Theiler's virus antigen detected in mouse spinal cord 2½ years after infection

Lipton, Howard L.; Kratochvil, Jon; Sethi, P; Canto, Mauro C. Dal

doi:10.1212/wnl.34.8.1117

Cited by 96 publications

(89 citation statements)

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“…Previous studies from our laboratory and others have demonstrated that one of the major differences between resistant C57BL/6 mice and susceptible SJL/J mice is the ability of TMEV to persistently infect the CNS (23,(25)(26)(27). C57BL/6 mice rapidly eliminate the virus from the CNS within 2-4 wk after infection, protecting against pathology and clinical symptoms (23).…”

Section: Prolonged Persistence Of Tmev In the Cns Of Male Micementioning

confidence: 99%

Gender Bias in Theiler’s Virus-Induced Demyelinating Disease Correlates with the Level of Antiviral Immune Responses

Fuller

Kang

et al. 2005

The Journal of Immunology

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Multiple sclerosis is an immune-mediated disease of the CNS and shows a sex-biased distribution in which 60–75% of all cases are female. A mouse model of multiple sclerosis, Theiler’s murine encephalomyelitis virus (TMEV)-induced demyelinating disease, also displays a gender bias. However, in the C57L/J strain of mice, males are susceptible to disease whereas females are completely resistant. In this study we determined the gender differences in the TMEV-specific immune response, which may be responsible for the gender bias in clinical disease. Our data clearly demonstrate that female C57L/J mice induce significantly higher levels of TMEV-specific neutralizing Ab as well as a stronger peripheral T cell response throughout the course of viral infection. In contrast, male mice have a higher level of TMEV-specific CD4+ and CD8+ T cell infiltration into the CNS as well as viral persistence. These results suggest that a higher level of the initial antiviral immune response in female mice may be able to effectively clear virus from the periphery and CNS and therefore prevent further disease manifestations. Male mice in contrast do not mount as effective an immune response, thereby allowing for eventual viral persistence in the CNS and continuous T cell expansion leading to clinical symptoms.

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Section: Prolonged Persistence Of Tmev In the Cns Of Male Micementioning

confidence: 99%

Gender Bias in Theiler’s Virus-Induced Demyelinating Disease Correlates with the Level of Antiviral Immune Responses

Fuller

Kang

et al. 2005

The Journal of Immunology

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“…Our corollary to that hypothesis is that the virus must also induce production of IL-23. We have shown that Theiler's murine encephalomyelitis virus (TMEV), which infects macrophages and induces an MS-like disease in SJL/J mice (18), triggers expression of both IL-23 subunits from the mouse macrophage cell line, RAW264.7 (19,20). However, our understanding of the mechanisms for expression of IL-23 is not complete.…”

mentioning

confidence: 99%

Promoter Analysis Reveals Critical Roles for SMAD-3 and ATF-2 in Expression of IL-23 p19 in Macrophages

Alsalleeh

Petro

2008

The Journal of Immunology

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IL-23 p19/p40, produced by macrophages and dendritic cells, is critical for development of Th17 in several autoimmune diseases. In this study, bone marrow-derived (BMM) and splenic macrophages (SPM) from SJL/J mice, susceptible to autoimmune demyelinating disease following Theiler’s virus (TMEV) infection, expressed IL-23 in response to TMEV. We identified potential binding sites for IFN response factor (IRF)-3 (nt −734 to −731), Sma- and Mad-related protein (SMAD)-3 (nt −584 to −581), activating transcription factor (ATF)-2 (nt −571 to −568), IRF-7 (nt −533 to-525), and NF-κB (nt −215 to −209) in the murine p19 promoter. The p19prom in the pGL3 promoter-reporter vector responded to TMEV or poly(I:C), a TLR3 agonist in the RAW264.7 macrophage cell line. Deletions upstream from the IRF-3 site and mutations at the IRF-3, SMAD-3, ATF-2, or NF-κB, but not the IRF-7, sites significantly reduced promoter activity. ATF-2 or SMAD-3, but not IRF-3, short-hairpin RNA reduced p19 promoter activity and protein expression in RAW264.7 cells responding to TMEV. Chromosomal DNA immunoprecipitation assays revealed that SMAD-3 and ATF-2 bind to the endogenous p19 promoter in RAW264.7 cells and SJL/J SPM following challenge with TMEV. TGF-β1, which activates SMAD-3, was induced in RAW264.7 cells, BMM, and SPM by TMEV. Neutralizing Ab to TGF-β1 eliminated TMEV-induced IL-23 production and SMAD-3 activation in RAW264.7 cells, BMM, and SPM. Activation of ATF-2 was JNK, but not p38 or ERK MAPK dependent. Inhibition of the JNK, but also the ERK MAPK pathways decreased expression of p19. These results suggest that ATF-2 and SMAD-3 are transcription factors, which are, in addition to NF-κB, essential for IL-23 p19 expression.

