Skip to main content
SpringerLink
Log in

A transgenic mouse that spontaneously develops pathogenic TSH receptor antibodies will facilitate study of antigen-specific immunotherapy for human Graves’ disease

  • Review
  • Published:
Endocrine Aims and scope Submit manuscript

Abstract

Graves’ hyperthyroidism can be treated but not cured. Antigen-specific immunotherapy would accomplish this goal, for which purpose an animal model is an invaluable tool. Two types of animal models are available. First, pathogenic TSHR antibodies (TSHRAb) can be induced by injecting mice with fibroblasts co-expressing the human TSHR (hTSHR) and MHC class II, or in mammals using plasmid or adenovirus vectors encoding the hTSHR or its A-subunit. Second, a mouse model that spontaneously develops pathogenic TSHRAb resembling those in human disease was recently described. This outcome was accomplished by transgenic intrathyroidal expression of the hTSHR A-subunit in NOD.H2h4 mice that are genetically predisposed to develop thyroiditis but, without the transgene, do not generate TSHRAb. Recently, novel approaches to antigen-specific immunotherapy have been tested, primarily in the induced model, by injecting TSHR A-subunit protein or cyclic TSHR peptides. T-cell tolerance has also been induced in “humanized” HLA-DR3 mice by injecting synthetic peptides predicted in silico to mimic naturally processed TSHR T-cell epitopes. Indeed, a phase 1 study based on the latter approach has been conducted in humans. In the spontaneous model (hTSHR/NOD.H2h mice), injection of soluble or nanoparticle-bearing hTSHR A-subunits had the unwanted effect of exacerbating pathogenic TSHRAb levels. A promising avenue for tolerance induction, successful in other conditions and yet to be tested with the TSHR, involves encapsulating the antigen. In conclusion, these studies provide insight into the potential outcome of immunotherapeutic approaches and emphasize the importance of a spontaneous model to test future novel, antigen-specific immunotherapies for Graves’ disease.

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

Abbreviations

hTSHR:

human thyrotropin receptor

hTSHR/NOD.H2 h4 :

NOD.H2h4 mice expressing the human TSHR A-subunit in the thyroid

ITE:

ligand for the endogenous aryl-hydrocarbon receptor (C14H10N2O3S)

TBI:

inhibition of TSH binding to the TSHR

Tg:

thyroglobulin

TPO:

thyroid peroxidase

References

  1. W.M. Wiersinga, Graves’ disease: can it be cured? Endocrinol. Metab. (Seoul) 34(1), 29–38 (2019). https://doi.org/10.3803/EnM.2019.34.1.29

    Article  CAS  Google Scholar 

  2. S.J. Peterson, A.R. Cappola, M.R. Castro, C.M. Dayan, A.P. Farwell, J.V. Hennessey, P.A. Kopp, D.S. Ross, M.H. Samuels, A.M. Sawka, P.N. Taylor, J. Jonklaas, A.C. Bianco, An online survey of hypothyroid patients demonstrates prominent dissatisfaction. Thyroid 28(6), 707–721 (2018). https://doi.org/10.1089/thy.2017.0681

    Article  CAS  PubMed  Google Scholar 

  3. O. Torring, T. Watt, G. Sjolin, K. Bystrom, M. Abraham-Nordling, J. Calissendorff, P.K. Cramon, H. Filipsson Nystrom, B. Hallengren, M. Holmberg, S. Khamisi, M. Lantz, G. Wallin, Impaired quality of life after radioiodine therapy compared to antithyroid drugs or surgical treatment for Graves’ hyperthyroidism: a long-term follow-up with the thyroid-related patient-reported outcome questionnaire and 36-item short form health status survey. Thyroid 29(3), 322–331 (2019). https://doi.org/10.1089/thy.2018.0315

    Article  CAS  PubMed  Google Scholar 

  4. B. Rapoport, S.M. McLachlan, The thyrotropin receptor in Graves’ disease. Thyroid 17(10), 911–922 (2007)

    CAS  PubMed  Google Scholar 

  5. J.A. Pearson, F.S. Wong, L. Wen, The importance of the Non Obese Diabetic (NOD) mouse model in autoimmune diabetes. J. Autoimmun. 66, 76–88 (2016). https://doi.org/10.1016/j.jaut.2015.08.019

