Theiler's Murine Encephalomyelitis Virus (TMEV)-Induced Demyelination: A Model for Human Multiple Sclerosis

Abstract

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 “bystander effect.”