The level of tumor necrosis factor-α producing cells in the spinal cord correlates with the degree of Theiler's murine encephalomyelitis virus-induced demyelinating disease

Inoue, Akira; Koh, Chang Sung; Yahikozawa, Hiroyuki; Yanagisawa, Nobuo; Yagita, Hideo; Ishihara, Yoshihiro; Kim, Byung S.

doi:10.1093/intimm/8.7.1001

Cited by 44 publications

(26 citation statements)

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“…The administration of recombinant TNF-␣ beginning prior to viral infection has been shown to reduce demyelination (38). In contrast, the administration of anti-TNF-␣ antibodies to TMEV-infected susceptible SJL mice confers resistance to the development of demyelinating disease (15). These results suggest that the temporal presence of TNF-␣ in conjunction with the time of viral infection may provide either protection or pathogenesis.…”

Section: Cd11bmentioning

confidence: 99%

Differential Virus Replication, Cytokine Production, and Antigen-Presenting Function by Microglia from Susceptible and Resistant Mice Infected with Theiler's Virus

Jin

Mohindru

Kang

et al. 2007

J Virol

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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...

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Section: Cd11bmentioning

confidence: 99%

Differential Virus Replication, Cytokine Production, and Antigen-Presenting Function by Microglia from Susceptible and Resistant Mice Infected with Theiler's Virus

Jin

Mohindru

Kang

et al. 2007

J Virol

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“…TMEV infects a variety of cells both in the CNS and in the periphery, including macrophages, dendritic cells, microglia, and astrocytes (9)(10)(11)(12). Infection of cells with TMEV triggers a proinflammatory response consisting of type I interferons, tumor necrosis factor alpha (TNF-␣), interleukin-6 (IL)-6, and various chemokines (13)(14)(15)(16)(17)(18). The extent of the proinflammatory response in the CNS and the timing of the release of proinflammatory cytokines such as IL-6 and TNF-␣ can lead to neuronal excitability prior to the induction of the adaptive immune response, thereby implicating a role for the innate immune system in the induction of seizures.…”

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confidence: 99%

Infiltrating Macrophages Are Key to the Development of Seizures following Virus Infection

Cusick

Libbey

Patel

et al. 2013

J Virol

100

173

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b Viral infections of the central nervous system (CNS) can trigger an antiviral immune response, which initiates an inflammatory cascade to control viral replication and dissemination. The extent of the proinflammatory response in the CNS and the timing of the release of proinflammatory cytokines can lead to neuronal excitability. Tumor necrosis factor alpha (TNF-␣) and interleukin-6 (IL-6), two proinflammatory cytokines, have been linked to the development of acute seizures in Theiler's murine encephalomyelitis virus-induced encephalitis. It is unclear the extent to which the infiltrating macrophages versus resident CNS cells, such as microglia, contribute to acute seizures, as both cell types produce TNF-␣ and IL-6. In this study, we show that following infection a significantly higher number of microglia produced TNF-␣ than did infiltrating macrophages. In contrast, infiltrating macrophages produced significantly more IL-6. Mice treated with minocycline or wogonin, both of which limit infiltration of immune cells into the CNS and their activation, had significantly fewer macrophages infiltrating the brain, and significantly fewer mice had seizures. Therefore, our studies implicate infiltrating macrophages as an important source of IL-6 that contributes to the development of acute seizures.

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“…In contrast, several lines of observation strongly suggest that Th1 response to viral Ag is critically important for the development of TMEV-induced demyelinating disease (21)(22)(23). In addition, treatments with Abs to various cytokines involved in inflammatory Th1 responses effectively reduced the demyelinating disease (7,24,25), strongly supporting the importance of Th1 response for pathogenesis. The major T cell populations specific for TMEV during the course of disease recognize three predominant viral epitopes (VP1 233-250 , VP2 74 -86 , and VP3 24 -37 ), one each on the external capsid proteins (21,22,26).…”

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confidence: 78%

Preferential Induction of IL-10 in APC Correlates with a Switch from Th1 to Th2 Response Following Infection with a Low Pathogenic Variant of Theiler’s Virus

Palma

Yauch

Kang

et al. 2002

The Journal of Immunology

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Theiler’s murine encephalomyelitis virus induces immune-mediated demyelination in susceptible mice after intracerebral inoculation. A naturally occurring, low pathogenic Theiler’s murine encephalomyelitis virus variant showed a single amino acid change within a predominant Th epitope from lysine to arginine at position 244 of VP1. This substitution is the only one present in the entire viral capsid proteins. In this paper, we demonstrate that the majority of T cells specific for VP1233–250 and VP274–86 from wild-type virus-infected mice are Th1 type and these VP1-specific cells poorly recognize the variant VP1 epitope (VP1K244R) containing the substituted arginine. In contrast, the Th2-type T cell population specific for these epitopes predominates in variant virus-infected mice. Immunization with UV-inactivated virus or VP1 epitope peptides could not duplicate the preferential Th1/Th2 responses following viral infection. Interestingly, the major APC populations, such as dendritic cells and macrophages, produce IL-12 on exposure to the pathogenic wild-type virus, whereas they preferentially produce IL-10 in response to the low pathogenic variant virus. Thus, such a spontaneous mutant virus may have a profoundly different capability to induce Th-type responses via selective production of cytokines involved in T cell differentiation and the consequent pathogenicity of virally induced immune-mediated inflammatory diseases.

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The level of tumor necrosis factor-α producing cells in the spinal cord correlates with the degree of Theiler's murine encephalomyelitis virus-induced demyelinating disease

Cited by 44 publications

References 0 publications

Differential Virus Replication, Cytokine Production, and Antigen-Presenting Function by Microglia from Susceptible and Resistant Mice Infected with Theiler's Virus

Differential Virus Replication, Cytokine Production, and Antigen-Presenting Function by Microglia from Susceptible and Resistant Mice Infected with Theiler's Virus

Infiltrating Macrophages Are Key to the Development of Seizures following Virus Infection

Preferential Induction of IL-10 in APC Correlates with a Switch from Th1 to Th2 Response Following Infection with a Low Pathogenic Variant of Theiler’s Virus

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