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Animal Models of Autoimmune Thyroid Disease

  • Marian Ludgate
Part of the Contemporary Endocrinology book series (COE)

Summary

Autoimmune thyroid diseases (AITD) cover the spectrum from hypothyroid Hashimoto’s thyroiditis (HT) to hyperthyroid Graves’ disease (GD). The main autoimmune targets are thyroglobulin (TG), thyroid peroxidase (TPO) and the thyrotropin receptor (TSHR). Autoantibodies and specific T cells directed against all three autoantigens can be detected in the circulation of HT and GD patients and also in a significant proportion of the healthy population. In AITD, as in other autoimmune conditions, the central question remains how is immune tolerance overcome? In vivo models, mostly induced in rodents, have contributed to our understanding of the mechanisms operating and many hundreds of papers, spanning from 1956 to the present day, have been published describing the results obtained. Most of the information has been derived from experimental autoimmune thyroiditis (EAT) models induced with TG, an antigen that, based on current knowledge, seems to be of lesser importance in human AITD. Nevertheless, many of the basic precepts underlying autoimmunity, for example the importance of the major histocompatability complex (MHC) II and the existence of immunoregulatory T cells, have been identified using TG-based models, and these are described. Reports based on induction of disease with TPO, the driving antigen in HT, are not very numerous but include a seminal paper that clearly demonstrates the redundancy of autoantibodies and the central role of T cells in pathogenesis. In contrast, autoantibodies to the TSHR cause GD and much of the chapter is devoted to models attempting to mimic GD, and these have been the subject of considerable effort since its cloning in 1998. This has culminated with the recent publication of monoclonal antibodies with thyroid stimulating activity (TSAB) either measured in vitro or in vivo.

Keywords

Hashimoto’s thyroiditis Graves’ disease animal models thyroiditis hyperthyroidism hypothyroidism autoantibodies thyrotropin receptor thyroglobulin thyroid peroxidase 

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References

  1. 1.
    Roitt IM, Doniach D, Campbell RN, Vaughan Hudson R. Autoantibodies in Hashimoto’s disease (lymphadenoid goiter). Lancet 1956;2:820–821.CrossRefGoogle Scholar
  2. 2.
    Rose NR, Witebsky E. Studies on organ specificity. V. Changes in thyroid glands of rabbits following active immunization with rabbit thyroid extracts. J Immunol 1956;76:417–427.PubMedGoogle Scholar
  3. 3.
    Ludgate M, Vassart G. The molecular-genetics of 3 thyroid autoantigens – thyroglobulin, thyroid peroxidase and the thyrotropin receptor. Autoimmunity 1990;7:201–211.PubMedCrossRefGoogle Scholar
  4. 4.
    Lorenz HM, Herrmann M, Kalden JR. The pathogenesis of autoimmune diseases. Scand J Clin Lab Invest 2001;61:16–26(Suppl. 235).CrossRefGoogle Scholar
  5. 5.
    Sundick RS, Bagchi N, Brown TR. The obese strain chicken as a model for human Hashimoto’s thyroiditis. Exp Clin Endocrinol Diabetes 1996;104:4–6(Suppl. 3).PubMedGoogle Scholar
  6. 6.
    Delemarre FGA, Simons PJ, Drexhage HA. The BB rat as a model for autoimmune thyroiditis: Relevance for the pathogenesis of human disease. Exp Clin Endocrinol Diabetes 1996;104:10–12(Suppl. 3).PubMedCrossRefGoogle Scholar
  7. 7.
    Weetman AP. Autoimmune thyroid disease: propagation and progression. Eur J Endocrinol 2003;148:1–9.PubMedCrossRefGoogle Scholar
  8. 8.
    Van de Graaf SAR, Ris-Stalpers C, Pauws E, Mendive FM, Targovnik HM, de Vijlder JJM. Structure update - up to date with human thyroglobulin. J Endocrinol 2001;170:307–321.PubMedCrossRefGoogle Scholar
  9. 9.
    Vladitui A, Rose N. Autoimmune murine thyroiditis. Relation to histocompatabiltiy (H-2) type. Science 1971;174:1137–1140.CrossRefGoogle Scholar
  10. 10.
    Kong, Y-CM, Giraldo, AA. Experimental autoimmune thyroiditis in the mouse and rat. In Autoimmune Disease Models (Irun Cohen, Ariel Miller, eds). Elsevier. Academic Press, San Diego; 1994;123–145.Google Scholar
  11. 11.
