Download PDF
Horm Metab Res 2023; 55(11): 745-751
DOI: 10.1055/a-2161-5417
Review

Graves’ Orbitopathy Models: Valuable Tools for Exploring Pathogenesis and Treatment

Ling Wang 
1   Department of Endocrinology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
,
Meng Zhang
1   Department of Endocrinology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
,
Yue Wang
1   Department of Endocrinology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
,
Bingyin Shi
1   Department of Endocrinology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
› Author Affiliations Funding Information National Natural Science Foundation of China – http://dx.doi.org/10.13039/501100001809; 81970679 Natural Science Foundation of Shaanxi Province – http://dx.doi.org/10.13039/501100007128; 2018JM70990
› Further Information
Also available at
   Permissions and Reprints

Abstract

Graves’ orbitopathy (GO) is the most common extrathyroidal complication of Graves’ disease (GD) and severely affects quality of life. However, its pathogenesis is still poorly understood, and therapeutic options are limited. Animal models are important tools for preclinical research. The animals in some previous models only exhibited symptoms of hyperthyroidism without ocular lesions. With the improvements achieved in modeling methods, some progressive animal models have been established. Immunization of mice with A subunit of the human thyroid stimulating hormone receptor (TSHR) by either adenovirus or plasmid (with electroporation) is widely used and convincing. These models are successful to identify that the gut microbiota influences the occurrence and severity of GD and GO, and sex-related risk factors may be key contributors to the female bias in the occurrence of GO rather than sex itself. Some data provide insight that macrophages and CD8+ T cells may play an important pathogenic role in the early stage of GO. Our team also replicated the time window from GD onset to GO onset and identified a group of CD4+ cytotoxic T cells. In therapeutic exploration, TSHR derived peptides, fingolimod, and rapamycin offer new potential options. Further clinical trials are needed to investigate these drugs. With the increasing use of these animal models and more in-depth studies of the new findings, scientists will gain a clearer understanding of the pathogenesis of GO and identify more treatments for patients.

Key words

Graves’ orbitopathy - animal model - plasmid - adenovirus - TSHR A subunit


Publication History

Received: 20 June 2023

Accepted after revision: 21 August 2023

Article published online:
30 October 2023

© 2023. Thieme. All rights reserved.

Georg Thieme Verlag KG
Rüdigerstraße 14, 70469 Stuttgart, Germany

 

