Demethylation analysis of the FOXP3 locus shows quantitative defects of regulatory T cells in IPEX-like syndrome

F. Barzaghi, L. Passerini, E. Gambineri, S. Ciullini Mannurita, T. Cornu, E. S. Kang, Y. H. Choe, C. Cancrini, S. Corrente, R. Ciccocioppo, M. Cecconi, G. Zuin, V. Discepolo, C. Sartirana, J. Schmidtko, A. Ikinciogullari, A. Ambrosi, M. G. Roncarolo, S. Olek, R. Bacchetta

Research output: Contribution to journalArticlepeer-review


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.

Original languageEnglish
Pages (from-to)49-58
Number of pages10
JournalJournal of Autoimmunity
Issue number1
Publication statusPublished - Feb 2012


  • Autoimmune enteropathy
  • Forkhead box p3 (FOXP3)
  • IPEX syndrome
  • IPEX-like syndrome
  • Primary immunodeficiency (PID)
  • Regulatory T (Treg) cells
  • Treg cell-specific-demethylated-region (TSDR)

ASJC Scopus subject areas

  • Immunology
  • Immunology and Allergy


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