{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,12]],"date-time":"2026-03-12T00:37:10Z","timestamp":1773275830539,"version":"3.50.1"},"reference-count":36,"publisher":"Oxford University Press (OUP)","issue":"1","license":[{"start":{"date-parts":[[2019,1,11]],"date-time":"2019-01-11T00:00:00Z","timestamp":1547164800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/journals\/pages\/open_access\/funder_policies\/chorus\/standard_publication_model"}],"funder":[{"DOI":"10.13039\/100000002","name":"NIH","doi-asserted-by":"publisher","award":["DK 54684"],"award-info":[{"award-number":["DK 54684"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"NIH","doi-asserted-by":"publisher","award":["DK19289"],"award-info":[{"award-number":["DK19289"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2019,3,18]]},"abstract":"<jats:title>Summary<\/jats:title>\n               <jats:p>NOD.H2h4 mice are the most commonly used model for human autoimmune thyroiditis. Because thyroid autoimmunity develops slowly (over months), NOD.H2h4 mice are usually exposed to excess dietary iodide to accelerate and amplify the process. However, unlike the female bias in human thyroid autoimmunity, autoantibodies to thyroglobulin (TgAb) are reported to be similar in male and female NOD.H2h4. We sought evidence for sexual dimorphism in other parameters in this strain maintained on regular or iodized water. Without iodide, TgAb levels are higher in males than in females, the reverse of human disease. In humans, autoantibodies to thyroid peroxidase (TPOAb) are a better marker of disease than TgAb. In NOD.H2h4 mice TPOAb develop more slowly than TgAb, being detectable at 6 months of age versus 4 months for the latter. Remarkably, unlike TgAb, TPOAb levels are higher in female than male NOD.H2h4 mice on both regular and iodized water. As previously observed, serum T4 levels are similar in both sexes. However, thyroid-stimulating hormone (TSH) levels are significantly higher in males than females with or without iodide exposure. TSH levels correlate with TgAb levels in male NOD.H2h4 mice, suggesting a possible role for TSH in TgAb development. However, there is no correlation between TSH and TPOAb levels, the latter more important than TgAb in human disease. In conclusion, if the goal of an animal model is to closely reflect human disease, TPOAb rather than TgAb should be measured in older female NOD.H2h4 mice, an approach requiring patience and the use of mouse TPO protein.<\/jats:p>","DOI":"10.1111\/cei.13249","type":"journal-article","created":{"date-parts":[[2018,12,19]],"date-time":"2018-12-19T15:20:16Z","timestamp":1545232816000},"page":"52-58","source":"Crossref","is-referenced-by-count":8,"title":["To reflect human autoimmune thyroiditis, thyroid peroxidase (not thyroglobulin) antibodies should be measured in female (not sex-independent) NOD.<i>H2h4<\/i> mice"],"prefix":"10.1093","volume":"196","author":[{"given":"S M","family":"McLachlan","sequence":"first","affiliation":[{"name":"Thyroid Autoimmune Disease Unit, Cedars-Sinai Research Institute and UCLA School of Medicine, Los Angeles, CA, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"H A","family":"Aliesky","sequence":"additional","affiliation":[{"name":"Thyroid Autoimmune Disease Unit, Cedars-Sinai Research Institute and UCLA School of Medicine, Los Angeles, CA, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"B","family":"Rapoport","sequence":"additional","affiliation":[{"name":"Thyroid Autoimmune Disease Unit, Cedars-Sinai Research Institute and UCLA School of Medicine, Los Angeles, CA, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"286","published-online":{"date-parts":[[2019,1,11]]},"reference":[{"key":"2021121023245586300_cei13249-bib-0001","doi-asserted-by":"crossref","first-page":"2187","DOI":"10.1172\/JCI78082","article-title":"Sexual dimorphism in autoimmunity","volume":"125","author":"Rubtsova","year":"2015","journal-title":"J Clin Invest"},{"key":"2021121023245586300_cei13249-bib-0002","first-page":"147","article-title":"Primary standardization for the ELISA of serum thyroperoxidase and thyroglobulin antibodies and their prevalence in a normal Welsh population","volume":"32","author":"Groves","year":"1990","journal-title":"J