title: Demethylation analysis of the FOXP3 locus shows quantitative defects of regulatory T cells in IPEX-like syndrome.
abstract: Immune dysregulation, Polyendocrinopathy, Enteropathy X-linked (IPEX) syndrome is a unique example of primary immunodeficiency characterized by autoimmune manifestations due to defective regulatory T (Treg) cells, in the presence of FOXP3 mutations. However, autoimmune symptoms phenotypically resembling IPEX often occur in the absence of detectable FOXP3 mutations. The cause of this "IPEX-like" syndrome presently remains unclear. To investigate whether a defect in Treg cells sustains the immunological dysregulation in IPEX-like patients, we measured the amount of peripheral Treg cells within the CD3(+) T cells by analysing demethylation of the Treg cell-Specific-Demethylated-Region (TSDR) in the FOXP3 locus and demethylation of the T cell-Specific-Demethylated-Region (TLSDR) in the CD3 locus, highly specific markers for stable Treg cells and overall T cells, respectively. TSDR demethylation analysis, alone or normalized for the total T cells, showed that the amount of peripheral Treg cells in a cohort of IPEX-like patients was significantly reduced, as compared to both healthy subjects and unrelated disease controls. This reduction could not be displayed by flow cytometric analysis, showing highly variable percentages of FOXP3(+) and CD25(+)FOXP3(+) T cells. These data provide evidence that a quantitative defect of Treg cells could be considered a common biological hallmark of IPEX-like syndrome. Since Treg cell suppressive function was not impaired, we propose that this reduction per se could sustain autoimmunity.
authors.affiliation: San Raffaele Telethon Institute for Gene Therapy, Division of Regenerative Medicine, Stem Cells and Gene Therapy, San Raffaele Scientific Institute, Via Olgettina 58, 20131 Milan, Italy.
authors.forename: F
authors.initials: F
authors.lastname: Barzaghi
authors.forename: L
authors.initials: L
authors.lastname: Passerini
authors.forename: E
authors.initials: E
authors.lastname: Gambineri
authors.forename: S
authors.initials: S
authors.lastname: Ciullini Mannurita
authors.forename: T
authors.initials: T
authors.lastname: Cornu
authors.forename: E S
authors.initials: ES
authors.lastname: Kang
authors.forename: Y H
authors.initials: YH
authors.lastname: Choe
authors.forename: C
authors.initials: C
authors.lastname: Cancrini
authors.forename: S
authors.initials: S
authors.lastname: Corrente
authors.forename: R
authors.initials: R
authors.lastname: Ciccocioppo
authors.forename: M
authors.initials: M
authors.lastname: Cecconi
authors.forename: G
authors.initials: G
authors.lastname: Zuin
authors.forename: V
authors.initials: V
authors.lastname: Discepolo
authors.forename: C
authors.initials: C
authors.lastname: Sartirana
authors.forename: J
authors.initials: J
authors.lastname: Schmidtko
authors.forename: A
authors.initials: A
authors.lastname: Ikinciogullari
authors.forename: A
authors.initials: A
authors.lastname: Ambrosi
authors.forename: M G
authors.initials: MG
authors.lastname: Roncarolo
authors.forename: S
authors.initials: S
authors.lastname: Olek
authors.forename: R
authors.initials: R
authors.lastname: Bacchetta
mesh_terms: D000293:Adolescent; D000328:Adult; D017252:CD3 Complex / Q000276:immunology / Q000378:metabolism; D002648:Child; D002675:Child, Preschool; D015331:Cohort Studies; D019175:DNA Methylation; D005260:Female; D005434:Flow Cytometry; D051858:Forkhead Transcription Factors / Q000235:genetics*; D040181:Genetic Diseases, X-Linked / Q000235:genetics / Q000276:immunology; D006801:Humans; D007153:Immunologic Deficiency Syndromes / Q000235:genetics / Q000276:immunology; D007223:Infant; D008297:Male; D016884:Polyendocrinopathies, Autoimmune / Q000235:genetics* / Q000276:immunology*; D013577:Syndrome; D050378:T-Lymphocytes, Regulatory / Q000276:immunology* / Q000378:metabolism*; D055815:Young Adult
chemical_list: D017252:CD3 Complex; C418974:FOXP3 protein, human; D051858:Forkhead Transcription Factors