Zheng Xiaoqing, Dozmorov Mikhail G, Espinoza Luis, Bowes Mckenna M, Bastacky Sheldon, Sawalha Amr H
Division of Rheumatology, Department of Pediatrics, Children's Hospital of Pittsburgh, University of Pittsburgh, Pittsburgh, PA, USA.
Department of Biostatistics, Virginia Commonwealth University, Richmond, VA, USA.
iScience. 2024 Oct 9;27(11):111114. doi: 10.1016/j.isci.2024.111114. eCollection 2024 Nov 15.
Systemic lupus erythematosus is a remitting relapsing autoimmune disease characterized by autoantibody production and multi-organ involvement. T cell epigenetic dysregulation plays an important role in the pathogenesis of lupus. We have previously demonstrated upregulation of the key epigenetic regulator EZH2 in CD4 T cells isolated from lupus patients. To further investigate the role of EZH2 in the pathogenesis of lupus, we generated a tamoxifen-inducible CD4 T cell conditional knockout mouse on the MRL/ lupus-prone background. We demonstrate that deletion abrogates lupus-like disease and prevents T cell differentiation. Single-cell analysis suggests impaired T cell function and activation of programmed cell death pathways in EZH2-deficient mice. deletion in CD4 T cells restricts TCR clonal repertoire and prevents kidney-infiltrating effector CD4 T cell expansion and tubulointerstitial nephritis, which has been linked to end-stage renal disease in patients with lupus nephritis.
系统性红斑狼疮是一种以自身抗体产生和多器官受累为特征的缓解复发型自身免疫性疾病。T细胞表观遗传失调在狼疮发病机制中起重要作用。我们之前已证明，从狼疮患者分离的CD4 T细胞中关键表观遗传调节因子EZH2上调。为进一步研究EZH2在狼疮发病机制中的作用，我们构建了在MRL/狼疮易感背景下的他莫昔芬诱导型CD4 T细胞条件性敲除小鼠。我们证明，基因缺失可消除狼疮样疾病并阻止T细胞分化。单细胞分析表明，EZH2缺陷小鼠的T细胞功能受损且程序性细胞死亡途径激活。CD4 T细胞中的基因缺失限制了TCR克隆库，并阻止肾浸润效应CD4 T细胞扩增及肾小管间质性肾炎，而后者与狼疮性肾炎患者的终末期肾病有关。
