{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,6]],"date-time":"2026-10-06T04:41:21Z","timestamp":1791261681530,"version":"4.1.0"},"reference-count":39,"publisher":"MDPI AG","issue":"2","license":[{"start":{"date-parts":[[2021,2,13]],"date-time":"2021-02-13T00:00:00Z","timestamp":1613174400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Genes"],"abstract":"<jats:p>Within immune system-related diseases, autoimmunity has always represented a field of great interest, although many aspects remain poorly understood even today. Genetic syndromes associated with immunity disorders are common and represent an interesting model for a better understanding of the underlying mechanism of autoimmunity predisposition. Among these conditions, Down syndrome (DS) certainly deserves special attention as it represents the most common genetic syndrome associated with immune dysregulation, involving both innate and adaptive immunity. Autoimmunity represents a well-known complication of DS: it is estimated that people affected by this disease present a risk four to six times higher than the normal population to develop autoimmune diseases such as celiac disease, type 1 diabetes mellitus, and hypo- or hyperthyroidism. Several factors have been considered as possible etiology, including genetic and epigenetic modifications and immune dysregulation. In times in which the life expectancy of people with DS has been extremely prolonged, thanks to improvements in the diagnosis and treatment of congenital heart disease and infectious complications, knowledge of the mechanisms and proper management of autoimmune diseases within this syndrome has become essential. In this short review, we aim to report the current literature regarding the genetic, immune, and environmental factors that have been proposed as the possible underlying mechanism of autoimmunity in individuals with DS, with the intent to provide insight for a comprehensive understanding of these diseases in genetic syndromes.<\/jats:p>","DOI":"10.3390\/genes12020268","type":"journal-article","created":{"date-parts":[[2021,2,14]],"date-time":"2021-02-14T02:08:12Z","timestamp":1613268492000},"page":"268","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":44,"title":["Autoimmunity and Genetic Syndromes: A Focus on Down Syndrome"],"prefix":"10.3390","volume":"12","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-4858-4028","authenticated-orcid":false,"given":"Marta","family":"Ferrari","sequence":"first","affiliation":[{"name":"Health Sciences Department, University of Florence, Anna Meyer Children\u2019s University Hospital, Viale Pieraccini 24, 50139 Florence, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2259-4685","authenticated-orcid":false,"given":"Stefano","family":"Stagi","sequence":"additional","affiliation":[{"name":"Health Sciences Department, University of Florence, Anna Meyer Children\u2019s University Hospital, Viale Pieraccini 24, 50139 Florence, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2021,2,13]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"543","DOI":"10.3389\/fendo.2020.00543","article-title":"Autoimmune Thyroid Disease in Specific Genetic Syndromes in Childhood and Adolescence","volume":"11","author":"Kyritsi","year":"2020","journal-title":"Front. Endocrinol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1077","DOI":"10.1002\/ajmg.a.35290","article-title":"Autoimmune disease and multiple autoantibodies in 42 patients with RASopathies","volume":"158A","author":"Quaio","year":"2012","journal-title":"Am. J. Med Genet. Part A"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"345","DOI":"10.1007\/s12026-015-8707-4","article-title":"Epigenetic control of the immune system: A lesson from Kabuki syndrome","volume":"64","author":"Stagi","year":"2016","journal-title":"Immunol. Res."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"135","DOI":"10.1016\/j.metabol.2017.09.017","article-title":"Klinefelter syndrome: More than hypogonadism","volume":"86","author":"Kanakis","year":"2018","journal-title":"Metabolism"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"102469","DOI":"10.1016\/j.autrev.2020.102469","article-title":"Understanding the immunopathogenesis of autoimmune diseases by animal studies using gene modulation: A comprehensive review","volume":"19","author":"Lee","year":"2020","journal-title":"Autoimmun. Rev."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"454","DOI":"10.1136\/adc.44.236.454","article-title":"Autoimmune thyroid disease in children with mongolism","volume":"44","author":"Aarskog","year":"1969","journal-title":"Arch. Dis. Child."