{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,11]],"date-time":"2026-02-11T18:56:20Z","timestamp":1770836180366,"version":"3.50.1"},"reference-count":44,"publisher":"Wiley","issue":"6","license":[{"start":{"date-parts":[[2009,5,28]],"date-time":"2009-05-28T00:00:00Z","timestamp":1243468800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Arthritis &amp; Rheumatism"],"published-print":{"date-parts":[[2009,6]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:sec><jats:title>Objective<\/jats:title><jats:p>Autoimmune regulator (Aire) promotes the ectopic expression of tissue\u2010restricted antigens in medullary thymic epithelial cells (mTECs), leading to negative selection of autoreactive T cells. This study was undertaken to determine whether loss of central tolerance renders Aire\u2010deficient (<jats:italic>Aire<\/jats:italic><jats:sup>\u2212\/\u2212<\/jats:sup>) mice more susceptible to the induction of autoimmune arthritis.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>Medullary TECs were isolated from <jats:italic>Aire<\/jats:italic><jats:sup>\u2212\/\u2212<\/jats:sup> and wild\u2010type C57BL\/6 mice for gene expression analysis. Collagen\u2010induced arthritis (CIA) was elicited by injection of chick type II collagen (CII) in adjuvant. Cellular and humoral immune responses to CII were evaluated. Chimeric mice were created by reconstituting lymphocyte\u2010deficient mice with either <jats:italic>Aire<\/jats:italic><jats:sup>\u2212\/\u2212<\/jats:sup> or wild\u2010type CD4 T cells and wild\u2010type B cells.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Wild\u2010type, but not <jats:italic>Aire<\/jats:italic><jats:sup>\u2212\/\u2212<\/jats:sup>, mTECs expressed the CII gene <jats:italic>Col2a1<\/jats:italic>. <jats:italic>Aire<\/jats:italic><jats:sup>\u2212\/\u2212<\/jats:sup> mice developed more rapid and severe CIA, showing elevated serum anti\u2010CII IgG levels, with earlier switching to arthritogenic IgG subclasses. No evidence was found of enhanced T cell responsiveness to CII in <jats:italic>Aire<\/jats:italic><jats:sup>\u2212\/\u2212<\/jats:sup> mice; however, <jats:italic>Aire<\/jats:italic><jats:sup>\u2212\/\u2212<\/jats:sup> CD4 T cells were more efficient at stimulating wild\u2010type B cells to produce anti\u2010CII IgG following immunization of chimeric mice with CII.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>Our findings indicate that Aire\u2010dependent expression of CII occurs in mTECs, implying that there is central tolerance to self antigens found in articular cartilage. Reduced central tolerance to CII in <jats:italic>Aire<\/jats:italic><jats:sup>\u2212\/\u2212<\/jats:sup> mice manifests as increased CD4 T cell help to B cells for cross\u2010reactive autoantibody production and enhanced CIA. Aire and central tolerance help prevent cross\u2010reactive autoimmune responses to CII initiated by environmental stimuli and limit spontaneous autoimmunity.<\/jats:p><\/jats:sec>","DOI":"10.1002\/art.24501","type":"journal-article","created":{"date-parts":[[2009,5,28]],"date-time":"2009-05-28T11:35:01Z","timestamp":1243510501000},"page":"1683-1693","source":"Crossref","is-referenced-by-count":29,"title":["Autoimmune regulator controls T cell help for pathogenetic autoantibody production in collagen\u2010induced arthritis"],"prefix":"10.1002","volume":"60","author":[{"given":"Ian K.","family":"Campbell","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sarah A.","family":"Kinkel","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sarah F.","family":"Drake","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Annemarie Van","family":"Nieuwenhuijze","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Fran\u00e7ois\u2010Xavier","family":"Hubert","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"David M.","family":"Tarlinton","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"William R.","family":"Heath","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hamish S.","family":"Scott","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ian