{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,27]],"date-time":"2026-09-27T12:30:15Z","timestamp":1790512215187,"version":"4.1.0"},"reference-count":50,"publisher":"Oxford University Press (OUP)","issue":"8","license":[{"start":{"date-parts":[[2014,10,1]],"date-time":"2014-10-01T00:00:00Z","timestamp":1412121600000},"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":[[2014,10,15]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:p>Down syndrome (DS), or trisomy of chromosome 21, is the most common genetic disorder associated with autoimmune diseases. Autoimmune regulator protein (AIRE), a transcription factor located on chromosome 21, plays a crucial role in autoimmunity by regulating promiscuous gene expression (pGE). To investigate if autoimmunity in DS is promoted by the reduction of pGE owing to dysregulation of AIRE, we assessed the expression of AIRE and of several peripheral tissue-restricted Ag genes by quantitative PCR in thymus samples from 19 DS subjects and 21 euploid controls. Strikingly, despite the 21 trisomy, AIRE expression was significantly reduced by 2-fold in DS thymuses compared with controls, which was also confirmed by fluorescent microscopy. Allele-specific quantification of intrathymic AIRE showed that despite its lower expression, the three copies are expressed. More importantly, decreased expression of AIRE was accompanied by a reduction of pGE because expression of tissue-restricted Ags, CHRNA1, GAD1, PLP1, KLK3, SAG, TG, and TSHR, was reduced. Of interest, thyroid dysfunction (10 cases of hypothyroidism and 1 of Graves disease) developed in 11 of 19 (57.9%) of the DS individuals and in none of the 21 controls. The thymuses of these DS individuals contained significantly lower levels of AIRE and thyroglobulin, to which tolerance is typically lost in autoimmune thyroiditis leading to hypothyroidism. Our findings provide strong evidence for the fundamental role of AIRE and pGE, namely, central tolerance, in the predisposition to autoimmunity of DS individuals.<\/jats:p>","DOI":"10.4049\/jimmunol.1400223","type":"journal-article","created":{"date-parts":[[2014,9,13]],"date-time":"2014-09-13T06:59:41Z","timestamp":1410591581000},"page":"3872-3879","source":"Crossref","is-referenced-by-count":98,"title":["Autoimmune Predisposition in Down Syndrome May Result from a Partial Central Tolerance Failure due to Insufficient Intrathymic Expression of <i>AIRE<\/i> and Peripheral Antigens"],"prefix":"10.1093","volume":"193","author":[{"given":"Mireia","family":"Gim\u00e9nez-Barcons","sequence":"first","affiliation":[{"name":"Divisi\u00f3 d'Immunologia, Hospital Universitari Vall d\u2019Hebron, Vall d\u2019Hebron Institut de Recerca , Barcelona 08035 ,","place":["Spain"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anna","family":"Caster\u00e0s","sequence":"additional","affiliation":[{"name":"Divisi\u00f3 d'Endocrinologia, Hospital Universitari Vall d\u2019Hebron, Vall d\u2019Hebron Institut de Recerca , Barcelona 08035 ,","place":["Spain"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maria del Pilar","family":"Armengol","sequence":"additional","affiliation":[{"name":"Institut d\u2019Investigaci\u00f3 en Ci\u00e8ncies de la Salut Germans Trias i Pujol , Badalona 08916 ,","place":["Spain"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eduard","family":"Porta","sequence":"additional","affiliation":[{"name":"Institut d\u2019Investigaci\u00f3 en Ci\u00e8ncies de la Salut Germans Trias i Pujol , Badalona 08916 ,","place":["Spain"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paula A","family":"Correa","sequence":"additional","affiliation":[{"name":"Institut d\u2019Investigaci\u00f3 en Ci\u00e8ncies de la Salut Germans Trias i Pujol , Badalona 08916 ,","place":["Spain"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ana","family":"Mar\u00edn","sequence":"additional","affiliation":[{"name":"Divisi\u00f3 d'Immunologia, Hospital Universitari Vall