{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,18]],"date-time":"2026-08-18T02:46:48Z","timestamp":1787021208545,"version":"build-2736575974"},"reference-count":38,"publisher":"The Endocrine Society","issue":"1","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2006,1,1]]},"abstract":"<jats:p>T helper type 1 (Th1) and Th2 cells have critical roles in the development of cell-mediated and humoral immune responses, respectively. This division of function predicts that Th1 cells mediate inflammatory diseases and Th2 cells promote antibody (Ab)-mediated autoimmunity. Our previous studies using HEK-293 cells expressing the extracellular domain of the TSH receptor (TSHR) showed that Stat4\u2212\/\u2212 mice, which lack Th1 cells, are susceptible, whereas Stat6\u2212\/\u2212 mice, which lack Th2 cells, are resistant to the induction of Graves\u2019 hyperthyroidism. To investigate the role of Stat4 and Stat6 genes in other murine models of hyperthyroidism, we injected wild-type BALB\/c, Stat4\u2212\/\u2212, and Stat6\u2212\/\u2212 mice with an adenovirus expressing amino acid residues 1\u2013289 of TSHR (TSHR-289-ad or 289-ad). The viral system induces a much stronger immune response with much more rapid onset of disease. Our results showed that 56% of wild-type, 75% of Stat4\u2212\/\u2212, and 39% of Stat6\u2212\/\u2212 mice developed hyperthyroidism. Hyperthyroid mice exhibited thyroid stimulatory Abs. The Stat4\u2212\/\u2212 mice developed a higher incidence and greater severity of hyperthyroidism compared with wild-type and Stat6\u2212\/\u2212 mice. BALB\/c and Stat4\u2212\/\u2212 mice showed significantly higher TSHR Abs of the IgG1 subclass and IL-4 compared with Stat6\u2212\/\u2212 mice. In contrast, Stat6\u2212\/\u2212 mice had predominantly the IgG2a subclass of TSHR Ab and produced significantly higher amounts of IFN-\u03b3 than BALB\/c and Stat4\u2212\/\u2212 mice. All hyperthyroid mice showed enlarged thyroid glands with hyperactivity. These results suggest that in the TSHR-289-ad model, the Th2 cells are more efficient in mediating disease, but in the absence of Th2 cells, Th1 cells may still initiate a reduced incidence of Graves\u2019 hyperthyroidism.<\/jats:p>","DOI":"10.1210\/en.2005-1031","type":"journal-article","created":{"date-parts":[[2005,9,29]],"date-time":"2005-09-29T20:33:37Z","timestamp":1128026017000},"page":"111-119","source":"Crossref","is-referenced-by-count":19,"title":["Differential Requirement of Signal Transducer and Activator of Transcription-4 (Stat4) and Stat6 in a Thyrotropin Receptor-289-Adenovirus-Induced Model of Graves\u2019 Hyperthyroidism"],"prefix":"10.1210","volume":"147","author":[{"given":"Kimberly J.","family":"Land","sequence":"first","affiliation":[{"name":"Department of Biochemistry and Molecular Biology, Indiana University School of Medicine (K.J.L., P.G., G.S.S.), Evansville, Indiana 47712"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Prathyusha","family":"Gudapati","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Molecular Biology, Indiana University School of Medicine (K.J.L., P.G., G.S.S.), Evansville, Indiana 47712"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mark H.","family":"Kaplan","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Immunology, Walther Oncology Center, Indiana University School of Medicine (M.H.K.), Indianapolis, Indiana 46202"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gattadahalli S.","family":"Seetharamaiah","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Molecular Biology, Indiana University School of Medicine (K.J.L., P.G., G.S.S.), Evansville, Indiana 47712"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"80","reference":[{"key":"2020071613260362100_R1","doi-asserted-by":"crossref","first-page":"106","DOI":"10.1210\/edrv-9-1-106","article-title":"Autoantibodies to the thyrotropin receptor.","volume":"9","author":"Rees Smith","year":"1988","journal-title":"Endocr Rev"},{"key":"2020071613260362100_R2","first-page":"673","article-title":"The thyrotropin (TSH) receptor: interaction with TSH and autoantibodies.","volume":"19","author":"Rapoport","year":"1998","journal-title":"Endocr