Hypomethylation and overexpression of ITGAL (CD11a) in CD4(+) T cells in systemic sclerosis.
Hypomethylation and overexpression of ITGAL (CD11a) in CD4(+) T cells in systemic sclerosis.
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系统性硬化症 CD4( ) T 细胞中 ITGAL (CD11a) 的低甲基化和过度表达
DOI：
10.1186/1868-7083-6-25
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发表时间：
2014
影响因子：
5.7
通讯作者：
Xiao R
中科院分区：
文献类型：
--
作者：
Wang Y;Shu Y;Xiao Y;Wang Q;Kanekura T;Li Y;Wang J;Zhao M;Lu Q;Xiao R
系统性硬化症(SSC)的发病机制和病因复杂且知之甚少。到目前为止，已有多项研究表明，免疫系统的激活无疑在SSC的发病机制中起着关键作用。活化的免疫效应T细胞有助于释放各种促炎细胞因子，并驱动SSC特异性自身抗体反应。这一点，以及促纤维化的环境，都是异常主动免疫反应的重要组成部分，可能导致SSC的病理性疾病。CD11a对炎症和免疫反应是必不可少的，调节CD4+T细胞与其他细胞之间的黏附和共刺激相互作用。尽管CD11a在SSC患者中过度表达，但导致这种过度表达的机制及其后果尚不清楚。DNA甲基化是一种主要的表观遗传修饰，在基因表达调控中发挥重要作用，并参与自身免疫性疾病的发病机制。本工作旨在研究DNA去甲基化对SSC CD4+T细胞CD11a表达的影响，并探讨其功能意义。用RT-PCR和流式细胞仪检测CD11a的表达。用亚硫酸氢盐测序确定CD11a调控区的甲基化状态。用抗CD11a抗体与抗原提呈细胞、B细胞或成纤维细胞共培养，检测细胞增殖、B细胞产生免疫球蛋白G及成纤维细胞COL1A2的表达水平。在SSC患者的CD4+T细胞中观察到CD11a表达水平升高；这些水平被发现与疾病活动性呈正相关。SSC患者CD11a调控序列甲基化水平低于对照组，且与CD11a基因表达呈负相关。用5-氮杂胞苷(5-azaC)处理CD4+T细胞后，CD11a启动子甲基化减少，导致CD11a过表达。SSC和5-azaC处理的CD_4~+T细胞均能促进CD_4~+T细胞的增殖，增加共培养的B细胞产生的免疫球蛋白G，并诱导共培养的成纤维细胞表达COL1A2。这些刺激作用可被抗CD11a抗体所消除。CD11a调节元件的去甲基化和随后的CD11a在CD4+T细胞中的过度表达可能参与了SSC的免疫异常和纤维化过程。
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. 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. Demethylation of CD11a regulatory elements and subsequent CD11a overexpression in CD4+ T cells may mediate immunological abnormalities and fibrotic processes in SSc.
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影响因子：
32.4
作者：
Arana, Eloisa;Vehlow, Anne;Batista, Facundo D.
通讯作者：
Batista, Facundo D.
影响因子：
2.1
作者：
Lei, W.;Luo, Y.;Lu, Q.
通讯作者：
Lu, Q.
影响因子：
6.4
作者：
López-Hoyos, M;Revilla, C;Merino, J
通讯作者：
Merino, J
影响因子：
32.4
作者：
Carrasco, YR;Fleire, SJ;Batista, FD
通讯作者：
Batista, FD
影响因子：
7
作者：
Lai AY;Mav D;Shah R;Grimm SA;Phadke D;Hatzi K;Melnick A;Geigerman C;Sobol SE;Jaye DL;Wade PA
通讯作者：
Wade PA