The Role of Iodine and Selenium in Autoimmune Thyroiditis

Abstract

Iodine and selenium (Se) are both essential elements to thyroid hormone economy, while they represent key players in the development of autoimmune thyroiditis.

Chronic high iodine intake has been associated in various studies with increased frequency of autoimmune thyroiditis. In susceptible individuals, iodine excess increases intra-thyroid infiltrating Th17 cells and inhibits T regulatory (TREG) cells development, while it triggers an abnormal expression of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) in thyrocytes, thus inducing apoptosis and parenchymal destruction. As was shown in a mouse model, high iodine supply leads to changes in the immunogenicity of the thyroglobulin molecule, upregulation of vascular intercellular adhesion molecule-1 (ICAM-1), and reactive oxygen species (ROS) generation in the thyrocytes. Serum Se levels were found decreased in Hashimoto thyroiditis and especially in Graves’ disease as well as in thyroid-associated ophthalmopathy patients, the levels being related to the pathogenesis and outcome. Selenium is strongly involved, via the variable selenoproteins, in antioxidant, redox, and anti-inflammatory processes. Selenium enhances CD4+/CD25 FOXP3 and T regulatory cells activity while suppressing cytokine secretion, thus preventing apoptosis of the follicular cells and providing protection from thyroiditis. Selenium supplementation may be useful in autoimmune thyroid diseases, though, while usually well-tolerated, it should not be universally recommended, and it is also likely to be helpful for those with low Se status and autoimmunity. Broadly speaking, the achievement and maintenance of “selenostasis” as well as adequate urinary iodine excretion are mandatory to control disease, while, putatively, they may additionally be critical to preventing disease.

