Current Insights into Animal Models of Graves’ Disease and Orbitopathy

 

 Buy Article Permissions and Reprints

Abstract

Graves’ disease (GD) is a systemic autoimmune disease that is characterized by hyperthyroidism, orbitopathy and in rare cases dermopathy. Graves’ orbitopathy (GO) is an inflammatory disease of eye and orbit which occurs in about 30–60% of patients. Hyperthyroidism occurs due to the presence of stimulating TSHR-autoantibodies (TRAbs) leading to increased serum levels of thyroid hormones. Attempts to induce Graves’ disease in mice by immunization against the hTSHR or its variants have resulted in production of TRAbs that stimulate thyroid follicular cells to increase thyroid hormone secretion. Graves’ like orbital changes, such as inflammation, adipogenesis and muscle fibrosis are more difficult to induce. In this review we summarize different methods used to induce murine Graves’-like disease and their impact on murine orbits.

• References

• 1 Wiersinga WM, Bartalena L. Epidemiology and prevention of Graves’ ophthalmopathy. Thyroid 2002; 12: 855-860
  Google Scholar
• 2 Zophel K, Roggenbuck D, von Landenberg P, Wunderlich G, Gruning T, Kotzerke J, Lackner KJ, Rees Smith B. TSH receptor antibody (TRAb) assays based on the human monoclonal autoantibody M22 are more sensitive than bovine TSH based assays. Horm Metab Res 2010; 42: 65-69
  Article in Thieme ConnectPubMedGoogle Scholar
• 3 Ludgate M, Crisp M, Lane C, Costagliola S, Vassart G, Weetman A, Daunerie C, Many MC. The thyrotropin receptor in thyroid eye disease. Thyroid 1998; 8: 411-413
  Google Scholar
• 4 Many MC, Costagliola S, Detrait M, Denef F, Vassart G, Ludgate MC. Development of an animal model of autoimmune thyroid eye disease. J Immunol 1999; 162: 4966-4974
  Google Scholar
• 5 Johnson KT, Wiesweg B, Schott M, Ehlers M, Müller M, Minich WB, Nagayama Y, Gulbins E, Eckstein AK, Berchner-Pfannschmidt U. 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; [Epub ahead of print]
  PubMedGoogle Scholar
• 6 Prabhakar BS, Bahn RS, Smith TJ. Current perspective on the pathogenesis of Graves’ disease and ophthalmopathy. Endocr Rev 2003; 24: 802-835
  CrossrefPubMedGoogle Scholar
• 7 Noh JY, Hamada N, Inoue Y, Abe Y, Ito K. Thyroid-stimulating antibody is related to Graves’ ophthalmopathy, but thyrotropin-binding inhibitor immunoglobulin is related to hyperthyroidism in patients with Graves’ disease. Thyroid 2000; 10: 809-813
  CrossrefPubMedGoogle Scholar
• 8 Subekti I, Boedisantoso A, Moeloek ND, Waspadji S, Mansyur M. Association of TSH receptor antibody, thyroid stimulating antibody, and thyroid blocking antibody with clinical activity score and degree of severity of graves ophthalmopathy. Acta Medica Indonesiana 2012; 44: 114-121
  PubMedGoogle Scholar
• 9 Eckstein AK, Plicht M, Lax H, Neuhauser M, Mann K, Lederbogen S, Heckmann C, Esser J, Morgenthaler NG. 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
  Google Scholar
• 10 Makino S, Kunimoto K, Muraoka Y, Mizushima Y, Katagiri K, Tochino Y. Breeding of a non-obese, diabetic strain of mice. Jikken Dobutsu Exp Animals 1980; 29: 1-13
  PubMedGoogle Scholar
• 11 Ludgate M, Baker G. Inducing Graves’ ophthalmopathy. J Endocrinol Invest 2004; 27: 211-215
  PubMedGoogle Scholar
• 12 Shimojo N, Kohno Y, Yamaguchi K, Kikuoka S, Hoshioka A, Niimi H, Hirai A, Tamura Y, Saito Y, Kohn LD, Tahara K. 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
  CrossrefPubMedGoogle Scholar
• 13 Kaithamana S, Fan J, Osuga Y, Liang SG, Prabhakar BS. Induction of experimental autoimmune Graves’ disease in BALB/c mice. J Immunol 1999; 163: 5157-5164
