Skip to main content

Advertisement

SpringerLink
Log in

Delineating the autoimmune mechanisms in Graves’ disease

  • Immunology at Mount Sinai
  • Published:
Immunologic Research Aims and scope Submit manuscript

Abstract

The immunologic processes involved in autoimmune thyroid disease (AITD), particularly Graves’ disease (GD), are similar to other autoimmune diseases with the emphasis on the antibodies as the most unique aspect. These characteristics include a lymphocytic infiltrate at the target organs, the presence of antigen-reactive T and B cells and antibodies, and the establishment of animal models of GD by antibody transfer or immunization with antigen. Similar to other autoimmune diseases, risk factors for GD include the presence of multiple susceptibility genes, including certain HLA alleles, and the TSHR gene itself. In addition, a variety of known risk factors and precipitators have been characterized including the influence of sex and sex hormones, pregnancy, stress, infection, iodine and other potential environmental factors. The pathogenesis of GD is likely the result of a breakdown in the tolerance mechanisms, both at central and peripheral levels. Different subsets of T and B cells together with their regulatory populations play important roles in the propagation and maintenance of the disease process. Understanding different mechanistic in the complex system biology interplay will help to identify unique factors contributing to the AITD pathogenesis.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6

Similar content being viewed by others

References

  1. Adams DD, Purves HD. Abnormal responses in the assay of thyrotropin. Proc Univ Otago Med School. 1956;34:11–2.

    Google Scholar 

  2. Vanderpump MP, Tunbridge WM, French JM, Appleton D, Bates D, Clark F, et al. The incidence of thyroid disorders in the community: a twenty-year follow-up of the Whickham Survey. Clin Endocrinol (Oxf). 1995;43(1):55–68.

    Google Scholar 

  3. McIver B, Morris JC. The pathogenesis of Graves’ disease. Endocrinol Metab Clin North Am. 1998;27(1):73–89.

    Article  CAS  PubMed  Google Scholar 

  4. Bahn RS, Heufelder AE. Pathogenesis of Graves’ ophthalmopathy. N Engl J Med. 1993;329(20):1468–75.

    Article  CAS  PubMed  Google Scholar 

  5. LiVolsi VA. The pathology of autoimmune thyroid disease: a review. Thyroid. 1994;4(3):333–9.

    Article  CAS  PubMed  Google Scholar 

  6. Rees SB, McLachlan SM, Furmaniak J. Autoantibodies to the thyrotropin receptor. Endocr Rev. 1988;9(1):106–21.

    Article  Google Scholar 

  7. Witebsky E, Rose NR, Terplan K, Paine JR, Egan RW. Chronic thyroiditis and autoimmunization. J Am Med Assoc. 1957;164(13):1439–47. Epub 1957/07/27.

    Google Scholar 

  8. Tomer Y. Genetic susceptibility to autoimmune thyroid disease: past, present, and future. Thyroid. 2010;20(7):715–25. Epub 2010/07/08.

    Google Scholar 

  9. Tomer Y, Menconi F, Davies TF, Barbesino G, Rocchi R, Pinchera A, et al. Dissecting genetic heterogeneity in autoimmune thyroid diseases by subset analysis. J Autoimmun. 2007;29(2–3):69–77.

    Article  CAS  PubMed  Google Scholar 

  10. Jacobson EM, Tomer Y. The genetic basis of thyroid autoimmunity. Thyroid. 2007;17(10):949–61. Epub 2007/09/11.

    Google Scholar 

  11. Davies TF. Infection and autoimmune thyroid disease. J Clin Endocrinol Metab. 2008;93(3):674–6.

    Article  CAS  PubMed  Google Scholar 

  12. Ladygina N, Martin BR, Altman A. Dynamic palmitoylation and the role of DHHC proteins in T cell activation and anergy. Adv Immunol. 2011;109:1–44. Epub 2011/05/17.

    Google Scholar 

  13. Meffre E, Wardemann H. B-cell tolerance checkpoints in health and autoimmunity. Curr Opin Immunol. 2008;20(6):632–8.

    Article  CAS  PubMed  Google Scholar 

  14. Latrofa F, Ricci D, Grasso L, Vitti P, Masserini L, Basolo F, et al. Characterization of thyroglobulin epitopes in patients with autoimmune and non-autoimmune thyroid diseases using recombinant human monoclonal thyroglobulin autoantibodies. J Clin Endocrinol Metab. 2008;93(2):591–6. Epub 2007/11/22.

    Google Scholar 

  15. Rebuffat SA, Nguyen B, Robert B, Castex F, Peraldi-Roux S. Antithyroperoxidase antibody-dependent cytotoxicity in autoimmune thyroid disease. J Clin Endocrinol Metab. 2008;93(3):929–34. Epub 2007/12/13.