    Article  CAS  PubMed  Google Scholar 

  6. C.S. Constantinescu, N. Farooqi, K. O’Brien, B. Gran, Experimental autoimmune encephalomyelitis (EAE) as a model for multiple sclerosis (MS). Br. J. Pharm. 164(4), 1079–1106 (2011). https://doi.org/10.1111/j.1476-5381.2011.01302.x

    Article  CAS  Google Scholar 

  7. H. Aliesky, C.L. Courtney, B. Rapoport, S.M. McLachlan, Thyroid autoantibodies are rare in nonhuman great apes and hypothyroidism cannot be attributed to thyroid autoimmunity. Endocrinology 154(12), 4896–4907 (2013)

    CAS  PubMed  PubMed Central  Google Scholar 

  8. M. Parmentier, F. Libert, C. Maenhaut, A. Lefort, C. Gerard, J. Perret, J. Van Sande, J.E. Dumont, G. Vassart, Molecular cloning of the thyrotropin receptor. Science 246, 1620–1622 (1989)

    CAS  PubMed  Google Scholar 

  9. Y. Nagayama, K.D. Kaufman, P. Seto, B. Rapoport, Molecular cloning, sequence and functional expression of the cDNA for the human thyrotropin receptor. Biochem. Biophys. Res. Commun. 165, 1184–1190 (1989)

    CAS  PubMed  Google Scholar 

  10. F. Libert, A. Lefort, C. Gerard, M. Parmentier, J. Perret, M. Ludgate, J.E. Dumont, G. Vassart, Cloning, sequencing and expression of the human thyrotropin (TSH) receptor: Evidence for binding of autoantibodies. Biochem. Biophys. Res. Commun. 165, 1250–1255 (1989)

    CAS  PubMed  Google Scholar 

  11. P.R. Buckland, C.R. Rickards, R.D. Howells, E. Davies Jones, B. Rees Smith, Photo-affinity labelling of the thyrotropin receptor. FEBS Lett. 145(2), 245–249 (1982)

    CAS  Google Scholar 

  12. J. Furmaniak, F.A. Hashim, P.R. Buckland, V.B. Petersen, K. Beever, R.D. Howells, B. Rees Smith, Photoaffinity labelling of the TSH receptor on FRTL5 cells. FEBS Lett. 215, 316–322 (1987)

    CAS  PubMed  Google Scholar 

  13. B. Rapoport, S.M. McLachlan, TSH receptor cleavage into subunits and shedding of the A-subunit; a molecular and clinical perspective. Endocr. Rev. 37, 114–134 (2016)

    CAS  PubMed  PubMed Central  Google Scholar 

  14. A.V. Misharin, Y. Nagayama, H. Aliesky, Y. Mizutori, B. Rapoport, S.M. McLachlan, Attenuation of induced hyperthyroidism in mice by pretreatment with thyrotropin receptor protein: deviation of thyroid-stimulating antibody to non-functional antibodies. Endocrinology 150(8), 3944–3952 (2009)

    CAS  PubMed  PubMed Central  Google Scholar 

  15. C.U. Frank, S. Braeth, J.W. Dietrich, D. Wanjura, U. Loos, Bridge technology with TSH receptor chimera for sensitive direct detection of TSH receptor antibodies causing Graves’ disease: analytical and clinical evaluation. Horm. Metab. Res 47(12), 880–888 (2015). https://doi.org/10.1055/s-0035-1554662

    Article  CAS  PubMed  Google Scholar 

  16. S.M. McLachlan, Y. Nagayama, B. Rapoport, Insight into Graves’ hyperthyroidism from animal models. Endocr. Rev. 26(6), 800–832 (2005)

    CAS  PubMed  Google Scholar 

  17. T. Hanafusa, R. Pujol-Borrell, L. Chiovato, R.C.G. Russell, D. Doniach, G.F. Bottazzo, M. Feldmann, Aberrant expression of HLA-DR antigen on thyrocytes in Graves’ disease: relevance for autoimmunity. Lancet ii, 1111–1115 (1983)

    Google Scholar 

  18. G.F. Bottazzo, R. Pujol-Borrell, T. Hanafusa, M. Feldmann, Role of aberrant HLA-DR expression and antigen presentation in induction of endocrine autoimmunity. Lancet 2, 1115–1119 (1983)