Clin Lab Immunol"},{"key":"2021121023245586300_cei13249-bib-0003","doi-asserted-by":"crossref","first-page":"639","DOI":"10.1530\/eje.0.1430639","article-title":"Prevalence of thyroid disease, thyroid dysfunction and thyroid peroxidase antibodies in a large, unselected population. The Health Study of Nord-Trondelag (HUNT)","volume":"143","author":"Bjoro","year":"2000","journal-title":"Eur J Endocrinol"},{"key":"2021121023245586300_cei13249-bib-0004","doi-asserted-by":"crossref","first-page":"489","DOI":"10.1210\/jcem.87.2.8182","article-title":"Serum TSH, T(4), and thyroid antibodies in the United States population (1988 to 1994): National Health and Nutrition Examination Survey (NHANES III)","volume":"87","author":"Hollowell","year":"2002","journal-title":"J Clin Endocrinol Metab"},{"key":"2021121023245586300_cei13249-bib-0005","doi-asserted-by":"crossref","first-page":"36","DOI":"10.1046\/j.1365-2265.2003.01633.x","article-title":"Thyroid peroxidase and thyroglobulin autoantibodies in a large survey of populations with mild and moderate iodine deficiency","volume":"58","author":"Pedersen","year":"2003","journal-title":"Clin Endocrinol (Oxf)"},{"key":"2021121023245586300_cei13249-bib-0006","doi-asserted-by":"crossref","first-page":"87","DOI":"10.1016\/j.cellimm.2015.02.004","article-title":"Suppressive effects of androgens on the immune system","volume":"294","author":"Trigunaite","year":"2015","journal-title":"Cell Immunol"},{"key":"2021121023245586300_cei13249-bib-0007","doi-asserted-by":"crossref","first-page":"21","DOI":"10.1111\/nyas.13529","article-title":"AIRE: A missing link to explain female susceptibility to autoimmune diseases","volume":"412","author":"Berrih-Aknin","year":"2018","journal-title":"Ann NY Acad Sci"},{"key":"2021121023245586300_cei13249-bib-0008","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/bs.ai.2014.11.001","article-title":"NOD.H-2h4 mice: An important and underutilized animal model of autoimmune thyroiditis and Sjogren's syndrome","volume":"126","author":"Braley-Mullen","year":"2015","journal-title":"Adv Immunol"},{"key":"2021121023245586300_cei13249-bib-0009","doi-asserted-by":"crossref","first-page":"287","DOI":"10.1006\/clin.1996.0191","article-title":"Iodine-induced autoimmune thyroiditis in NOD-H2h4 mice","volume":"81","author":"Rasooly","year":"1996","journal-title":"Clin Immunol Immunopathol"},{"key":"2021121023245586300_cei13249-bib-0010","doi-asserted-by":"crossref","first-page":"157","DOI":"10.1006\/jaut.1999.0272","article-title":"Spontaneous autoimmune thyroiditis in NOD.H-2h4 mice","volume":"12","author":"Braley-Mullen","year":"1999","journal-title":"J Autoimmun"},{"key":"2021121023245586300_cei13249-bib-0011","doi-asserted-by":"crossref","first-page":"113","DOI":"10.1006\/cimm.1998.1446","article-title":"Both CD4(+) T cells and CD8(+) T cells are required for iodine accelerated thyroiditis in NOD mice","volume":"192","author":"Hutchings","year":"1999","journal-title":"Cell Immunol"},{"key":"2021121023245586300_cei13249-bib-0012","doi-asserted-by":"crossref","first-page":"1170","DOI":"10.1089\/thy.2013.0676","article-title":"Apoptosis of NOD.H2h4 thyrocytes by low concentrations of iodide is associated with impaired control of oxidative stress","volume":"24","author":"Kolypetri","year":"2014","journal-title":"Thyroid"},{"key":"2021121023245586300_cei13249-bib-0013","doi-asserted-by":"crossref","first-page":"361ra137","DOI":"10.1126\/scitranslmed.aag0367","article-title":"Autoimmune manifestations in aged mice arise from early-life immune dysregulation","volume":"8","author":"Mahmoud","year":"2016","journal-title":"Sci Transl Med"},{"key":"2021121023245586300_cei13249-bib-0014","doi-asserted-by":"crossref","first-page":"195","DOI":"10.1016\/j.jaut.2007.07.008","article-title":"CD4+CD25+ naturally occurring regulatory T cells and not lymphopenia play a role in the pathogenesis of iodide-induced autoimmune thyroiditis in NOD-H2h4 mice","volume":"29","author":"Nagayama","year":"2007","journal-title":"J Autoimmun"},{"key":"2021121023245586300_cei13249-bib-0015","doi-asserted-by":"crossref","first-page":"1117","DOI":"10.1089\/thy.2016.0092","article-title":"Exacerbation of autoimmune thyroiditis by