{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,25]],"date-time":"2026-09-25T02:46:08Z","timestamp":1790304368390,"version":"4.1.0"},"reference-count":30,"publisher":"The Endocrine Society","issue":"9","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2013,9,1]]},"abstract":"<jats:p>Graves' orbitopathy (GO) is a complication in Graves' disease (GD) but mechanistic insights into pathogenesis remain unresolved, hampered by lack of animal model. The TSH receptor (TSHR) and perhaps IGF-1 receptor (IGF-1R) are considered relevant antigens. We show that genetic immunization of human TSHR (hTSHR) A-subunit plasmid leads to extensive remodeling of orbital tissue, recapitulating GO. Female BALB\/c mice immunized with hTSHR A-subunit or control plasmids by in vivo muscle electroporation were evaluated for orbital remodeling by histopathology and magnetic resonance imaging (MRI). Antibodies to TSHR and IGF-1R were present in animals challenged with hTSHR A-subunit plasmid, with predominantly TSH blocking antibodies and were profoundly hypothyroid. Orbital pathology was characterized by interstitial inflammation of extraocular muscles with CD3+ T cells, F4\/80+ macrophages, and mast cells, accompanied by glycosaminoglycan deposition with resultant separation of individual muscle fibers. Some animals showed heterogeneity in orbital pathology with 1) large infiltrate surrounding the optic nerve or 2) extensive adipogenesis with expansion of retrobulbar adipose tissue. A striking finding that underpins the new model were the in vivo MRI scans of mouse orbital region that provided clear and quantifiable evidence of orbital muscle hypertrophy with protrusion (proptosis) of the eye. Additionally, eyelid manifestations of chemosis, including dilated and congested orbital blood vessels, were visually apparent. Immunization with control plasmids failed to show any orbital pathology. Overall, these findings support TSHR as the pathogenic antigen in GO. Development of a new preclinical model will facilitate molecular investigations on GO and evaluation of new therapeutic interventions.<\/jats:p>","DOI":"10.1210\/en.2013-1576","type":"journal-article","created":{"date-parts":[[2013,7,31]],"date-time":"2013-07-31T03:17:18Z","timestamp":1375240638000},"page":"3008-3015","source":"Crossref","is-referenced-by-count":111,"title":["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"],"prefix":"10.1210","volume":"154","author":[{"given":"Sajad","family":"Moshkelgosha","sequence":"first","affiliation":[{"name":"Division of Diabetes and Nutritional Sciences (S.M., J.P.B.), King's College London School of Medicine; London, United Kingdom SE5 9NU"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Po-Wah","family":"So","sequence":"first","affiliation":[{"name":"Division of Preclinical Imaging Unit (P.-W.S.), King's College London, London, United Kingdom SE5 9NU"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Neil","family":"Deasy","sequence":"first","affiliation":[{"name":"Department of Neuroimaging, Department of Neuroradiology (N.D.), Institute of Psychiatry, King's College London, London, United Kingdom SE5 9NU"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Salvador","family":"Diaz-Cano","sequence":"first","affiliation":[{"name":"King's College Hospital NHS Trust (S.D.-C.), Department of Pathology, London, United Kingdom SE5 9RS"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"J Paul","family":"Banga","sequence":"first","affiliation":[{"name":"Division of Diabetes and Nutritional Sciences (S.M., J.P.B.), King's College London School of Medicine; London, United Kingdom SE5 9NU"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"80","published-online":{"date-parts":[[2013,7,30]]},"reference":[{"key":"2020071612090313000_B1","doi-asserted-by":"crossref","first-page":"1236","DOI":"10.1056\/NEJM200010263431707","article-title":"Graves' disease","volume":"343","author":"Weetman","year":"2000","journal-title":"New Engl J Med"},{"key":"2020071612090313000_B2","doi-asserted-by":"crossref","first-page":"191","DOI":"10.1007\/s12026-012-8312-8","article-title":"Delineating the autoimmune mechanisms in Graves' disease","volume":"54","author":"Morshed","year":"2012","journal-title":"Immunol Res"},{"key":"2020071612090313000_B3","doi-asserted-by":"crossref","first-page":"726","DOI":"10.1056\/NEJMra0905750","article-title":"Graves' ophthalmopathy","volume":"362","author":"Bahn","year":"2010","journal-title":"N Engl J Med"},{"key":"2020071612090313000_B4","first-page":"1","volume-title":"Graves' Orbitopathy : A Multidisciplinary Approach\u2014Questions And Answers","author":"Dickinson","year":"2010","edition":"2nd