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"426","DOI":"10.1016\/S1081-1206(10)60516-9","article-title":"Follow-up study of immune defects in patients with dysmorphic disorders","volume":"102","author":"Cruz","year":"2009","journal-title":"Ann. Allergy Asthma Immunol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"840","DOI":"10.3389\/fimmu.2020.00840","article-title":"Immune Defect in Adults with Down Syndrome: Insights Into a Complex Issue","volume":"11","author":"Jeljeli","year":"2020","journal-title":"Front. Immunol."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"483","DOI":"10.1038\/icb.2012.9","article-title":"The interferons and their receptors\u2014distribution and regulation","volume":"90","author":"Nguyen","year":"2012","journal-title":"Immunol. Cell Biol."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"769","DOI":"10.1007\/s10571-017-0514-0","article-title":"Chromosome 21-Encoded microRNAs (mRNAs): Impact on Down\u2019s Syndrome and Trisomy-21 Linked Disease","volume":"38","author":"Alexandrov","year":"2017","journal-title":"Cell. Mol. Neurobiol."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"2683","DOI":"10.3389\/fimmu.2018.02683","article-title":"Dysregulated miR-155 and miR-125b Are Related to Impaired B-cell Responses in Down Syndrome","volume":"9","author":"Farroni","year":"2018","journal-title":"Front. Immunol."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"73","DOI":"10.3389\/fped.2020.00073","article-title":"Immune Dysregulation in Children with Down Syndrome","volume":"8","author":"Huggard","year":"2020","journal-title":"Front. Pediatr."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"791","DOI":"10.1007\/s10875-020-00805-7","article-title":"Inborn Errors of Adaptive Immunity in Down Syndrome","volume":"40","author":"Verstegen","year":"2020","journal-title":"J. Clin. Immunol."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"600","DOI":"10.1002\/eji.1830050904","article-title":"Derangements of immunoglobulin levels, phytohemagglutinin responsiveness and T and B cell markers in Down\u2019s syndrome at different ages","volume":"5","author":"Burgio","year":"1975","journal-title":"Eur. J. Immunol."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"447","DOI":"10.3389\/fimmu.2019.00447","article-title":"Thymic Epithelium Abnormalities in DiGeorge and Down Syndrome Patients Contribute to Dysregulation in T Cell Development","volume":"10","author":"Marcovecchio","year":"2019","journal-title":"Front. Immunol."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"24231","DOI":"10.1073\/pnas.1908129116","article-title":"Trisomy 21 dysregulates T cell lineages toward an autoimmunity-prone state associated with interferon hyperactivity","volume":"116","author":"Araya","year":"2019","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"436","DOI":"10.1111\/j.1365-3083.2012.02671.x","article-title":"Paediatric Reference Values for the Peripheral T cell Compartment","volume":"75","author":"Gemen","year":"2012","journal-title":"Scand. J. Immunol."},{"key":"ref_18","first-page":"8","article-title":"Lymphocyte subsets in healthy children from birth through 18 years of age: The Pediatric AIDS Clinical Trials Group P1009 study","volume":"112","author":"Shearer","year":"2003","journal-title":"Basic Clin. Immunol."},{"key":"ref_19","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":"ref_20","doi-asserted-by":"crossref","first-page":"2187","DOI":"10.4049\/jimmunol.1400742","article-title":"Altered Expression of Autoimmune Regulator in Infant Down Syndrome Thymus, a Possible Contributor to an Autoimmune Phenotype","volume":"193","author":"Skogberg","year":"2014","journal-title":"J. Immunol."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"3872","DOI":"10.4049\/jimmunol.1400223","article-title":"Autoimmune Predisposition in Down Syndrome May Result from a Partial Central Tolerance Failure due to Insufficient Intrathymic Expression of AIRE and Peripheral Antigens","volume":"193","author":"Armengol","year":"2014","journal-title":"J. Immunol."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"238","DOI":"10.1111\/j.1365-2249.2012.04610.x","article-title":"Down syndrome, autoimmunity and T regulatory cells","volume":"169","author":"Pellegrini","year":"2012","journal-title":"Clin. Exp. Immunol."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"4068734","DOI":"10.1155\/2019\/4068734","article-title":"Altered Toll-Like Receptor Signalling in Children with Down Syndrome","volume":"2019","author":"Huggard","year":"2019","journal-title":"Mediat. Inflamm."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"100019","DOI":"10.1016\/j.xcrm.2020.100019","article-title":"Down Syndrome and COVID-19: A Perfect Storm?","volume":"1","author":"Espinosa","year":"2020","journal-title":"Cell Rep. Med."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1155\/2018\/6539548","article-title":"Interleukin 6 and 10 Serum Levels and Genetic Polymorphisms in Children with Down Syndrome","volume":"2018","author":"Mattos","year":"2018","journal-title":"Mediat. Inflamm."