CTLA-4 blockade: A role for IFNgamma-induced indoleamine 2, 3-dioxygenase","volume":"26","author":"Sharma","year":"2016","journal-title":"Thyroid"},{"key":"2021121023245586300_cei13249-bib-0016","doi-asserted-by":"crossref","first-page":"235","DOI":"10.3109\/08820139.2012.753611","article-title":"Effects of green tea polyphenols on iodide-induced autoimmune thyroiditis in nonobese diabetic mice","volume":"42","author":"Hoshikawa","year":"2013","journal-title":"Immunol Invest"},{"key":"2021121023245586300_cei13249-bib-0017","doi-asserted-by":"crossref","first-page":"4583","DOI":"10.1210\/en.2010-0321","article-title":"Antibodies to thyroid peroxidase arise spontaneously with age in NOD.H-2h4 mice and appear after thyroglobulin antibodies","volume":"151","author":"Chen","year":"2010","journal-title":"Endocrinology"},{"key":"2021121023245586300_cei13249-bib-0018","doi-asserted-by":"crossref","first-page":"702","DOI":"10.1210\/en.2016-1875","article-title":"Genes outside the Major Histocompatibility Complex Locus are linked to the development of thyroid autoantibodies and thyroiditis in NOD.H2h4 mice","volume":"158","author":"McLachlan","year":"2017","journal-title":"Endocrinology"},{"key":"2021121023245586300_cei13249-bib-0019","doi-asserted-by":"crossref","first-page":"e43517","DOI":"10.1371\/journal.pone.0043517","article-title":"Breaking tolerance in transgenic mice expressing the human TSH receptor A-subunit: Thyroiditis, epitope spreading and adjuvant as a \u2018double edged sword\u2019","volume":"7","author":"McLachlan","year":"2012","journal-title":"PLOS ONE"},{"key":"2021121023245586300_cei13249-bib-0020","doi-asserted-by":"crossref","first-page":"1265","DOI":"10.1089\/thy.1999.9.1265","article-title":"Improved radioimmunoassay for measurement of mouse thyrotropin in serum: Strain differences in thyrotropin concentration and thyrotroph sensitivity to thyroid hormone","volume":"9","author":"Pohlenz","year":"1999","journal-title":"Thyroid"},{"key":"2021121023245586300_cei13249-bib-0021","doi-asserted-by":"crossref","first-page":"268","DOI":"10.1038\/gene.2015.7","article-title":"Evidence that MHC I-E dampens thyroid autoantibodies and prevents spreading to a second thyroid autoantigen in I-A NOD mice","volume":"16","author":"Pelletier","year":"2015","journal-title":"Genes Immun"},{"key":"2021121023245586300_cei13249-bib-0022","doi-asserted-by":"crossref","first-page":"4154","DOI":"10.4049\/jimmunol.1500126","article-title":"A unique mouse strain that develops spontaneous, iodine-accelerated, pathogenic antibodies to the human thyrotrophin receptor","volume":"194","author":"Rapoport","year":"2015","journal-title":"J Immunol"},{"key":"2021121023245586300_cei13249-bib-0023","first-page":"63","article-title":"Aberrant iodide autoregulation induces hypothyroidism in a mouse strain in the absence of thyroid autoimmunity","volume":"29","author":"McLachlan","year":"2017","journal-title":"J Endocrine Soc"},{"key":"2021121023245586300_cei13249-bib-0024","doi-asserted-by":"crossref","first-page":"51","DOI":"10.1007\/s10238-008-0014-0","article-title":"Experimental study on the effects of chronic iodine excess on thyroid function, structure, and autoimmunity in autoimmune-prone NOD.H-2h4 mice","volume":"9","author":"Teng","year":"2009","journal-title":"Clin Exp Med"},{"key":"2021121023245586300_cei13249-bib-0025","doi-asserted-by":"crossref","first-page":"859","DOI":"10.1210\/jcem-46-6-859","article-title":"Association of serum antithyroid antibodies with lymphocytic infiltration of the thyroid gland: Studies of seventy autopsied cases","volume":"46","author":"Yoshida","year":"1978","journal-title":"J Clin Endocrinol Metab"},{"key":"2021121023245586300_cei13249-bib-0026","doi-asserted-by":"crossref","first-page":"55","DOI":"10.1111\/j.1365-2265.1995.tb01894.x","article-title":"The incidence of thyroid disorders in the community: A twenty-year follow-up of the Whickham survey","volume":"43","author":"Vanderpump","year":"1995","journal-title":"Clin Endocrinol"},{"key":"2021121023245586300_cei13249-bib-0027","doi-asserted-by":"crossref","first-page":"40","DOI":"10.2337\/diab.41.1.40","article-title":"High incidence of thyroiditis and anti-thyroid autoantibodies in NOD