rev. ed"},{"key":"2020071612090313000_B5","doi-asserted-by":"crossref","first-page":"281","DOI":"10.1016\/j.beem.2011.10.003","article-title":"Immunopathogenesis of Graves' ophthalmopathy: the role of the TSH receptor","volume":"26","author":"Iyer","year":"2012","journal-title":"Best Pract Res Clin Endocrinol Metab"},{"key":"2020071612090313000_B6","doi-asserted-by":"crossref","first-page":"251","DOI":"10.3109\/08916939309014643","article-title":"Autoantibodies to IGF-1 binding sites in thyroid associated ophthalmopathy","volume":"16","author":"Weightman","year":"1993","journal-title":"Autoimmunity"},{"key":"2020071612090313000_B7","doi-asserted-by":"crossref","first-page":"343","DOI":"10.1016\/j.ecl.2009.01.003","article-title":"Toward better models of hyperthyroid Graves' disease","volume":"38","author":"Da\u011fdelen","year":"2009","journal-title":"Endocrinol Metab Clin North Am"},{"key":"2020071612090313000_B8","doi-asserted-by":"crossref","first-page":"549","DOI":"10.1055\/s-0033-1343451","article-title":"Current insights into animal models of Graves' disease and orbitopathy","volume":"45","author":"Wiesweg","year":"2013","journal-title":"Horm Metab Res"},{"key":"2020071612090313000_B9","doi-asserted-by":"crossref","first-page":"4966","DOI":"10.4049\/jimmunol.162.8.4966","article-title":"Development of an animal model of autoimmune thyroid eye disease","volume":"162","author":"Many","year":"1999","journal-title":"J Immunol"},{"key":"2020071612090313000_B10","doi-asserted-by":"crossref","first-page":"835","DOI":"10.1210\/en.2004-1015","article-title":"Reevaluating thyrotropin receptor-induced mouse models of graves' disease and ophthalmopathy","volume":"146","author":"Baker","year":"2005","journal-title":"Endocrinology"},{"key":"2020071612090313000_B11","doi-asserted-by":"crossref","first-page":"401","DOI":"10.1055\/s-0032-1333224","article-title":"Examination of orbital tissues in murine models of Graves' disease reveals expression of UCP-1 and the TSHR in retrobulbar adipose tissues","volume":"45","author":"Johnson","year":"2013","journal-title":"Horm Metab Res"},{"key":"2020071612090313000_B12","doi-asserted-by":"crossref","first-page":"260","DOI":"10.1210\/en.2002-220688","article-title":"Contrasting activities of thyrotropin receptor antibodies in experimental models of Graves' disease induced by injection of transfected fibroblasts or deoxyribonucleic acid vaccination","volume":"144","author":"Rao","year":"2003","journal-title":"Endocrinology"},{"key":"2020071612090313000_B13","doi-asserted-by":"crossref","first-page":"5084","DOI":"10.4049\/jimmunol.176.8.5084","article-title":"Monoclonal pathogenic antibodies to the thyroid-stimulating hormone receptor in Graves' disease with potent thyroid-stimulating activity but differential blocking activity activate multiple signaling pathways","volume":"176","author":"Gilbert","year":"2006","journal-title":"J Immunol"},{"key":"2020071612090313000_B14","doi-asserted-by":"crossref","first-page":"2335","DOI":"10.1210\/en.2006-1077","article-title":"An improved Graves' disease model established by using in vivo electroporation exhibited long-term immunity to hyperthyroidism in BALB\/c mice","volume":"148","author":"Kaneda","year":"2007","journal-title":"Endocrinology"},{"key":"2020071612090313000_B15","doi-asserted-by":"crossref","first-page":"369","DOI":"10.1530\/JOE-11-0162","article-title":"Orbital fibrosis in a mouse model of Graves' disease induced by genetic immunization of thyrotropin receptor cDNA","volume":"210","author":"Zhao","year":"2011","journal-title":"J Endocrinol"},{"key":"2020071612090313000_B16","volume-title":"Systematic Evaluation of the Mouse Eye: Anatomy, Pathology, and Biomethods","author":"Smith","year":"2002"},{"key":"2020071612090313000_B17","doi-asserted-by":"crossref","first-page":"2107","DOI":"10.4155\/bio.11.208","article-title":"Evaluation of two ELISA methods to detect therapeutic anti-IGF1R antibodies in clinical study samples of dalotuzumab","volume":"3","author":"Yin","year":"2011","journal-title":"Bioanalysis"},{"key":"2020071612090313000_B18","doi-asserted-by":"crossref","first-page":"724","DOI":"10.1136\/bjo.2004.050807","article-title":"Quantification of cells expressing the thyrotropin receptor in extraocular muscles in thyroid associated orbitopathy","volume":"89","author":"Boschi","year":"2005","journal-title":"Br J Ophthalmol"},{"key":"2020071612090313000_B19","doi-asserted-by":"crossref","first-page":"2789","DOI":"10.4049\/jimmunol.168.6.2789","article-title":"A novel murine model of Graves' hyperthyroidism with intramuscular injection of adenovirus expressing the thyrotropin receptor","volume":"168","author":"Nagayama","year":"2002","journal-title":"J