    Google Scholar 

  16. Kohno Y, Naito N, Hiyama Y, Shimojo N, Suzuki N, Tarutani O, et al. Thyroglobulin and thyroid peroxidase share common epitopes recognized by autoantibodies in patients with chronic autoimmune thyroiditis. J Clin Endocrinol Metab. 1988;67(5):899–907. Epub 1988/11/01.

    Google Scholar 

  17. Latrofa F, Pichurin P, Guo J, Rapoport B, McLachlan SM. Thyroglobulin-thyroperoxidase autoantibodies are polyreactive, not bispecific: analysis using human monoclonal autoantibodies. J Clin Endocrinol Metab. 2003;88(1):371–8. Epub 2003/01/10.

    Google Scholar 

  18. 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(3):998–1002.

    Article  CAS  PubMed  Google Scholar 

  19. Misrahi M, Ghinea N, Sar S, Saunier B, Jolivet A, Loosfelt H, et al. Processing of the precursors of the human thyroid-stimulating hormone receptor in various eukaryotic cells (human thyrocytes, transfected L cells and baculovirus-infected insect cells). Eur J Biochem. 1994;222(2):711–9.

    Article  CAS  PubMed  Google Scholar 

  20. Chazenbalk GD, Pichurin P, Chen CR, Latrofa F, Johnstone AP, McLachlan SM, et al. Thyroid-stimulating autoantibodies in Graves disease preferentially recognize the free A subunit, not the thyrotropin holoreceptor. J Clin Invest. 2002;110(2):209–17.

    CAS  PubMed  Google Scholar 

  21. Kajita Y, Rickards CR, Buckland PR, Howells RD, Rees SB. Analysis of thyrotropin receptors by photoaffinity labelling. Orientation of receptor subunits in the cell membrane. Biochem J. 1985;227(2):413–20.

    Google Scholar 

  22. Loosfelt H, Pichon C, Jolivet A, Misrahi M, Caillou B, Jamous M, et al. Two-subunit structure of the human thyrotropin receptor. Proc Natl Acad Sci USA. 1992;89(9):3765–9.

    Article  CAS  PubMed  Google Scholar 

  23. Latif R, Morshed SA, Zaidi M, Davies TF. The thyroid-stimulating hormone receptor: impact of thyroid-stimulating hormone and thyroid-stimulating hormone receptor antibodies on multimerization, cleavage, and signaling. Endocrinol Metab Clin North Am. 2009;38(2):319–41.

    Article  CAS  PubMed  Google Scholar 

  24. Davies TF, Ando T, Lin RY, Tomer Y, Latif R. Thyrotropin receptor-associated diseases: from adenomata to Graves disease. J Clin Invest. 2005;115(8):1972–83.

    Article  CAS  PubMed  Google Scholar 

  25. Vlase H, Davies TF. Insights into the molecular mechanisms of the autoimmune thyroid diseases. In: Eisenbarth GS editor. Endocrine and organ specific autoimmunity. CA: R.G. Landes Co.; 1999. pp. 98–132.

  26. Lipsky PE. Systemic lupus erythematosus: an autoimmune disease of B cell hyperactivity. Nat Immunol. 2001;2(9):764–6.

    Article  CAS  PubMed  Google Scholar 

  27. De Groot LJ, Shin YH, Pan D, Gopalakrishnan G, Hennessey JV. Evaluation of T cell stimulation by thyrotropin-receptor epitopes in Graves’ disease. J Endocrinol Invest. 2009;32(1):52–6. Epub 2009/04/02.

    Google Scholar 

  28. Caturegli P, Kimura H, Rocchi R, Rose NR. Autoimmune thyroid disease. Curr Opin Rheumatol. 2007;19(1):44–8.

    Article  PubMed  Google Scholar 

  29. Ando T, Davies TF. Monoclonal antibodies to the thyrotropin receptor. Clin Dev Immunol. 2005;12(2):137–43.

    Article  CAS  PubMed  Google Scholar 

  30. Ando T, Latif R, Pritsker A, Moran T, Nagayama Y, Davies TF. A monoclonal thyroid-stimulating antibody. J Clin Invest. 2002;110(11):1667–74.

    CAS  PubMed  Google Scholar 

  31. Ando T, Latif R, Davies TF. Antibody-induced modulation of TSH receptor post-translational processing. J Endocrinol. 2007;195(1):179–86.

    Article  CAS  PubMed  Google Scholar 

  32. Morshed SA, Latif R, Davies TF. Characterization of thyrotropin receptor antibody-induced signaling cascades. Endocrinology. 2009;150(1):519–29.

    Article  CAS  PubMed  Google Scholar 

  33. Ando T, Latif R, Daniel S, Eguchi K, Davies TF. Dissecting linear and conformational epitopes on the native thyrotropin receptor. Endocrinology. 2004;145(11):5185–93.