Rev"},{"key":"2020071613260362100_R3","doi-asserted-by":"crossref","first-page":"802","DOI":"10.1210\/er.2002-0020","article-title":"Current perspective on the pathogenesis of Graves\u2019 disease and ophthalmopathy.","volume":"24","author":"Prabhakar","year":"2003","journal-title":"Endocr Rev"},{"key":"2020071613260362100_R4","doi-asserted-by":"crossref","first-page":"145","DOI":"10.1146\/annurev.iy.07.040189.001045","article-title":"TH1 and TH2 cells: different patterns of lymphokine secretion lead to different functional properties.","volume":"7","author":"Mosmann","year":"1989","journal-title":"Annu Rev Immunol"},{"key":"2020071613260362100_R5","doi-asserted-by":"crossref","first-page":"55","DOI":"10.1038\/nri705","article-title":"TH1 and TH2 cells: a historical perspective.","volume":"2","author":"Liew","year":"2002","journal-title":"Nat Rev Immunol"},{"key":"2020071613260362100_R6","doi-asserted-by":"crossref","first-page":"174","DOI":"10.1038\/382174a0","article-title":"Impaired IL-12 responses and enhanced development of Th2 cells in Stat4-deficient mice.","volume":"382","author":"Kaplan","year":"1996","journal-title":"Nature"},{"key":"2020071613260362100_R7","doi-asserted-by":"crossref","first-page":"171","DOI":"10.1038\/382171a0","article-title":"Requirement for Stat4 in interleukin-12-mediated responses of natural killer and T cells.","volume":"382","author":"Thierfelder","year":"1996","journal-title":"Nature"},{"key":"2020071613260362100_R8","doi-asserted-by":"crossref","first-page":"231","DOI":"10.1385\/IR:31:3:231","article-title":"STAT4 A critical regulator of inflammation in vivo.","volume":"32","author":"Kaplan","year":"2005","journal-title":"Immunol Res"},{"key":"2020071613260362100_R9","doi-asserted-by":"crossref","first-page":"313","DOI":"10.1016\/S1074-7613(00)80439-2","article-title":"Stat 6 is required for mediating responses to IL-4 and for the development of Th2 cells.","volume":"4","author":"Kaplan","year":"1996","journal-title":"Immunity"},{"key":"2020071613260362100_R10","doi-asserted-by":"crossref","first-page":"627","DOI":"10.1038\/380627a0","article-title":"Essential role of Stat6 in IL-4 signaling.","volume":"380","author":"Takeda","year":"1996","journal-title":"Nature"},{"key":"2020071613260362100_R11","doi-asserted-by":"crossref","first-page":"739","DOI":"10.1172\/JCI200112563","article-title":"Effect of targeted disruption of STAT4 and STAT6 on the induction of experimental autoimmune encephalomyelitis.","volume":"108","author":"Chitnis","year":"2001","journal-title":"J Clin Invest"},{"key":"2020071613260362100_R12","doi-asserted-by":"crossref","first-page":"5374","DOI":"10.4049\/jimmunol.163.10.5374","article-title":"Disruption of the STAT4 signaling pathway protects from autoimmune diabetes while retaining antiviral immune competence.","volume":"163","author":"Holz","year":"1999","journal-title":"J Immunol"},{"key":"2020071613260362100_R13","doi-asserted-by":"crossref","first-page":"4818","DOI":"10.4049\/jimmunol.170.9.4818","article-title":"Differential contribution of IL-4 and Stat 6 vs Stat4 to the development of lupus nephritis.","volume":"170","author":"Singh","year":"2003","journal-title":"J Immunol"},{"key":"2020071613260362100_R14","doi-asserted-by":"crossref","first-page":"1564","DOI":"10.4049\/jimmunol.171.3.1564","article-title":"Pivotal role of Stat4 and Stat6 in the pathogenesis of the lupus-like disease in the New Zealand mixed 2328 mice.","volume":"171","author":"Jacob","year":"2003","journal-title":"J Immunol"},{"key":"2020071613260362100_R15","doi-asserted-by":"crossref","first-page":"483","DOI":"10.1038\/82725","article-title":"Control of target cell survival in thyroid autoimmunity by T helper cytokines via regulation of apoptotic proteins.","volume":"1","author":"Stassi","year":"2000","journal-title":"Nat Immunol"},{"key":"2020071613260362100_R16","doi-asserted-by":"crossref","first-page":"723","DOI":"10.1172\/JCI114768","article-title":"Thyroid-stimulating antibody activity between different immunoglobulin G subclasses.","volume":"86","author":"Weetman","year":"1990","journal-title":"J Clin Invest"},{"key":"2020071613260362100_R17","first-page":"1070","article-title":"Cell-mediated