Hypomethylation and overexpression of ITGAL (CD11a) in CD4+ T cells in systemic sclerosis

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• 作者：YaoYao Wang (1) (2)
  Ye Shu (3)
  YangFan Xiao (1)
  Qing Wang (1)
  Takuro Kanekura (4)
  YaPing Li (1)
  JiuCun Wang (5)
  Ming Zhao (1) (6)
  QianJin Lu (1) (6)
  Rong Xiao (1)
  
  1. Department of Dermatology ; Second Xiangya Hospital ; Central South University ; 139 Ren-Min Road ; Changsha ; 410011 ; China
  2. Department of Dermatology ; Sir Run Run Shaw Hospital ; Zhejiang University ; 3 East Qingchun Road ; Hangzhou ; 310016 ; China
  3. Department of Dermatology ; Hunan Children鈥檚 Hospital ; 86 Zi-Yuan Road ; Changsha ; 410007 ; China
  4. Department of Dermatology ; Kagoshima University Graduate School of Medical and Dental Sciences ; 8-35-1 Sakuragaoka ; Kagoshima ; 890-8520 ; Japan
  5. Ministry of Education (MOE) Key Laboratory of Contemporary Anthropology and State Key Laboratory of Genetic Engineering ; School of Life Sciences ; Fudan University ; 220 Handan Road ; 200433 ; Shanghai ; China
  6. Hunan Key Laboratory of Medical Epigenomics ; 139 Ren-Min Road ; Changsha ; 410011 ; China
  
• 关键词：CD11a ; CD4+ T cells ; COL1A2 ; DNA methylation ; Systemic sclerosis
• 刊名：Clinical Epigenetics
• 出版年：2014
• 出版时间：December 2014
• 年：2014
• 卷：6
• 期：1
• 全文大小：1,271 KB
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• 刊物主题：Human Genetics; Gene Function;
• 出版者：BioMed Central
• ISSN：1868-7083

文摘

Background The pathogenesis and etiology of systemic sclerosis (SSc) are complex and poorly understood. To date, several studies have demonstrated that the activation of the immune system undoubtedly plays a pivotal role in SSc pathogenesis. Activated immune effector T cells contribute to the release of various pro-inflammatory cytokines and drive the SSc-specific autoantibody responses. This, and a profibrotic environment, are all-important components of abnormal active immune responses that can lead to pathological disorders of SSc. CD11a is essential to inflammatory and immune responses, regulating adhesive and co-stimulatory interactions between CD4+ T cells and other cells. Although CD11a is overexpressed in SSc patients, the mechanisms leading to this overexpression and its consequences remain unclear. DNA methylation, a main epigenetic modification, plays an important role in the regulation of gene expression and is involved in the pathogenesis of autoimmune diseases. This work aims to investigate the effect of DNA demethylation on CD11a expression in SSc CD4+ T cells and to determine its functional significance. CD11a expression was measured using RT-PCR and flow cytometry. Bisulfite sequencing was used to determine the methylation status of the CD11a regulatory region. CD4+ T cells were co-cultured with antigen-presenting cells, B cells, or fibroblasts with and without anti-CD11a, and proliferation of CD4+ T cells, IgG production by B cells, and expression levels of COL1A2 mRNA by fibroblasts were evaluated. Results Elevated CD11a expression levels were observed in CD4+ T cells from SSc patients; these levels were found to be positively correlated with disease activity. The methylation levels of the CD11a regulatory sequences were lower in SSc patients than in controls and inversely correlated with CD11a mRNA expression. Treatment of CD4+ T cells with 5-azacytidine (5-azaC) decreased CD11a promoter methylation and caused CD11a overexpression. SSc CD4+ T cells and 5-azaC-treated CD4+ T cells showed increased proliferation of CD4+ T cells, increased production of IgG by co-cultured B cells, and induced expression of COL1A2 mRNA by co-cultured fibroblasts. These stimulatory effects were abrogated by anti-CD11a. Conclusions Demethylation of CD11a regulatory elements and subsequent CD11a overexpression in CD4+ T cells may mediate immunological abnormalities and fibrotic processes in SSc.