HLA-DQ Polymorphism Influences Progression of Demyelination and Neurologic Deficits in a Viral Model of Multiple Sclerosis

Pavelko, Kevin D.; Drescher, Kristen M.; McGavern, Dorian B.; David, Chella S.; Rodriguez, Moses

doi:10.1006/mcne.2000.0843

Cited by 11 publications

(8 citation statements)

References 45 publications

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“…The use of CD4 and CD8 knockout mice confirms this finding [56]. This is in contrast to the infection of double deficient Aβ 0 .β2m 0 mice, which fail to clear the acute virus encephalitis and die possibly before demyelination occurs in the spinal cord [48]. In the present experiment, the disease in Aβ 0 .β2m 0 .Hβ2m + .A11 + and Aβ 0 .β2m 0 .Hβ2m + .B27 + mice was similar to the established model.…”

Section: Discussionsupporting

confidence: 55%

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Human class I major histocompatibility complex alleles determine central nervous system injury versus repair

Wootla

Denic

Watzlawik

et al. 2016

J Neuroinflammation

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BackgroundWe investigated the role of human HLA class I molecules in persistent central nervous system (CNS) injury versus repair following virus infection of the CNS.MethodsHuman class I A11+ and B27+ transgenic human beta-2 microglobulin positive (Hβ2m+) mice of the H-2b background were generated on a combined class I-deficient (mouse beta-2 microglobulin deficient, β2m0) and class II-deficient (mouse Aβ0) phenotype. Intracranial infection with Theiler’s murine encephalomyelitis virus (TMEV) in susceptible SJL mice results in acute encephalitis with prominent injury in the hippocampus, striatum, and cortex.ResultsFollowing infection with TMEV, a picornavirus, the Aβ0.β2m0 mice lacking active immune responses died within 18 to 21 days post-infection. These mice showed severe encephalomyelitis due to rapid replication of the viral genome. In contrast, transgenic Hβ2m mice with insertion of a single human class I MHC gene in the absence of human or mouse class II survived the acute infection. Both A11+ and B27+ mice significantly controlled virus RNA expression by 45 days and did not develop late-onset spinal cord demyelination. By 45 days post-infection (DPI), B27+ transgenic mice showed almost complete repair of the virus-induced brain injury, but A11+ mice conversely showed persistent severe hippocampal and cortical injury.ConclusionsThe findings support the hypothesis that the expression of a single human class I MHC molecule, independent of persistent virus infection, influences the extent of sub frequent chronic neuronal injury or repair in the absence of a class II MHC immune response.Electronic supplementary materialThe online version of this article (doi:10.1186/s12974-016-0759-4) contains supplementary material, which is available to authorized users.

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Section: Discussionsupporting

confidence: 55%

“…Previous experiments performed with Aβ 0 .β2m 0 mice demonstrated that these mice die of overwhelming virus-induced encephalomyelitis within 16 to 18 dpi with TMEV [48]. We infected Aβ 0 .β2m 0 mice ( N = 25) with TMEV, and mice were either moribund or dead by 18 dpi.…”

Section: Resultsmentioning

confidence: 99%

Human class I major histocompatibility complex alleles determine central nervous system injury versus repair

Wootla

Denic

Watzlawik

et al. 2016

J Neuroinflammation

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“…Immunocytochemistry was performed on paraffin-embedded sections as previously described (27). Slides were deparaffinized in xylene and rehydrated through an ethanol series (absolute, 95, 70, and 50%).…”

Section: Methodsmentioning

confidence: 99%

Transgenic Expression of the 3D Polymerase Inhibits Theiler's Virus Infection and Demyelination

Kerkvliet¹,

Zoecklein²,

Papke³

et al. 2009

J Virol

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The RNA-dependent RNA polymerase 3D pol is required for the elongation of positive-and negative-stranded picornavirus RNA. During the course of investigating the effect of the transgenic expression of viral genes on the host immune response, we evaluated the viral load present in the host after infection. To our surprise, we found that 3D transgenic expression in genetically susceptible FVB mice led to substantially lower viral loads after infection with Theiler's murine encephalomyelitis virus (TMEV). As a result, spinal cord damage caused by chronic viral infection in the central nervous system was reduced in FVB mice that expressed 3D. This led to the preservation of large-diameter axons and motor function in these mice. The 3D transgene also lowered early viral loads when expressed in FVB-D b mice resistant to persistent TMEV infection. The protective effect of 3D transgenic expression was not altered in FVB-Rag ؊/؊ .3D mice that are deficient in T and B cells, thus ruling out a mechanism by which the overexpression of 3D enhanced the adaptive immune clearance of the virus. Understanding how endogenously overexpressed 3D polymerase inhibits viral replication may lead to new strategies for targeting therapies to all picornaviruses.

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“…The subsequent disease course depends decisively upon the genetic background of the used mice strain. Thus, while the virus is eliminated in resistant C57BL/6 mice after the initial phase, an inadequate antiviral immune response leads to prolonged viral infection in susceptible SJL/J mice [2,3,4]. Hereby, viral antigen-induced delayed-type hypersensitivity and myelin-specific autoimmunity induce inflammatory demyelination predominantly in the spinal cord of susceptible mice strains, resembling the chronic progressive form of MS.…”

Section: Introductionmentioning

confidence: 99%

Periventricular Demyelination and Axonal Pathology Is Associated with Subependymal Virus Spread in a Murine Model for Multiple Sclerosis

et al. 2012

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Objectives: Theiler’s murine encephalomyelitis virus (TMEV) infection of mice is a widely used animal model for demyelinating disorders, such as multiple sclerosis (MS). The aim of the present study was to identify topographical differences of TMEV spread and demyelination in the brain of experimentally infected susceptible SJL/J mice and resistant C57BL/6 mice. Methods: Demyelination was confirmed by Luxol fast blue and cresyl violet staining and axonal damage by neurofilament-specific and β-amyloid precursor protein-specific immunohistochemistry. Viral dissemination within the central nervous system (CNS) was quantified by immunohistochemistry and in situ hybridization. Further, the phenotype of infected cells was determined by confocal laser scanning microscopy. Results: An early transient infection of periventricular cells followed by demyelination and axonopathies around the fourth ventricle in SJL/J mice was noticed. Periventricular and brain stem demyelination was associated with a predominant infection of microglia/macrophages and oligodendrocytes. Conclusions: Summarized, the demonstration of ependymal infection and subjacent spread into the brain parenchyma as well as regional virus clearance despite ongoing demyelination and axonal damage in other CNS compartments allows new insights into TME pathogenesis. This novel aspect of TMEV CNS interaction will enhance the understanding of region-specific susceptibilities to injury and regenerative capacities of the brain in this MS model.

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HLA-DQ Polymorphism Influences Progression of Demyelination and Neurologic Deficits in a Viral Model of Multiple Sclerosis

Cited by 11 publications

References 45 publications

Human class I major histocompatibility complex alleles determine central nervous system injury versus repair

Human class I major histocompatibility complex alleles determine central nervous system injury versus repair

Transgenic Expression of the 3D Polymerase Inhibits Theiler's Virus Infection and Demyelination

Periventricular Demyelination and Axonal Pathology Is Associated with Subependymal Virus Spread in a Murine Model for Multiple Sclerosis

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