    Penhale WJA, Farmer A, McKenna RP, Irvine WJ. Spontaneous thyroiditis in thymectomised and irradiated Wistar rats. Clin Exp Immunol 1973;15:122.Google Scholar
  12. 12.
    Ahmed SA, Young PR, Penhale WJ. Beneficial effect of testosterone in the treatment of chronic autoimmune thyroiditis in rats. J Immunol 1986;136:143–147.Google Scholar
  13. 13.
    Singh VK, Mehrotra S, Agarwal SS. The paradigm of Th1 and Th2 cytokines: its relevance to autoimmunity and allergy. Immunol Res 1999;20:147–161.PubMedCrossRefGoogle Scholar
  14. 14.
    Coles AJ, Wing N, Smith S et al. Pulsed monoclonal antibody treatment and autoimmune thyroid disease in multiple sclerosis. Lancet 1999;354:1691–1695.PubMedCrossRefGoogle Scholar
  15. 15.
    Chen F, Day SL, Metcalfe RA et al. Characteristics of autoimmune thyroid disease occurring as a late complication of immune reconstitution in patients with advanced human immunodeficiency virus (HIV) disease. Medicine 2005;84:98–106.PubMedCrossRefGoogle Scholar
  16. 16.
    Saoudi A, Seddon B, Fowell D, Mason D. The thymus contains a high frequency of cells that prevent autoimmune diabetes on transfer into prediabetic recipients. J Exp Med 1996;184:2393–2398.PubMedCrossRefGoogle Scholar
  17. 17.
    Seddon B, Mason D. Regulatory T cells in the control of autoimmunity: the essential role of transforming growth factor beta and interleukin 4 in the prevention of autoimmune thyroiditis in rats by peripheral CD4(+)CD45RC- cells and CD4(+)CD8(-) thymocytes. J Exp Med 1999;189:279–288.PubMedCrossRefGoogle Scholar
  18. 18.
    Seddon B, Mason D. Peripheral autoantigen induces regulatory T cells that prevent autoimmunity. J Exp Med 1999;189:877–882.PubMedCrossRefGoogle Scholar
  19. 19.
    Volpe R. Suppressor T lymphocyte dysfunction is important in the pathogenesis of autoimmune thyroid disease: a perspective. Thyroid 1993;3:345–352.PubMedGoogle Scholar
  20. 20.
    Dayan CM, Daniels GH. Chronic autoimmune thyroiditis. N Engl J Med 1996;335:99–107.PubMedCrossRefGoogle Scholar
  21. 21.
    Hammond LJ, Palazzo FF, Shattock M, Goode AW, Mirakian R. Thyrocyte targets and effectors of autoimmunity: a role for death receptors? Thyroid 2001;11:919–927.PubMedCrossRefGoogle Scholar
  22. 22.
    Wu Z, Podack ER, McKenzie JM, Olsen KJ, Zakarija M. Perforin expression by thyroid-infiltrating T cells in autoimmune thyroid disease. Clin Exp Immunol 1994;98:470–477.PubMedCrossRefGoogle Scholar
  23. 23.
    Barry M, Bleackley RC. Cytotoxic T lymphocytes: all roads lead to death. Nat Rev Immunol 2002;2:401–409.PubMedGoogle Scholar
  24. 24.
    Stassi G, De Maria R. Autoimmune thyroid disease: new models of cell death in autoimmunity. Nat Rev Immunol 2002;2:195–204.PubMedCrossRefGoogle Scholar
  25. 25.
    Stepp SE, Mathew PA, Bennett M, de Saint Basile G, Kumar V. Perforin: more than just an effector molecule. Immunol Today 2000;21:254–256.PubMedCrossRefGoogle Scholar
  26. 26.
    De Maria R, Testi R. Fas-FasL interactions: a common pathogenetic mechanism in organ-specific autoimmunity. Immunol Today 1998;19:121–125.PubMedCrossRefGoogle Scholar
  27. 27.
    Giordano C, Stassi G, De Maria R, Todaro M, Richiusa P, Papoff G, Ruberti G, Bagnasco M, Testi R, Galluzzo A. Potential involvement of Fas and its ligand in the pathogenesis of Hashimoto’s thyroiditis. Science 1997;275:960–963.PubMedGoogle Scholar
  28. 28.
