Theiler's murine encephalomyelitis virus (TMEV)-induced demyelination: A model for human multiple sclerosis
Theiler's murine encephalomyelitis virus (TMEV)-induced demyelination: A model for human multiple sclerosis
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DOI：
10.1006/meth.1996.0123
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发表时间：
1996-01-01
期刊：
影响因子：
--
通讯作者：
Melvold, Roger W.
中科院分区：
文献类型：
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作者：
Dal Canto, Mauro C.;Kim, Byung S.;Melvold, Roger W.
大量研究表明，在适当的遗传背景下，病毒感染可能在多发性硬化症（MS）的发展中起重要的发病作用。在过去二十年中已经研究的几种脱髓鞘病毒模型中，Theiler小鼠脑脊髓炎病毒（TMEV）诱导的脱髓鞘疾病已成为最好的模型之一，因为与MS类似，它基于病毒-免疫联合发病机制。这篇综述强调了该模型的以下显著特征。tmev诱导的脱髓鞘病是一个慢性过程，会持续一生。病变包括界限清晰的脱髓鞘斑块，这与单核细胞浸润的存在密切相关。髓鞘变性不是由于直接的病毒细胞病变作用，而是依赖于宿主的免疫反应。对疾病的易感性/抗性是遗传调控的，主要组织相容性复合体内外的多个基因似乎都参与其中。与易感性相关的最佳免疫学参数是小鼠菌株对一个或多个病毒表位产生延迟型超敏反应（DTH）的能力。针对病毒的DTH反应在疾病发病机制中的重要性得到了TH1 t辅助细胞的普遍作用的支持，已知TH1 t辅助细胞负责发炎的中枢神经系统组织中的DTH反应。DTH反应在脱髓鞘发病机制中的作用是由受影响的中枢神经系统中大量巨噬细胞的存在以及巨噬细胞的数量、它们在组织中的持久性和病变严重程度之间的直接关系所支持的。此外，巨噬细胞是中枢神经系统中病毒的主要储存库，其传染性与疾病过程的易感性相关。据推测，在DTH对病毒的反应之后，活化的淋巴细胞招募其他炎症细胞，特别是巨噬细胞，进入受感染的中枢神经系统组织。这些非特异性募集的细胞会分泌一些促炎分子和蛋白酶，这些分子和蛋白酶会破坏髓磷脂，这是一种“旁观者效应”。
Numerous studies suggest that a viral infection, on the appropriate genetic background, may play an important pathogenetic role in the development of multiple sclerosis (MS). Among the several viral models of demyelination that have been investigated during the past two decades, Theiler's murine encephalomyelitis virus (TMEV)-induced demyelinating disease has emerged as one of the best because, ,similarly to MS, it is based on a combined viral-immune pathogenesis. This review highlights the following salient features of this model. TMEV-induced demyelinating disease is a chronic process, lasting for the life of the animals. Lesions consist of well-demarcated plaques of demyelination, which are strictly related to the presence of mononuclear cell infiltrates. Myelin degeneration is not due to direct viral cytopathic effects, but is rather dependent on the host immune response. Susceptibility/resistance to the disease is genetically regulated, and multiple genes both in and outside the major histocompatibility complex appear to be involved. The best immunological parameter that correlates with susceptibility is the ability of a murine strain to mount a delayed-type hypersensitivity (DTH) response to one or more viral epitopes. The importance of the DTH response against the virus in the pathogenesis of the disease is supported by the prevalent role of TH1 T-helper cells, known to be responsible for DTH responses, in inflamed CNS tissues. The role of DTH responses in the pathogenesis of demyelination is supported by the presence of numerous macrophages in affected CNS and by a direct relationship between the number of macrophages, their persistence in tissues, and the severity of lesions. Macrophages, in addition, are the main reservoir of the virus in the CNS, and their infectability correlates with susceptibility to the disease process. It is hypothesized that following the DTH response to the virus, activated lymphocytes recruit other inflammatory cells, particularly macrophages, into the infected CNS tissues. These nonspecifically recruited cells would secrete a number of proinflammatory molecules and proteases that would destroy myelin as a "by-stander effect."