d\u2019Hebron, Vall d\u2019Hebron Institut de Recerca , Barcelona 08035 ,","place":["Spain"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ricardo","family":"Pujol-Borrell","sequence":"additional","affiliation":[{"name":"Divisi\u00f3 d'Immunologia, Hospital Universitari Vall d\u2019Hebron, Vall d\u2019Hebron Institut de Recerca , Barcelona 08035 ,","place":["Spain"]},{"name":"Departament de Biologia Cellular, de Fisiologia i d'Immunologia, Universitat Aut\u00f2noma de Barcelona , Bellaterra 08193 ,","place":["Spain"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Roger","family":"Colobran","sequence":"additional","affiliation":[{"name":"Divisi\u00f3 d'Immunologia, Hospital Universitari Vall d\u2019Hebron, Vall d\u2019Hebron Institut de Recerca , Barcelona 08035 ,","place":["Spain"]},{"name":"Departament de Biologia Cellular, de Fisiologia i d'Immunologia, Universitat Aut\u00f2noma de Barcelona , Bellaterra 08193 ,","place":["Spain"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2014,10,15]]},"reference":[{"key":"2025030707393488100_r1","doi-asserted-by":"crossref","first-page":"73","DOI":"10.1093\/ageing\/27.1.73","article-title":"The premature ageing syndromes: insights into the ageing process","volume":"27","author":"Dyer","year":"1998","journal-title":"Age Ageing"},{"key":"2025030707393488100_r2","doi-asserted-by":"crossref","first-page":"213","DOI":"10.1002\/(SICI)1096-8628(19981116)80:3<213::AID-AJMG6>3.0.CO;2-8","article-title":"Population-based study of congenital heart defects in Down syndrome","volume":"80","author":"Freeman","year":"1998","journal-title":"Am. J. Med. Genet."},{"key":"2025030707393488100_r3","doi-asserted-by":"crossref","first-page":"246","DOI":"10.1016\/j.braindev.2004.07.008","article-title":"Down syndrome, Alzheimer\u2019s disease and seizures","volume":"27","author":"Men\u00e9ndez","year":"2005","journal-title":"Brain Dev."},{"key":"2025030707393488100_r4","doi-asserted-by":"crossref","first-page":"80","DOI":"10.1542\/peds.63.1.80","article-title":"Thymic deficiency in Down\u2019s syndrome","volume":"63","author":"Levin","year":"1979","journal-title":"Pediatrics"},{"key":"2025030707393488100_r5","first-page":"225","article-title":"Morphological and immunohistochemical study of Down syndrome thymus","volume":"7","author":"Larocca","year":"1990","journal-title":"Am. J. Med. Genet. Suppl."},{"key":"2025030707393488100_r6","doi-asserted-by":"crossref","first-page":"393","DOI":"10.1542\/peds.2011-1605","article-title":"Health supervision for children with Down syndrome","volume":"128","author":"Bull","year":"2011","journal-title":"Pediatrics"},{"key":"2025030707393488100_r7","first-page":"238","article-title":"Relationship of autoimmunity to thyroid dysfunction in children and adults with Down syndrome","volume":"7","author":"Zori","year":"1990","journal-title":"Am. J. Med. Genet. Suppl."},{"key":"2025030707393488100_r8","doi-asserted-by":"crossref","first-page":"436","DOI":"10.1002\/ajmg.a.20356","article-title":"Hypothyroidism in Down syndrome: screening guidelines and testing methodology","volume":"124A","author":"Hardy","year":"2004","journal-title":"Am. J. Med. Genet. A."},{"key":"2025030707393488100_r9","doi-asserted-by":"crossref","first-page":"160","DOI":"10.1002\/(SICI)1096-9136(199802)15:2<160::AID-DIA537>3.0.CO;2-J","article-title":"Type 1 diabetes mellitus and Down\u2019s syndrome: prevalence, management and diabetic complications","volume":"15","author":"Anwar","year":"1998","journal-title":"Diabet. Med."},{"key":"2025030707393488100_r10","doi-asserted-by":"crossref","first-page":"623","DOI":"10.1111\/j.1365-2230.2006.02164.x","article-title":"Dermatological manifestations of Down\u2019s syndrome","volume":"31","author":"Madan","year":"2006","journal-title":"Clin. Exp. Dermatol."},{"key":"2025030707393488100_r11","doi-asserted-by":"crossref","first-page":"563","DOI":"10.1046\/j.1440-1746.2000.2184a.x","article-title":"Images of interest. Hepatobiliary and pancreatic: computed tomography in liver disease","volume":"15","author":"Kaushik","year":"2000","journal-title":"J. Gastroenterol. Hepatol."