Department of Biomedical Sciences, University of Sassari, Sassari, Italy.
PLoS One. 2013 Nov 13;8(11):e78474. doi: 10.1371/journal.pone.0078474. eCollection 2013.
The etiology of multiple sclerosis (MS) is still unclear. The immuno-pathogenic phenomena leading to neurodegeneration are thought to be triggered by environmental (viral?) factors operating on predisposing genetic backgrounds. Among the proposed co-factors are the Epstein Barr virus (EBV), and the potentially neuropathogenic HERV-W/MSRV/Syncytin-1 endogenous retroviruses. The ascertained links between EBV and MS are history of late primary infection, possibly leading to infectious mononucleosis (IM), and high titers of pre-onset IgG against EBV nuclear antigens (anti-EBNA IgG). During MS, there is no evidence of MS-specific EBV expression, while a continuous expression of HERV-Ws occurs, paralleling disease behaviour. We found repeatedly extracellular HERV-W/MSRV and MSRV-specific mRNA sequences in MS patients (in blood, spinal fluid, and brain samples), and MRSV presence/load strikingly paralleled MS stages and active/remission phases. Aim of the study was to verify whether HERV-W might be activated in vivo, in hospitalized young adults with IM symptoms, that were analyzed with respect to expression of HERV-W/MSRV transcripts and proteins. Healthy controls were either EBV-negative or latently EBV-infected with/without high titers of anti-EBNA-1 IgG. The results show that activation of HERV-W/MSRV occurs in blood mononuclear cells of IM patients (2Log10 increase of MSRV-type env mRNA accumulation with respect to EBV-negative controls). When healthy controls are stratified for previous EBV infection (high and low, or no anti-EBNA-1 IgG titers), a direct correlation occurs with MSRV mRNA accumulation. Flow cytometry data show increased percentages of cells exposing surface HERV-Wenv protein, that occur differently in specific cell subsets, and in acute disease and past infection. Thus, the data indicate that the two main links between EBV and MS (IM and high anti-EBNA-1-IgG titers) are paralleled by activation of the potentially neuropathogenic HERV-W/MSRV. These novel findings suggest HERV-W/MSRV activation as the missing link between EBV and MS, and may open new avenues of intervention.
多发性硬化症（MS）的病因仍不清楚。导致神经退行性变的免疫发病现象被认为是由环境（病毒？）因素触发的，这些因素作用于易患遗传背景。在提出的协同因素中，有 EBV、潜在的神经致病性 HERV-W/MSRV/Syncytin-1 内源性逆转录病毒。EBV 与 MS 之间已确定的联系是晚期原发性感染史，可能导致传染性单核细胞增多症（IM）和 EBV 核抗原（抗-EBNA IgG）的前发病 IgG 高滴度。在 MS 期间，没有证据表明 EBV 有特异性表达，而 HERV-W 的持续表达发生，与疾病行为平行。我们在 MS 患者（血液、脊髓液和脑组织样本）中反复发现细胞外 HERV-W/MSRV 和 MSRV 特异性 mRNA 序列，并且 MRSV 的存在/载量与 MS 阶段和活动/缓解阶段惊人地平行。研究目的是验证 HERV-W 是否可能在患有 IM 症状的住院年轻成年人中体内激活，针对 HERV-W/MSRV 转录本和蛋白质的表达对其进行分析。健康对照者要么 EBV 阴性，要么 EBV 潜伏感染，抗-EBNA-1 IgG 高滴度。结果表明，HERV-W/MSRV 在 IM 患者的血液单核细胞中激活（与 EBV 阴性对照相比，MSRV 型 env mRNA 积累增加 2Log10）。当根据以前的 EBV 感染（高和低，或无抗-EBNA-1 IgG 滴度）对健康对照者进行分层时，与 MSRV mRNA 积累直接相关。流式细胞术数据显示，暴露表面 HERV-Wenv 蛋白的细胞百分比增加，这些细胞在特定细胞亚群中不同，在急性疾病和过去感染中也不同。因此，这些数据表明 EBV 与 MS 之间的两个主要联系（IM 和高抗-EBNA-1-IgG 滴度）与潜在神经致病性 HERV-W/MSRV 的激活平行。这些新发现表明 HERV-W/MSRV 激活是 EBV 与 MS 之间缺失的环节，并可能开辟新的干预途径。