  • References

  • 1 Bartalena L, Fatourechi V. Extrathyroidal manifestations of Graves' disease: a 2014 update. J Endocrinol Invest 2014; 37: 691-700
    CrossrefPubMedGoogle Scholar
  • 2 Bartalena L, Baldeschi L, Boboridis K. et al. The 2016 European thyroid association/European group on Graves' orbitopathy guidelines for the management of Graves' orbitopathy. Eur Thyroid J 2016; 5: 9-26
    CrossrefPubMedGoogle Scholar
  • 3 Fang S, Lu Y, Huang Y. et al. Mechanisms that underly T cell immunity in Graves' orbitopathy. Front Endocrinol 2021; 12: 648732
    CrossrefPubMedGoogle Scholar
  • 4 Bahn RS. Graves' ophthalmopathy. N Engl J Med 2010; 362: 726-738
    CrossrefPubMedGoogle Scholar
  • 5 Bartley GB. The epidemiologic characteristics and clinical course of ophthalmopathy associated with autoimmune thyroid disease in Olmsted County, Minnesota. Trans Am Ophthalmol Soc 1994; 92: 477-588
    PubMedGoogle Scholar
  • 6 Eckstein AK, Losch C, Glowacka D. et al. Euthyroid and primarily hypothyroid patients develop milder and significantly more asymmetrical Graves ophthalmopathy. Br J Ophthalmol 2009; 93: 1052-1056
    CrossrefPubMedGoogle Scholar
  • 7 Farid M, Roch-Levecq AC, Levi L. et al. Psychological disturbance in Graves ophthalmopathy. Arch Ophthalmol 2005; 123: 491-496
    CrossrefPubMedGoogle Scholar
  • 8 Abraham-Nordling M, Wallin G, Traisk F. et al. Thyroid-associated ophthalmopathy; quality of life follow-up of patients randomized to treatment with antithyroid drugs or radioiodine. Eur J Endocrinol 2010; 163: 651-657
    CrossrefPubMedGoogle Scholar
  • 9 Taylor PN, Zhang L, Lee RWJ. et al. New insights into the pathogenesis and nonsurgical management of Graves orbitopathy. Nat Rev Endocrinol 2020; 16: 104-116
    CrossrefPubMedGoogle Scholar
  • 10 Kahaly GJ, Petrak F, Hardt J. et al. Psychosocial morbidity of Graves' orbitopathy. Clin Endocrinol (Oxf) 2005; 63: 395-402
    CrossrefPubMedGoogle Scholar
  • 11 Wiersinga WM. Advances in treatment of active, moderate-to-severe Graves' ophthalmopathy. Lancet Diabetes Endocrinol 2017; 5: 134-142
    CrossrefPubMedGoogle Scholar
  • 12 Genere N, Stan MN. Current and emerging treatment strategies for Graves' orbitopathy. Drugs 2019; 79: 109-124
    CrossrefPubMedGoogle Scholar
  • 13 Smith TJ, Kahaly GJ, Ezra DG. et al. Teprotumumab for thyroid-associated ophthalmopathy. N Engl J Med 2017; 376: 1748-1761
    CrossrefPubMedGoogle Scholar
  • 14 Douglas RS, Kahaly GJ, Patel A. et al. Teprotumumab for the treatment of active thyroid eye disease. N Engl J Med 2020; 382: 341-352
    CrossrefPubMedGoogle Scholar
  • 15 Winn BJ, Kersten RC. Teprotumumab: interpreting the clinical trials in the context of thyroid eye disease pathogenesis and current therapies. Ophthalmology 2021; 128: 1627-1651
    CrossrefPubMedGoogle Scholar
  • 16 Salvi M, Vannucchi G, Curro N. et al. Efficacy of B-cell targeted therapy with rituximab in patients with active moderate to severe Graves' orbitopathy: a randomized controlled study. J Clin Endocrinol Metab 2015; 100: 422-431
    CrossrefPubMedGoogle Scholar
  • 17 Stan MN, Garrity JA, Carranza Leon BG. et al. Randomized controlled trial of rituximab in patients with Graves' orbitopathy. J Clin Endocrinol Metab 2015; 100: 432-441
    CrossrefPubMedGoogle Scholar
  • 18 Perez-Moreiras JV, Gomez-Reino JJ, Maneiro JR. et al. Efficacy of tocilizumab in patients with moderate-to-severe corticosteroid-resistant Graves orbitopathy: a randomized clinical trial. Am J Ophthalmol 2018; 195: 181-190
    CrossrefPubMedGoogle Scholar
  • 19 Rajendram R, Taylor PN, Wilson VJ. et al. Combined immunosuppression and radiotherapy in thyroid eye disease (CIRTED): a multicentre, 2 x 2 factorial, double-blind, randomised controlled trial. Lancet Diabetes Endocrinol 2018; 6: 299-309
    CrossrefPubMedGoogle Scholar
  • 20 Khong JJ, McNab AA, Ebeling PR. et al. Pathogenesis of thyroid eye disease: review and update on molecular mechanisms. Br J Ophthalmol 2016; 100: 142-150
