Infection with Theiler's murine encephalomyelitis virus (TMEV) in the central nervous system (CNS) causes an immune system-mediated demyelinating disease similar to human multiple sclerosis in susceptible but not resistant strains of mice. To understand the underlying mechanisms of differential susceptibility, we analyzed viral replication, cytokine production, and costimulatory molecule expression levels in microglia and macrophages in the CNS of virus-infected resistant C57BL/6 (B6) and susceptible SJL/J (SJL) mice. Our results indicated that message levels of TMEV, tumor necrosis factor alpha, beta interferon, and interleukin-6 were consistently higher in microglia from virus-infected SJL mice than in those from B6 mice. However, the levels of costimulatory molecule expression, as well as the ability to stimulate allogeneic T cells, were significantly lower in TMEV-infected SJL mice than in B6 mice. In addition, microglia from uninfected naïve mice displayed differential viral replication, T-cell stimulation, and cytokine production, similar to those of microglia from infected mice. These results strongly suggest that different levels of intrinsic susceptibility to TMEV infection, cytokine production, and T-cell activation ability by microglia contribute to the levels of viral persistence and antiviral T-cell responses in the CNS, which are critical for the differential susceptibility to TMEV-induced demyelinating disease between SJL and B6 mice.BeAn and DA are members of Theiler's original subgroup of Theiler's murine encephalitis virus (TMEV) (52). Intracerebral inoculation of susceptible mice, such as SJL/J (SJL) mice, with either of these viruses results in a biphasic disease characterized by early encephalitis and late chronic demyelination (24). Infection of susceptible mice with these viruses results in a chronic, white matter-demyelinating disease similar to human multiple sclerosis (24). In susceptible strains, infection of the central nervous system (CNS) with TMEV leads to a chronic immune response to viral antigens, which eventually leads to autoimmune responses against myelin autoantigens (29). In contrast, resistant mouse strains, such as C57BL/6 (B6), rapidly clear virus from the CNS and do not develop demyelinating disease, suggesting that viral persistence in these mice corresponds to susceptibility to disease (26,42,45). Demyelination in susceptible mice is considered to be immunity mediated, as removal of immune components reduces the clinical onset and severity of demyelinating disease (9,25,44,47).In particular, infiltration of proinflammatory CD4 ϩ Th1-type cells has been associated with tissue destruction and demyelination (41, 56). A number of CD4 ϩ T cells specific for TMEV during the course of disease in SJL mice recognize four predominant viral capsid epitopes (VP1 233-250 , VP2 74-86 , VP3 24-37 , and VP4 51-70 ), with one each on the external and internal capsid proteins (10,19,55,56). The external capsid epitopes appear to account for the majority (ϳ80%) of major histocompatibili...
Theiler's murine encephalomyelitis virus-induced demyelinating disease has been extensively studied as an attractive infectious model for human multiple sclerosis. Virus-specific inflammatory Th1 cell responses followed by autoimmune responses to myelin antigens play a crucial role in the pathogenic processes leading to demyelination. Antibody and cytotoxic T cells (CTL) responses to virus appears to be primarily protective from demyelinating disease. Although the role of Th1 and CTL responses in the induction of demyelinating disease is controversial, assessment of cytokines produced locally in the central nervous system (CNS) during the course of disease and the effects of altered inflammatory cytokine levels strongly support the importance of Th1 responses in this virus-induced demyelinating disease. Induction of various chemokines and cytokines in different glial and antigen presenting cells upon viral infection appears to be an important initiation mechanism for inflammatory Th1 responses in the CNS. Coupled with the initial inflammatory responses, viral persistence in the CNS may be a critical factor for sustaining inflammatory responses and consequent immune-mediated demyelinating disease.
Central nervous system (CNS) infection by Theiler's murine encephalomyelitis virus (TMEV) causes an immune‐mediated demyelinating disease similar to human multiple sclerosis in susceptible mice. To understand the pathogenic mechanisms, we analyzed the level, specificity, and function of CD4+ Th cells in susceptible SJL/J and resistant C57BL/6 mice. Compared to resistant mice, susceptible mice have three‐ to fourfold higher levels of overall CNS‐infiltrating CD4+ T cells during acute infection. CD4+ T cells in the CNS of both strains display various activation markers and produce high levels of IFN‐γ upon stimulation with anti‐CD3 antibody. However, susceptible mice display significantly fewer (tenfold) IFN‐γ‐producing Th1 cells specific for viral capsid epitopes as compared to resistant mice. Furthermore, preimmunization with capsid‐epitope peptides significantly increased capsid‐specific CD4+ T cells in the CNS during the early stages of viral infection and delayed the development of demyelinating disease in SJL/J mice. This suggests a protective role of capsid‐reactive Th cells during early viral infection. Therefore, a low level of the protective Th1 response to viral capsid proteins, in conjunction with Th1 responses to unknown epitopes may delay viral clearance in susceptible mice leading to pathogenesis of demyelination during acute infection, as compared to resistant mice.
Theiler's murine encephalomyelitis virus (TMEV) establishes a persistent infection in the central nervous system (CNS). To examine the role of type I interferon (IFN-I)-mediated signals in TMEV infection, mice lacking a subunit of the type I IFN receptor (IFN-IR KO mice) were utilized. In contrast to wildtype mice, IFN-IR KO mice developed rapid fatal encephalitis accompanied with greater viral load and infiltration of immune cells to the CNS. The proportion of virus-specific CD4 + and CD8 + T cell responses in the CNS was significantly lower in IFN-IR KO mice during the early stage of infection. Levels of IFN-γ and IL-17 produced by isolated primed CD4 + T cells in response to DCs from TMEV-infected IFN-IRKO mice were also lower than those stimulated by DCs from TMEV-infected wildtype control mice. The less efficient stimulation of virus-specific T cells by virus-infected antigen presenting cells is attributable in part to the low level expression of activation markers on TMEV-infected cells from IFN-IR KO mice. However, due to high levels of cellular infiltration and viral loads in the CNS, the overall numbers of virus-specific T cells are higher in IFN-IR KO mice during the later stage of viral infection. These results suggest that IFN-I-mediated signals play important roles in controlling cellular infiltration to the CNS and shaping local T cell immune responses.
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