},{"key":"2025030707393488100_r12","doi-asserted-by":"crossref","first-page":"287","DOI":"10.1146\/annurev.immunol.25.022106.141532","article-title":"Aire","volume":"27","author":"Mathis","year":"2009","journal-title":"Annu. Rev. Immunol."},{"key":"2025030707393488100_r13","doi-asserted-by":"crossref","first-page":"105","DOI":"10.1196\/annals.1443.018","article-title":"The thymus medulla slowly yields its secrets","volume":"1143","author":"Tykocinski","year":"2008","journal-title":"Ann. N. Y. Acad. Sci."},{"key":"2025030707393488100_r14","doi-asserted-by":"crossref","first-page":"33","DOI":"10.1084\/jem.20050471","article-title":"Promiscuous gene expression in thymic epithelial cells is regulated at multiple levels","volume":"202","author":"Derbinski","year":"2005","journal-title":"J. Exp. Med."},{"key":"2025030707393488100_r15","doi-asserted-by":"crossref","first-page":"301","DOI":"10.1038\/86302","article-title":"Thymic selection of CD4+CD25+ regulatory T cells induced by an agonist self-peptide","volume":"2","author":"Jordan","year":"2001","journal-title":"Nat. Immunol."},{"key":"2025030707393488100_r16","doi-asserted-by":"crossref","first-page":"393","DOI":"10.1038\/ng1297-393","article-title":"Positional cloning of the APECED gene","volume":"17","author":"Nagamine","year":"1997","journal-title":"Nat. Genet."},{"key":"2025030707393488100_r17","doi-asserted-by":"crossref","first-page":"3422","DOI":"10.4049\/jimmunol.1003053","article-title":"Decreased AIRE expression and global thymic hypofunction in Down syndrome","volume":"187","author":"Lima","year":"2011","journal-title":"J. Immunol."},{"key":"2025030707393488100_r18","doi-asserted-by":"crossref","first-page":"1093","DOI":"10.1101\/gr.6028507","article-title":"Accurate quantitation of allele-specific expression patterns by analysis of DNA melting","volume":"17","author":"Jeong","year":"2007","journal-title":"Genome Res."},{"key":"2025030707393488100_r19","doi-asserted-by":"crossref","first-page":"3415","DOI":"10.1093\/hmg\/ddr247","article-title":"Association of an SNP with intrathymic transcription of TSHR and Graves\u2019 disease: a role for defective thymic tolerance","volume":"20","author":"Colobran","year":"2011","journal-title":"Hum. Mol. Genet."},{"key":"2025030707393488100_r20","doi-asserted-by":"crossref","first-page":"52","DOI":"10.1038\/nature09298","article-title":"Integrating common and rare genetic variation in diverse human populations","volume":"467","author":"Altshuler","year":"2010","journal-title":"Nature"},{"key":"2025030707393488100_r21","doi-asserted-by":"crossref","first-page":"446","DOI":"10.1210\/jc.2011-1429","article-title":"Overexpression of metallothionein I\/II: a new feature of thyroid follicular cells in Graves\u2019 disease","volume":"97","author":"Ruiz-Riol","year":"2012","journal-title":"J. Clin. Endocrinol. Metab."},{"key":"2025030707393488100_r22","doi-asserted-by":"crossref","first-page":"671","DOI":"10.1038\/nmeth.2089","article-title":"NIH Image to ImageJ: 25 years of image analysis","volume":"9","author":"Schneider","year":"2012","journal-title":"Nat. Methods"},{"key":"2025030707393488100_r23","volume-title":"A Language and Environment for Statistical Computing.","author":"R Development Core Team","year":"2008"},{"key":"2025030707393488100_r24","doi-asserted-by":"crossref","first-page":"25","DOI":"10.3104\/reviews.95","article-title":"Down syndrome and thyroid disorders: a review","volume":"6","author":"Prasher","year":"1999","journal-title":"Downs Syndr. Res. Pract."},{"key":"2025030707393488100_r25","doi-asserted-by":"crossref","first-page":"1395","DOI":"10.1126\/science.1075958","article-title":"Projection of an immunological self shadow within the thymus by the aire protein","volume":"298","author":"Anderson","year":"2002","journal-title":"Science"},{"key":"2025030707393488100_r26","doi-asserted-by":"crossref","first-page":"221","DOI":"10.1007\/BF00300707","article-title":"Cytokeratin expression in human thymus: immunohistochemical mapping","volume":"279","author":"Shezen","year":"1995","journal-title":"Cell Tissue Res."