    CAS  PubMed  Google Scholar 

  19. N. Shimojo, Y. Kohno, K.-I. Yamaguchi, S.-I. Kikuoka, A. Hoshioka, H. Niimi, A. Hirai, Y. Tamura, Y. Saito, L.D. Kohn, K. Tahara, Induction of Graves-like disease in mice by immunization with fibroblasts transfected with the thyrotropin repector and a class II molecule. Proc. Natl Acad. Sci. USA 93, 11074–11079 (1996)

    CAS  PubMed  Google Scholar 

  20. T. Ando, M. Imaizumi, P. Graves, P. Unger, T.F. Davies, Induction of thyroid-stimulating hormone receptor autoimmunity in hamsters. Endocrinol 144(2), 671–680 (2003)

    CAS  Google Scholar 

  21. S. Kaithamana, J. Fan, Y. Osuga, S.G. Liang, B.S. Prabhakar, Induction of experimental autoimmune Graves’ disease in BALB/c mice. J. Immunol. 163(9), 5157–5164 (1999)

    CAS  PubMed  Google Scholar 

  22. S. Costagliola, P. Rodien, M.-C. Many, M. Ludgate, G. Vassart, Genetic immunization against the human thyrotropin receptor causes thyroiditis and allows production of monoclonal antibodies recognizing the native receptor. J. Immunol. 160, 1458–1465 (1998)

    CAS  PubMed  Google Scholar 

  23. S.X. Zhao, S. Tsui, A. Cheung, R.S. Douglas, T.J. Smith, J.P. Banga, Orbital fibrosis in a mouse model of Graves’ disease induced by genetic immunization of thyrotropin receptor cDNA. J. Endocrinol. 210(3), 369–377 (2011)

    CAS  PubMed  PubMed Central  Google Scholar 

  24. T. Kaneda, A. Honda, A. Hakozaki, T. Fuse, A. Muto, T. Yoshida, An improved Graves’ disease model established by using in vivo electroporation exhibited long-term immunity to hyperthyroidism in BALB/c mice. Endocrinology 148(5), 2335–2344 (2007)

    CAS  PubMed  Google Scholar 

  25. Y. Nagayama, M. Kita-Furuyama, T. Ando, K. Nakao, H. Mizuguchi, T. Hayakawa, K. Eguchi, M. Niwa, A novel murine model of Graves’ hyperthyroidism with intramuscular injection of adenovirus expressing the thyrotropin receptor. J. Immunol. 168(6), 2789–2794 (2002)

    CAS  PubMed  Google Scholar 

  26. C.-R. Chen, P. Pichurin, Y. Nagayama, F. Latrofa, B. Rapoport, S.M. McLachlan, The thyrotropin receptor autoantigen in Graves’ disease is the culprit as well as the victim. J. Clin. Investig. 111(12), 1897–1904 (2003)

    CAS  PubMed  Google Scholar 

  27. S.M. McLachlan, B. Rapoport, Breaking tolerance to thyroid antigens: changing concepts in thyroid autoimmunity. Endocr. Rev. 35(1), 59–105 (2014)

    CAS  PubMed  Google Scholar 

  28. Y. Wang, L.P. Wu, J. Fu, H.J. Lv, X.Y. Guan, L. Xu, P. Chen, C.Q. Gao, P. Hou, M.J. Ji, B.Y. Shi, Hyperthyroid monkeys: a nonhuman primate model of experimental Graves’ disease. J. Endocrinol. 219(3), 183–193 (2013)

    CAS  PubMed  Google Scholar 

  29. G.D. Chazenbalk, P. Pichurin, C.R. Chen, F. Latrofa, A.P. Johnstone, S.M. McLachlan, B. Rapoport, Thyroid-stimulating autoantibodies in Graves disease preferentially recognize the free A subunit, not the thyrotropin holoreceptor. J. Clin. Invest. 110(2), 209–217 (2002)

    CAS  PubMed  PubMed Central  Google Scholar 

  30. Y. Mizutori, C.R. Chen, F. Latrofa, S.M. McLachlan, B. Rapoport, Evidence that shed TSH receptor A-subunits drive affinity maturation of autoantibodies causing Graves’ disease. J. Clin. Endocrinol. Metab. 94(3), 927–935 (2009)

    CAS  PubMed  Google Scholar 

  31. S.M. McLachlan, K. Alpi, B. Rapoport, Hypothesis and review: does Graves’ disease develop in non-human great apes? Thyroid 21(12), 1359–1366 (2011)