Key words

iodine - selenium - autoimmune thyroiditis - TREG cells

Publication History

Received: 24 March 2015

Accepted: 09 July 2015

Article published online:
11 September 2015

• References

• 1 Hollowell JG, Staehling NW, Flanders WD, Hannon WH, Gunter EW, Spencer CA, Braverman LE. Serum TSH, T(4), and thyroid antibodies in the United States population (1988 to 1994): National Health and Nutrition Examination Survey (NHANES III). J Clin Endocrinol Metab 2002; 87: 489-499
• 2 Lind P, Langsteger W, Molnar M, Gallowitsch HJ, Mikosch P, Gomez I. Epidemiology of thyroid diseases in iodine sufficiency. Thyroid 1998; 8: 1179-1183
• 3 Bülow Pedersen I, Knudsen N, Jørgensen T, Perrild H, Ovesen L, Laurberg P. Large differences in incidences of overt hyper- and hypothyroidism associated with a small difference in iodine intake: a prospective comparative register-based population survey. J Clin Endocrinol Metab 2002; 87: 4462-4469
• 4 Duntas LH. Environmental factors and autoimmune thyroiditis. Nat Clin Pract Endocrinol Metab 2008; 4: 454-460
• 5 Burek CL, Talor MV. Environmental triggers of autoimmune thyroiditis. J Autoimmun 2009; 33: 183-189
• 6 Rose NR. The genetics of autoimmune thyroiditis: the first decade. J Autoimmun 2011; 37: 88-94
• 7 Duntas LH. Environmental factors and thyroid autoimmunity. Ann Endocrinol (Paris) 2011; 72: 108-113
• 8 Tanda ML, Piantanida E, Lai A, Lombardi V, Dalle Mule I, Liparulo L, Pariani N, Bartalena L. Thyroid autoimmunity and environment. Horm Metab Res 2009; 41: 436-442
• 9 Eschler DC, Hasham A, Tomer Y. Cutting edge: the etiology of autoimmune thyroid diseases. Clin Rev Allergy Immunol 2011; 41: 190-197
• 10 Miranda DM, Massom JN, Catarino RM, Santos RT, Toyoda SS, Marone MM, Tomimori EK, Monte O. Impact of nutritional iodine optimization on rates of thyroid hypoechogenicity and autoimmune thyroiditis: a cross-sectional, comparative study. Thyroid 2015; 25: 118-124
• 11 Pedersen IB, Knudsen N, Carlé A, Vejbjerg P, Jørgensen T, Perrild H, Ovesen L, Rasmussen LB, Laurberg P. A cautious iodization programme bringing iodine intake to a low recommended level is associated with an increase in the prevalence of thyroid autoantibodies in the population. Clin Endocrinol (Oxf) 2011; 75: 120-126
• 12 Camargo RY, Tomimori EK, Neves SC, GS Rubio I, Galrão AL, Knobel M, Medeiros-Neto G. Thyroid and the environment: exposure to excessive nutritional iodine increases the prevalence of thyroid disorders in Sao Paulo, Brazil. Eur J Endocrinol 2008; 159: 293-299
• 13 Vanderpump M. Thyroid autoimmunity following an iodization programme. Clin Endocrinol (Oxf) 201 75: 10-11
• 14 Teng X, Shan Z, Chen Y, Lai Y, Yu J, Shan L, Bai X, Li Y, Li N, Li Z, Wang S, Xing Q, Xue H, Zhu L, Hou X, Fan C, Teng W. More than adequate iodine intake may increase subclinical hypothyroidism and autoimmune thyroiditis: a cross-sectional study based on two Chinese communities with different iodine intake levels. Eur J Endocrinol 2011; 164: 943-950
• 15 Aghini Lombardi F, Fiore E, Tonacchera M, Antonangeli L, Rago T, Frigeri M, Provenzale AM, Montanelli L, Grasso L, Pinchera A, Vitti P. The effect of voluntary iodine prophylaxis in a small rural community: the Pescopagano survey 15 years later. J Clin Endocrinol Metab 2013; 98: 1031-1039
• 16 Laurberg P, Cerqueira C, Ovesen L, Rasmussen LB, Perrild H, Andersen S, Pedersen IB, Carlé A. Iodine intake as a determinant of thyroid disorders in populations. Best Pract Res Clin Endocrinol Metab 2010; 24: 13-27
• 17 Allen EM, Appel MC, Braverman LE. The effect of iodide ingestion on the development of spontaneous lymphocytic thyroiditis in the diabetes-prone BB/W rat. Endocrinology 1986; 118: 1977-1981
• 18 Rasooly L, Burek CL, Rose NR. Iodine-induced autoimmune thyroiditis in NOD-H-2h4 mice. Clin Immunol Immunopathol 1996; 81: 287-292
• 19 Rose NR, Witebsky E. Changes in the thyroid glands of rabbits following active immunization with rabbit thyroid extract. J Immunol 1956; 76: 417-427
• 20 Carayanniotis G. Molecular parameters linking thyroglobulin iodination with autoimmune thyroiditis. Hormones 2011; 10: 27-35
• 21 Latrofa F, Fiore E, Rago T, Antonangeli L, Montanelli L, Ricci D, Provenzale MA, Scutari M, Frigeri M, Tonacchera M, Vitti P. Iodine contributes to thyroid autoimmunity in humans by unmasking a cryptic epitope on thyroglobulin. J Clin Endocrinol Metab 2013; 98: E1768-E1774
• 22 Rose NR, Saboori AM, Rasooly L, Burek CL. The role of iodine in autoimmune thyroiditis. Crit Rev Immunol 1997; 17: 511-517
