, Volume 9, Issue 2, pp 151–160 | Cite as

Iodine content of thyroglobulin in NOD.H2h4 mice developing iodine-accelerated autoimmune thyroiditis

  • Panayota Kolypetri
  • Natasha A. Noel
  • Karen A. Carayanniotis
  • George CarayanniotisEmail author
Research paper


OBJECTIVE: In NOD.H2h4 mice, high dietary iodine intake has been known to cause Iodineaccelerated Spontaneous Autoimmune Thyroiditis (ISAT) via an unknown mechanism. The aim of the study was to examine whether the NOD.H2h4 genetic background predisposes to enhanced iodine organification in thyroglobulin (Tg), a target autoantigen in ISAT. DESIGN: To avoid issues associated with an ongoing anti-Tg antibody response, we assessed Tg iodination levels in iodine-fed, B-cell deficient NOD.H2h4 mice. Additionally, we tested whether humoral or cellular immune responses of iodine-fed NOD.H2h4 mice are preferentially directed to Tg with increased iodine content (I-Tg) or known pathogenic Tg peptides that contained iodine. RESULTS: The iodine content of Tg was not significantly different between control (9.0±2.7 I atoms per monomer) and iodine-fed mice (10.9±0.3 I atoms per monomer). Furthermore, in iodine-fed NOD.H2h4 mice developing ISAT, strong but equivalent serum IgG responses were detected to both Tg or I-Tg, whereas their lymphoid cells were stimulated weakly but equally well by Tg or I-Tg in vitro and did not show reactivity against a panel of five pathogenic Tg peptides that contained iodine. CONCLUSIONS: The results suggest that development of ISAT in NOD.H2h4 mice is not associated with enhanced iodine organification or differential B- or T-cell responses to iodinated determinants in Tg.

Key words

Autoimmune thyroid disease Hashimoto’s thyroiditis Iodine NOD.H2h4 mice Thyroglobulin Thyroiditis 