    Article  CAS  PubMed  Google Scholar 

  34. Davies TF, Bobovnikova Y, Weiss M, Vlase H, Moran T, Graves PN. Development and characterization of monoclonal antibodies specific for the murine thyrotropin receptor. Thyroid. 1998;8(8):693–701.

    Article  CAS  PubMed  Google Scholar 

  35. Sanders J, Jeffreys J, Depraetere H, Evans M, Richards T, Kiddie A, et al. Characteristics of a human monoclonal autoantibody to the thyrotropin receptor: sequence structure and function. Thyroid. 2004;14(8):560–70.

    Article  CAS  PubMed  Google Scholar 

  36. Nagy EV, Burch HB, Mahoney K, Lukes YG, Morris JC III, Burman KD. Graves’ IgG recognizes linear epitopes in the human thyrotropin receptor. Biochem Biophys Res Commun. 1992;188(1):28–33.

    Article  CAS  PubMed  Google Scholar 

  37. Sanders J, Chirgadze DY, Sanders P, Baker S, Sullivan A, Bhardwaja A, et al. Crystal structure of the TSH receptor in complex with a thyroid-stimulating autoantibody. Thyroid. 2007;17(5):395–410.

    Article  CAS  PubMed  Google Scholar 

  38. Sanders J, Bolton J, Sanders P, Jeffreys J, Nakatake N, Richards T, et al. Effects of TSH receptor mutations on binding and biological activity of monoclonal antibodies and TSH. Thyroid. 2006;16(12):1195–206.

    Article  CAS  PubMed  Google Scholar 

  39. Latif R, Michalek, K, Teixeira, A, Davies TF. Protecting TSH receptor antibody binding pockets reveals both leucine rich repeats and non-leucine rich domains. 81st Annual Meeting of the American Thyroid Association; CA, USA. 2011.

  40. Morshed SA, Latif R, Davies TF. TSHR antibodies induce fibroblast proliferation and apoptosis: implications for Graves’ disease. 81st Annual Meeting of the American Thyroid Association; CA, USA. 2011.

  41. Minich WB, Lenzner C, Morgenthaler NG. Antibodies to TSH-receptor in thyroid autoimmune disease interact with monoclonal antibodies whose epitopes are broadly distributed on the receptor. Clin Exp Immunol. 2004;136(1):129–36.

    Article  CAS  PubMed  Google Scholar 

  42. Sanders J, Jeffreys J, Depraetere H, Richards T, Evans M, Kiddie A, et al. Thyroid-stimulating monoclonal antibodies. Thyroid. 2002;12(12):1043–50.

    Article  PubMed  Google Scholar 

  43. Schwarz-Lauer L, Pichurin PN, Chen CR, Nagayama Y, Paras C, Morris JC, et al. The cysteine-rich amino terminus of the thyrotropin receptor is the immunodominant linear antibody epitope in mice immunized using naked deoxyribonucleic acid or adenovirus vectors. Endocrinology. 2003;144(5):1718–25.

    Article  CAS  PubMed  Google Scholar 

  44. Ando T, Latif R, Davies TF. Concentration-dependent regulation of thyrotropin receptor function by thyroid-stimulating antibody. J Clin Invest. 2004;113(11):1589–95.

    CAS  PubMed  Google Scholar 

  45. Minich WB, Loos U. Detection of functionally different types of pathological autoantibodies against thyrotropin receptor in Graves’ patients sera by luminescent immunoprecipitation analysis. Exp Clin Endocrinol Diabetes. 2000;108(2):110–9.

    Article  CAS  PubMed  Google Scholar 

  46. Kakinuma A, Chazenbalk GD, Tanaka K, Nagayama Y, McLachlan SM, Rapoport B. An N-linked glycosylation motif from the noncleaving luteinizing hormone receptor substituted for the homologous region (Gly367 to Glu369) of the thyrotropin receptor prevents cleavage at its second, downstream site. J Biol Chem. 1997;272(45):28296–300.

    Article  CAS  PubMed  Google Scholar 

  47. Sanders P, Young S, Sanders J, Kabelis K, Baker S, Sullivan A, et al. Crystal structure of the TSH receptor (TSHR) bound to a blocking-type TSHR autoantibody. J Mol Endocrinol. 2011;46(2):81–99. Epub 2011/01/21.

    Google Scholar 

  48. Costagliola S, Rodien P, Many MC, Ludgate M, Vassart G. Genetic immunization against the human thyrotropin receptor causes thyroiditis and allows production of monoclonal antibodies recognizing the native receptor. J Immunol. 1998;160(3):1458–65.

