TY - JOUR
T1 - Demethylation analysis of the FOXP3 locus shows quantitative defects of regulatory T cells in IPEX-like syndrome
AU - Barzaghi, F.
AU - Passerini, L.
AU - Gambineri, E.
AU - Ciullini Mannurita, S.
AU - Cornu, T.
AU - Kang, E. S.
AU - Choe, Y. H.
AU - Cancrini, C.
AU - Corrente, S.
AU - Ciccocioppo, R.
AU - Cecconi, M.
AU - Zuin, G.
AU - Discepolo, V.
AU - Sartirana, C.
AU - Schmidtko, J.
AU - Ikinciogullari, A.
AU - Ambrosi, A.
AU - Roncarolo, M. G.
AU - Olek, S.
AU - Bacchetta, R.
PY - 2012/2
Y1 - 2012/2
N2 - 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.
AB - 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.
KW - Autoimmune enteropathy
KW - Forkhead box p3 (FOXP3)
KW - IPEX syndrome
KW - IPEX-like syndrome
KW - Primary immunodeficiency (PID)
KW - Regulatory T (Treg) cells
KW - Treg cell-specific-demethylated-region (TSDR)
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U2 - 10.1016/j.jaut.2011.12.009
DO - 10.1016/j.jaut.2011.12.009
M3 - Article
C2 - 22264504
AN - SCOPUS:84856667596
VL - 38
SP - 49
EP - 58
JO - Journal of Autoimmunity
JF - Journal of Autoimmunity
SN - 0896-8411
IS - 1
ER -