  1. 1.
    Podolin PL, Pressey A, DeLarato NH, Fischer PA, Peterson LB, Wicker LS, 1993 I-E+ nonobese diabetic mice develop insulitis and diabetes. J Exp Med 178: 793–803.CrossRefGoogle Scholar
  2. 2.
    Braley-Mullen H, Sharp GC, Medling B, Tang H, 1999 Spontaneous autoimmune thyroiditis in NOD.H-2h4 mice. J Autoimmun 12: 157–165.CrossRefGoogle Scholar
  3. 3.
    Burek CL, Sharma RB, Rose NR, 2003 NKT cell regulation of autoimmune thyroiditis. Autoimmunity 36: 405–408.CrossRefGoogle Scholar
  4. 4.
    Hutchings PR, Verma S, Phillips JM, Harach SZ, Howlett S, Cooke A, 1999 Both CD4(+) T cells and CD8(+) T cells are required for iodine accelerated thyroiditis in NOD mice. Cell Immunol 192: 113–121.CrossRefGoogle Scholar
  5. 5.
    Rasooly L, Burek CL, Rose NR, 1996 Iodine-induced autoimmune thyroiditis in NOD-H-2h4 mice. Clin Immunol Immunopathol 81: 287–292.CrossRefGoogle Scholar
  6. 6.
    Bagchi N, Brown TR, Urdanivia E, Sundick RS, 1985 Induction of autoimmune thyroiditis in chickens by dietary iodine. Science 230: 325–327.CrossRefGoogle Scholar
  7. 7.
    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.CrossRefGoogle Scholar
  8. 8.
    Bournaud C, Orgiazzi JJ, 2003 Iodine excess and thyroid autoimmunity. J Endocrinol Invest 26: 49–56.CrossRefGoogle Scholar
  9. 9.
    Konno N, Makita H, Yuri K, Iizuka N, Kawasaki K, 1994 Association between dietary iodine intake and prevalence of subclinical hypothyroidism in the coastal regions of Japan. J Clin Endocrinol Metab 78: 393–397.PubMedGoogle Scholar
  10. 10.
    Markou K, Georgopoulos N, Kyriazopoulou V, Vagenakis AG, 2001 Iodine-Induced hypothyroidism. Thyroid 11: 501–510.CrossRefGoogle Scholar
  11. 11.
    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.PubMedGoogle Scholar
  12. 12.
    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.CrossRefGoogle Scholar
  13. 13.
    Sundick RS, Herdegen DM, Brown TR, Bagchi N, 1987 The incorporation of dietary iodine into thyroglobulin increases its immunogenicity. Endocrinology 120: 2078–2084.CrossRefGoogle Scholar
  14. 14.
    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.CrossRefPubMedPubMedCentralGoogle Scholar
  15. 15.
    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.CrossRefPubMedPubMedCentralGoogle Scholar
  16. 16.
    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.CrossRefPubMedPubMedCentralGoogle Scholar
  17. 17.
    Li HS, Carayanniotis G, 2006 Iodination of tyrosyls in thyroglobulin generates neoantigenic determinants that cause thyroiditis. J Immunol 176: 4479–4483.CrossRefGoogle Scholar
  18. 18.
    Li HS, Carayanniotis G, 2007 Induction of goitrous hypothyroidism by dietary iodide in SJL mice. Endocrinology 148: 2747–2752.CrossRefGoogle Scholar
  19. 19.
    Carayanniotis G, 2007 Recognition of thyroglobulin by T cells: the role of iodine. Thyroid 17: 963–973.CrossRefGoogle Scholar
  20. 20.
    Li HS, Jiang HY, Carayanniotis G, 2007 Modifying effects of iodine on the immunogenicity of thyroglobulin peptides. J Autoimmun 28: 171–176.CrossRefGoogle Scholar
  21. 21.
    Verginis P, Stanford MM, Carayanniotis G, 2002 Delineation of five thyroglobulin T cell epitopes with pathogenic potential in experimental autoimmune thyroiditis. J Immunol 169: 5332–5337.CrossRefGoogle Scholar
  22. 22.
    Palumbo G, Tecce MF, Ambrosio G, 1982 A nonincinerative rate-sensing method for the determination of iodine in iodoproteins. Anal Biochem 123: 183–189.CrossRefGoogle Scholar
  23. 23.
    Saboori AM, Rose NR, Butscher WG, Burek CL, 1993 Modification of a nonincinerative method for determination of iodine in iodoproteins. Anal Biochem 214: 335–338.CrossRefGoogle Scholar
  24. 24.
    Rao VP, Kajon AE, Spindler KR, Carayanniotis G, 1999 Involvement of epitope mimicry in potentiation but not initiation of autoimmune disease. J Immunol 162: 5888–5893.PubMedGoogle Scholar
  25. 25.
    Braley-Mullen H, Yu S, 2000 Early requirement for B cells for development of spontaneous autoimmune thyroiditis in NOD.H-2h4 mice. J Immunol 165: 7262–7269.CrossRefGoogle Scholar
  26. 26.
    Anderson MS, Bluestone JA, 2005 The NOD mouse: a model of immune dysregulation. Annu Rev Immunol 23: 447–485.CrossRefGoogle Scholar
  27. 27.
    Verma S, Hutchings P, Guo J, McLachlan S, Rapoport B, Cooke A, 2000 Role of MHC class I expression and CD8(+) T cells in the evolution of iodine-induced thyroiditis in NOD-H2(h4) and NOD mice. Eur J Immunol 30: 1191–1202.CrossRefGoogle Scholar
  28. 28.
    Kaufman DL, Tisch R, Sarvetnick N et al, 2001 Report from the 1st International NOD Mouse T-Cell Workshop and the follow-up mini-workshop. Diabetes 50: 2459–2463.CrossRefGoogle Scholar
  29. 29.
    Thomas JW, Kendall PL, Mitchell HG, 2002 The natural autoantibody repertoire of nonobese diabetic mice is highly active. J Immunol 169: 6617–6624.CrossRefGoogle Scholar
  30. 30.
    Weetman AP, McGregor AM, Campbell H, Lazarus JH, Ibbertson HK, Hall R, 1983 Iodide enhances IgG synthesis by human peripheral blood lymphocytes in vitro. Acta Endocrinol (Copenh) 103: 210–215.CrossRefGoogle Scholar
  31. 31.
    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.CrossRefGoogle Scholar
  32. 32.
    Ruwhof C, Drexhage HA, 2001 Iodine and thyroid autoimmune disease in animal models. Thyroid 11: 427–436.CrossRefGoogle Scholar
  33. 33.
    Rose NR, Bonita R, Burek CL, 2002 Iodine: an environmental trigger of thyroiditis. Autoimmun Rev 1: 97–103.CrossRefGoogle Scholar
  34. 34.
    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.CrossRefGoogle Scholar
  35. 35.
    Burek CL, Rose NR, 2008 Autoimmune thyroiditis and ROS. Autoimmun Rev 7: 530–537.CrossRefGoogle Scholar
  36. 36.
    Bonita RE, Rose NR, Rasooly L, Caturegli P, Burek CL, 2002 Adhesion molecules as susceptibility factors in spontaneous autoimmune thyroiditis in the NOD-H2h4 mouse. Exp Mol Pathol 73: 155–163.CrossRefGoogle Scholar
  37. 37.
    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.CrossRefPubMedPubMedCentralGoogle Scholar
  38. 38.
    Strid J, Lopes L, Marcinkiewicz J et al, 2001 A defect in bone marrow derived dendritic cell maturation in the nonobesediabetic mouse. Clin Exp Immunol 123: 375–381.CrossRefPubMedPubMedCentralGoogle Scholar
  39. 39.
    Nagayama Y, Horie I, Saitoh O, Nakahara M, Abiru N, 2007 CD4+CD25+ naturally occurring regulatory T cells and not lymphopenia play a role in the pathogenesis of iodide-induced autoimmune thyroiditis in NOD-H2h4 mice. J Autoimmun 29: 195–202.CrossRefGoogle Scholar
  40. 40.
    Nakahara M, Nagayama Y, Saitoh O, Sogawa R, Tone S, Abiru N, 2008 Expression of Immuno-Regulatory Molecules by Thyrocytes Protects NOD-H2h4 Mice from Developing Autoimmune Thyroiditis. Endocrinology 150: 1545–1551CrossRefGoogle Scholar
  41. 41.
    Yu S, Maiti PK, Dyson M, Jain R, Braley-Mullen H, 2006 B cell-deficient NOD.H-2h4 mice have CD4+CD25+ T regulatory cells that inhibit the development of spontaneous autoimmune thyroiditis. J Exp Med 203: 349–358.CrossRefPubMedPubMedCentralGoogle Scholar

Copyright information

© Hellenic Endocrine Society 2010

Authors and Affiliations

  • Panayota Kolypetri
    • 1
  • Natasha A. Noel
    • 1
  • Karen A. Carayanniotis
    • 1
  • George Carayanniotis
    • 1
    Email author
  1. 1.Divisions of Endocrinology and Biomedical Sciences, Faculty of MedicineMemorial University of Newfoundland, St. John’s NLCanada

Personalised recommendations