},{"key":"2025030707393488100_r27","doi-asserted-by":"crossref","first-page":"838","DOI":"10.1002\/eji.200636962","article-title":"Highly variable expression of tissue-restricted self-antigens in human thymus: implications for self-tolerance and autoimmunity","volume":"37","author":"Taubert","year":"2007","journal-title":"Eur. J. Immunol."},{"key":"2025030707393488100_r28","doi-asserted-by":"crossref","first-page":"1253","DOI":"10.1172\/JCI14321","article-title":"Thyroid autoimmunity","volume":"108","author":"Rapoport","year":"2001","journal-title":"J. Clin. Invest."},{"key":"2025030707393488100_r29","doi-asserted-by":"crossref","first-page":"393","DOI":"10.1146\/annurev-immunol-020711-074953","article-title":"Monogenic autoimmunity","volume":"30","author":"Cheng","year":"2012","journal-title":"Annu. Rev. Immunol."},{"key":"2025030707393488100_r30","doi-asserted-by":"crossref","first-page":"289","DOI":"10.1038\/ng0397-289","article-title":"Insulin expression in human thymus is modulated by INS VNTR alleles at the IDDM2 locus","volume":"15","author":"Vafiadis","year":"1997","journal-title":"Nat. Genet."},{"key":"2025030707393488100_r31","doi-asserted-by":"crossref","first-page":"293","DOI":"10.1038\/ng0397-293","article-title":"The insulin gene is transcribed in the human thymus and transcription levels correlated with allelic variation at the INS VNTR-IDDM2 susceptibility locus for type 1 diabetes","volume":"15","author":"Pugliese","year":"1997","journal-title":"Nat. Genet."},{"key":"2025030707393488100_r32","doi-asserted-by":"crossref","first-page":"934","DOI":"10.1038\/nature06066","article-title":"An IRF8-binding promoter variant and AIRE control CHRNA1 promiscuous expression in thymus","volume":"448","author":"Giraud","year":"2007","journal-title":"Nature"},{"key":"2025030707393488100_r33","doi-asserted-by":"crossref","first-page":"841","DOI":"10.1002\/pd.2783","article-title":"Sonographic thymic measurements in Down syndrome fetuses","volume":"31","author":"De Leon-Luis","year":"2011","journal-title":"Prenat. Diagn."},{"key":"2025030707393488100_r34","doi-asserted-by":"crossref","first-page":"2827","DOI":"10.1084\/jem.20080046","article-title":"Aire controls the differentiation program of thymic epithelial cells in the medulla for the establishment of self-tolerance","volume":"205","author":"Yano","year":"2008","journal-title":"J. Exp. Med."},{"key":"2025030707393488100_r35","doi-asserted-by":"crossref","first-page":"5225","DOI":"10.4049\/jimmunol.181.8.5225","article-title":"Alterations of the medullary epithelial compartment in the Aire-deficient thymus: implications for programs of thymic epithelial differentiation","volume":"181","author":"Dooley","year":"2008","journal-title":"J. Immunol."},{"key":"2025030707393488100_r36","doi-asserted-by":"crossref","first-page":"3007","DOI":"10.4049\/jimmunol.178.5.3007","article-title":"Aire-dependent alterations in medullary thymic epithelium indicate a role for Aire in thymic epithelial differentiation","volume":"178","author":"Gillard","year":"2007","journal-title":"J. Immunol."},{"key":"2025030707393488100_r37","doi-asserted-by":"crossref","first-page":"210","DOI":"10.3389\/fimmu.2013.00210","article-title":"Which model better fits the role of aire in the establishment of self-tolerance: the transcription model or the maturation model?","volume":"4","author":"Matsumoto","year":"2013","journal-title":"Front. Immunol."},{"key":"2025030707393488100_r38","doi-asserted-by":"crossref","first-page":"209","DOI":"10.1006\/clin.1996.0031","article-title":"Immune dysfunction in Down\u2019s syndrome: primary immune deficiency or early senescence of the immune system?","volume":"78","author":"Cuadrado","year":"1996","journal-title":"Clin. Immunol. Immunopathol."