    CAS  PubMed  Google Scholar 

  49. Nagayama Y, Kita-Furuyama M, Ando T, Nakao K, Mizuguchi H, Hayakawa T, et al. A novel murine model of Graves’ hyperthyroidism with intramuscular injection of adenovirus expressing the thyrotropin receptor. J Immunol. 2002;168(6):2789–94.

    CAS  PubMed  Google Scholar 

  50. Jeffreys J, Depraetere H, Sanders J, Oda Y, Evans M, Kiddie A, et al. Characterization of the thyrotropin binding pocket. Thyroid. 2002;12(12):1051–61.

    Article  CAS  PubMed  Google Scholar 

  51. Gilbert JA, Kalled SL, Moorhead J, Hess DM, Rennert P, Li Z, et al. Treatment of autoimmune hyperthyroidism in a murine model of Graves’ disease with tumor necrosis factor-family ligand inhibitors suggests a key role for B cell activating factor in disease pathology. Endocrinology. 2006;147(10):4561–8.

    Article  CAS  PubMed  Google Scholar 

  52. Lai Kwan LQ, King Hung KO, Zheng BJ, Lu L. Local BAFF gene silencing suppresses Th17-cell generation and ameliorates autoimmune arthritis. Proc Natl Acad Sci USA. 2008;105(39):14993–8.

    Google Scholar 

  53. Salvi M, Vannucchi G, Campi I, Rossi S, Bonara P, Sbrozzi F, et al. Efficacy of rituximab treatment for thyroid-associated ophthalmopathy as a result of intraorbital B-cell depletion in one patient unresponsive to steroid immunosuppression. Eur J Endocrinol. 2006;154(4):511–7.

    Article  CAS  PubMed  Google Scholar 

  54. Chen CR, McLachlan SM, Rapoport B. Suppression of thyrotropin receptor constitutive activity by a monoclonal antibody with inverse agonist activity. Endocrinology. 2007;148(5):2375–82.

    Article  CAS  PubMed  Google Scholar 

  55. Stassi G, De MR. Autoimmune thyroid disease: new models of cell death in autoimmunity. Nat Rev Immunol. 2002;2(3):195–204.

    Article  CAS  PubMed  Google Scholar 

  56. Wang SH, Baker JR. The role of apoptosis in thyroid autoimmunity. Thyroid. 2007;17(10):975–9. Epub 2007/09/29.

    Google Scholar 

  57. Mao C, Wang S, Xiao Y, Xu J, Jiang Q, Jin M, et al. Impairment of regulatory capacity of CD4+ CD25+ regulatory T cells mediated by dendritic cell polarization and hyperthyroidism in Graves’ disease. J Immunol. 2011;186(8):4734–43. Epub 2011/03/15.

    Google Scholar 

  58. Bossowski A, Czarnocka B, Bardadin K, Stasiak-Barmuta A, Urban M, Dadan J, et al. Identification of apoptotic proteins in thyroid gland from patients with Graves’ disease and Hashimoto’s thyroiditis. Autoimmunity. 2008;41(2):163–73. Epub 2008/03/08.

    Google Scholar 

  59. Bossowski A, Czarnocka B, Bardadin K, Urban M, Niedziela M, Dadan J. Expression of Bcl-2 family proteins in thyrocytes from young patients with immune and nonimmune thyroid diseases. Horm Res. 2008;70(3):155–64. Epub 2008/07/30.

    Google Scholar 

  60. Newby PR, Roberts-Davies EL, Brand OJ, Heward JM, Franklyn JA, Gough SCL, et al. Tag SNP screening of the PDCD1 gene for association with Graves’ disease. Clin Endocrinol. 2007;67(1):125–8.

    Article  CAS  Google Scholar 

  61. Morshed SA, Ando T, Latif R, Davies TF. Neutral antibodies to the TSH receptor are present in Graves’ disease and regulate selective signaling cascades. Endocrinology. 2010;151(11):5537–49. Epub 2010/09/17.

    Google Scholar 

  62. Kawashima A, Tanigawa K, Akama T, Wu H, Sue M, Yoshihara A, et al. Fragments of genomic DNA released by injured cells activate innate immunity and suppress endocrine function in the thyroid. Endocrinology. 2011;152(4):1702–12. Epub 2011/02/10.

    Google Scholar 

  63. Nakamura H, Usa T, Motomura M, Ichikawa T, Nakao K, Kawasaki E, et al. Prevalence of interrelated autoantibodies in thyroid diseases and autoimmune disorders. J Endocrinol Invest. 2008;31(10):861–5.

    CAS  PubMed  Google Scholar 

  64. Endo T, Kogai T, Nakazato M, Saito T, Kaneshige M, Onaya T. Autoantibody against Na+/I- symporter in the sera of patients with autoimmune thyroid disease. Biochem Biophys Res Commun. 1996;224(1):92–5.