mice","volume":"41","author":"Bernard","year":"1992","journal-title":"Diabetes"},{"key":"2021121023245586300_cei13249-bib-0028","doi-asserted-by":"crossref","first-page":"5135","DOI":"10.1210\/en.2009-0434","article-title":"T helper type 17 immune response plays an indispensable role for development of iodine-induced autoimmune thyroiditis in nonobese diabetic-H2h4 mice","volume":"150","author":"Horie","year":"2009","journal-title":"Endocrinology"},{"key":"2021121023245586300_cei13249-bib-0029","doi-asserted-by":"crossref","first-page":"288","DOI":"10.1007\/s12011-014-9958-y","article-title":"Effect of iodine excess on Th1, Th2, Th17, and Treg cell subpopulations in the thyroid of NOD.H-2h4 mice","volume":"159","author":"Yang","year":"2014","journal-title":"Biol Trace Elem Res"},{"key":"2021121023245586300_cei13249-bib-0030","doi-asserted-by":"crossref","first-page":"1191","DOI":"10.1002\/(SICI)1521-4141(200004)30:4<1191::AID-IMMU1191>3.0.CO;2-L","article-title":"Role of MHC class I expression and CD8(+) T cells in the evolution of iodine-induced thyroiditis in NOD-H2(h4) and NOD mice","volume":"30","author":"Verma","year":"2000","journal-title":"Eur J Immunol"},{"key":"2021121023245586300_cei13249-bib-0031","doi-asserted-by":"crossref","first-page":"1080","DOI":"10.1089\/thy.2014.0003","article-title":"Sex, genetics and the control of thyroxine and thyrotropin in mice","volume":"24","author":"McLachlan","year":"2014","journal-title":"Thyroid"},{"key":"2021121023245586300_cei13249-bib-0032","doi-asserted-by":"crossref","first-page":"378","DOI":"10.1111\/j.1749-6632.2009.04760.x","article-title":"Sex differences in a murine model of Sj\u00f6gren's syndrome","volume":"1781173","author":"Cih\u00e1kov\u00e1","year":"2009","journal-title":"Ann NY Acad Sci"},{"key":"2021121023245586300_cei13249-bib-0033","doi-asserted-by":"crossref","first-page":"A465","DOI":"10.1016\/j.autrev.2011.11.009","article-title":"Prolactin and autoimmunity","volume":"11","author":"Shelly","year":"2012","journal-title":"Autoimmun Rev"},{"key":"2021121023245586300_cei13249-bib-0034","doi-asserted-by":"crossref","first-page":"S58","DOI":"10.1002\/art.1780210908","article-title":"Natural history of murine lupus. Modulation by sex hormones","volume":"21","author":"Talal","year":"1978","journal-title":"Arthritis Rheum"},{"key":"2021121023245586300_cei13249-bib-0035","doi-asserted-by":"crossref","first-page":"1568","DOI":"10.1084\/jem.147.6.1568","article-title":"Effect of castration and sex hormone treatment on survival, anti-nucleic acid antibodies and glomerulonephritis in NZB\/NZW F1 mice","volume":"147","author":"Roubinian","year":"1978","journal-title":"J Exp Med"},{"key":"2021121023245586300_cei13249-bib-0036","doi-asserted-by":"crossref","first-page":"449","DOI":"10.1089\/thy.2015.0620","article-title":"The influence of dihydrotestosterone on the development of Graves' disease in female BALB\/c mice","volume":"26","author":"Liu","year":"2016","journal-title":"Thyroid"}],"container-title":["Clinical and Experimental Immunology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/api.wiley.com\/onlinelibrary\/tdm\/v1\/articles\/10.1111%2Fcei.13249","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1111\/cei.13249","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/full-xml\/10.1111\/cei.13249","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/academic.oup.com\/cei\/article-pdf\/196\/1\/52\/41637962\/cei13249.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/cei\/article-pdf\/196\/1\/52\/41637962\/cei13249.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,1,1]],"date-time":"2022-01-01T16:26:04Z","timestamp":1641054364000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/cei\/article\/196\/1\/52\/6403599"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2019,1,11]]},"references-count":36,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2019,1,11]]},"published-print":{"date-parts":[[2019,3,18]]}},"URL":"https:\/\/doi.org\/10.1111\/cei.13249","relation":{},"ISSN":["1365-2249","0009-9104"],"issn-type":[{"value":"1365-2249","type":"electronic"},{"value":"0009-9104","type":"print"}],"subject":[],"published-other":{"date-parts":[[2019,4]]},"published":{"date-parts":[[2019,1,11]]}}}