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

被引：61

作者：

Barzaghi, F. ^{[1
,2
]}

Passerini, L. ^{[1
]}

Gambineri, E. ^{[3
]}

Mannurita, S. Ciullini ^{[3
]}

Cornu, T. ^{[4
]}

Kang, E. S. ^{[5
]}

Choe, Y. H. ^{[6
]}

Cancrini, C. ^{[7
,8
]}

Corrente, S. ^{[7
,8
]}

Ciccocioppo, R. ^{[9
]}

Cecconi, M. ^{[10
]}

Zuin, G. ^{[11
]}

Discepolo, V. ^{[12
]}

Sartirana, C. ^{[1
]}

Schmidtko, J. ^{[13
,14
]}

Ikinciogullari, A. ^{[15
]}

Ambrosi, A. ^{[2
]}

Roncarolo, M. G. ^{[1
,2
]}

Olek, S. ^{[4
]}

Bacchetta, R. ^{[1
]}

机构：

[1] Ist Sci San Raffaele, San Raffaele Telethon Inst Gene Therapy HSR TIGET, Div Regenerat Med Stem Cells & Gene Therapy, I-20131 Milan, Italy

[2] Univ Vita Salute San Raffaele, I-20131 Milan, Italy

[3] Univ Florence, Anna Meyer Childrens Hosp, Dept Sci Woman & Childs Hlth, I-50139 Florence, Italy

[4] Epiontis GmbH, D-12489 Berlin, Germany

[5] Sungkyunkwan Univ, Sch Med, Samsung Med Ctr, Dept Lab Med & Genet, Seoul 135710, South Korea

[6] Sungkyunkwan Univ, Sch Med, Samsung Med Ctr, Dept Pediat, Seoul 135710, South Korea

[7] Childrens Hosp Bambino Gesu, Dept Pediat, I-00165 Rome, Italy

[8] Univ Roma Tor Vergata, Sch Med, I-00165 Rome, Italy

[9] Univ Pavia, Fdn IRCSS Policlin San Matteo, Med Clin 1, I-27100 Pavia, Italy

[10] Osped Galliera, Human Genet Labs, I-16128 Genoa, Italy

[11] Vittore Buzzi Childrens Hosp, Dept Pediat, I-20154 Milan, Italy

[12] Univ Naples Federico II, Dept Pediat, European Lab Invest Food Induced Dis ELFID, I-80131 Naples, Italy

[13] CHU Vaudois, Serv Nephrol, CH-1011 Lausanne, Switzerland

[14] CHU Vaudois, Hypertens & Transplantat Ctr, CH-1011 Lausanne, Switzerland

[15] Ankara Univ, Sch Med, Dept Pediat Immunol & Allergy, TR-6100 Ankara, Turkey

来源：

JOURNAL OF AUTOIMMUNITY | 2012年 / 38卷 / 01期

关键词：

IPEX syndrome; IPEX-like syndrome; Regulatory T (Treg) cells; Forkhead box p3 (FOXP3); Treg cell-specific-demethylated-region (TSDR); Autoimmune enteropathy; Primary immunodeficiency (PID); DNA METHYLATION ANALYSIS; AUTOIMMUNE ENTEROPATHY; IMMUNE DYSREGULATION; CUTTING EDGE; EXPRESSION; POLYENDOCRINOPATHY; MICE; IMMUNODEFICIENCY; TOLERANCE; MUTATION;

D O I：

10.1016/j.jaut.2011.12.009

中图分类号：

R392 [医学免疫学]; Q939.91 [免疫学];

学科分类号：

100102 ;

摘要：

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. (C) 2011 Elsevier Ltd. All rights reserved.

引用

页码：49 / 58

页数：10

共 37 条

[1] Activation-induced FOXP3 in human T effector cells does not suppress proliferation or cytokine production [J].