• 23 Kolypetri P, Noel NA, Carayanniotis KA, Carayanniotis G. Iodine content of thyroglobulin in Nod.H2h4 mice developing iodine-accelerated autoimmune thyroiditis. Hormones (Athens) 2010; 9: 151-160
• 24 Weetman AP, Cohen S, Makgoba MW, Borysiewicz LK. Expression of an intercellular adhesion molecule, ICAM-1, by human thyroid cells. J Endocrinol 1989; 122: 185-191
• 25 Burek CL, Rose NR. Autoimmune thyroiditis and ROS. Autoimmun Rev 2008; 7: 530-537
• 26 Colin IM, Poncin S, Levêque P, Gallez B, Gérard AC. Differential regulation of the production of reactive oxygen species in Th1 cytokine-treated thyroid cells. Thyroid 2014; 24: 441-452
• 27 Sharma RB, Alegria JD, Talor MV, Rose NR, Caturegli P, Burek CL. Iodine and IFN-gamma synergistically enhance intercellular adhesion molecule 1 expression on NOD.H2h4 mouse thyrocytes. J Immunol 2005; 174: 7740-7745
• 28 O’Shea JJ, Ma A, Lipsky P. Cytokines and autoimmunity. Nat Rev Immunol 2002; 2: 37-45
• 29 Barin JG, Afanasyeva M, Talor MV, Rose NR, Burek CL, Caturegli P. Thyroid-specific expression of IFN-limits experimental autoimmune thyroiditis by suppressing lymphocyte activation in cervical lymph nodes. J Immunol 2003; 170: 5523-5529
• 30 Gadina MD, Hilton JA, Johnston A, Morinobu A, Lighvani YJ, Zhou R, Visconti J, O’Shea J. Signaling by type I and II cytokine receptors: ten years after. Curr Opin Immunol 2001; 13: 363-373
• 31 Horie I, Abiru N, Nagayama Y, Kuriya G, Saitoh O, Ichikawa T, Iwakura Y, Eguchi K. T helper type 17 immune response plays an indispensable role for development of iodine-induced autoimmune thyroiditis in nonobese diabetic-H2h4 mice. Endocrinology 2009; 150: 5135-5142
• 32 Ruffilli I, Ferrari SM, Colaci M, Ferri C, Fallahi P, Antonelli A. IP-10 in autoimmune thyroiditis. Horm Metab Res 2014; 46: 597-602
• 33 Cui SL, Yu J, Shoujun L. Iodine Intake Increases IP-10 Expression in the Serum and Thyroids of Rats with Experimental Autoimmune Thyroiditis. Int J Endocrinol 2014; 2014: 581069
• 34 Li D, Cai W, Gu R, Zhang Y, Zhang H, Tang K, Xu P, Katirai F, Shi W, Wang L, Huang T, Huang B. Th17 cell plays a role in the pathogenesis of Hashimoto’s thyroiditis in patients. Clin Immunol 2013; 149: 411-420
• 35 Yang X, Gao T, Shi R, Zhou X, Qu J, Xu J, Shan Z, Teng W. Effect of iodine excess on Th1, Th2, Th17, and Treg cell subpopulations in the thyroid of NOD.H-2h4 mice. Biol Trace Elem Res 2014; 159: 288-296
• 36 Kristensen B, Hegedüs L, Madsen HO, Smith TJ, Nielsen CH. Altered balance between self-reactive Th17 cells and Th10 cells and between full-length FOXP3 and FOXP3 splice variants in Hashimoto’s thyroiditis. Clin Exp Immunol 2015; 180: 58-69
• 37 Ban Y, Tozaki T, Tobe T, Ban Y, Jacobson EM, Concepcion ES, Tomer Y. The regulatory T cell gene FOXP3 and genetic susceptibility to thyroid autoimmunity: an association analysis in Caucasian and Japanese cohorts. J Autoimmun 2007; 28: 201-207
• 38 Ehlers M, Thiel A, Papewalis C, Domröse A, Stenzel W, Bernecker C, Haase M, Allelein S, Schinner S, Willenberg HS, Feldkamp J, Schott M. Enhanced iodine supplementation alters the immune process in a transgenic mouse model for autoimmune thyroiditis. Thyroid 2014; 24: 888-896
• 39 Kolypetri P, Carayanniotis G. Apoptosis of NOD.H2 h4 thyrocytes by low concentrations of iodide is associated with impaired control of oxidative stress. Thyroid 2014; 24: 1170-1178
• 40 Yu X, Li L, Li Q, Zang X, Liu Z. TRAIL and DR5 promote thyroid follicular cell apoptosis in iodine excess-induced experimental autoimmune thyroiditis in NOD mice. Biol Trace Elem Res 2011; 143: 1064-1076
• 41 Aaseth J, Frey H, Glattre E, Norheim G, Ringstad J, Thomassen Y. Selenium concentrations in the human thyroid gland. Biol Trace Elem Res 1990; 24: 147-152
• 42 Beckett GJ, Arthur JR. Selenium and endocrine systems. J Endocrinol 2005; 184: 455-465
• 43 Duntas LH. Selenium and the thyroid: a close-knit connection. J Clin Endocrinol Metab 2010; 95: 5180-5188
• 44 Toulis KA, Anastasilakis AD, Tzellos TG, Goulis DG, Kouvelas D. Selenium supplementation in the treatment of Hashimoto's thyroiditis: a systematic review and a meta-analysis. Thyroid 2010; 20: 1163-1173
• 45 Fan Y, Xu S, Zhang H, Cao W, Wang K, Chen G, Di H, Cao M, Liu C. Selenium supplementation for autoimmune thyroiditis: a systematic review and meta-analysis. Int J Endocrinol 2014; 2014: 904573
• 46 van Zuuren EJ, Albusta AY, Fedorowicz Z, Carter B, Pijl H. Selenium Supplementation for Hashimoto's Thyroiditis: Summary of a Cochrane Systematic Review. Eur Thyroid J 2014; 3: 25-31