    CrossrefPubMedGoogle Scholar
  • 21 Dik WA, Virakul S, van Steensel L. Current perspectives on the role of orbital fibroblasts in the pathogenesis of Graves' ophthalmopathy. Exp Eye Res 2016; 142: 83-91
    CrossrefPubMedGoogle Scholar
  • 22 Weightman DR, Perros P, Sherif IH. et al. Autoantibodies to IGF-1 binding-sites in thyroid-associated ophthalmopathy. Autoimmunity 1993; 16: 251-257
    CrossrefPubMedGoogle Scholar
  • 23 Feliciello A, Porcellini A, Ciullo I. et al. Expression of thyrotropin-receptor messenger-RNA in healthy and Graves-disease retro-orbital tissue. Lancet 1993; 342: 337-338
    CrossrefPubMedGoogle Scholar
  • 24 Pritchard J, Han R, Horst N. et al. 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: 6348-6354
    CrossrefPubMedGoogle Scholar
  • 25 Douglas RS, Naik V, Hwang CJ. et al. B cells from patients with Graves' disease aberrantly express the IGF-1 receptor: implications for disease pathogenesis. J Immunol 2008; 181: 5768-5774
    CrossrefPubMedGoogle Scholar
  • 26 Smith TJ. TSH-receptor-expressing fibrocytes and thyroid-associated ophthalmopathy. Nat Rev Endocrinol 2015; 11: 171-181
    CrossrefPubMedGoogle Scholar
  • 27 Pappa A, Lawson JM, Calder V. et al. T cells and fibroblasts in affected extraocular muscles in early and late thyroid associated ophthalmopathy. Br J Ophthalmol 2000; 84: 517-522
    CrossrefPubMedGoogle Scholar
  • 28 Xia N, Zhou S, Liang Y. et al. CD4+ T cells and the Th1/Th2 imbalance are implicated in the pathogenesis of Graves' ophthalmopathy. Int J Mol Med 2006; 17: 911-916
    PubMedGoogle Scholar
  • 29 Han R, Smith TJ. T helper type 1 and type 2 cytokines exert divergent influence on the induction of prostaglandin E2 and hyaluronan synthesis by interleukin-1beta in orbital fibroblasts: implications for the pathogenesis of thyroid-associated ophthalmopathy. Endocrinology 2006; 147: 13-19
    CrossrefPubMedGoogle Scholar
  • 30 Huang Y, Fang S, Li D. et al. The involvement of T cell pathogenesis in thyroid-associated ophthalmopathy. Eye (Lond) 2019; 33: 176-182
    CrossrefPubMedGoogle Scholar
  • 31 Fang S, Huang Y, Wang S. et al. IL-17A exacerbates fibrosis by promoting the proinflammatory and profibrotic function of orbital fibroblasts in TAO. J Clin Endocrinol Metab 2016; 101: 2955-2965
    CrossrefPubMedGoogle Scholar
  • 32 Fang S, Huang Y, Zhong S. et al. Regulation of orbital fibrosis and adipogenesis by pathogenic Th17 cells in Graves orbitopathy. J Clin Endocrinol Metab 2017; 102: 4273-4283
    CrossrefPubMedGoogle Scholar
  • 33 Wang Y, Chen Z, Wang T. et al. A novel CD4+ CTL subtype characterized by chemotaxis and inflammation is involved in the pathogenesis of Graves' orbitopathy. Cell Mol Immunol 2021; 18: 735-745
    CrossrefPubMedGoogle Scholar
  • 34 Eckstein AK, Plicht M, Lax H. et al. Thyrotropin receptor autoantibodies are independent risk factors for graves' ophthalmopathy and help to predict severity and outcome of the disease. J Clin Endocrinol Metab 2006; 91: 3464-3470
    CrossrefPubMedGoogle Scholar
  • 35 Stohr M, Oeverhaus M, Lytton SD. et al. Predicting the relapse of hyperthyroidism in treated Graves' disease with orbitopathy by serial measurements of TSH-receptor autoantibodies. Horm Metab Res 2021; 53: 235-244
    Article in Thieme ConnectPubMedGoogle Scholar
  • 36 Stohr M, Oeverhaus M, Lytton SD. et al. Predicting the course of Graves' orbitopathy using serially measured TSH-receptor autoantibodies by automated binding immunoassays and the functional bioassay. Horm Metab Res 2021; 53: 435-443
    Article in Thieme ConnectPubMedGoogle Scholar
  • 37 Ludgate M, Baker G. Inducing Graves' ophthalmopathy. J Endocrinol Invest 2004; 27: 211-215
    CrossrefPubMedGoogle Scholar
  • 38 Smelser GK. Experimental production of exophthalmos resembling that found in Graves disease. Proc Soc Exp Biol Med 1936; 35: 128-130
    CrossrefPubMedGoogle Scholar
  • 39 Many MC, Costagliola S, Detrait M. et al. Development of an animal model of autoimmune thyroid eye disease. J Immunol 1999; 162: 4966-4974