    Phelps E, Wu P, Bretz J, Baker JR Jr. Thyroid cell apoptosis. A new understanding of thyroid autoimmunity. Endocrinol Metab Clin North Am 2000;29:375–388.PubMedCrossRefGoogle Scholar
  29. 29.
    Batteux F, Lores P, Bucchini D, Chiocchia G. Transgenic expression of Fas ligand on thyroid follicular cells prevents autoimmune thyroiditis. J Immunol 2000;164:1681–1688.PubMedGoogle Scholar
  30. 30.
    Wei Y, Chen K, Sharp GC, Yagita H, Braley-Mullen H. Expression and regulation of Fas and Fas ligand on thyrocytes and infiltrating cells during induction and resolution of granulomatous experimental autoimmune thyroiditis. J Immunol 2001;167:6678–6686.PubMedGoogle Scholar
  31. 31.
    Libert F, Ruel J, Ludgate M, Swillens S, Alexander N, Vassart G, Dinsart C. Thyroperoxidase, an auto-antigen with a mosaic structure made of nuclear and mitochondrial gene modules. EMBO J 1987;6:4193–4196.PubMedGoogle Scholar
  32. 32.
    McLachlan SM, Rapoport B. The molecular biology of thyroid peroxidase: cloning, expression and role as autoantigen in autoimmune thyroid disease. Endocr Revs 1992;13:192–206.CrossRefGoogle Scholar
  33. 33.
    Kotani T, Umeki K, Hirai K, Ohtaki S. Experimental murine thyroiditis induced by porcine thyroid peroxidase and its transfer by the antigen-specific T cell line. Clin Exp Immunol 1990;80:11–18.PubMedCrossRefGoogle Scholar
  34. 34.
    Kotani T, Umeki K, Yagihashi S, Hirai K, Ohtaki S. Identification of thyroiditogenic epitope on porcine thyroid peroxidase for C57bl/6 mice. J Immunol 1992;148:2084–2089.PubMedGoogle Scholar
  35. 35.
    Flynn JC, Gardas A, Wan Q, Gora M, Alsharabi G, Wei WZ, Giraldo AA, David CS, Kong YM, Banga JP. Superiority of thyroid peroxidase DNA over protein immunization in replicating human thyroid autoimmunity in HLA-DRB1* 0301. Clin Exp Immunol 2004;137:503–512.PubMedCrossRefGoogle Scholar
  36. 36.
    Ng HP, Banga JP, Kung AWC. Development of a murine model of autoimmune thyroiditis induced with homologous mouse thyroid peroxidase. Endocrinology 2004;145:809–816.PubMedCrossRefGoogle Scholar
  37. 37.
    Quaratino S, Badami E, Pang YY, Bartok I, Dyson J, Kioussis D, Londei M, Maiuri L. Degenerate self-reactive human T-cell receptor causes spontaneous autoimmune disease in mice. Nat Med 2004;10:920–926.PubMedCrossRefGoogle Scholar
  38. 38.
    Badami E, Maiuri L, Quaratino S. High incidence of spontaneous autoimmune thyroiditis in immunocompetent self-reactive human T cell receptor transgenic mice. J Autoimmun 2005;24:85–91.PubMedCrossRefGoogle Scholar
  39. 39.
    Rees Smith B, Mclachlan S, Furmaniak J. Autoantibodies to the thyrotropin receptor. Endocr Rev 1998;9:106–120.Google Scholar
  40. 40.
    Vassart G, Dumont JE. The thyrotropin receptor and the regulation of thyrocyte function and growth. Endocr Rev 1992;13:596–611.PubMedCrossRefGoogle Scholar
  41. 41.
    Paschke R, Ludgate M. The thyrotropin receptor and thyroid disease. N Engl J Med 1997;337: 1675–1681.PubMedCrossRefGoogle Scholar
  42. 42.
    Khoo DHC, Ho SC, Seah LL et al. The combination of absent thyroid peroxidase antibodies and high thyroid stimulating immunoglobulins identifies a group at markedly increased risk of ophthalmopathy. Thyroid 1999;9:1175–1180.PubMedGoogle Scholar
  43. 43.
    Crisp M, Lane C, Halliwell M et al. Thyrotropin receptor transcripts in human adipose tissue. J Clin Endocrinol Metab 1997;82:2003–2005.PubMedGoogle Scholar
  44. 44.