Immunol"},{"key":"2020071612090313000_B20","doi-asserted-by":"crossref","first-page":"1897","DOI":"10.1172\/JCI200317069","article-title":"The thyrotropin receptor autoantigen in Graves disease is the culprit as well as the victim","volume":"111","author":"Chen","year":"2003","journal-title":"J Clin Invest"},{"key":"2020071612090313000_B21","doi-asserted-by":"crossref","first-page":"3817","DOI":"10.2174\/138161206778559740","article-title":"Electrically-assisted nucleic acids delivery to tissues in vivo: where do we stand?","volume":"12","author":"Cemazar","year":"2006","journal-title":"Curr Pharm Des"},{"key":"2020071612090313000_B22","doi-asserted-by":"crossref","first-page":"228","DOI":"10.1210\/en.2003-1134","article-title":"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","volume":"145","author":"Chen","year":"2004","journal-title":"Endocrinology"},{"key":"2020071612090313000_B23","doi-asserted-by":"crossref","first-page":"931","DOI":"10.1089\/thy.2012.0008","article-title":"Role of self-tolerance and chronic stimulation in the long-term persistence of adenovirus-induced thyrotropin receptor antibodies in wild-type and transgenic mice","volume":"22","author":"McLachlan","year":"2012","journal-title":"Thyroid"},{"key":"2020071612090313000_B24","doi-asserted-by":"crossref","first-page":"2034","DOI":"10.1210\/en.2011-1846","article-title":"Adoptive transfer of antithyrotropin receptor (TSHR) autoimmunity from TSHR knockout mice to athymic nude mice","volume":"153","author":"Nakahara","year":"2012","journal-title":"Endocrinology"},{"key":"2020071612090313000_B25","doi-asserted-by":"crossref","first-page":"14","DOI":"10.1089\/thy.2012.0374","article-title":"Thyrotropin-blocking autoantibodies and thyroid-stimulating autoantibodies: potential mechanisms involved in the pendulum swinging from hypothyroidism to hyperthyroidism or vice versa","volume":"23","author":"McLachlan","year":"2013","journal-title":"Thyroid"},{"key":"2020071612090313000_B26","doi-asserted-by":"crossref","first-page":"2386","DOI":"10.1210\/jc.2011-0307","article-title":"Autoimmunity in Graves' ophthalmopathy: the result of an unfortunate marriage between TSH receptors and IGF-1 receptors?","volume":"96","author":"Wiersinga","year":"2011","journal-title":"J Clin Endocrinol Metab"},{"key":"2020071612090313000_B27","doi-asserted-by":"crossref","first-page":"259","DOI":"10.1016\/j.beem.2011.11.009","article-title":"Neuroimaging of Graves' orbitopathy","volume":"26","author":"M\u00fcller-Forell","year":"2012","journal-title":"Best Pract Res Clin Endocrinol Metab"},{"key":"2020071612090313000_B28","doi-asserted-by":"crossref","first-page":"2738","DOI":"10.1172\/JCI117289","article-title":"Retrobulbar T cells from patients with Graves' ophthalmopathy are CD8+ and specifically recognize autologous fibroblasts","volume":"93","author":"Grubeck-Loebenstein","year":"1994","journal-title":"J Clin Invest"},{"key":"2020071612090313000_B29","doi-asserted-by":"crossref","first-page":"E781","DOI":"10.1210\/jc.2011-2931","article-title":"Complete inhibition of rhTSH-, Graves' Disease IgG-, and M22-Induced cAMP production in differentiated orbital fibroblasts by a low-molecular-weight TSHR antagonist","volume":"97","author":"van Zeijl","year":"2012","journal-title":"J Clin Endocrinol Metab"},{"key":"2020071612090313000_B30","doi-asserted-by":"crossref","first-page":"2153","DOI":"10.1210\/jc.2013-1149","article-title":"A small molecule antagonist inhibits thyrotropin receptor antibody-induced orbital fibroblast functions involved in the pathogenesis of graves ophthalmopathy","volume":"98","author":"Turcu","year":"2013","journal-title":"J Clin Endocrinol Metab"}],"container-title":["Endocrinology"],"original-title":[],"language":"en","link":[{"URL":"http:\/\/academic.oup.com\/endo\/article-pdf\/154\/9\/3008\/8983265\/endo3008.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"http:\/\/academic.oup.com\/endo\/article-pdf\/154\/9\/3008\/8983265\/endo3008.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,7,3]],"date-time":"2023-07-03T11:16:28Z","timestamp":1688382988000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/endo\/article\/154\/9\/3008\/2423062"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2013,7,30]]},"references-count":30,"journal-issue":{"issue":"9","published-print":{"date-parts":[[2013,9,1]]}},"URL":"https:\/\/doi.org\/10.1210\/en.2013-1576","relation":{"has-review":[{"id-type":"doi","id":"10.3410\/f.718052713.793485497","asserted-by":"object"}]},"ISSN":["0013-7227","1945-7170"],"issn-type":[{"value":"0013-7227","type":"print"},{"value":"1945-7170","type":"electronic"}],"subject":[],"published":{"date-parts":[[2013,7,30]]}}}