},{"key":"2025030707393488100_r39","first-page":"213","article-title":"Precocious aging of the immune system in Down syndrome: alteration of B lymphocytes, T-lymphocyte subsets, and cells with natural killer markers","volume":"7","author":"Cossarizza","year":"1990","journal-title":"Am. J. Med. Genet. Suppl."},{"key":"2025030707393488100_r40","doi-asserted-by":"crossref","first-page":"573","DOI":"10.1089\/rej.2007.0648","article-title":"Homeostatic cytokines and expansion of regulatory T cells accompany thymic impairment in children with Down syndrome","volume":"11","author":"Roat","year":"2008","journal-title":"Rejuvenation Res."},{"key":"2025030707393488100_r41","doi-asserted-by":"crossref","first-page":"182","DOI":"10.1111\/j.1440-1754.2007.01229.x","article-title":"Autoantibodies in patients with Down syndrome: early senescence of the immune system or precocious markers for immunological diseases?","volume":"44","author":"da Rosa Utiyama","year":"2008","journal-title":"J. Paediatr. Child Health"},{"key":"2025030707393488100_r42","doi-asserted-by":"crossref","first-page":"189","DOI":"10.1111\/j.1365-2249.2009.03890.x","article-title":"Intrinsic defect of the immune system in children with Down syndrome: a review","volume":"156","author":"Kusters","year":"2009","journal-title":"Clin. Exp. Immunol."},{"key":"2025030707393488100_r43","doi-asserted-by":"crossref","first-page":"475","DOI":"10.1086\/520000","article-title":"Classification of human chromosome 21 gene-expression variations in Down syndrome: impact on disease phenotypes","volume":"81","author":"A\u00eft Yahya-Graison","year":"2007","journal-title":"Am. J. Hum. Genet."},{"key":"2025030707393488100_r44","doi-asserted-by":"crossref","first-page":"252","DOI":"10.1086\/519248","article-title":"Natural gene-expression variation in Down syndrome modulates the outcome of gene-dosage imbalance","volume":"81","author":"Prandini","year":"2007","journal-title":"Am. J. Hum. Genet."},{"key":"2025030707393488100_r45","doi-asserted-by":"crossref","first-page":"278","DOI":"10.1016\/j.gene.2013.07.055","article-title":"Identification of dysregulated microRNAs in lymphocytes from children with Down syndrome","volume":"530","author":"Xu","year":"2013","journal-title":"Gene"},{"key":"2025030707393488100_r46","doi-asserted-by":"crossref","first-page":"540","DOI":"10.4161\/rna.7.5.12685","article-title":"Trisomy-21 gene dosage over-expression of miRNAs results in the haploinsufficiency of specific target proteins","volume":"7","author":"Elton","year":"2010","journal-title":"RNA Biol."},{"key":"2025030707393488100_r47","doi-asserted-by":"crossref","first-page":"451","DOI":"10.1159\/000330884","article-title":"Abnormal microRNA expression in Ts65Dn hippocampus and whole blood: contributions to Down syndrome phenotypes","volume":"33","author":"Keck-Wherley","year":"2011","journal-title":"Dev. Neurosci."},{"key":"2025030707393488100_r48","doi-asserted-by":"crossref","first-page":"100","DOI":"10.1016\/j.neulet.2009.04.052","article-title":"Micro-RNA abundance and stability in human brain: specific alterations in Alzheimer\u2019s disease temporal lobe neocortex","volume":"459","author":"Sethi","year":"2009","journal-title":"Neurosci. Lett."},{"key":"2025030707393488100_r49","doi-asserted-by":"crossref","first-page":"175","DOI":"10.1097\/00043426-200103000-00012","article-title":"Relationship of chromosome 21 and acute leukemia in children with Down syndrome","volume":"23","author":"Taub","year":"2001","journal-title":"J. Pediatr. Hematol. Oncol."},{"key":"2025030707393488100_r50","doi-asserted-by":"crossref","first-page":"1769","DOI":"10.1002\/eji.201343343","article-title":"An evolutionarily conserved mutual interdependence between Aire and microRNAs in promiscuous gene expression","volume":"43","author":"Ucar","year":"2013","journal-title":"Eur. J. 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