Roles of Treg/Th17 Cell Imbalance and Neuronal Damage in the Visual Dysfunction Observed in Experimental Autoimmune Optic Neuritis Chronologically
Roles of Treg/Th17 Cell Imbalance and Neuronal Damage in the Visual Dysfunction Observed in Experimental Autoimmune Optic Neuritis Chronologically
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DOI：
10.1007/s12017-015-8368-4
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发表时间：
2015-12-01
影响因子：
3.5
通讯作者：
Yan, Hua
中科院分区：
文献类型：
--
作者：
Liu, Yuanyuan;You, Caiyun;Yan, Hua
多发性硬化相关性视神经炎及其动物模型实验性自身免疫性视神经炎（EAON）以炎症、T细胞活化、脱髓鞘和神经元损伤为特征，可导致永久性视力丧失。阐明这些特征之间的时间关系对于脱髓鞘性视神经炎的治疗至关重要。用髓鞘少突胶质细胞糖蛋白皮下免疫C57 BL/6小鼠，诱导EAON，于免疫后7、11、14、19、23、28 d用闪光视觉诱发电位（flash-visual evoked potential，F-VEP）检测视功能。用末端脱氧核苷酸转移酶介导的缺口末端标记法检测视网膜神经节细胞（RGC）凋亡。脱髓鞘和轴突损伤分别用髓鞘碱性蛋白（MBP）和β-淀粉样前体蛋白染色进行验证。实时聚合酶链反应定量IL-17、IL-1 β、TGF-β、FoxP 3、IL-6和IL-10 mRNA在视神经中的表达，以及FoxP 3和IL-17染色。流式细胞术检测脾脏Th 17和Treg细胞的系统性变化。F-VEP潜伏期在第11天延长，在第23天达到峰值，与脱髓鞘相当。然而，F-VEP振幅在轴突损伤前11天降低，并在23天检测到RGC凋亡峰值时加剧。Th 17细胞早在第7天就上调，并在第11天达到峰值，而Treg细胞与Th 17细胞变化相反地下调，如通过IL-17和FoxP 3表达所证实的;脾细胞样品略有不同，表明在第14天发生显著变化。视神经中Treg/Th 17细胞失衡先于并可能引发轴突和RGC的神经元损伤。这些变化与F-VEP所反映的视觉功能障碍的表现是相称的，因此可能为视力保护提供一种新的治疗途径。
Optic neuritis associated with multiple sclerosis and its animal model, experimental autoimmune optic neuritis (EAON), is characterized by inflammation, T cell activation, demyelination, and neuronal damage, which might induce permanent vision loss. Elucidating the chronological relationship among the features is critical for treatment of demyelinating optic neuritis. EAON was induced in C57BL/6 mice immunized with myelin oligodendrocyte glycoprotein subcutaneously, and visual function was assessed by flash-visual evoked potential (F-VEP) at days 7, 11, 14, 19, 23, 28 post-immunization. Retinal ganglion cell (RGC) apoptosis was measured by terminal-deoxynucleotidyl transferase-mediated nick-end labeling. Demyelination and axonal damage were verified with myelin basic protein (MBP) and beta-amyloid precursor protein staining, respectively. Real-time polymerase chain reaction quantified IL-17, IL-1 beta, TGF-beta, FoxP3, IL-6, and IL-10 mRNA expression in the optic nerve, as well as FoxP3 and IL-17 staining. Systemic changes of Th17 and Treg cells were tested by flow cytometry in spleen. F-VEP latency was prolonged at 11 days and peaked at 23 days commensurate with demyelination. However, F-VEP amplitude was reduced at 11 days, preceding axon damage, and was exacerbated at 23 days when a peak in RGC apoptosis was detected. Th17 cells up-regulated as early as 7 days and peaked at 11 days, while Treg cells down-regulated inversely compared to Th17 cells change as verified by IL-17 and FoxP3 expression; spleen cell samples were slightly different, demonstrating marked changed at 14 days. Treg/Th17 cell imbalance in the optic nerve precedes and may initiate neuronal damage of axons and RGCs. These changes are commensurate with the appearances of visual dysfunction reflected in F-VEP and hence may offer a novel therapeutic avenue for vision preservation.