van Horssen Jack, van der Pol Susanne, Nijland Philip, Amor Sandra, Perron Hervé
Department of Molecular Cell Biology and Immunology, VU University Medical Center, Amsterdam, The Netherlands.
Department of Pathology, VU University Medical Center, Amsterdam, The Netherlands.
Mult Scler Relat Disord. 2016 Jul;8:11-8. doi: 10.1016/j.msard.2016.04.006. Epub 2016 Apr 22.
Attempts to identify a causative agent of Multiple Sclerosis (MS) among environmental viruses have consistently failed suggesting that development of MS is a result from gene-environment interactions. A new pathogenic player within human genes, a human endogenous retrovirus (HERV) was identified from MS cells, named MS-associated retrovirus element (MSRV) and unveiled homologous multicopy HERVs (HERV-W). As independent studies revealed biological features of HERV-W on immune-mediated inflammation and on remyelinating cells, the present study characterized the presence of HERV-W envelope protein (MSRV-Env) at the cellular level, in different MS lesion stages to extend and validate previous studies.
Immunohistological analysis of HERV-W envelope cellular expression in different lesion stages from a cohort of MS brains versus controls, using well-characterized and highly specific monoclonal antibodies.
HERV-W envelope protein was detected in all MS brains and quite essentially in lesions. Immunohistochemistry showed dominant expression in macrophages and microglia, coinciding with areas of active demyelination, spread over the active lesions, or limited to the rim of active microglia in chronic active lesions or in few surviving astrocytes of inactive plaques. Weak expression was seen in MS normal appearing white matter. In active plaques, few lymphoid cells and astrocytes were also stained. This HERV-W expression was not observed in control brains.
HERV-W was expressed in demyelinated lesions from MS brains, which were all positive for this endogenous pathogenic protein. Pronounced HERV-W immunoreactivity in active MS lesions was intimately associated with areas of active demyelination throughout the successive stages of lesion evolution in MS brains. Based on its pathogenic potential, this HERV-W (MSRV) endogenous toxin thus appears to be a novel therapeutic target in MS. It also has a unique positioning as an early and lifelong expressed pathogenic agonist, acting upstream the pathways in which dysregulated physiological effectors are usually targeted by present therapeutic strategies for MS.
在环境病毒中寻找多发性硬化症（MS）病原体的尝试一直未成功，这表明MS的发病是基因与环境相互作用的结果。在人类基因中发现了一个新的致病因子，即从MS细胞中鉴定出的人类内源性逆转录病毒（HERV），命名为MS相关逆转录病毒元件（MSRV），并发现了同源多拷贝HERV（HERV-W）。由于独立研究揭示了HERV-W在免疫介导的炎症和髓鞘再生细胞上的生物学特性，本研究在细胞水平上对不同MS病变阶段HERV-W包膜蛋白（MSRV-Env）的存在进行了表征，以扩展和验证先前的研究。
使用特征明确且高度特异的单克隆抗体，对一组MS脑与对照的不同病变阶段的HERV-W包膜细胞表达进行免疫组织学分析。
在所有MS脑中均检测到HERV-W包膜蛋白，且主要存在于病变中。免疫组织化学显示在巨噬细胞和小胶质细胞中表达占主导，与活跃脱髓鞘区域一致，分布于活跃病变区，或局限于慢性活跃病变中活跃小胶质细胞的边缘，或不活跃斑块中少数存活的星形胶质细胞中。在MS正常外观的白质中可见弱表达。在活跃斑块中，少数淋巴细胞和星形胶质细胞也被染色。在对照脑中未观察到这种HERV-W表达。
HERV-W在MS脑的脱髓鞘病变中表达，这些病变对这种内源性致病蛋白均呈阳性。在活跃的MS病变中，明显的HERV-W免疫反应性与MS脑病变演变连续阶段中活跃脱髓鞘区域密切相关。基于其致病潜力，这种HERV-W（MSRV）内毒素似乎是MS的一个新的治疗靶点。它还具有独特的定位，作为一种早期且终身表达的致病激动剂，作用于目前MS治疗策略通常针对的失调生理效应器所在途径的上游。