    Article  CAS  PubMed  Google Scholar 

  65. Yoshida A, Hisatome I, Taniguchi S, Shirayoshi Y, Yamamoto Y, Miake J, et al. Pendrin is a novel autoantigen recognized by patients with autoimmune thyroid diseases. J Clin Endocrinol Metab. 2009;94(2):442–8.

    Article  CAS  PubMed  Google Scholar 

  66. Benvenga S, Trimarchi F, Robbins J. Circulating thyroid hormone autoantibodies. J Endocrinol Invest. 1987;10(6):605–19. Epub 1987/12/01.

    Google Scholar 

  67. Tachi J, Amino N, Tamaki H, Aozasa M, Iwatani Y, Miyai K. Long term follow-up and HLA association in patients with postpartum hypothyroidism. J Clin Endocrinol Metab. 1988;66(3):480–4. Epub 1988/03/01.

    Google Scholar 

  68. Katakura M, Yamada T, Aizawa T, Hiramatsu K, Yukimura Y, Ishihara M, et al. Presence of antideoxyribonucleic acid antibody in patients with hyperthyroidism of Graves’ disease. J Clin Endocrinol Metab. 1987;64(3):405–8. Epub 1987/03/01.

    Google Scholar 

  69. Marino M, Chiovato L, Friedlander JA, Latrofa F, Pinchera A, McCluskey RT. Serum antibodies against megalin (GP330) in patients with autoimmune thyroiditis. J Clin Endocrinol Metab. 1999;84(7):2468–74. Epub 1999/07/15.

    Google Scholar 

  70. Douglas RS, Naik V, Hwang CJ, Afifiyan NF, Gianoukakis AG, Sand D, et al. B cells from patients with Graves’ disease aberrantly express the IGF-1 receptor: implications for disease pathogenesis. J Immunol. 2008;181(8):5768–74.

    CAS  PubMed  Google Scholar 

  71. Smith TJ. Insulin-like growth factor-I regulation of immune function: a potential therapeutic target in autoimmune diseases? Pharmacol Rev. 2010;62(2):199–236. Epub 2010/04/16.

    Google Scholar 

  72. Davies TF, Yin X, Latif R. The genetics of the thyroid stimulating hormone receptor: history and relevance. Thyroid. 2010;20(7):727–36. Epub 2010/06/29.

    Google Scholar 

  73. Kong YC, Flynn JC, Wan Q, David CS. HLA and H2 class II transgenic mouse models to study susceptibility and protection in autoimmune thyroid disease. Autoimmunity. 2003;36(6–7):397–404. Epub 2003/12/13.

    Google Scholar 

  74. Menconi F, Huber A, Osman R, Concepcion E, Jacobson EM, Stefan M, et al. Tg.2098 is a major human thyroglobulin T-cell epitope. J Autoimmun. 2010;35(1):45–51. Epub 2010/03/23.

    Google Scholar 

  75. Ban Y, Tomer Y. The contribution of immune regulatory and thyroid specific genes to the etiology of Graves’ and Hashimoto’s diseases. Autoimmunity. 2003;36(6–7):367–79. Epub 2003/12/13.

    Google Scholar 

  76. Han S, Zhang S, Zhang W, Li R, Li Y, Wang Z, et al. CTLA4 polymorphisms and ophthalmopathy in Graves’ disease patients: association study and meta-analysis. Hum Immunol. 2006;67(8):618–26. Epub 2006/08/19.

    Google Scholar 

  77. Zhang J, Zahir N, Jiang Q, Miliotis H, Heyraud S, Meng X, et al. The autoimmune disease-associated PTPN22 variant promotes calpain-mediated Lyp/Pep degradation associated with lymphocyte and dendritic cell hyperresponsiveness. Nat Genet. 2011;43(9):902–7. Epub 2011/08/16.

    Google Scholar 

  78. Ban Y, Tozaki T, Taniyama M, Tomita M. Association of a C/T single-nucleotide polymorphism in the 5′ untranslated region of the CD40 gene with Graves’ disease in Japanese. Thyroid. 2006;16(5):443–6. Epub 2006/06/08.

    Google Scholar 

  79. Chistiakov DA, Chistiakova EI, Voronova NV, Turakulov RI, Savost’anov KV. A variant of the Il2ra/Cd25 gene predisposing to graves’ disease is associated with increased levels of soluble interleukin-2 receptor. Scand J Immunol. 2011;74(5):496–501. Epub 2011/08/06.

  80. Simmonds MJ, Heward JM, Carr-Smith J, Foxall H, Franklyn JA, Gough SC. Contribution of single nucleotide polymorphisms within FCRL3 and MAP3K7IP2 to the pathogenesis of Graves’ disease. J Clin Endocrinol Metab. 2006;91(3):1056–61. Epub 2005/12/31.