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1038\/s41598-017-13858-3","article-title":"Trisomy 21 causes changes in the circulating proteome indicative of chronic autoinflammation","volume":"7","author":"Sullivan","year":"2017","journal-title":"Sci. Rep."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"108407","DOI":"10.1016\/j.celrep.2020.108407","article-title":"JAK1 Inhibition Blocks Lethal Immune Hypersensitivity in a Mouse Model of Down Syndrome","volume":"33","author":"Tuttle","year":"2020","journal-title":"Cell Rep."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"1893","DOI":"10.1016\/j.celrep.2019.10.038","article-title":"Mass Cytometry Reveals Global Immune Remodeling with Multi-lineage Hypersensitivity to Type I Interferon in Down Syndrome","volume":"29","author":"Waugh","year":"2019","journal-title":"Cell Rep."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1155\/2020\/6876920","article-title":"Autoimmune Mechanisms of Interferon Hypersensitivity and Neurodegenerative Diseases: Down Syndrome","volume":"2020","author":"Jagadeesh","year":"2020","journal-title":"Autoimmune Dis."},{"key":"ref_30","doi-asserted-by":"crossref","unstructured":"Smatti, M.K., Cyprian, F.S., Nasrallah, G.K., Al Thani, A.A., Almishal, R.O., and Yassine, H.M. (2019). Viruses and Autoimmunity: A Review on the Potential Interaction and Molecular Mechanisms. Viruses, 11.","DOI":"10.3390\/v11080762"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"599","DOI":"10.1146\/annurev-immunol-042718-041841","article-title":"Gut Microbiota Regulation of T Cells During Inflammation and Autoimmunity","volume":"37","author":"Brown","year":"2019","journal-title":"Annu. Rev. Immunol."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"181","DOI":"10.1016\/j.ridd.2016.06.018","article-title":"Overweight and obesity in children and adolescents with Down syndrome\u2014prevalence, determinants, consequences, and interventions: A literature review","volume":"57","author":"Bertapelli","year":"2016","journal-title":"Res. Dev. Disabil."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1155\/2015\/896758","article-title":"Determinants of Vitamin D Levels in Children and Adolescents with Down Syndrome","volume":"2015","author":"Stagi","year":"2015","journal-title":"Int. J. Endocrinol."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"J266","DOI":"10.1016\/j.jaut.2009.11.012","article-title":"Drugs and autoimmunity\u2014A contemporary review and mechanistic approach","volume":"34","author":"Chang","year":"2010","journal-title":"J. Autoimmun."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1186\/s13052-018-0478-9","article-title":"Epidemiological and clinical aspects of autoimmune thyroid diseases in children with Down\u2019s syndrome","volume":"44","author":"Aversa","year":"2018","journal-title":"Ital. J. Pediatr."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"252","DOI":"10.1097\/MPG.0000000000002742","article-title":"Routine Screening for Celiac Disease in Children with Down Syndrome Improves Case Finding","volume":"71","author":"Liu","year":"2020","journal-title":"J. Pediatr. Gastroenterol. Nutr."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1007\/s11892-020-01318-8","article-title":"Early Onset of Autoimmune Diabetes in Children with Down Syndrome\u2014Two Separate Aetiologies or an Immune System Pre-Programmed for Autoimmunity?","volume":"20","author":"Mortimer","year":"2020","journal-title":"Curr. Diabetes Rep."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"1539","DOI":"10.1002\/ajmg.a.38219","article-title":"Thyroid dysfunction in patients with Down syndrome: Results from a multi-institutional registry study","volume":"173","author":"Lavigne","year":"2017","journal-title":"Am. J. Med Genet. Part A"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"170","DOI":"10.1159\/000457952","article-title":"Characterization of Thyroid Abnormalities in a Large Cohort of Children with Down Syndrome","volume":"87","author":"Pierce","year":"2017","journal-title":"Horm. Res. Paediatr."}],"container-title":["Genes"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2073-4425\/12\/2\/268\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T05:23:38Z","timestamp":1760160218000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2073-4425\/12\/2\/268"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,2,13]]},"references-count":39,"journal-issue":{"issue":"2","published-online":{"date-parts":[[2021,2]]}},"alternative-id":["genes12020268"],"URL":"https:\/\/doi.org\/10.3390\/genes12020268","relation":{},"ISSN":["2073-4425"],"issn-type":[{"value":"2073-4425","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,2,13]]}}}