    CrossrefPubMedGoogle Scholar
  • 40 Baker G, Mazziotti G, von Ruhland C. et al. Reevaluating thyrotropin receptor-induced mouse models of Graves' disease and ophthalmopathy. Endocrinology 2005; 146: 835-844
    CrossrefPubMedGoogle Scholar
  • 41 Costagliola S, Many MC, Denef JF. et al. Genetic immunization of outbred mice with thyrotropin receptor cDNA provides a model of Graves' disease. J Clin Invest 2000; 105: 803-811
    CrossrefPubMedGoogle Scholar
  • 42 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
    CrossrefPubMedGoogle Scholar
  • 43 Johnson KTM, Wiesweg B, Schott M. et al. Examination of orbital tissues in murine models of Graves' disease reveals expression of UCP-1 and the TSHR in retrobulbar adipose tissues. Horm Metab Res 2013; 45: 401-407
    Article in Thieme ConnectPubMedGoogle Scholar
  • 44 Loosfelt H, Pichon C, Jolivet A. et al. Two-subunit structure of the human thyrotropin receptor. Proc Natl Acad Sci U S A 1992; 89: 3765-3769
    CrossrefPubMedGoogle Scholar
  • 45 Paschke R, Ludgate M. The thyrotropin receptor in thyroid diseases. N Engl J Med 1997; 337: 1675-1681
    CrossrefPubMedGoogle Scholar
  • 46 Chen CR, Hubbard PA, Salazar LM. et al. Crystal structure of a TSH receptor monoclonal antibody: insight into Graves' disease pathogenesis. Mol Endocrinol 2015; 29: 99-107
    CrossrefPubMedGoogle Scholar
  • 47 Chen CR, Pichurin P, Nagayama Y. et al. The thyrotropin receptor autoantigen in Graves disease is the culprit as well as the victim. J Clin Invest 2003; 111: 1897-1904
    CrossrefPubMedGoogle Scholar
  • 48 Kaneda T, Honda A, Hakozaki A. et al. An improved Graves' disease model established by using in vivo electroporation exhibited long-term immunity to hyperthyroidism in BALB/c mice. Endocrinology 2007; 148: 2335-2344
    CrossrefPubMedGoogle Scholar
  • 49 Zhao SX, Tsui S, Cheung A. et al. Orbital fibrosis in a mouse model of Graves' disease induced by genetic immunization of thyrotropin receptor cDNA. J Endocrinol 2011; 210: 369-377
    CrossrefPubMedGoogle Scholar
  • 50 Moshkelgosha S, So PW, Deasy N. et al. Cutting edge: retrobulbar inflammation, adipogenesis, and acute orbital congestion in a preclinical female mouse model of Graves' orbitopathy induced by thyrotropin receptor plasmid-in vivo electroporation. Endocrinology 2013; 154: 3008-3015
    CrossrefPubMedGoogle Scholar
  • 51 Berchner-Pfannschmidt U, Moshkelgosha S, Diaz-Cano S. et al. Comparative assessment of female mouse model of Graves' orbitopathy under different environments, accompanied by proinflammatory cytokine and T-cell responses to thyrotropin hormone receptor antigen. Endocrinology 2016; 157: 1673-1682
    CrossrefPubMedGoogle Scholar
  • 52 Masetti G, Moshkelgosha S, Kohling HL. et al. Gut microbiota in experimental murine model of Graves' orbitopathy established in different environments may modulate clinical presentation of disease. Microbiome 2018; 6: 97
    CrossrefPubMedGoogle Scholar
  • 53 Moshkelgosha S, Verhasselt HL, Masetti G. et al. Modulating gut microbiota in a mouse model of Graves' orbitopathy and its impact on induced disease. Microbiome 2021; 9: 45
    CrossrefPubMedGoogle Scholar
  • 54 Dagdelen S, Kong YC, Banga JP. Toward better models of hyperthyroid Graves' disease. Endocrinol Metab Clin North Am 2009; 38: 343-354 viii
    CrossrefPubMedGoogle Scholar
  • 55 Nagayama Y, Kita-Furuyama M, Ando T. et al. A novel murine model of Graves' hyperthyroidism with intramuscular injection of adenovirus expressing the thyrotropin receptor. J Immunol 2002; 168: 2789-2794
    CrossrefPubMedGoogle Scholar
  • 56 Chen CR, Pichurin P, Chazenbalk GD. 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
    CrossrefPubMedGoogle Scholar
  • 57 McLachlan SM, Aliesky HA, Chen CR. et al. Role of self-tolerance and chronic stimulation in the long-term persistence of adenovirus-induced thyrotropin receptor antibodies in wild-type and transgenic mice. Thyroid 2012; 22: 931-937