    CAS  PubMed  PubMed Central  Google Scholar 

  32. M.A. Wolfert, G.J. Boons, Adaptive immune activation: glycosylation does matter. Nat. Chem. Biol. 9(12), 776–784 (2013). https://doi.org/10.1038/nchembio.1403

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. B. Rapoport, H.A. Aliesky, B. Banuelos, C.R. Chen, S.M. McLachlan, A unique mouse strain that develops spontaneous, iodine-accelerated, pathogenic antibodies to the human thyrotrophin receptor. J. Immunol. 194(9), 4154–4161 (2015)

    CAS  PubMed  PubMed Central  Google Scholar 

  34. S.M. McLachlan, Y. Nagayama, P.N. Pichurin, Y. Mizutori, C.R. Chen, A. Misharin, H.A. Aliesky, B. Rapoport, The link between Graves’ disease and Hashimoto’s thyroiditis: a role for regulatory T cells. Endocrinology 148(12), 5724–5733 (2007)

    CAS  PubMed  Google Scholar 

  35. L. Rasooly, C.L. Burek, N.R. Rose, Iodine-induced autoimmune thyroiditis in NOD-H2h4 mice. Clin. Immunol. Immunopathol. 81, 287–292 (1996)

    CAS  PubMed  Google Scholar 

  36. H. Braley-Mullen, G.C. Sharp, B. Medling, H. Tang, Spontaneous autoimmune thyroiditis in NOD.H-2h4 mice. J. Autoimmun. 12(3), 157–165 (1999)

    CAS  PubMed  Google Scholar 

  37. P.R. Hutchings, S. Verma, J.M. Phillips, S.Z. Harach, S. Howlett, A. Cooke, Both CD4(+) T cells and CD8(+) T cells are required for iodine accelerated thyroiditis in NOD mice. Cell Immunol. 192(2), 113–121 (1999)

    CAS  PubMed  Google Scholar 

  38. C.R. Chen, S. Hamidi, H. Braley-Mullen, Y. Nagayama, C. Bresee, H.A. Aliesky, B. Rapoport, S.M. McLachlan, Antibodies to thyroid peroxidase arise spontaneously with age in NOD.H-2h4 mice and appear after thyroglobulin antibodies. Endocrinology 151(9), 4583–4593 (2010)

    CAS  PubMed  PubMed Central  Google Scholar 

  39. G.D. Chazenbalk, J.C. Jaume, S.M. McLachlan, B. Rapoport, Engineering the human thyrotropin receptor ectodomain from a non-secreted form to a secreted, highly immunoreactive glycoprotein that neutralizes autoantibodies in Graves’ patients’ sera. J. Biol. Chem. 272, 18959–18965 (1997)

    CAS  PubMed  Google Scholar 

  40. S.M. McLachlan, H. Aliesky, B. Rapoport, A mouse TSH receptor A-subunit transgene expressed in thyroiditis-prone mice may provide insight into why Graves’ disease only occurs in humans. Thyroid (2019). https://doi.org/10.1089/thy.2019.0260

    CAS  PubMed  Google Scholar 

  41. C.R. Chen, H. Aliesky, P.N. Pichurin, Y. Nagayama, S.M. McLachlan, B. Rapoport, Susceptibility rather than resistance to hyperthyroidism is dominant in a thyrotropin receptor adenovirus-induced animal model of Graves’ disease as revealed by BALB/c-C57BL/6 hybrid mice. Endocrinology 145, 4927–4933 (2004)

    CAS  PubMed  Google Scholar 

  42. B. Rapoport, R.W. Williams, C.R. Chen, S.M. McLachlan, Immunoglobulin heavy chain variable region genes contribute to the induction of thyroid stimulating antibodies in recombinant inbred mice. Genes Immun. 11(3), 254–263 (2010)

    CAS  PubMed  PubMed Central  Google Scholar 

  43. S.M. McLachlan, H. Braley-Mullen, C.R. Chen, H. Aliesky, P.N. Pichurin, B. Rapoport, Dissociation between iodide-induced thyroiditis and antibody-mediated hyperthyroidism in NOD.H-2h4 mice. Endocrinology 146, 294–300 (2005)