    Google Scholar 

  81. Ban Y, Greenberg DA, Concepcion E, Skrabanek L, Villanueva R, Tomer Y. Amino acid substitutions in the thyroglobulin gene are associated with susceptibility to human and murine autoimmune thyroid disease. Proc Natl Acad Sci USA. 2003;100(25):15119–24. Epub 2003/12/06.

    Google Scholar 

  82. Yin X, Latif R, Bahn R, Tomer Y, Davies TF. Influence of the TSH receptor gene on susceptibility to Graves’ disease and Graves’ ophthalmopathy. Thyroid. 2008;18(11):1201–6. Epub 2008/10/18.

    Google Scholar 

  83. Tsatsoulis A. The role of stress in the clinical expression of thyroid autoimmunity. Ann N Y Acad Sci. 2006;1088:382–95. Epub 2006/12/29.

  84. Davies TF, Martin A, Concepcion ES, Graves P, Cohen L, Ben-Nun A. Evidence of limited variability of antigen receptors on intrathyroidal T cells in autoimmune thyroid disease. N Engl J Med. 1991;325(4):238–44.

    Article  CAS  PubMed  Google Scholar 

  85. Davies TF, Martin A, Concepcion ES, Graves P, Lahat N, Cohen WL, et al. Evidence for selective accumulation of intrathyroidal T lymphocytes in human autoimmune thyroid disease based on T cell receptor V gene usage. J Clin Invest. 1992;89(1):157–62.

    Article  CAS  PubMed  Google Scholar 

  86. Dayan CM, Londei M, Corcoran AE, Grubeck-Loebenstein B, James RF, Rapoport B, et al. Autoantigen recognition by thyroid-infiltrating T cells in Graves disease. Proc Natl Acad Sci USA. 1991;88(16):7415–9.

    Article  CAS  PubMed  Google Scholar 

  87. Jackson RA, Haynes BF, Burch WM, Shimizu K, Bowring MA, Eisenbarth GS. Ia+ T cells in new onset Graves’ disease. J Clin Endocrinol Metab. 1984;59(2):187–90.

    Article  CAS  PubMed  Google Scholar 

  88. Wall JR, Baur R, Schleusener H, Bandy-Dafoe P. Peripheral blood and intrathyroidal mononuclear cell populations in patients with autoimmune thyroid disorders enumerated using monoclonal antibodies. J Clin Endocrinol Metab. 1983;56(1):164–9.

    Article  CAS  PubMed  Google Scholar 

  89. Martin A, Nakashima M, Zhou A, Aronson D, Werner AJ, Davies TF. Detection of major T cell epitopes on human thyroid stimulating hormone receptor by overriding immune heterogeneity in patients with Graves’ disease. J Clin Endocrinol Metab. 1997;82(10):3361–6.

    Article  CAS  PubMed  Google Scholar 

  90. Martin A, Barbesino G, Davies TF. T-cell receptors and autoimmune thyroid disease—signposts for T-cell-antigen driven diseases. Int Rev Immunol. 1999;18(1–2):111–40.

    Article  CAS  PubMed  Google Scholar 

  91. Ziegler SF. FOXP3: of mice and men. Annu Rev Immunol. 2006;24:209–26.

    Article  CAS  PubMed  Google Scholar 

  92. Sakaguchi S. Naturally arising Foxp3-expressing CD25+ CD4+ regulatory T cells in immunological tolerance to self and non-self. Nat Immunol. 2005;6(4):345–52.

    Article  CAS  PubMed  Google Scholar 

  93. McLachlan SM, Nagayama Y, Pichurin PN, Mizutori Y, Chen CR, Misharin A, et al. The link between Graves’ disease and Hashimoto’s thyroiditis: a role for regulatory T cells. Endocrinology. 2007;148(12):5724–33.

    Article  CAS  PubMed  Google Scholar 

  94. Saitoh O, Nagayama Y. Regulation of Graves’ hyperthyroidism with naturally occurring CD4+ CD25+ regulatory T cells in a mouse model. Endocrinology. 2006;147(5):2417–22.

    Article  CAS  PubMed  Google Scholar 

  95. Saitoh O, Abiru N, Nakahara M, Nagayama Y. CD8+ CD122+ T cells, a newly identified regulatory T subset, negatively regulate Graves’ hyperthyroidism in a murine model. Endocrinology. 2007;148(12):6040–6.

    Article  CAS  PubMed  Google Scholar 

  96. Marazuela M, Garcia-Lopez MA, Figueroa-Vega N, de la FH, varado-Sanchez B, Monsivais-Urenda A, et al. Regulatory T cells in human autoimmune thyroid disease. J Clin Endocrinol Metab. 2006;91(9):3639–46.

