TMEV-induced demyelination is partly mediated by direct viral lysis of oligodendrocytes (Roos and Wollmann, 1984). In addition, CD4+ T cells also play a major role in mediating CNS demyelination by generating both antivirus and antimyelin autoimmune responses (Welsh et al., 1987,1989, 1990; Miller et al., 1997; Borrow et al., 1998; Dal Canto et al., 2000). Susceptibility to inflammation and demyelination of the spinal cord are strongly related to the ability of the mouse to mount a delayed-type hyper-sensitivity (DTH) response to viral antigen. Other evidence suggests that demyelination is initiated by virus-specific T cells that target the virus presented by persistently infected macrophages/microglia in the CNS. This leads to initial myelin destruction due to proinflammatory cytokines produced by TMEV-specific Th1 cells that target CNS-persistent virus. As the disease progresses, myelin destruction induces epitope spreading, characterized by the development of myelin-epitope specific autoreactive Th1 cells (Miller et al., 2001; Croxford et al., 2002; Olson et al., 2004). The autoimmune aspects of this disease enhance bystander demyelination mediated by virus-specific DTH T cells (Clatch et al., 1987; Gerety et al., 1991) and cytotoxic T-cell reactivity (Rodriguez and Sriram, 1988).
In summary,TMEV infection provides a well-characterized animal model of MS in which to study the effects of social stress on disease course. Using this model, we have previously examined the impact of restraint stress on disease course to gain a better understanding of how stress impacts the human disease (for a recent review, see Welsh et al., this volume). In the following sections, we will review evidence that social stress can alter immune function and TMEV disease vulnerability.
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