    CAS  PubMed  Google Scholar 

  44. M. Dedecjus, M. Stasiolek, J. Brzezinski, K. Selmaj, A. Lewinski, Thyroid hormones influence human dendritic cells’ phenotype, function, and subsets distribution. Thyroid 21(5), 533–540 (2011)

    CAS  PubMed  Google Scholar 

  45. C. Mao, S. Wang, Y. Xiao, J. Xu, Q. Jiang, M. Jin, X. Jiang, H. Guo, G. Ning, Y. Zhang, Impairment of regulatory capacity of CD4+CD25+ regulatory T cells mediated by dendritic cell polarization and hyperthyroidism in Graves’ disease. J. Immunol. 186(8), 4734–4743 (2011)

    CAS  PubMed  Google Scholar 

  46. M.D.M. Montesinos, C. Pellizas, Thyroid hormone action on innate immunity. Front. Endocrinol. (Lausanne) 10, 350 (2019). https://doi.org/10.3389/fendo.2019.00350

    Article  Google Scholar 

  47. H.J. Lee, C.W. Li, S.S. Hammerstad, M. Stefan, Y. Tomer, Immunogenetics of autoimmune thyroid diseases: a comprehensive review. J. Autoimmun. 64, 82–90 (2015)

    CAS  PubMed  PubMed Central  Google Scholar 

  48. S.M. McLachlan, H. Aliesky, B. Banuelos, J. Magana, R.W. Williams, B. Rapoport, Immunoglobulin heavy chain variable region and major histocompatibility region genes are linked to induced graves’ disease in females from two very large families of recombinant inbred mice. Endocrinology 155(10), 4094–4103 (2014)

    PubMed  PubMed Central  Google Scholar 

  49. F. Latrofa, G.D. Chazenbalk, P. Pichurin, C.-R. Chen, S.M. McLachlan, B. Rapoport, Characterization of TSH receptor autoantibodies affinity-enriched to near purity from the serum of Graves’ patients. Thyroid 13(7), 734–734 (2003)

    Google Scholar 

  50. A.P. Weetman, M.E. Yateman, P.A. Ealey, C.M. Black, C.B. Reimer, R.C. Williams Jr. B. Shine, N.J. Marshall, Thyroid-stimulating antibody activity between different immunoglobulin G subclasses. J. Clin. Invest. 86, 723–727 (1990)

    CAS  PubMed  PubMed Central  Google Scholar 

  51. B. Rapoport, S.M. McLachlan, Graves’ hyperthyroidism is antibody-mediated but is predominantly a Th1-type cytokine disease. J. Clin. Endocrinol. Metab. 99(11), 4060–4061 (2014). https://doi.org/10.1210/jc.2014-3011

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Y. Nagayama, O. Saitoh, S.M. McLachlan, B. Rapoport, H. Kano, Y. Kumazawa, TSHR receptor-adenovirus-induced Graves’ hyperthyroidism is attenuated in both interferon-g and interleukin-4 knockout mice: Implications for the Th1/Th2 paradigm. Clin. Exp. Immunol. 138, 417–422 (2004)

    CAS  PubMed  PubMed Central  Google Scholar 

  53. O. Saitoh, Y. Mizutori, N. Takamura, H. Yamasaki, A. Kita, H. Kuwahara, Y. Nagayama, Adenovirus-mediated gene delivery of interleukin-10, but not transforming growth factor beta, ameliorates the induction of Graves’ hyperthyroidism in BALB/c mice. Clin. Exp. Immunol. 141(3), 405–411 (2005)

    CAS  PubMed  PubMed Central  Google Scholar 

  54. J.W. Kappler, N. Roehm, P. Marrack, T cell tolerance by clonal elimination in the thymus. Cell 49(2), 273–280 (1987)

    CAS  PubMed  Google Scholar 

  55. M. Stefan, C. Wei, A. Lombardi, C.W. Li, E.S. Concepcion, W.B. Inabnet III, R. Owen, W. Zhang, Y. Tomer, Genetic-epigenetic dysregulation of thymic TSH receptor gene expression triggers thyroid autoimmunity. Proc. Natl Acad. Sci. USA 111(34), 12562–12567 (2014)

    CAS  PubMed  Google Scholar 

  56. R. Colobran, M.P. Armengol, R. Faner, M. Gartner, L.O. Tykocinski, A. Lucas, M. Ruiz, M. Juan, B. Kyewski, R. Pujol-Borrell, Association of an SNP with intrathymic transcription of TSHR and Graves’ disease: a role for defective thymic tolerance. Hum. Mol. Genet. 20(17), 3415–3423 (2011)