    Google Scholar 

  97. Owen CJ, Eden JA, Jennings CE, Wilson V, Cheetham TD, Pearce SH. Genetic association studies of the FOXP3 gene in Graves’ disease and autoimmune Addison’s disease in the United Kingdom population. J Mol Endocrinol. 2006;37(1):97–104.

    Article  CAS  PubMed  Google Scholar 

  98. Ban Y, Tozaki T, Tobe T, 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(4):201–7. Epub 2007/04/10.

    Google Scholar 

  99. Bettelli E, Carrier Y, Gao W, Korn T, Strom TB, Oukka M, et al. Reciprocal developmental pathways for the generation of pathogenic effector TH17 and regulatory T cells. Nature. 2006;441(7090):235–8.

    Article  CAS  PubMed  Google Scholar 

  100. Fossiez F, Djossou O, Chomarat P, Flores-Romo L, it-Yahia S, Maat C, et al. T cell interleukin-17 induces stromal cells to produce proinflammatory and hematopoietic cytokines. J Exp Med. 1996;183(6):2593–603.

    Google Scholar 

  101. Lubberts E, Joosten LA, van de Loo FA, Schwarzenberger P, Kolls J, Van Den Berg WB. Overexpression of IL-17 in the knee joint of collagen type II immunized mice promotes collagen arthritis and aggravates joint destruction. Inflamm Res. 2002;51(2):102–4.

    Article  CAS  PubMed  Google Scholar 

  102. Afzali B, Lombardi G, Lechler RI, Lord GM. The role of T helper 17 (Th17) and regulatory T cells (Treg) in human organ transplantation and autoimmune disease. Clin ExpImmunol. 2007;148(1):32–46.

    CAS  Google Scholar 

  103. Bohgaki T, Atsumi T, Koike T. Autoimmune disease after autologous hematopoietic stem cell transplantation. Autoimmun Rev. 2008;7(3):198–203.

    Article  PubMed  Google Scholar 

  104. Bohgaki T, Atsumi T, Koike T. Multiple autoimmune diseases after autologous stem-cell transplantation. N Engl J Med. 2007;357(26):2734–6.

    Article  CAS  PubMed  Google Scholar 

  105. Baker JR Jr. The nature of apoptosis in the thyroid and the role it may play in autoimmune thyroid disease. Thyroid. 2001;11(3):245–7.

    Article  PubMed  Google Scholar 

  106. Giordano C, Richiusa P, Bagnasco M, Salmaso C, Pizzolanti G, Galluzzo A. Thyrocytes–not innocent bystanders in autoimmune disease. Nat Immunol. 2001;2(3):183.

    Article  CAS  PubMed  Google Scholar 

  107. Giordano C, Richiusa P, Bagnasco M, Pizzolanti G, Di BF, Sbriglia MS, et al. Differential regulation of Fas-mediated apoptosis in both thyrocyte and lymphocyte cellular compartments correlates with opposite phenotypic manifestations of autoimmune thyroid disease. Thyroid. 2001;11(3):233–44.

    Article  CAS  PubMed  Google Scholar 

  108. Hamilton F, Black M, Farquharson MA, Stewart C, Foulis AK. Spatial correlation between thyroid epithelial cells expressing class II MHC molecules and interferon-gamma-containing lymphocytes in human thyroid autoimmune disease. Clin Exp Immunol. 1991;83(1):64–8.

    Article  CAS  PubMed  Google Scholar 

  109. Sawai Y, DeGroot LJ. Binding of human thyrotropin receptor peptides to a Graves’ disease-predisposing human leukocyte antigen class II molecule. J Clin Endocrinol Metab. 2000;85(3):1176–9.

    Article  CAS  PubMed  Google Scholar 

  110. McKenzie JM, Zakarija M. Fetal and neonatal hyperthyroidism and hypothyroidism due to maternal TSH receptor antibodies. Thyroid. 1992;2(2):155–9.

    Article  CAS  PubMed  Google Scholar 

  111. Lira SA, Martin AP, Marinkovic T, Furtado GC. Mechanisms regulating lymphocytic infiltration of the thyroid in murine models of thyroiditis. Crit Rev Immunol. 2005;25(4):251–62.

    Article  CAS  PubMed  Google Scholar 

  112. Martin AP, Coronel EC, Sano G, Chen SC, Vassileva G, Canasto-Chibuque C, et al. A novel model for lymphocytic infiltration of the thyroid gland generated by transgenic expression of the CC chemokine CCL21. J Immunol. 2004;173(8):4791–8.

    CAS  PubMed  Google Scholar 

  113. Kita-Furuyama M, Nagayama Y, Pichurin P, McLachlan SM, Rapoport B, Eguchi K. Dendritic cells infected with adenovirus expressing the thyrotrophin receptor induce Graves’ hyperthyroidism in BALB/c mice. ClinExp Immunol. 2003;131(2):234–40.

