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DNA hypermethylation of the forkhead box protein 3 ( FOXP 3 ) promoter in CD 4+ T cells of patients with systemic sclerosis
Author(s) -
Wang Y.Y.,
Wang Q.,
Sun X.H.,
Liu R.Z.,
Shu Y.,
Kanekura T.,
Huang J.H.,
Li Y.P.,
Wang J.C.,
Zhao M.,
Lu Q.J.,
Xiao R.
Publication year - 2014
Publication title -
british journal of dermatology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.304
H-Index - 179
eISSN - 1365-2133
pISSN - 0007-0963
DOI - 10.1111/bjd.12913
Subject(s) - foxp3 , dna methylation , biology , methylation , immune system , immunology , pathogenesis , gene silencing , microbiology and biotechnology , regulatory t cell , cancer research , gene expression , t cell , il 2 receptor , gene , genetics
Summary Background Systemic sclerosis ( SS c) is a complex autoimmune disease that involves dysregulation of immune homeostasis. The failure of impaired regulatory T cells (Tregs) to maintain immune homeostasis plays a major role in the development of SS c. Transcriptional silencing of the forkhead box protein 3 gene ( FOXP 3 ) via hypermethylation of regulatory regions has been identified as a hallmark of committed Tregs and several autoimmune disorders. Objectives To investigate whether aberrant expression and methylation of FOXP 3 occurs in CD 4+ T cells of patients with SS c and their roles in the pathogenesis of SS c. Methods FOXP 3 expression in CD 4+ T cells was measured by real‐time quantitative reverse‐itranscriptase polymerase chain reaction and western blot. Bisulfite sequencing was performed to determine the methylation status of the FOXP 3 proximal promoter sequence. The percentage of Treg cells was estimated by flow cytometry. Results Decreased FOXP3 expression was observed in CD4+ T cells from patients with SSc. The methylation levels of the FOXP3 regulatory sequences were elevated and inversely correlated with FOXP3 m RNA expression in patients with SS c. The number of Tregs was significantly reduced in patients with SS c. Treatment of SS c CD4+ T cells with a DNA methylation inhibitor, 5‐azacytidine, reduced the mean methylation levels, and enhanced FOXP 3 expression and Treg generation. The promoter methylation status and expression level of FOXP 3 are significantly associated with disease activity. Conclusions The contribution of the hypermethylation of the FOXP 3 promoter to decreased FOXP 3 expression and the subsequent quantitative defects of Tregs may mediate the immune dysfunction in SS c.