    CAS  PubMed  Google Scholar 

  57. M. Nakahara, N. Mitsutake, H. Sakamoto, C.R. Chen, B. Rapoport, S.M. McLachlan, Y. Nagayama, Enhanced response to mouse thyroid-stimulating hormone (TSH) receptor immunization in TSH receptor-knockout mice. Endocrinology 151(8), 4047–4054 (2010)

    CAS  PubMed  Google Scholar 

  58. A. Schluter, M. Horstmann, S. Diaz-Cano, S. Plohn, K. Stahr, S. Mattheis, M. Oeverhaus, S. Lang, U. Flogel, U. Berchner-Pfannschmidt, A. Eckstein, J.P. Banga, Genetic immunization with mouse thyrotrophin hormone receptor plasmid breaks self-tolerance for a murine model of autoimmune thyroid disease and Graves’ orbitopathy. Clin. Exp. Immunol. 191(3), 255–267 (2018). https://doi.org/10.1111/cei.13075

    Article  CAS  PubMed  Google Scholar 

  59. A.V. Misharin, Y. Nagayama, H.A. Aliesky, B. Rapoport, S.M. McLachlan, Studies in mice deficient for the autoimmune regulator (Aire) and transgenic for the thyrotropin receptor reveal a role for Aire in tolerance for thyroid autoantigens. Endocrinology 150(6), 2948–2956 (2009)

    CAS  PubMed  PubMed Central  Google Scholar 

  60. S.M. McLachlan, H.A. Aliesky, B. Banuelos, S. Lesage, R. Collin, B. Rapoport, High-level intrathymic thyrotrophin receptor expression in thyroiditis-prone mice protects against the spontaneous generation of pathogenic thyrotrophin receptor autoantibodies. Clin. Exp. Immunol. 188(2), 243–253 (2017)

    CAS  PubMed  PubMed Central  Google Scholar 

  61. C.-R. Chen, P. Pichurin, G.D. Chazenbalk, H. Aliesky, Y. Nagayama, S.M. McLachlan, B. Rapoport, 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 145(1), 228–233 (2004)

    CAS  PubMed  Google Scholar 

  62. H.L. Kohling, S.F. Plummer, J.R. Marchesi, K.S. Davidge, M. Ludgate, The microbiota and autoimmunity: their role in thyroid autoimmune diseases. Clin. Immunol. 183, 63–74 (2017). https://doi.org/10.1016/j.clim.2017.07.001

    Article  CAS  PubMed  Google Scholar 

  63. S. Moshkelgosha, G. Masetti, U. Berchner-Pfannschmidt, H.L. Verhasselt, M. Horstmann, S. Diaz-Cano, A. Noble, B. Edelman, D. Covelli, S. Plummer, J.R. Marchesi, M. Ludgate, F. Biscarini, A. Eckstein, J.P. Banga, Gut microbiome in BALB/c and C57BL/6J mice undergoing experimental thyroid autoimmunity associate with differences in immunological responses and thyroid function. Horm. Metab. Res. 50(12), 932–941 (2018). https://doi.org/10.1055/a-0653-3766

    Article  CAS  PubMed  Google Scholar 

  64. K. Rubtsova, P. Marrack, A.V. Rubtsov, Sexual dimorphism in autoimmunity. J. Clin. Invest. 125(6), 2187–2193 (2015)

    PubMed  PubMed Central  Google Scholar 

  65. N. Manji, J.D. Carr-Smith, K. Boelaert, A. Allahabadia, M. Armitage, V.K. Chatterjee, J.H. Lazarus, S.H. Pearce, B. Vaidya, S.C. Gough, J.A. Franklyn, Influences of age, gender, smoking, and family history on autoimmune thyroid disease phenotype. J. Clin. Endocrinol. Metab. 91(12), 4873–4880 (2006). https://doi.org/10.1210/jc.2006-1402

    Article  CAS  PubMed  Google Scholar 

  66. J.C. Jaume, B. Rapoport, S.M. McLachlan, Lack of female bias in a mouse model of autoimmune hyperthyroidism (Graves’ disease). Autoimmunity 29(4), 269–272 (1999)