or humoral immunity in Graves\u2019 ophthalmopathy? Profiles of T-cell cytokines amplified by polymerase chain reaction from orbital tissue.","volume":"78","author":"McLachlan","year":"1994","journal-title":"J Clin Endocrinol Metab"},{"key":"2020071613260362100_R18","doi-asserted-by":"crossref","first-page":"97","DOI":"10.1089\/thy.1996.6.97","article-title":"Different cytokine mRNA profiles in Graves\u2019 disease, Hashimoto\u2019s thyroiditis, and nonautoimmune thyroid disorders determined by quantitative reverse transcriptase polymerase chain reaction (RT-PCR).","volume":"6","author":"Heuer","year":"1996","journal-title":"Thyroid"},{"key":"2020071613260362100_R19","doi-asserted-by":"crossref","first-page":"417","DOI":"10.1111\/j.1365-2249.2004.02641.x","article-title":"TSHR-receptor-adenovirus induced Graves\u2019 disease is attenuated in both interferon-\u03b3 and interleukin-4 knockout mice: implications for Th1\/Th2 paradigm.","volume":"138","author":"Nayagama","year":"2004","journal-title":"Clin Exp Immunol"},{"key":"2020071613260362100_R20","doi-asserted-by":"crossref","first-page":"2195","DOI":"10.4049\/jimmunol.170.4.2195","article-title":"Absence of IL-4, and not suppression of the Th2 response, prevents development of experimental autoimmune Graves\u2019 disease.","volume":"170","author":"Dogan","year":"2003","journal-title":"J Immunol"},{"key":"2020071613260362100_R21","doi-asserted-by":"crossref","first-page":"3724","DOI":"10.1210\/en.2004-0352","article-title":"Signal transducer and activator of transcription (Stat)-6-dependent, but not Stat4-dependent, immunity is required for the development of autoimmunity in Graves\u2019 hyperthyroidism.","volume":"145","author":"Land","year":"2004","journal-title":"Endocrinology"},{"key":"2020071613260362100_R22","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":"2020071613260362100_R23","doi-asserted-by":"crossref","first-page":"2789","DOI":"10.4049\/jimmunol.168.6.2789","article-title":"A novel murine model of Graves\u2019 hyperthyroidism with intramuscular injection of adenovirus expressing the thyrotropin receptor.","volume":"168","author":"Nagayama","year":"2002","journal-title":"J Immunol"},{"key":"2020071613260362100_R24","doi-asserted-by":"crossref","first-page":"7498","DOI":"10.1128\/JVI.70.11.7498-7509.1996","article-title":"Evaluation of the concentration and bioactivity of adenovirus vectors for gene therapy.","volume":"70","author":"Mittereder","year":"1996","journal-title":"J Virol"},{"key":"2020071613260362100_R25","doi-asserted-by":"crossref","first-page":"21","DOI":"10.3109\/08916939908995969","article-title":"Glycosylated ectodomain of the human thyrotropin receptor induces antibodies capable of reacting with multiple blocking antibody epitopes.","volume":"29","author":"Seetharamaiah","year":"1999","journal-title":"Autoimmunity"},{"key":"2020071613260362100_R26","doi-asserted-by":"crossref","first-page":"315","DOI":"10.1677\/jme.0.0230315","article-title":"Regulation of thyrotropin receptor expression in insect cells.","volume":"23","author":"Seetharamaiah","year":"1999","journal-title":"J Mol Endocrinol"},{"key":"2020071613260362100_R27","doi-asserted-by":"crossref","first-page":"205","DOI":"10.1006\/jaut.1999.0311","article-title":"Comparison of immune responses to extracellular domains of mouse and human thyrotropin receptor.","volume":"13","author":"Patibandla","year":"1999","journal-title":"J Autoimmun"},{"key":"2020071613260362100_R28","doi-asserted-by":"crossref","first-page":"2798","DOI":"10.4049\/jimmunol.158.6.2798","article-title":"Requirement of glycosylation of the human thyrotropin receptor ectodomain for its reactivity with autoantibodies in patients\u2019 sera.","volume":"158","author":"Seetharamaiah","year":"1997","journal-title":"J Immunol"},{"key":"2020071613260362100_R29","doi-asserted-by":"crossref","first-page":"18959","DOI":"10.1074\/jbc.272.30.18959","article-title":"Engineering the human thyrotropin receptor ectodomain from a non-secreted form to a secreted, highly immunoreactive glycoprotein that neutralizes autoantibodies in Graves\u2019 patients\u2019 