DNA hypermethylation of the forkhead box protein 3 (FOXP3) promoter in CD4+ T cells of patients with systemic sclerosis. (6th July 2014)

• Record Type: Journal Article
• Authors: 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.
• Is Part Of: British journal of dermatology. Volume 171:Number 1(2014:Jul.)
• Page Start: 39
• Page End: 47
• Publication Date: 2014-07-06
• Subjects: Dermatology -- Periodicals; Skin -- Diseases -- Periodicals; 616.5
• DOI: 10.1111/bjd.12913
• Languages: English
• ISSNs: 0007-0963

Abstract

<abstract abstract-type="main" id="bjd12913-abs-0001"> <title>Summary</title> <sec id="bjd12913-sec-0001" sec-type="section"> <title>Background</title> <p>Systemic sclerosis (SSc) 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 SSc. Transcriptional silencing of the forkhead box protein 3 gene (<italic>FOXP3</italic>) via hypermethylation of regulatory regions has been identified as a hallmark of committed Tregs and several autoimmune disorders.</p> </sec> <sec id="bjd12913-sec-0002" sec-type="section"> <title>Objectives</title> <p>To investigate whether aberrant expression and methylation of <italic>FOXP3</italic> occurs in CD4+ T cells of patients with SSc and their roles in the pathogenesis of SSc.</p> </sec> <sec id="bjd12913-sec-0003" sec-type="section"> <title>Methods</title> <p> <italic>FOXP3</italic> expression in CD4+ 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 <italic>FOXP3</italic> proximal promoter sequence. The percentage of Treg cells was estimated by flow cytometry.</p> </sec> <sec id="bjd12913-sec-0004" sec-type="section"> <title>Results</title> <p>Decreased <italic>FOXP3</italic> expression was observed in CD4+ T cells from patients with SSc. The methylation levels of the <italic>FOXP3</italic> regulatory sequences were elevated and inversely correlated with <italic>FOXP3</italic> mRNA expression in patients with SSc. The number of Tregs was significantly reduced in patients with SSc. Treatment of SSc CD4+ T cells with a DNA methylation inhibitor, 5‐azacytidine, reduced the mean methylation levels, and enhanced <italic>FOXP3</italic> expression and Treg generation. The promoter methylation status and expression level of <italic>FOXP3</italic> are significantly associated with disease activity.</p> </sec> <sec id="bjd12913-sec-0005" sec-type="section"> <title>Conclusions</title> <p>The contribution of the hypermethylation of the <italic>FOXP3</italic> promoter to decreased <italic>FOXP3</italic> expression and the subsequent quantitative defects of Tregs may mediate the immune dysfunction in SSc.</p> </sec> </abstract>