  Google Scholar
• 14 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. Clin Exp Immunol 2003; 131: 234-240
  CrossrefPubMedGoogle Scholar
• 15 Nagayama Y, Kita-Furuyama M, Ando T, Nakao K, Mizuguchi H, Hayakawa T, Eguchi K, Niwa M. A novel murine model of Graves’ hyperthyroidism with intramuscular injection of adenovirus expressing the thyrotropin receptor. J Immunol 2002; 168: 2789-2794
  Google Scholar
• 16 Chen CR, Pichurin P, Nagayama Y, Latrofa F, Rapoport B, McLachlan SM. The thyrotropin receptor autoantigen in Graves disease is the culprit as well as the victim. J Clin Invest 2003; 111: 1897-1904
  Google Scholar
• 17 Smelser GK. The histology of orbital and other fat tissue deposits in animals with experimentally produced exophthalmos. Am J Pathol 1939; 15: 341-352
  PubMedGoogle Scholar
• 18 Costagliola S, Alcalde L, Tonacchera M, Ruf J, Vassart G, Ludgate M. Induction of thyrotropin receptor (TSH-R) autoantibodies and thyroiditis in mice immunised with the recombinant TSH-R. Biochem Biophys Res Commun 1994; 199: 1027-1034
  CrossrefPubMedGoogle Scholar
• 19 Patibandla SA, Fan JL, Prabhakar BS, Seetharamaiah GS. Comparison of immune responses to extracellular domains of mouse and human thyrotropin receptor. J Autoimmun 1999; 13: 205-213
  CrossrefPubMedGoogle Scholar
• 20 Bottazzo GF, Pujol-Borrell R, Hanafusa T, Feldmann M. Role of aberrant HLA-DR expression and antigen presentation in induction of endocrine autoimmunity. Lancet 1983; 2: 1115-1119
  PubMedGoogle Scholar
• 21 Ando T, Imaizumi M, Graves P, Unger P, Davies TF. Induction of thyroid-stimulating hormone receptor autoimmunity in hamsters. Endocrinology 2003; 144: 671-680
  CrossrefPubMedGoogle Scholar
• 22 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
  CrossrefPubMedGoogle Scholar
• 23 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
  CrossrefPubMedGoogle Scholar
• 24 Land KJ, Moll JS, Kaplan MH, Seetharamaiah GS. Signal transducer and activator of transcription (Stat)-6-dependent, but not Stat4-dependent, immunity is required for the development of autoimmunity in Graves’ hyperthyroidism. Endocrinology 2004; 145: 3724-3730
  CrossrefPubMedGoogle Scholar
• 25 McLachlan SM, Nagayama Y, Rapoport B. Insight into Graves’ hyperthyroidism from animal models. Endocr Rev 2005; 26: 800-832
  Google Scholar
• 26 Mizutori Y, Saitoh O, Eguchi K, Nagayama Y. Adenovirus encoding the thyrotropin receptor A-subunit improves the efficacy of dendritic cell-induced Graves’ hyperthyroidism in mice. J Autoimmun 2006; 26: 32-36
  Google Scholar
• 27 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: 1458-1465
  Google Scholar
• 28 Baker G, Mazziotti G, von Ruhland C, Ludgate M. Reevaluating thyrotropin receptor-induced mouse models of Graves’ disease and ophthalmopathy. Endocrinology 2005; 146: 835-844
  CrossrefPubMedGoogle Scholar
• 29 Yamada M, Li AW, West KA, Chang CH, Wall JR. Experimental model for ophthalmopathy in BALB/c and outbred (CD-1) mice genetically immunized with G2s and the thyrotropin receptor. Autoimmunity 2002; 35: 403-413
  CrossrefPubMedGoogle Scholar
• 30 Costagliola S, Many MC, Denef JF, Pohlenz J, Refetoff S, Vassart G. Genetic immunization of outbred mice with thyrotropin receptor cDNA provides a model of Graves disease. J Clin Invest 2000; 105: 803-811
  Google Scholar
• 31 Ho SC, Goh SS, Kee IH, Chow PK, Yeo CP, Khoo DH. Effects of genetic immunization of Swiss outbred mice with human thyroid stimulating hormone receptor cDNA plasmids harboring gain-of-function mutations. J Mol Endocrinol 2007; 38: 277-288
