C57BL/6 mice transgenic for human MeCP2 (B6.Mecp2Tg1) were phenotyped, including autoantibody profiling through antigen array, analysis of cellularity and activation of splenic immune cells through flow cytometry, and measurement of proteinuria. Behavioral tests were conducted to explore their neuropsychiatric functions. Immunofluorescence analyses were used to reveal altered neurogenesis and brain inflammation. Various signaling molecules implicated in lupus pathogenesis were examined using western blotting.
B6.Mecp2Tg1 exhibits elevated proteinuria and an overall increase in autoantibodies, particularly in female B6.Mecp2Tg1 mice. An increase in CD3+CD4+ T cells in the transgenic mice was observed, along with activated germinal center cells and activated CD11b+F4/80+ macrophages. Moreover, the transgenic mice displayed reduced locomotor activity, heightened anxiety and depression, and impaired short-term memory. Immunofluorescence analysis revealed IgG deposition and immune cell infiltration in the kidneys and brains of transgenic mice, as well as altered neurogenesis, activated microglia, and compromised blood-brain barrier (BBB). Additionally, protein levels of various key signaling molecules were found to be differentially modulated upon MeCP2 overexpression, including GFAP, BDNF, Albumin, NCoR1, mTOR, and NLRP3.
Collectively, this work demonstrates that B6.Mecp2Tg1 mice exhibit lupus-like phenotypes as well as robust CNS dysfunctions, suggesting its utility as a new animal model for NPSLE.
■人MeCP2转基因的C57BL/6小鼠(B6。Mecp2Tg1)进行表型分析,包括通过抗原阵列的自身抗体谱分析,通过流式细胞术分析脾免疫细胞的细胞性和活化,和蛋白尿的测量。进行行为测试以探索其神经精神功能。免疫荧光分析用于揭示改变的神经发生和脑部炎症。使用蛋白质印迹检查了与狼疮发病机理有关的各种信号分子。
■B6。Mecp2Tg1表现出升高的蛋白尿和自身抗体的整体增加,尤其是女性B6。Mecp2Tg1小鼠。观察到转基因小鼠中CD3+CD4+T细胞的增加,以及激活的生发中心细胞和激活的CD11b+F4/80+巨噬细胞。此外,转基因小鼠表现出降低的运动活性,焦虑和抑郁加剧,和短期记忆受损。免疫荧光分析显示转基因小鼠的肾脏和大脑中IgG沉积和免疫细胞浸润,以及改变的神经发生,激活的小胶质细胞,和受损的血脑屏障(BBB)。此外,发现各种关键信号分子的蛋白质水平在MeCP2过表达时受到差异调节,包括GFAP,BDNF,白蛋白,NCoR1,mTOR,NLRP3。
■集体,这项工作证明了B6。Mecp2Tg1小鼠表现出狼疮样表型以及强大的中枢神经系统功能障碍,表明它作为一种新的NPSLE动物模型的实用性。