
Champion BR, Rayner DC, Byfield PG, Page KR, Chan CT, Roitt IM, 1987 Critical role of iodination for T cell recognition of thyroglobulin in experimental murine thyroid autoimmunity. J Immunol 139: 3665–3670.
Ebner SA, Lueprasitsakul W, Alex S, Fang SL, Appel MC, Braverman LE, 1992 Iodine content of rat thyroglobulin affects its antigenicity in inducing lymphocytic thyroiditis in the BB/Wor rat. Autoimmunity 13: 209–214.
Rose NR, Rasooly L, Saboori AM, Burek CL, 1999 Linking iodine with autoimmune thyroiditis. Environ Health Perspect 107: Suppl 5: 749–752.
Sundick RS, Herdegen DM, Brown TR, Bagchi N, 1987 The incorporation of dietary iodine into thyroglobulin increases its immunogenicity. Endocrinology 120: 2078–2084.
Allen EM, Thupari JN, 1995 Thyroglobulin-reactive T lymphocytes in thyroiditis-prone BB/Wor rats. J Endocrinol Invest 18: 45–49.
Li HS, Carayanniotis G, 2007 Induction of goitrous hypothyroidism by dietary iodide in SJL Mice. Endocrinology 148: 2747–2752.
Kolypetri P, Noel NA, Carayanniotis KA, Carayanniotis G, 2010 Iodine content of thyroglobulin in NOD.H-2h4 mice developing iodine-accelerated autoimmune thyroiditis. Hormones (Athens) 9: 151–160.
Rasooly L, Rose NR, Saboori AM, Ladenson PW, Burek CL, 1998 Iodine is essential for human T cell recognition of human thyroglobulin. Autoimmunity 27: 213–219.
Shimojo N, Saito K, Kohno Y, Sasaki N, Tarutani O, Nakajima H, 1988 Antigenic determinants on thyroglobulin: comparison of the reactivities of different thyroglobulin preparations with serum antibodies and T cells of patients with chronic thyroiditis. J Clin En-docrinol Metab 66: 689–695.
Bagchi N, Brown TR, Sundick RS, 1995 Thyroid cell injury is an initial event in the induction of autoimmune thyroiditis by iodine in obese strain chickens. Endocrinology 136: 5054–5060.
Belshaw BE, Becker DV, 1973 Necrosis of follicular cells and discharge of thyroidal iodine induced by administering iodide to iodine-deficient dogs. J Clin Endocrinol Metab 36: 466–474.
Follis RH, Jr, 1959 Thyroiditis resulting from administration of excess iodine to hamsters with hyperplastic goiters. Proc Soc Exp Biol Med 102: 425–429.
Li M, Eastman CJ, Boyages SC, 1993 Iodine induced lymphocytic thyroiditis in the BB/W rat: early and late immune phenomena. Autoimmunity 14: 181–187.
Mahmoud I, Colin I, Many MC, Denef JF, 1986 Direct toxic effect of iodide in excess on iodine-deficient thyroid glands: epithelial necrosis and inflammation associated with lipofuscin accumulation. Exp Mol Pathol 44: 259–271.
Many MC, Denef JF, Hamudi S, Cornette C, Haumont S, Beckers C, 1986 Effects of iodide and thyroxine on iodine-deficient mouse thyroid: a morphological and functional study. J Endocrinol 110: 203–210.
Many MC, Mestdagh C, van den Hove MF, Denef JF, 1992 In vitro study of acute toxic effects of high iodide doses in human thyroid follicles. Endocrinology 131: 621–630.
Many MC, Maniratunga S, Varis I, Dardenne M, Drexhage HA, Denef JF, 1995 Two-step development of Hashimoto-like thyroiditis in genetically autoimmune prone non-obese diabetic mice: effects of iodine-induced cell necrosis. J Endocrinol 147: 311–320.
Kahaly GJ, Dienes HP, Beyer J, Hommel G, 1998 Iodide induces thyroid autoimmunity in patients with endemic goitre: a randomised, double-blind, placebo-controlled trial. Eur J Endocrinol 139: 290–297.
Mizukami Y, Michigishi T, Nonomura A, et al, 1993 Iodine-induced hypothyroidism: a clinical and histologi-cal study of 28 patients. J Clin Endocrinol Metab 76: 466–471.
Tajiri J, Higashi K, Morita M, Umeda T, Sato T, 1986 Studies of hypothyroidism in patients with high iodine intake. J Clin Endocrinol Metab 63: 412–417.
Weaver DK, Batsakis JG, Nishiyama RH, 1969 Relationship of iodine to “lymphocytic goiters”. Arch Surg 98: 183–186.
Bonita RE, Rose NR, Rasooly L, Caturegli P, Burek CL, 2002 Adhesion molecules as susceptibility factors in spontaneous autoimmune thyroiditis in the NOD-H-2h4 mouse. Exp Mol Pathol 73: 155–163.
Sharma RB, Alegria JD, Talor MV, Rose NR, Caturegli P, Burek CL, 2005 Iodine and IFN-gamma synergistically enhance intercellular adhesion molecule 1 expression on NOD.H-2h4 mouse thyrocytes. J Immunol 174: 7740–7745.
Burek CL, Rose NR, 2008 Autoimmune thyroiditis and ROS. Autoimmun Rev 7: 530–537.
Sharma R, Traore K, Trush MA, Rose NR, Burek CL, 2008 Intracellular adhesion molecule-1 up-regulation on thyrocytes by iodine of non-obese diabetic. H2(h4) mice is reactive oxygen species-dependent. Clin Exp Immunol 152: 13–20.
Bagchi N, Brown TR, Herdegen DM, Dhar A, Sundick RS, 1990 Antioxidants delay the onset of thyroiditis in obese strain chickens. Endocrinology 127: 1590–1595.
Beckett GJ, Arthur JR, 2005 Selenium and endocrine systems. J Endocrinol 184: 455–465
Duthoit C, Estienne V, Giraud A, et al, 2001 Hydrogen peroxide-induced production of a 40 kDa immunoreactive thyroglobulin fragment in human thyroid cells: the onset of thyroid autoimmunity? Biochem J 360: 557–562.
Teng X, Shan Z, Teng W, Fan C, Wang H, Guo R, 2009 Experimental study on the effects of chronic iodine excess on thyroid function, structure, and autoimmunity in autoimmune-prone NOD.H-2h4 mice. Clin Exp Med 9: 51–59.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Carayanniotis, G. Molecular parameters linking thyroglobulin iodination with autoimmune thyroiditis. Hormones 10, 27–35 (2011). https://doi.org/10.14310/horm.2002.1290
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.14310/horm.2002.1290