• 47 Mao J, Pop VJ, Bath SC, Vader HL, Redman CW, Rayman MP. Effect of low-dose selenium on thyroid autoimmunity and thyroid function in UK pregnant women with mild-to-moderate iodine deficiency. Eur J Nutr. 2014 [Epub ahead of print]
• 48 Duntas LH, Benvenga S. Selenium: an element for life. Endocrine 2015; 48: 756-775
• 49 Wimmer I, Hartmann T, Brustbauer R, Minear G, Dam K. Selenium levels in patients with autoimmune thyroiditis and controls in lower Austria. Horm Metab Res 2014; 46: 707-709
• 50 Bülow Pedersen I, Knudsen N, Carlé A, Schomburg L, Köhrle J, Jørgensen T, Rasmussen LB, Ovesen L, Laurberg P. Serum selenium is low in newly diagnosed Graves’ disease: a population-based study. Clin Endocrinol (Oxf) 2013; 79: 584-590
• 51 Wertenbruch T, Willenberg HS, Sagert C, Nguyen TB, Bahlo M, Feldkamp J, Groeger C, Hermsen D, Scherbaum WA, Schott M. Serum selenium levels in patients with remission and relapse of graves’ disease. Med Chem 2007; 3: 281-284
• 52 Khong JJ, Goldstein RF, Sanders KM, Schneider H, Pope J, Burdon KP, Craig JE, Ebeling PR. Serum selenium status in Graves’ disease with and without orbitopathy: a case-control study. Clin Endocrinol (Oxf) 2014; 80: 905-910
• 53 Marcocci C, Kahaly GJ, Krassas GE, Bartalena L, Prummel M, Stahl M, Altea MA, Nardi M, Pitz S, Boboridis K, Sivelli P, von Arx G, Mourits MP, Baldeschi L, Bencivelli W, Wiersinga W. Selenium and the course of mild Graves' orbitopathy. European Group on Graves’ Orbitopathy. N Engl J Med 2011; 364: 1920-1931
• 54 Hoffmann FW, Hashimoto AC, Shafer LA, Dow S, Berry MJ, Hoffmann PR. Dietary selenium modulates activation and differentiation of CD4+ T cells in mice through a mechanism involving cellular free thiols. J Nutr 2010; 140: 1155-1161
• 55 Hoffmann PR. Mechanisms by which selenium influences immune responses. Arch Immunol Ther Exp (Warsz) 2007; 55: 289-297
• 56 Carlson BA, Yoo MH, Sano Y, Sengupta A, Kim JY, Irons R, Gladyshev VN, Hatfield DL, Park JM. Selenoproteins regulate macrophage invasiveness and extracellular matrix related gene expression. BMC Immunol 2009; 10: 57
• 57 Huang Z, Rose AH, Hoffmann PR. The role of selenium in inflammation and immunity: from molecular mechanisms to therapeutic opportunities. Antioxid Redox Signal 2012; 16: 705-743
• 58 Fisfalen 1 ME, Soltani K, Kaplan E, Palmer EM, van Seventer GA, Straus FH, Diaz M, Ober C, DeGroot LJ. Evaluating the role of Th0 and Th1 clones in autoimmune thyroid disease by use of Hu-SCID chimeras. Clin Immunol Immunopathol 1997; 85: 253-264
• 59 Takahashi T, Sakaguchi S. Naturally arising CD25+CD4+ regulatory T cells in maintaining immunologic self-tolerance and preventing autoimmune disease. Curr Mol Med 2003; 3: 693-706
• 60 Flynn JC, Meroueh C, Snower DP, David CS, Kong YM. Depletion of CD4+CD25+ regulatory T cells exacerbates sodium iodide-induced experimental autoimmune thyroiditis in human leucocyte antigen DR3 (DRB1*0301) transgenic class II-knock-out non-obese diabetic mice. Clin Exp Immunol 2007; 147: 547-554
• 61 Balázs C, Kaczur V. Effect of Selenium on HLA-DR expression of thyrocytes. Autoimmune Dis 2012; 74635
• 62 Tan L, Sang ZN, Shen J, Wu YT, Yao ZX, Zhang JX, Zhao N, Zhang WQ. Selenium supplementation alleviates autoimmune thyroiditis by regulating expression of TH1/TH2 cytokines. Biomed Environ Sci 2013; 26: 920-925
• 63 Krysiak R, Okopien B. The effect of levothyroxine and selenomethionine on lymphocyte and monocyte cytokine release in women with Hashimoto’s thyroiditis. J Clin Endocrinol Metab 2011; 96: 2206-2215
• 64 Gordon S, Taylor PR. Monocyte and macrophage heterogeneity. Nat Rev Immunol 2005; 5: 953-964
• 65 Parnham MJ, Winkelmann J, Leyck S. Macrophage, lymphocyte and chronic inflammatory responses in selenium deficient rodents. Association with decreased glutathione peroxidase activity. Int J Immunopharmacol 1983; 5455-5461
• 66 Carlson BA, Yoo MH, Conrad M, Gladyshev VN, Hatfield DL, Park JM. Protein kinase-regulated expression and immune function of thioredoxin reductase 1 in mouse macrophages. Mol Immunol 2011; 49: 311-316
• 67 Santos LR, Durães C, Mendes A, Prazeres H, Alvelos MI, Moreira CS, Canedo P, Esteves C, Neves C, Carvalho D, Sobrinho-Simões M, Soares P. A polymorphism in the promoter region of the selenoprotein S gene (SEPS1) contributes to Hashimoto’s thyroiditis susceptibility. J Clin Endocrinol Metab 2014; 99: E719-E723
• 68 Sutmuller R, Garritsen A, Adema GJ. Regulatory T cells and toll-like receptors: regulating the regulators. Ann Rheum Dis 2007; 66 (Suppl. 03) iii91-iii95