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“…After i.c. inoculation with TMEV, an initial viremia is followed by a persistent low level of CNS infection (Lipton et al, 1984). TMEV is known to infect neurons, glial cells, and macrophages in the spinal cord (Brahic et al, 1981;Clatch et al, 1990).…”

Section: Discussionmentioning

confidence: 99%

“…TMEV-IDD is considered an infectious mouse model for MS because the disease displays histopathologic, genetic, and clinical similarities to human MS (Dal Canto and Lipton, 1975;Nathanson and Miller, 1978;Kurtzke and Hyllested, 1986;Kappel et al, 1991). The demyelination is linked to persistent TMEV infection in the CNS (Lipton et al, 1991), and histological findings are characterized by perivascular inflammatory cell infiltrates and primary demyelination in CNS (Lehrich, Arnason, 1976;Lipton et al, 1984). TMEV persists in the white matter of the spinal cord, mainly in microglia/macrophages, but also in astrocytes and oligodendrocytes throughout the life of a mouse (Lipton et al, 1984;Lipton et al, 1995).…”

Section: Introductionmentioning

confidence: 99%

“…The demyelination is linked to persistent TMEV infection in the CNS (Lipton et al, 1991), and histological findings are characterized by perivascular inflammatory cell infiltrates and primary demyelination in CNS (Lehrich, Arnason, 1976;Lipton et al, 1984). TMEV persists in the white matter of the spinal cord, mainly in microglia/macrophages, but also in astrocytes and oligodendrocytes throughout the life of a mouse (Lipton et al, 1984;Lipton et al, 1995). Persistent CNS virus infection in susceptible mouse strains triggers clonal expansion and differentiation of TMEV-specific T cells that are poorly controlled by normal immunoregulatory mechanism.…”

Section: Introductionmentioning

confidence: 99%

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Role of the Programmed Death-1 (PD-1) pathway in regulation of Theiler's murine encephalomyelitis virus-induced demyelinating disease

Takizawa

Kaneyama

Tsugane

et al. 2014

Journal of Neuroimmunology

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Programmed death-1 (PD-1) belongs to the CD28 family of co-stimulatory and co-inhibitory molecules and regulates adaptive immunity. This molecule induces the development of regulatory T cells, T cell tolerance, or apoptosis. We examined the role of PD-1 pathway in Theiler's murine encephalomyelitis virus (TMEV)-induced demyelinating disease (TMEV-IDD) mice. Up-regulation of PD-1 and PD-1 ligand-1 (PD-L1) mRNA expression in bone marrow-derived dendritic cells were induced by TMEV infection in vitro. Furthermore, PD-1 and PD-L1 mRNA expression was increased in the spinal cords of the TMEV-infected mice in vivo. Treatment with a blocking monoclonal antibody (mAb) against PD-1, especially during the effector phase, resulted in significant deterioration of the TMEV-IDD both clinically and histologically. Flow cytometric analysis revealed a dramatically increase of CD4 + T cells producing Th1 cytokines such as IFN-γ and TNF-α in the spinal cord of anti-PD-1 mAbtreated mice. These results indicate that the PD-1 pathway plays a pivotal regulatory role in the development of TMEV-IDD.

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Theiler's virus antigen detected in mouse spinal cord 2½ years after infection

Cited by 96 publications

References 0 publications

Gender Bias in Theiler’s Virus-Induced Demyelinating Disease Correlates with the Level of Antiviral Immune Responses

Gender Bias in Theiler’s Virus-Induced Demyelinating Disease Correlates with the Level of Antiviral Immune Responses

Promoter Analysis Reveals Critical Roles for SMAD-3 and ATF-2 in Expression of IL-23 p19 in Macrophages

Role of the Programmed Death-1 (PD-1) pathway in regulation of Theiler's murine encephalomyelitis virus-induced demyelinating disease

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