    CrossrefPubMedGoogle Scholar
  • 58 Holthoff HP, Goebel S, Li Z. et al. Prolonged TSH receptor A subunit immunization of female mice leads to a long-term model of Graves' disease, tachycardia, and cardiac hypertrophy. Endocrinology 2015; 156: 1577-1589
    CrossrefPubMedGoogle Scholar
  • 59 Jabbar A, Pingitore A, Pearce SH. et al. Thyroid hormones and cardiovascular disease. Nat Rev Cardiol 2017; 14: 39-55
    CrossrefPubMedGoogle Scholar
  • 60 Holthoff HP, Li Z, Fassbender J. et al. Cyclic peptides for effective treatment in a long-term model of Graves disease and orbitopathy in female mice. Endocrinology 2017; 158: 2376-2390
    CrossrefPubMedGoogle Scholar
  • 61 Fassbender J, Holthoff HP, Li ZM. et al. Therapeutic effects of short cyclic and combined epitope peptides in a long-term model of Graves' disease and orbitopathy. Thyroid 2019; 29: 258-267
    CrossrefPubMedGoogle Scholar
  • 62 Diana T, Ungerer M, Wuster C. et al. A cyclic peptide significantly improves thyroid function, thyrotropin-receptor antibodies and orbital mucine /collagen content in a long-term Graves' disease mouse model. J Autoimmun 2021; 122: 102666
    CrossrefPubMedGoogle Scholar
  • 63 Zhang M, Ding X, Wu LP. et al. A promising mouse model of Graves' orbitopathy induced by adenovirus expressing thyrotropin receptor A subunit. Thyroid 2021; 31: 638-648
    CrossrefPubMedGoogle Scholar
  • 64 Zhang M, Chong KKL, Chen Z-y. et al. Rapamycin improves Graves’ orbitopathy by suppressing CD4+ cytotoxic T lymphocytes. JCI Insight 2023; 8: e160377
    CrossrefPubMedGoogle Scholar
  • 65 Laukens D, Brinkman BM, Raes J. et al. Heterogeneity of the gut microbiome in mice: guidelines for optimizing experimental design. FEMS Microbiol Rev 2016; 40: 117-132
    CrossrefPubMedGoogle Scholar
  • 66 Moshkelgosha S, Masetti G, Berchner-Pfannschmidt U. et al. 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 2018; 50: 932-941
    Article in Thieme ConnectPubMedGoogle Scholar
  • 67 Ishaq HM, Mohammad IS, Shahzad M. et al. Molecular alteration analysis of human gut microbial composition in Graves' disease patients. Int J Biol Sci 2018; 14: 1558-1570
    CrossrefPubMedGoogle Scholar
  • 68 Shi TT, Xin Z, Hua L. et al. Alterations in the intestinal microbiota of patients with severe and active Graves' orbitopathy: a cross-sectional study. J Endocrinol Invest 2019; 42: 967-978
    CrossrefPubMedGoogle Scholar
  • 69 Shi TT, Xin Z, Hua L. et al. Comparative assessment of gut microbial composition and function in patients with Graves' disease and Graves' orbitopathy. J Endocrinol Invest 2021; 44: 297-310
    CrossrefPubMedGoogle Scholar
  • 70 Su XH, Yin XL, Liu Y. et al. Gut dysbiosis contributes to the imbalance of Treg and Th17 Cells in Graves' disease patients by propionic acid. J Clin Endocrinol Metab 2020; 105
    PubMedGoogle Scholar
  • 71 Kendler DL, Lippa J, Rootman J. The initial clinical characteristics of Graves orbitopathy vary with age and sex. Arch Ophthalmol 1993; 111: 197-201
    CrossrefPubMedGoogle Scholar
  • 72 Bartalena L, Piantanida E, Gallo D. et al. Epidemiology, natural history, risk factors, and prevention of Graves' orbitopathy. Front Endocrinol 2020; 11
    PubMedGoogle Scholar
  • 73 Schluter A, Flogel U, Diaz-Cano S. et al. Graves' orbitopathy occurs sex-independently in an autoimmune hyperthyroid mouse model. Sci Rep 2018; 8: 13096
    CrossrefPubMedGoogle Scholar
  • 74 Philipp S, Horstmann M, Hose M. et al. An early wave of macrophage infiltration intertwined with antigen-specific proinflammatory T cells and browning of adipose tissue characterizes the onset of orbital inflammation in a mouse model of Graves' orbitopathy. Thyroid 2022; 32: 283-293
    CrossrefPubMedGoogle Scholar
  • 75 Plohn S, Hose M, Schluter A. et al. Fingolimod improves the outcome of experimental Graves' disease and associated orbitopathy by modulating the autoimmune response to the thyroid-stimulating hormone receptor. Thyroid 2019; 29: 1286-1301
    CrossrefPubMedGoogle Scholar