Department of Dermatology, Hunan Key Laboratory of Medical Epigenomics, The Second Xiangya Hospital, Central South University, Changsha, Hunan 410011 China.
Department of Pharmaceutics, The Third Xiangya Hospital, Central South University, Changsha, Hunan 410013 China.
Clin Epigenetics. 2017 Sep 22;9:104. doi: 10.1186/s13148-017-0405-8. eCollection 2017.
Systemic lupus erythematosus (SLE) is an autoimmune disease that is characterized by lymphocytic infiltration and overproduction of autoantibodies, leading to significant morbidity and mortality. However, the pathogenesis of this disorder has not yet been completely elucidated. It has been reported that CD70, a B cell costimulatory molecule encoded by the gene (tumor necrosis factor ligand superfamily member 7), is overexpressed in CD4 T cells from patients with SLE due to the demethylation of its promoter. We aimed to investigate the expression patterns of MBD4 (methyl-CpG binding domain protein 4) in CD4 T cells and its contribution to the pathogenesis of SLE by increasing CD70 expression through epigenetic regulation.
Our results showed that the expression of MBD4 was significantly decreased in CD4 T cells from SLE patients. We verified that transfection of MBD4 siRNA into healthy CD4 T cells upregulated expression of CD70 and decreased the methylation level of the CD70 promoter. Overexpression of MBD4 inhibited CD70 expression and enhanced the DNA methylation level of CD70 in CD4 T cells of SLE patients.
Our results indicated that downregulation of MBD4 contributed to overexpression and hypomethylation of the CD70 gene in SLE CD4 T cells. This modulation of MBD4 may provide a novel therapeutic approach for SLE.
系统性红斑狼疮（SLE）是一种自身免疫性疾病，其特征为淋巴细胞浸润和自身抗体的过度产生，导致发病率和死亡率显著增加。然而，这种疾病的发病机制尚未完全阐明。据报道，由于其启动子的去甲基化，SLE 患者的 CD4 T 细胞中 CD70（一种由基因编码的 B 细胞共刺激分子[肿瘤坏死因子配体超家族成员 7]）表达过度。我们旨在通过表观遗传调控增加 CD70 表达来研究 CD4 T 细胞中 MBD4（甲基-CpG 结合域蛋白 4）的表达模式及其对 SLE 发病机制的贡献。
我们的结果表明，SLE 患者的 CD4 T 细胞中 MBD4 的表达明显降低。我们验证了将 MBD4 siRNA 转染到健康的 CD4 T 细胞中会上调 CD70 的表达并降低 CD70 启动子的甲基化水平。在 SLE 患者的 CD4 T 细胞中，过表达 MBD4 会抑制 CD70 的表达并增强 CD70 基因的 DNA 甲基化水平。
我们的结果表明，MBD4 的下调导致了 SLE CD4 T 细胞中 CD70 基因的过度表达和低甲基化。这种 MBD4 的调节可能为 SLE 提供一种新的治疗方法。
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