title: Autoimmune predisposition in Down syndrome may result from a partial central tolerance failure due to insufficient intrathymic expression of AIRE and peripheral antigens.
abstract: 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.
authors.affiliation: Divisió d'Immunologia, Hospital Universitari Vall d'Hebron, Vall d'Hebron Institut de Recerca, Barcelona 08035, Spain;
authors.forename: Mireia
authors.initials: M
authors.lastname: Giménez-Barcons
authors.affiliation: Divisió d'Endocrinologia, Hospital Universitari Vall d'Hebron, Vall d'Hebron Institut de Recerca, Barcelona 08035, Spain;
authors.forename: Anna
authors.initials: A
authors.lastname: Casteràs
authors.affiliation: Institut d'Investigació en Ciències de la Salut Germans Trias i Pujol, Badalona 08916, Spain; and.
authors.forename: Maria del Pilar
authors.initials: Mdel P
authors.lastname: Armengol
authors.affiliation: Institut d'Investigació en Ciències de la Salut Germans Trias i Pujol, Badalona 08916, Spain; and.
authors.forename: Eduard
authors.initials: E
authors.lastname: Porta
authors.affiliation: Institut d'Investigació en Ciències de la Salut Germans Trias i Pujol, Badalona 08916, Spain; and.
authors.forename: Paula A
authors.initials: PA
authors.lastname: Correa
authors.affiliation: Divisió d'Immunologia, Hospital Universitari Vall d'Hebron, Vall d'Hebron Institut de Recerca, Barcelona 08035, Spain;
authors.forename: Ana
authors.initials: A
authors.lastname: Marín
authors.affiliation: Divisió d'Immunologia, Hospital Universitari Vall d'Hebron, Vall d'Hebron Institut de Recerca, Barcelona 08035, Spain; Departament de Biologia Cellular, de Fisiologia i d'Immunologia, Universitat Autònoma de Barcelona, Bellaterra 08193, Spain rpujol@vhebron.net.
authors.forename: Ricardo
authors.initials: R
authors.lastname: Pujol-Borrell
authors.affiliation: Divisió d'Immunologia, Hospital Universitari Vall d'Hebron, Vall d'Hebron Institut de Recerca, Barcelona 08035, Spain; Departament de Biologia Cellular, de Fisiologia i d'Immunologia, Universitat Autònoma de Barcelona, Bellaterra 08193, Spain.
authors.forename: Roger
authors.initials: R
authors.lastname: Colobran
mesh_terms: D000293:Adolescent; D000328:Adult; D001327:Autoimmune Diseases / Q000150:complications / Q000235:genetics / Q000276:immunology*; D015551:Autoimmunity / Q000235:genetics / Q000276:immunology*; D061167:Central Tolerance; D002648:Child; D002675:Child, Preschool; D004314:Down Syndrome / Q000150:complications / Q000235:genetics / Q000276:immunology*; D005260:Female; D015870:Gene Expression; D006801:Humans; D007037:Hypothyroidism / Q000150:complications; D007223:Infant; D008297:Male; D013950:Thymus Gland / Q000378:metabolism; D013954:Thyroglobulin / Q000096:biosynthesis / Q000276:immunology; D014157:Transcription Factors / Q000096:biosynthesis* / Q000276:immunology; D055815:Young Adult; D000096927:AIRE Protein
chemical_list: D013954:Thyroglobulin; D014157:Transcription Factors; D000096927:AIRE Protein