    CAS  PubMed  Google Scholar 

  67. B. Rapoport, H.A. Aliesky, C.R. Chen, S.M. McLachlan, Evidence that TSH receptor A-subunit multimers, not monomers, drive antibody affinity maturation in Graves’ disease. J. Clin. Endocrinol. Metab. 100(6), E871–E875 (2015)

    CAS  PubMed  PubMed Central  Google Scholar 

  68. C.R. Chen, P.A. Hubbard, L.M. Salazar, S.M. McLachlan, R. Murali, B. Rapoport, Crystal structure of a TSH receptor monoclonal antibody: insight into Graves’ disease pathogenesis. Mol. Endocrinol. 29(1), 99–107 (2015)

    PubMed  Google Scholar 

  69. J. Sanders, D.Y. Chirgadze, P. Sanders, S. Baker, A. Sullivan, A. Bhardwaja, J. Bolton, M. Reeve, N. Nakatake, M. Evans, T. Richards, M. Powell, R.N. Miguel, T.L. Blundell, J. Furmaniak, B.R. Smith, Crystal structure of the TSH receptor in complex with a thyroid-stimulating autoantibody. Thyroid 17(5), 395–410 (2007)

    CAS  PubMed  Google Scholar 

  70. J.A. Gilbert, S.L. Kalled, J. Moorhead, D.M. Hess, P. Rennert, Z. Li, M.Z. Khan, J.P. Banga, 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 147(10), 4561–4568 (2006)

    CAS  PubMed  Google Scholar 

  71. A.K. Shakya, K.S. Nandakumar, Antigen-specific tolerization and targeted delivery as therapeutic Strategies for Autoimmune Diseases. Trends Biotechnol. 36(7), 686–699 (2018). https://doi.org/10.1016/j.tibtech.2018.02.008

    Article  CAS  PubMed  Google Scholar 

  72. L. Wu, L. Xun, J. Yang, L. Xu, Z. Tian, S. Gao, Y. Zhang, P. Hou, B. Shi, Induction of murine neonatal tolerance against Graves’ disease using recombinant adenovirus expressing the TSH receptor A-subunit. Endocrinology 152(3), 1165–1171 (2011)

    CAS  PubMed  Google Scholar 

  73. H.P. Holthoff, Z. Li, J. Fassbender, A. Reimann, K. Adler, G. Munch, M. Ungerer, Cyclic peptides for effective treatment in a long-term model of Graves disease and orbitopathy in female mice. Endocrinology 158(7), 2376–2390 (2017). https://doi.org/10.1210/en.2016-1845

    Article  PubMed  Google Scholar 

  74. J. Fassbender, H. P. Holthoff, Z. Li, M. Ungerer, Therapeutic effects of short cyclic and combined epitope peptides in a long-term model of Graves disease and orbitopathy. Thyroid (2019). https://doi.org/10.1089/thy.2018.0326

    PubMed  Google Scholar 

  75. L. Jansson, K. Vrolix, A. Jahraus, K.F. Martin, D.C. Wraith, Immunotherapy with apitopes blocks the immune response to TSH receptor in HLA-DR transgenic mice. Endocrinology 159(9), 3446–3457 (2018). https://doi.org/10.1210/en.2018-00306

    Article  PubMed  Google Scholar 

  76. B. Rapoport, B. Banuelos, H.A. Aliesky, N. Hartwig Trier, S.M. McLachlan, Critical differences between induced and spontaneous mouse models of Graves’ disease with implications for antigen-specific immunotherapy in humans. J. Immunol. 197, 4560–4568 (2016)

    CAS  PubMed  PubMed Central  Google Scholar 

  77. A.M. McGregor, M.M. Petersen, R. Capiferri, D.C. Evered, B.R. Smith, R. Hall, Effects of radioiodine on thyrotrophin binding inhibiting immunoglobulins in Graves’ disease. Clin. Endocrinol. 11(4), 437–444 (1979)

    CAS  Google Scholar 

  78. N. Nakazato, K. Yoshida, K. Mori, Y. Kiso, N. Sayama, J.I. Tani, Y. Nakagawa, S. Ito, Antithyroid drugs inhibit radioiodine-induced increases in thyroid autoantibodies in hyperthyroid Graves’ disease. Thyroid 9(8), 775–779 (1999). https://doi.org/10.1089/thy.1999.9.775