P.","family":"Wicks","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2009,5,28]]},"reference":[{"key":"e_1_2_7_2_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.1159407"},{"key":"e_1_2_7_3_2","doi-asserted-by":"publisher","DOI":"10.1038\/nri2136"},{"key":"e_1_2_7_4_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.it.2007.05.004"},{"key":"e_1_2_7_5_2","doi-asserted-by":"publisher","DOI":"10.1006\/bbrc.1999.0308"},{"key":"e_1_2_7_6_2","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.180.6.3824"},{"key":"e_1_2_7_7_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.1075958"},{"key":"e_1_2_7_8_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.it.2008.03.004"},{"key":"e_1_2_7_9_2","doi-asserted-by":"publisher","DOI":"10.1093\/hmg\/11.4.397"},{"key":"e_1_2_7_10_2","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.174.4.1862"},{"key":"e_1_2_7_11_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.molimm.2007.05.014"},{"key":"e_1_2_7_12_2","doi-asserted-by":"publisher","DOI":"10.1046\/j.1365-2567.2001.01267.x"},{"key":"e_1_2_7_13_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0806874105"},{"key":"e_1_2_7_14_2","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.181.6.4072"},{"key":"e_1_2_7_15_2","doi-asserted-by":"crossref","first-page":"2103","DOI":"10.4049\/jimmunol.148.7.2103","article-title":"Induction of arthritis with monoclonal antibodies to collagen","volume":"148","author":"Terato K","year":"1992","journal-title":"J Immunol"},{"key":"e_1_2_7_16_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.92.19.8955"},{"key":"e_1_2_7_17_2","doi-asserted-by":"publisher","DOI":"10.1084\/jem.20020205"},{"key":"e_1_2_7_18_2","doi-asserted-by":"publisher","DOI":"10.1002\/1521-4141(200006)30:6<1568::AID-IMMU1568>3.0.CO;2-R"},{"key":"e_1_2_7_19_2","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.169.8.4332"},{"key":"e_1_2_7_20_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.7689748"},{"key":"e_1_2_7_21_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0022-1759(01)00493-8"},{"key":"e_1_2_7_22_2","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gng015"},{"key":"e_1_2_7_23_2","doi-asserted-by":"publisher","DOI":"10.2202\/1544-6115.1027"},{"key":"e_1_2_7_24_2","doi-asserted-by":"publisher","DOI":"10.1189\/jlb.68.1.144"},{"key":"e_1_2_7_25_2","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.159.2.565"},{"key":"e_1_2_7_26_2","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.170.8.4002"},{"key":"e_1_2_7_27_2","doi-asserted-by":"publisher","DOI":"10.1038\/sj.gene.6364042"},{"key":"e_1_2_7_28_2","doi-asserted-by":"publisher","DOI":"10.1084\/jem.20050693"},{"key":"e_1_2_7_29_2","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.0802124"},{"key":"e_1_2_7_30_2","doi-asserted-by":"publisher","DOI":"10.1084\/jem.20040581"},{"key":"e_1_2_7_31_2","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.151.9.5081"},{"key":"e_1_2_7_32_2","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.140.5.1477"},{"key":"e_1_2_7_33_2","doi-asserted-by":"publisher","DOI":"10.1002\/eji.1830220722"},{"key":"e_1_2_7_34_2","doi-asserted-by":"publisher","DOI":"10.1002\/eji.200535240"},{"key":"e_1_2_7_35_2","doi-asserted-by":"publisher","DOI":"10.1084\/jem.162.6.1878"},{"key":"e_1_2_7_36_2","doi-asserted-by":"publisher","DOI":"10.1016\/0076-6879(88)62091-X"},{"key":"e_1_2_7_37_2","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.177.1.290"},{"key":"e_1_2_7_38_2","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.180.8.5384"},{"key":"e_1_2_7_39_2","doi-asserted-by":"publisher","DOI":"10.1186\/ar380"},{"key":"e_1_2_7_40_2","doi-asserted-by":"publisher","DOI":"10.1096\/fasebj.6.3.1740236"},{"key":"e_1_2_7_41_2","doi-asserted-by":"publisher","DOI":"10.1002\/art.1780300211"},{"key":"e_1_2_7_42_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0709160104"},{"key":"e_1_2_7_43_2","doi-asserted-by":"publisher","DOI":"10.1038\/nri1224"},{"key":"e_1_2_7_44_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.immuni.2005.07.005"},{"key":"e_1_2_7_45_2","doi-asserted-by":"publisher","DOI":"10.1172\/JCI26971"}],"container-title":["Arthritis &amp; Rheumatism"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/api.wiley.com\/onlinelibrary\/tdm\/v1\/articles\/10.1002%2Fart.24501","content-type":"unspecified","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/art.24501","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,10,10]],"date-time":"2023-10-10T22:35:07Z","timestamp":1696977307000},"score":1,"resource":{"primary":{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/10.1002\/art.24501"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2009,5,28]]},"references-count":44,"journal-issue":{"issue":"6","published-print":{"date-parts":[[2009,6]]}},"alternative-id":["10.1002\/art.24501"],"URL":"https:\/\/doi.org\/10.1002\/art.24501","archive":["Portico"],"relation":{},"ISSN":["0004-3591","1529-0131"],"issn-type":[{"value":"0004-3591","type":"print"},{"value":"1529-0131","type":"electronic"}],"subject":[],"published":{"date-parts":[[2009,5,28]]}}}