    Bahn R, Dutton C, Natt N et al. Thyrotropin receptor expression in Graves’ orbital adipose/ connective tissues; potential autoantigen in Graves’ Ophthalmopathy. J Clin Endocrinol Metab 1998;83:998–1002.PubMedCrossRefGoogle Scholar
  45. 45.
    Crisp M, Starkey K, Ham J et al. Adipogenesis in thyroid eye disease. Invest Ophthalmol Vis Sci 2000;41:3249–3255.PubMedGoogle Scholar
  46. 46.
    Misrahi M, Loosfelt H, Gross B, Atger M, Jolivet A, Savouret JF, Milgrom E. Characterization of the thyroid stimulating hormone receptor. Curr Opin Endocrinol Diabetes 1994;175:175–183.CrossRefGoogle Scholar
  47. 47.
    Rapoport B, Chazenbalk GD, Juame JC, McLachlan SM. The thyrotropin (TSH) receptor: interaction with TSH and autoantibodies. Endocr Rev 1998;19:673–716.PubMedCrossRefGoogle Scholar
  48. 48.
    Vlaeminck-Guillem V, Ho SC, Rodien P, Vassart G, Costagliola S. Activation of the cAMP pathway by the TSH receptor involves switching of the ectodomain from a tethered inverse agonist to an agonist. Mol Endocrinol 2002;16:736–746.PubMedCrossRefGoogle Scholar
  49. 49.
    Costagliola S, Paneels V, Bonomi M, Koch J, Many MC, Smits G, Vassart G. Tyrosine sulfation is required for agonist recognition by glycoprotein hormone receptors. EMBO J 2002;21:504–513.PubMedCrossRefGoogle Scholar
  50. 50.
    Costagliola S, Khoo D, Vassart G. Production of bioactive amino-terminal domain of the thyrotropin receptor via insertion in the plasma membrane by a glycosylphosphatidylinositol anchor. FEBS Lett 1998;436:427–433.PubMedCrossRefGoogle Scholar
  51. 51.
    Chazenbalk GD, Pichurin P, Chen CR, Latrofa F, Johnstone AP, McLachlan SM, Rapoport B. Thyroid stimulating autoantibodies in Graves’ disease preferentially recognise the free A subunit, not the thyrotropin holoreceptor. J Clin Invest 2002;110:209–217.PubMedCrossRefGoogle Scholar
  52. 52.
    Ludgate M. Animal models of Graves’ disease. Eur J Endo 2000;142:1–8.CrossRefGoogle Scholar
  53. 53.
    Shimojo N, Kohno Y, Yamaguchi KI et al. Induction of Graves’-like disease in mice by immunization with fibroblasts transfected with the thyrotropin receptor and a class II molecule. Proc Natl Acad Sci USA 1996;93:11074–11079.PubMedCrossRefGoogle Scholar
  54. 54.
    Kikuoka S, Shimojo N, Yamaguchi KI et al. The formation of thyrotropin receptor (TSHR) antibodies in a Graves’ animal model requires the N-terminal segment of the TSHR extracellular domain. Endocrinology 1998;139:1891–1898.PubMedCrossRefGoogle Scholar
  55. 55.
    Kita M, Ahmad L, Marians RC et al. Regulation and transfer of a murine model of thyrotropin receptor antibody mediated Graves’ Disease. Endocrinology 1999;140:1392–1398.PubMedCrossRefGoogle Scholar
  56. 56.
    Kaithamana S, Fan JL, Osuga Y et al. Induction of experimental autoimmune Graves’ disease in BALB/c mice. J Immunol 1999;163:5157–5167.PubMedGoogle Scholar
  57. 57.
    Yan XM, Guo J, Pichurin P, Tanaka K, Jaume JC, Rapoport B, McLachlan SM. Cytokines, IgG subclasses and costimulation in a mouse model of thyroid autoimmunity induced by injection of fibroblasts co-expressing MHC class II and thyroid autoantigens. Clin Exp Immunol 2000;122:170–179.PubMedCrossRefGoogle Scholar
  58. 58.
    Costagliola S, Many MC, StalmansFalys M et al. Transfer of thyroiditis, with syngeneic spleen-cells sensitized with the human thyrotropin receptor, to naive BALB/c and nod mice. Endocrinology 1996;137:4637–4643.PubMedCrossRefGoogle Scholar
  59. 59.
