Jing Yukai, Zhang Yunfei, Wang Xiaocui, Wang Yufen, Hu Ying, Wen Bin, Dai Xin, Duan Xuemei, Li Haonan, Dong Shumin, Yan Ze, Fan Yufeng, Wang Cong-Yi, Liu Xiansheng, Zhang Ruiping
Department of Clinical Laboratory, Third Hospital of Shanxi Medical University, Shanxi Bethune Hospital, Shanxi Academy of Medical Sciences, Tongji Shanxi Hospital, Taiyuan, China.
Institute of Clinical Medicine, Central People's Hospital of Zhanjiang, Zhanjiang, China.
Cell Death Dis. 2025 Jun 4;16(1):433. doi: 10.1038/s41419-025-07750-6.
Systemic lupus erythematosus (SLE) is a typical autoimmune disease characterized by the overproduction of autoantibodies and type I interferon, which damages its own tissues, causing multiple organ damage. B cells are thought to play a major role in the pathogenesis of SLE. As a DNA methylation reader, Methyl-CpG-binding domain protein 2 (MBD2) has been extensively studied in the contexts of innate immunity, adaptive immunity, and autoimmune diseases. However, its specific role in B cells and SLE remains unexamined. Herein, we found that MBD2 was highly expressed in B cells of SLE patients and positively correlated with disease activity. Knockout of MBD2 in B cells disturbed B-cell differentiation, dampened B-cell activation, B-cell receptor (BCR) signaling, and T-cell-dependent humoral immune responses in mice. What's more, MBD2 deficiency effectively attenuated lupus-like symptoms, reduced the germinal center responses, and decreased anti-dsDNA antibodies in lupus model mice. Mechanistically, MBD2 selectively bound to the methylated CpG of Lef-1 induced by IFN-α, inhibiting the transcription and expression of Lef-1, which repressed Pten transcription and expression, thereby promoting PI3K-Akt-mTOR signaling. This study first demonstrated the role of MBD2 in the pathogenesis of SLE and provided a new target for SLE.
系统性红斑狼疮（SLE）是一种典型的自身免疫性疾病，其特征在于自身抗体和I型干扰素过度产生，从而损害自身组织，导致多器官损伤。B细胞被认为在SLE的发病机制中起主要作用。作为一种DNA甲基化阅读器，甲基化CpG结合域蛋白2（MBD2）已在先天免疫、适应性免疫和自身免疫性疾病的背景下得到广泛研究。然而，其在B细胞和SLE中的具体作用仍未得到研究。在此，我们发现MBD2在SLE患者的B细胞中高表达，且与疾病活动呈正相关。在小鼠中敲除B细胞中的MBD2会扰乱B细胞分化，抑制B细胞活化、B细胞受体（BCR）信号传导以及T细胞依赖性体液免疫反应。此外，MBD2缺陷有效减轻了狼疮模型小鼠的狼疮样症状，减少了生发中心反应，并降低了抗双链DNA抗体水平。机制上，MBD2选择性结合IFN-α诱导的Lef-1的甲基化CpG，抑制Lef-1的转录和表达，而Lef-1可抑制Pten的转录和表达，从而促进PI3K-Akt-mTOR信号传导。本研究首次证明了MBD2在SLE发病机制中的作用，并为SLE提供了一个新的靶点。