sera.","volume":"272","author":"Chazenbalk","year":"1997","journal-title":"J Biol Chem"},{"key":"2020071613260362100_R30","first-page":"1287","article-title":"A prion-like shift between two conformational forms of a recombinant thyrotropin receptor A-subunit module: purification and stabilization using chemical chaperones of the form reactive with Graves\u2019 autoantibodies.","volume":"86","author":"Chazenbalk","year":"2001","journal-title":"J Clin Endocrinol Metab"},{"key":"2020071613260362100_R31","doi-asserted-by":"crossref","first-page":"671","DOI":"10.1210\/endo.139.2.5748","article-title":"Soluble ecto-domain mutant of thyrotropin (TSH) receptor incapable of binding TSH neutralizes the action of thyroid-stimulating antibodies from Graves\u2019 patients.","volume":"139","author":"Osuga","year":"1998","journal-title":"Endocrinology"},{"key":"2020071613260362100_R32","doi-asserted-by":"crossref","first-page":"5157","DOI":"10.4049\/jimmunol.163.9.5157","article-title":"Induction of experimental autoimmune Graves\u2019 disease in BALB\/c mice.","volume":"163","author":"Kaithamana","year":"1999","journal-title":"J Immunol"},{"key":"2020071613260362100_R33","doi-asserted-by":"crossref","first-page":"6536","DOI":"10.4049\/jimmunol.163.12.6536","article-title":"Stat6-dependent and -independent pathways for IL-4 production.","volume":"163","author":"Kaplan","year":"1999","journal-title":"J Immunol"},{"key":"2020071613260362100_R34","doi-asserted-by":"crossref","first-page":"1235","DOI":"10.1002\/(SICI)1521-4141(199904)29:04<1235::AID-IMMU1235>3.0.CO;2-0","article-title":"STAT6-independent production of IL-4 by mast cells.","volume":"29","author":"Sherman","year":"1999","journal-title":"Eur J Immunol"},{"key":"2020071613260362100_R35","doi-asserted-by":"crossref","first-page":"4927","DOI":"10.1210\/en.2004-0716","article-title":"Susceptibility rather than resistance to hyperthyroidism is dominant in a thyrotropin receptor adenovirus-induced animal model of Graves\u2019 disease as revealed by BALB\/c-C57BL\/6 hybrid mice.","volume":"145","author":"Chen","year":"2004","journal-title":"Endocrinology"},{"key":"2020071613260362100_R36","doi-asserted-by":"crossref","first-page":"1157","DOI":"10.1093\/intimm\/dxh293","article-title":"Stat4-null non-obese diabetic mice: protection from diabetes and experimental allergic encephalomyelitis, but with concomitant epitope spread.","volume":"17","author":"Boyton","year":"2005","journal-title":"Int Immunol"},{"key":"2020071613260362100_R37","doi-asserted-by":"crossref","first-page":"299","DOI":"10.1016\/j.clim.2004.11.001","article-title":"Effect of targeted disruption of signal transducer and activator of transcription (Stat)4 and Stat6 genes on the autoimmune diabetes development induced by multiple low doses of streptozotocin.","volume":"114","author":"Cetkovic-Cvrlje","year":"2005","journal-title":"Clin Immunol"},{"key":"2020071613260362100_R38","doi-asserted-by":"crossref","first-page":"97","DOI":"10.4049\/jimmunol.172.1.97","article-title":"The susceptibility to experimental myasthenia gravis of STAT6\u2212\/\u2212 and STAT4\u2212\/\u2212 BALB\/c mice suggests a pathogenic role of Th1 cells.","volume":"172","author":"Wang","year":"2004","journal-title":"J Immunol"}],"container-title":["Endocrinology"],"original-title":[],"language":"en","link":[{"URL":"http:\/\/academic.oup.com\/endo\/article-pdf\/147\/1\/111\/10727569\/endo0111.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"http:\/\/academic.oup.com\/endo\/article-pdf\/147\/1\/111\/10727569\/endo0111.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,5,4]],"date-time":"2023-05-04T16:52:20Z","timestamp":1683219140000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/endo\/article\/147\/1\/111\/2500117"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2006,1,1]]},"references-count":38,"journal-issue":{"issue":"1","published-print":{"date-parts":[[2006,1,1]]}},"URL":"https:\/\/doi.org\/10.1210\/en.2005-1031","relation":{},"ISSN":["0013-7227","1945-7170"],"issn-type":[{"value":"0013-7227","type":"print"},{"value":"1945-7170","type":"electronic"}],"subject":[],"published":{"date-parts":[[2006,1,1]]}}}