    Article  CAS  PubMed  Google Scholar 

  79. A. Yeste, M.C. Takenaka, I.D. Mascanfroni, M. Nadeau, J.E. Kenison, B. Patel, A.M. Tukpah, J.A. Babon, M. DeNicola, S.C. Kent, D. Pozo, F.J. Quintana, Tolerogenic nanoparticles inhibit T cell-mediated autoimmunity through SOCS2. Sci. Signal. 9(433), ra61 (2016)

    PubMed  Google Scholar 

  80. A. Yeste, M. Nadeau, E.J. Burns, H.L. Weiner, F.J. Quintana, Nanoparticle-mediated codelivery of myelin antigen and a tolerogenic small molecule suppresses experimental autoimmune encephalomyelitis. Proc. Natl Acad. Sci. USA 109(28), 11270–11275 (2012). https://doi.org/10.1073/pnas.1120611109

    Article  PubMed  Google Scholar 

  81. S.M. McLachlan, H.A. Aliesky, B. Rapoport, T.S.H. Nanoparticles Bearing, Receptor protein and a tolerogenic molecule do not induce immune tolerance but exacerbate thyroid autoimmunity in hTSHR/NOD.H2(h4) mice. J. Immunol. 202(9), 2570–2577 (2019). https://doi.org/10.4049/jimmunol.1900038

    Article  CAS  PubMed  Google Scholar 

  82. S.H.S. Pearce, C. Dayan, D.C. Wraith, K. Barrell, N. Olive, L. Jansson, T. Walker-Smith, C. Carnegie, K.F. Martin, K. Boelaert, J. Gilbert, C.E. Higham, I. Muller, R.D. Murray, P. Perros, S. Razvi, B. Vaidya, F. Wernig, G.J. Kahaly, Antigen-specific immunotherapy with thyrotropin receptor peptides in Graves’ hyperthyroidism: a phase I study. Thyroid (2019). https://doi.org/10.1089/thy.2019.0036

    CAS  PubMed  PubMed Central  Google Scholar 

  83. A.J. Coles, M. Wing, S. Smith, F. Coraddu, S. Greer, C. Taylor, A. Weetman, G. Hale, V.K. Chatterjee, H. Waldmann, A. Compston, Pulsed monoclonal antibody treatment and autoimmune thyroid disease in multiple sclerosis. Lancet 354(9191), 1691–1695 (1999)

    CAS  PubMed  Google Scholar 

  84. C.B. Smarr, W.T. Yap, T.P. Neef, R.M. Pearson, Z.N. Hunter, I. Ifergan, D.R. Getts, P.J. Bryce, L.D. Shea, S.D. Miller, Biodegradable antigen-associated PLG nanoparticles tolerize Th2-mediated allergic airway inflammation pre- and postsensitization. Proc. Natl Acad. Sci. USA 113(18), 5059–5064 (2016). https://doi.org/10.1073/pnas.1505782113

    Article  CAS  PubMed  Google Scholar 

  85. D.P. McCarthy, J.W. Yap, C.T. Harp, W.K. Song, J. Chen, R.M. Pearson, S.D. Miller, L.D. Shea, An antigen-encapsulating nanoparticle platform for TH1/17 immune tolerance therapy. Nanomedicine 13(1), 191–200 (2017). https://doi.org/10.1016/j.nano.2016.09.007

    Article  CAS  PubMed  Google Scholar 

  86. S.M. McLachlan, B. Rapoport, Thyroid autoantibodies display both “original antigenic sin” and epitope spreading. Front. Immunol. 8, 1845 (2017). https://doi.org/10.3389/fimmu.2017.01845.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Medicine, University of California Los Angeles, 100 Medical Plaza Driveway, Los Angeles, CA, 90095, USA

    Sandra M. McLachlan & Basil Rapoport

Authors
  1. Sandra M. McLachlan
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Basil Rapoport
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Basil Rapoport.

Ethics declarations

Conflict of interest

The authors declare that they have no conflict of interest.

Additional information

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

McLachlan, S.M., Rapoport, B. A transgenic mouse that spontaneously develops pathogenic TSH receptor antibodies will facilitate study of antigen-specific immunotherapy for human Graves’ disease. Endocrine 66, 137–148 (2019). https://doi.org/10.1007/s12020-019-02083-9

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12020-019-02083-9

Keywords

Search

Navigation