{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,8]],"date-time":"2026-07-08T04:54:03Z","timestamp":1783486443747,"version":"3.55.0"},"reference-count":50,"publisher":"Oxford University Press (OUP)","issue":"1","license":[{"start":{"date-parts":[[2014,7,1]],"date-time":"2014-07-01T00:00:00Z","timestamp":1404172800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/pages\/standard-publication-reuse-rights"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2014,7,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:p>Enhanced iodide ingestion is known to accelerate the incidence and severity of spontaneous autoimmune thyroiditis [iodide-accelerated spontaneous autoimmune thyroiditis (ISAT)] in NOD.H2h4 mice. CD4+ cells are required for the development and maintenance of ISAT, but their target epitopes remain unknown. In this study, we show that the previously identified thyroglobulin (Tg) T cell epitope p2549\u20132560 containing thyroxine at position 2553 (T4p2553) induces thyroiditis as well as strong specific T and B cell responses in NOD.H2h4 mice. In ISAT, activated CD4+ T cells specific for T4p2553 are detected before the disease onset in thyroid-draining cervical lymph nodes only in mice placed on an iodide-rich diet and not in age-matched controls. In addition, selective enrichment of CD4+ IFN-\u03b3+ T4p2553-specific cells is observed among cervical lymph node cells and intrathyroidal lymphocytes. T4p2553 was equally detectable on dendritic cells obtained ex vivo from cervical lymph node cells of NaI-fed or control mice, suggesting that the iodide-rich diet contributes to the activation of autoreactive cells rather than the generation of the autoantigenic epitope. Furthermore, spontaneous T4p2553-specific IgG are not detectable within the strong Tg-specific autoantibody response. To our knowledge, these data identify for the first time a Tg T cell epitope as a spontaneous target in ISAT.<\/jats:p>","DOI":"10.4049\/jimmunol.1400561","type":"journal-article","created":{"date-parts":[[2014,5,31]],"date-time":"2014-05-31T02:01:19Z","timestamp":1401501679000},"page":"96-101","source":"Crossref","is-referenced-by-count":10,"title":["The Thyroxine-Containing Thyroglobulin Peptide (aa 2549\u20132560) Is a Target Epitope in Iodide-Accelerated Spontaneous Autoimmune Thyroiditis"],"prefix":"10.1093","volume":"193","author":[{"given":"Panayota","family":"Kolypetri","sequence":"first","affiliation":[{"name":"Division of Endocrinology, Faculty of Medicine, Memorial University of Newfoundland , St. John's, Newfoundland and Labrador A1B 3V6 ,","place":["Canada"]},{"name":"Division of Biomedical Sciences, Faculty of Medicine, Memorial University of Newfoundland , St. John's, Newfoundland and Labrador A1B 3V6 ,","place":["Canada"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Karen","family":"Carayanniotis","sequence":"additional","affiliation":[{"name":"Division of Endocrinology, Faculty of Medicine, Memorial University of Newfoundland , St. John's, Newfoundland and Labrador A1B 3V6 ,","place":["Canada"]},{"name":"Division of Biomedical Sciences, Faculty of Medicine, Memorial University of Newfoundland , St. John's, Newfoundland and Labrador A1B 3V6 ,","place":["Canada"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shofiur","family":"Rahman","sequence":"additional","affiliation":[{"name":"Department of Chemistry, Memorial University of Newfoundland , St. John's, Newfoundland and Labrador A1B 3X7 ,","place":["Canada"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paris E","family":"Georghiou","sequence":"additional","affiliation":[{"name":"Department of Chemistry, Memorial University of Newfoundland , St. John's, Newfoundland and Labrador A1B 3X7 ,","place":["Canada"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vassiliki","family":"Magafa","sequence":"additional","affiliation":[{"name":"Department of Pharmacy, University of Patras , Patras 25604 ,","place":["Greece"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paul","family":"Cordopatis","sequence":"additional","affiliation":[{"name":"Department of Pharmacy, University of Patras , Patras 25604 ,","place":["Greece"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"George","family":"Carayanniotis","sequence":"additional","affiliation":[{"name":"Division of Endocrinology, Faculty of Medicine, Memorial University of Newfoundland , St. John's, Newfoundland and Labrador A1B 3V6 ,","place":["Canada"]},{"name":"Division of Biomedical Sciences, Faculty of Medicine, Memorial University of Newfoundland , St. John's, Newfoundland and Labrador A1B 3V6 ,","place":["Canada"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2014,7,1]]},"reference":[{"key":"2025030707192505500_r1","doi-asserted-by":"crossref","first-page":"179","DOI":"10.1146\/annurev.iy.13.040195.001143","article-title":"Genetic control of autoimmune diabetes in the NOD mouse","volume":"13","author":"Wicker","year":"1995","journal-title":"Annu. 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Immunol."},{"key":"2025030707192505500_r5","doi-asserted-by":"crossref","first-page":"405","DOI":"10.1080\/08916930310001603064","article-title":"NKT cell regulation of autoimmune thyroiditis","volume":"36","author":"Burek","year":"2003","journal-title":"Autoimmunity"},{"key":"2025030707192505500_r6","doi-asserted-by":"crossref","first-page":"793","DOI":"10.1084\/jem.178.3.793","article-title":"I-E+ nonobese diabetic mice develop insulitis and diabetes","volume":"178","author":"Podolin","year":"1993","journal-title":"J. Exp. Med."},{"key":"2025030707192505500_r7","doi-asserted-by":"crossref","first-page":"287","DOI":"10.1006\/clin.1996.0191","article-title":"Iodine-induced autoimmune thyroiditis in NOD-H-2h4 mice","volume":"81","author":"Rasooly","year":"1996","journal-title":"Clin. Immunol. 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