  CrossrefPubMedGoogle Scholar
• 32 Chazenbalk GD, Pichurin P, Chen CR, Latrofa F, Johnstone AP, McLachlan SM, Rapoport B. Thyroid-stimulating autoantibodies in Graves disease preferentially recognize the free A subunit, not the thyrotropin holoreceptor. J Clin Invest 2002; 110: 209-217
  Google Scholar
• 33 Chen CR, Pichurin P, Chazenbalk GD, Aliesky H, Nagayama Y, McLachlan SM, Rapoport B. 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
• 34 Land KJ, Gudapati P, Kaplan MH, Seetharamaiah GS. Differential requirement of signal transducer and activator of transcription-4 (Stat4) and Stat6 in a thyrotropin receptor-289-adenovirus-induced model of Graves’ hyperthyroidism. Endocrinology 2006; 147: 111-119
  CrossrefPubMedGoogle Scholar
• 35 Gilbert JA, Kalled SL, Moorhead J, Hess DM, Rennert P, Li Z, Khan MZ, Banga JP. 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: 4561-4568
  Google Scholar
• 36 Wu L, Xun L, Yang J, Xu L, Tian Z, Gao S, Zhang Y, Hou P, Shi B. Induction of murine neonatal tolerance against Graves’ disease using recombinant adenovirus expressing the TSH receptor A-subunit. Endocrinology 2011; 152: 1165-1171
  CrossrefPubMedGoogle Scholar
• 37 Ye F, Hou P, Wu X, Ma X, Gao L, Wu L, Xu L, Shi B. The significance of immune-related molecule expression profiles in an animal model of Graves’ disease. Autoimmunity 2012; 45: 143-152
  CrossrefPubMedGoogle Scholar
• 38 Saitoh O, Nagayama Y. Regulation of Graves’ hyperthyroidism with naturally occurring CD4+CD25+ regulatory T cells in a mouse model. Endocrinology 2006; 147: 2417-2422
  CrossrefPubMedGoogle Scholar
• 39 Jacobs B, Papewalis C, Ehlers M, Schott M. Endocrine organs under the control of the immune system: potential implications for cellular therapies. Horm Metab Res 2010; 42: 912-917
  Article in Thieme ConnectPubMedGoogle Scholar
• 40 Zhao SX, Tsui S, Cheung A, Douglas RS, Smith TJ, Banga JP. Orbital fibrosis in a mouse model of Graves’ disease induced by genetic immunization of thyrotropin receptor cDNA. J Endocrinol 2011; 210: 369-377
  Google Scholar
• 41 Weightman DR, Perros P, Sherif IH, Kendall-Taylor P. Autoantibodies to IGF-1 binding sites in thyroid associated ophthalmopathy. Autoimmunity 1993; 16: 251-257
  Google Scholar
• 42 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: 6348-6354
  Google Scholar
• 43 Smith TJ. The putative role of fibroblasts in the pathogenesis of Graves’ disease: evidence for the involvement of the insulin-like growth factor-1 receptor in fibroblast activation. Autoimmunity 2003; 36: 409-415
  Google Scholar
• 44 Endo T, Kobayashi T. Thyroid-stimulating hormone receptor in brown adipose tissue is involved in the regulation of thermogenesis. American journal of physiology Endocrinology and metabolism 2008; 295: E514-E518
  CrossrefPubMedGoogle Scholar
• 45 Zhang L, Baker G, Janus D, Paddon CA, Fuhrer D, Ludgate M. Biological effects of thyrotropin receptor activation on human orbital preadipocytes. Invest Ophthalmol Vis Sci 2006; 47: 5197-5203
  CrossrefPubMedGoogle Scholar
• 46 Nakahara M, Johnson K, Eckstein A, Taguchi R, Yamada M, Abiru N, Nagayama Y. Adoptive transfer of antithyrotropin receptor (TSHR) autoimmunity from TSHR knockout mice to athymic nude mice. Endocrinology 2012; 153: 2034-2042
  CrossrefPubMedGoogle Scholar
• 47 Nakahara M, Mitsutake N, Sakamoto H, Chen CR, Rapoport B, McLachlan SM, Nagayama Y. Enhanced response to mouse thyroid-stimulating hormone (TSH) receptor immunization in TSH receptor-knockout mice. Endocrinology 2010; 151: 4047-4054
  CrossrefPubMedGoogle Scholar