    Many MC, Costagliola S, Detrait M et al. Development of an animal model of autoimmune thyroid eye disease. J Immunol 1999;162:4966–4974.PubMedGoogle Scholar
  60. 60.
    Costagliola S, Rodien P, Many MC et al. Genetic immunization against the human thyrotropin receptor causes thyroiditis and allows production of monoclonal antibodies recognizing the native receptor. J Immunol 1998;160:1458–1465.PubMedGoogle Scholar
  61. 61.
    Costagliola S, Many MC, Denef JF et al. Genetic immunisation of outbred mice with thyrotropin receptor cDNA provides a model of Graves’ disease. J Clin Invest 2000;105:803–811.PubMedGoogle Scholar
  62. 62.
    Baker G, Mazziotti G, von Ruhland C, Ludgate M. Re-evaluating thyrotropin receptor induced mouse models of Graves’ disease & ophthalmopathy. Endocrinology 2005;146:835–844.PubMedCrossRefGoogle Scholar
  63. 63.
    Caturegli P, Rose N, Kimura M, Kimura H, Tzou S. Studies on murine thyroiditis: new insights from organ flow cytometry. Thyroid 2003;13:419–426.PubMedCrossRefGoogle Scholar
  64. 64.
    Vladutiu A, Rose N. Aberrant thymus tissue in rat and mouse thyroid. Experientia 1972;28:79–81.PubMedCrossRefGoogle Scholar
  65. 65.
    Muhlendyck H, Syed A. Fixation artefacts in the external eye muscles in biopsy examinations. (A light microscopy and electron microscopy study). Buch Augenarzt 1978;73:181–191.PubMedGoogle Scholar
  66. 66.
    Mooij P, de Wit H, Drexhage H. A high iodine intake in Wistar rats results in the development of a thyroid-associated ectopic thymic tissue and is accompanied by a low thyroid autoimmune reactivity. Immunology 1994;81:309–316.PubMedGoogle Scholar
  67. 67.
    Pichurin P, Yan XM, Farilla L, Guo J, Chazenbalk GD, Rapoport B, McLachlan SM. Naked TSH receptor DNA vaccination: A TH1 T cell response in which interferon-gamma production, rather than antibody, dominates the immune response in mice. Endocrinology 2001;142:3530–3536.PubMedCrossRefGoogle Scholar
  68. 68.
    Rao PV, Watson PF, Weetman AP, Carayanniotis G, Banga JP. Contrasting activities of thyrotropin receptor antibodies in experimental models of Graves’ disease induced by injection of transfected fibroblasts or deoxyribonucleic acid vaccination. Endocrinology 2003;144:260–266.PubMedCrossRefGoogle Scholar
  69. 69.
    Bach JF. A Toll-like trigger for autoimmune disease. Nat Med 2005;11:120–121.PubMedCrossRefGoogle Scholar
  70. 70.
    Lang et al. Toll-like receptor engagement converts T-cell autoreactivity into overt autoimmune disease. Nat Med 2005;11:138–145.PubMedCrossRefGoogle Scholar
  71. 71.
    Hemmi H et al. A toll-like receptor recognizes bacterial DNA. Nature 2000;408:740–745.PubMedCrossRefGoogle Scholar
  72. 72.
    Bhattacharyya KK, Coenen MJ, Bahn RS. Effect of environmental pathogens on the TSHR-directed immune response in an animal model of Graves’ disease. Thyroid 2005;15:422–426.PubMedCrossRefGoogle Scholar
  73. 73.
    Nagayama Y et al. A novel murine model of Graves’ hyperthyroidism with intramuscular injection of adenovirus expressing the thyrotropin receptor. J Immunol 2002;168:2789–2794.PubMedGoogle Scholar
  74. 74.
    Chen CR et al. The thyrotropin receptor autoantigen in Graves’ disease is the culprit as well as the victim. J Clin Invest 2003;111:1897–1904.PubMedCrossRefGoogle Scholar
  75. 75.
    Metcalfe R, Jordan N, Watson P, Gullu S, Wiltshire M, Crisp M, Evans C, Weetman A, Ludgate M. Demonstration of IgG, IgA and IgE autoantibodies to the human thyrotropin receptor using flow cytometry. J Clin Endocrinol Metab 2002;87:1754–1761.PubMedCrossRefGoogle Scholar
  76. 76.
    Fentiman IS, Thomas BS, Balkwill FR, Rubens RD, Hayward JL. Primary hypothyroidism associated with interferon therapy of breast cancer. Lancet 1985;1:1166.PubMedCrossRefGoogle Scholar
  77. 77.