    Article  CAS  Google Scholar 

  114. Kabel PJ, Voorbij HA, De HM, van der Gaag RD, Drexhage HA. Intrathyroidal dendritic cells. J Clin Endocrinol Metab. 1988;66(1):199–207.

    Article  CAS  PubMed  Google Scholar 

  115. Quadbeck B, Eckstein AK, Tews S, Walz M, Hoermann R, Mann K, et al. Maturation of thyroidal dendritic cells in Graves’ disease. Scand J Immunol. 2002;55(6):612–20.

    Article  CAS  PubMed  Google Scholar 

  116. Brigl M, Brenner MB. CD1: antigen presentation and T cell function. Annu Rev Immunol. 2004;22:817–90.

    Article  CAS  PubMed  Google Scholar 

  117. Roura-Mir C, Catalfamo M, Cheng TY, Marqusee E, Besra GS, Jaraquemada D, et al. CD1a and CD1c activate intrathyroidal T cells during Graves’ disease and Hashimoto’s thyroiditis. J Immunol. 2005;174(6):3773–80.

    CAS  PubMed  Google Scholar 

  118. Moody DB. TLR gateways to CD1 function. Nat Immunol. 2006;7(8):811–7.

    Article  CAS  PubMed  Google Scholar 

  119. Hutchings P, Rayner DC, Champion BR, Marshall-Clarke S, Macatonia S, Roitt I, et al. High efficiency antigen presentation by thyroglobulin-primed murine splenic B cells. Eur J Immunol. 1987;17(3):393–8.

    Article  CAS  PubMed  Google Scholar 

  120. Villanueva R, Inzerillo AM, Tomer Y, Barbesino G, Meltzer M, Concepcion ES, et al. Limited genetic susceptibility to severe Graves’ ophthalmopathy: no role for CTLA-4 but evidence for an environmental etiology. Thyroid. 2000;10(9):791–8. Epub 2000/10/21.

    Google Scholar 

  121. Bahn RS. Graves’ ophthalmopathy. N Engl J Med. 2010;362(8):726–38. Epub 2010/02/26.

  122. Zhang L, Grennan-Jones F, Lane C, Rees DA, Dayan CM, Ludgate M. Adipose tissue depot-specific differences in the regulation of hyaluronan production of relevance to Graves' orbitopathy. J Clin Endocrinol Metab. 2012;97(2):653–62.

    Article  CAS  PubMed  Google Scholar 

  123. 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(3):267–71. Epub 2000/03/16.

    Google Scholar 

  124. Vannucchi G, Campi I, Bonomi M, Covelli D, Dazzi D, Curro N, et al. Rituximab treatment in patients with active Graves’ orbitopathy: effects on proinflammatory and humoral immune reactions. Clin Exp Immunol. 2010;161(3):436–43. Epub 2010/06/10.

    Google Scholar 

  125. Konuk O, Hondur A, Akyurek N, Unal M. Apoptosis in orbital fibroadipose tissue and its association with clinical features in Graves’ ophthalmopathy. Ocul Immunol Inflamm. 2007;15(2):105–11. Epub 2007/06/15.

    Google Scholar 

  126. Pritchard J, Horst N, Cruikshank W, Smith TJ. Igs from patients with Graves’ disease induce the expression of T cell chemoattractants in their fibroblasts. J Immunol. 2002;168(2):942–50.

    CAS  PubMed  Google Scholar 

  127. Pritchard J, Han R, Horst N, Cruikshank WW, Smith TJ. Immunoglobulin activation of T cell chemoattractant expression in fibroblasts from patients with Graves’ disease is mediated through the insulin-like growth factor I receptor pathway. J Immunol. 2003;170(12):6348–54.

    CAS  PubMed  Google Scholar 

Download references

Acknowledgments

Supported in part by NIH grants DK069713, DK052464 and the VA Merit Award Program. We thank Dr. Xiaoming Yin for help with the manuscript.

Author information

Authors and Affiliations

  1. Thyroid Research Unit, Mount Sinai School of Medicine, Room 2F-26, James J. Peters VA Medical Center, 130 West Kingsbridge Rd, Bronx, New York, NY, 10468, USA

    Syed A. Morshed, Rauf Latif & Terry F. Davies

Authors
  1. Syed A. Morshed
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Rauf Latif
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Terry F. Davies
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Syed A. Morshed.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Morshed, S.A., Latif, R. & Davies, T.F. Delineating the autoimmune mechanisms in Graves’ disease. Immunol Res 54, 191–203 (2012). https://doi.org/10.1007/s12026-012-8312-8

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12026-012-8312-8

Keywords

Search

Navigation