    Sequeira M, Jasani B, Fuhrer D, Wheeler M, Ludgate M. Demonstration of reduced in vivo surface expression of activating mutant thyrotropin receptors in thyroid sections. Eur J Endocrinol 2002;146:163–171.PubMedCrossRefGoogle Scholar
  78. 78.
    Starkey KJ, Janezic A, Jones G, Jordan N, Baker G, Ludgate M. Adipose thyrotropin receptor expression is elevated in Graves’ and thyroid eye diseases ex vivo and indicates adipogenesis in progress in vivo. J Mol Endocrinol 2003;30:369–380.PubMedCrossRefGoogle Scholar
  79. 79.
    Dechairo BM et al. Association of the TSHR gene with Graves’ disease: the first disease specific locus. Eur J Hum Genetics 2005;13:1223–1230.CrossRefGoogle Scholar
  80. 80.
    Chen CR et al. Low dose immunization with adenovirus expressing the thyroid stimulating hormone receptor A-subunit deviates the antibody response toward that of autoantibodies in human Graves’ disease. Endocrinology 2004;145:228–233.PubMedCrossRefGoogle Scholar
  81. 81.
    Pichurin PN, Chen CR, Nagayama Y, Pichurina O, Rapoport B, McLachlan SM. Evidence that factors other than particular thyrotropin receptor T cell epitopes contribute to the development of hyperthyroidism in murine Graves’ disease. Clin Exp Immunol 2004;135:391–397.PubMedCrossRefGoogle Scholar
  82. 82.
    Chen CR, Aliesky H, Pichurin PN, Nagayama Y, McLachlan SM, Rapoport B. Susceptibility rather than resistance to hyperthyroidism is a dominant in a thyrotropin receptor adenovirus-induced animal model of Graves’ disease as revealed by BALB/c-C57BL/6 hybrid mice. Endocrinology 2004;145:4927–4933.PubMedCrossRefGoogle Scholar
  83. 83.
    McLachlan SM, Nagayama Y, Rapoport B. Insight into Graves’ hyperthyroidism from animal models. Endocr Rev 2005;26:800–832.PubMedCrossRefGoogle Scholar
  84. 84.
    Amagai M, Tsunoda K, Suzuki H, Nishifuji K, Koyasu S, Nishikawa T. Use of autoantigen-knockout mice in developing an active autoimmune disease model for pemphigus. J Clin Invest 2000;105:625–631PubMedCrossRefGoogle Scholar
  85. 85.
    Harrington CJ, Paez A, Hunkapiller T, Mannikko V, Brabb T, Ahearn M, Beeson C, Goverman J. Differential tolerance is induced in T cells recognizing distinct epitopes of myelin basic protein. Immunity 1998;8:571–580PubMedCrossRefGoogle Scholar
  86. 86.
    Pichurin PN et al. Thyrotropin receptor knockout mice: studies on immunological tolerance to a major thyroid autoantigen. Endocrinology 2004;145:1294–1301.PubMedCrossRefGoogle Scholar
  87. 87.
    Ando T, Latif R, Protsker A, Moran T, Nagayama Y, Davies TF. A monoclonal thyroid stimulating antibody. J Clin Invest 2002;110:1667–1674.PubMedCrossRefGoogle Scholar
  88. 88.
    Sanders J et al. Thyroid-stimulating monoclonal antibodies. Thyroid 2002;12:1043–1050.PubMedCrossRefGoogle Scholar
  89. 89.
    Costagliola S et al. Generation of a mouse monoclonal TSH receptor antibody with stimulating activity. Biochem Biophys Res Commun 2002;299:891–896.PubMedCrossRefGoogle Scholar
  90. 90.
    Costagliola S et al. Delineation of the discontinuous-conformational epitope of a monoclonal antibody displaying full in vitro and in vivo thyrotropin activity. Mol Endocrinol 2004;18:3020–3034.PubMedCrossRefGoogle Scholar
  91. 91.
    Rifkin IR, Leadbetter EA, Busconi L, Viglianti G, Marshak-Rothstein A. Toll-like receptors, endogenous ligands, and systemic autoimmune disease. Immunol Rev 2005;204:27–42.PubMedCrossRefGoogle Scholar

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© Humana Press Inc. 2007

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  • Marian Ludgate

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