Experimental Neuropathology of Chronic Demyelination Induced by a JHM Virus Variant (DS)

Erlich, Stephanie S.; Fleming, John O.; Stohlman, Stephen A.; Weiner, Leslie P.

doi:10.1001/archneur.1987.00520200043016

Cited by 26 publications

(19 citation statements)

References 23 publications

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“…These data contrast with an ultrastructural examination of the CNS of mice approximately 1 year p.i. with a distinct variant of JHMV, which suggested preferential retention of plasma cells in the meninges [34]. Retention of ASC within the CNS parenchyma, associated with intrathecal Ab production, is consistent with an increased CSF to serum ratio of anti-viral Ab observed following JHMV infection in both mice and rats [35][36][37].…”

Section: Cns Asc Retentionsupporting

confidence: 69%

CNS viral infection diverts homing of antibody‐secreting cells from lymphoid organs to the CNS

et al. 2006

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Neurotropic coronavirus infection of mice results in acute encephalomyelitis followed by viral persistence. Whereas cellular immunity controls acute infection, humoral immunity regulates central nervous system (CNS) persistence. Maintenance of serum Ab was correlated with tissue distribution of virus-specific Ab-secreting cells (ASC). Although virus-specific ASC declined in cervical lymph node and spleen after infectious virus clearance, virus-specific serum Ab was sustained at steady levels, with a delay in neutralizing Ab. Virus-specific ASC within the CNS peaked rapidly 1 wk after control of infectious virus and were retained throughout chronic infection, consistent with intrathecal Ab synthesis. Surprisingly, frequencies of ASC in the BM remained low and only increased gradually. Nevertheless, virus-specific ASC induced by peripheral infection localized to both spleen and BM. The data suggest that CNS infection provides strong stimuli to recruit ASC into the inflamed tissue through sustained up-regulation of the CXCR3 ligands CXCL9 and CXCL10. Irrespective of Ag deprivation, CNS retention of ASC coincided with elevated BAFF expression and ongoing differentiation of class II + to class II -CD138 + CD19 + plasmablasts. These results confirm the CNS as a major ASCsupporting environment, even after resolution of viral infection and in the absence of chronic ongoing inflammation. IntroductionThe preeminent goal of the immune system is to eliminate pathogens and establish immunological memory [1]. Both T cells and Ab participate in eliminating a variety of pathogens; however, sustained serum Ab is an important criteria for many vaccination strategies, as they provide the first line of defense against re-infection [2]. Upon Ag encounter in regional lymph nodes, B cells undergo clonal expansion in extrafollicular foci and within germinal centers [3,4].Rapidly activated B cells secrete low-affinity Ab but can undergo isotype switching and limited BCR hypermutation as they differentiate into plasmablasts [3]. In the milieu of accessory cells and cytokines, germinal center B cells undergo affinity maturation and ultimately differentiate into both Ab-secreting cells (ASC) and memory B cells. As Ag is depleted, ASC and memory B cells are detected with increasing frequency in BM [2], where both stromal cells and other resident cells provide soluble as well as contact-dependent survival signals, including CXCL12 and BAFF [5]. Ab secretion by terminally differentiated plasma cells is independent of both Ag and T cell regulation [2,6]. Long-lived ASC in BM and spleen maintain serum Ab, thus providing protective immunity to re-infection, sometimes for the [4,6]. In contrast to Ag encountered in the periphery, the regulation of B cell activation by Ag sequestered within the central nervous system (CNS) is less clear. The absence of dedicated lymphatic drainage and the presence of the blood brain barrier (BBB) limits Ag transport from the CNS into secondary lymphoid tissue as well as trafficking of both cells and macromolecule...

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Section: Cns Asc Retentionsupporting

confidence: 69%

CNS viral infection diverts homing of antibody‐secreting cells from lymphoid organs to the CNS

et al. 2006

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“…Indeed, it has been suggested that direct viral cytolysis/cytotoxicity may be operational during the early phase (7-10 days) of disease and an immune-mediated component (with or without viral involvement) in the later subacute phase. 24 In the experiments reported here, we took advantage of the availability of/?2M -/mice 21 to investigate the role CD8 ÷ T cells play in MHV-induced subacute demyelination. If CD8 ÷ T cells are significant in the induction of demyelination, the subacute disease might be expected to decrease substantially.…”

Section: Resultsmentioning

confidence: 99%

Mouse hepatitis virus A59-induced demyelination can occur in the absence of CD8+ T cells

Gombold

Sutherland

Lavi

et al. 1995

Microbial Pathogenesis

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Mouse hepatitis virus causes a chronic demyelinating disease in C57BL/6 mice. While early studies suggested demyelination is due to direct cytolytic effects of virus on oligodendrocytes, there is increasing evidence for the involvement of the immune system in the mechanism of demyelination. In this study we have asked whether demyelination can occur in the absence of functional MHC class I expression and CD8+ T cells. We infected transgenic mice lacking expression of beta 2 microglobulin (beta 2 M -/- mice) with MHV-A59. In beta 2M-/- mice, virus was much more lethal than in either of the parental strains used to produce the mice; furthermore, while clearance from the CNS did occur in beta 2M-/- mice, it was slower than in C57BL/6 mice. This is consistent with the importance of CD8+ cells in viral clearance. Because of the increased sensitivity of the beta 2M-/- mice to infection, only low levels of virus could be used to evaluate chronic disease. Even at these low levels, demyelination did occur in some animals. To compare infection in beta 2M-/- and C57BL/6 mice we used a higher dose of an attenuated variant of MHV-A59, C12. The attenuated variant induced less demyelination in C57BL/6 mice compared to wild type A59, but the levels observed were not significantly different from those seen in beta 2M-/- mice. Thus, MHV-induced demyelination can occur in some animals in the absence of MHC class I and CD8+ cells.

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“…Finally, it has been suggested that the acute demyelination observed early in the infection may be a result of cytolysis of oligodendrocytes and the subacute or chronic demyelination to immune-mediated mechanisms . 30 The increase in MHC antigen expression on astrocytes and oligodendrocytes during MHV-A59 infections is well established ." We show here that this increase is likely to be the result of an elevation of MHC mRNA .…”

Section: Discussionmentioning

confidence: 99%

Mouse hepatitis virus A59 increases steady-state levels of MHC mRNAs in primary glial cell cultures and in the murine central nervous system

Gombold

Weiss

1992

Microbial Pathogenesis

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Infection of mixed glial cell cultures with mouse hepatitis virus (MHV)-A59 results in an approximately six-fold increase in the level of major histocompatibility complex (MHC) class I mRNA. In situ hybridization of glial cell cultures infected with MHV-A59 again showed enhanced MHC mRNA expression, both in infected and uninfected cells. These results extend our earlier finding that MHC surface antigens are enhanced on astrocytes and oligodendrocytes after MHV-A59 infection and suggest that this enhancement is a result of an increase in the steady-state level of MHC mRNA. We further demonstrate that increases in MHC mRNA occur in the murine central nervous system (CNS) following infection in vivo. Northern blot analysis of RNA from the brains of infected animals showed transient expression of both MHC class I and class II mRNA over the first 14 days of infection. Expression coincided with viral replication and clearance. In situ hybridization of brain sections from infected animals showed that class I and class II expression was widespread throughout all portions of the brain and in uninfected as well as infected cells. Viral RNA, in contrast, was observed in small foci of cells and mostly within the limbic system. Thus enhancement of MHC mRNA was not restricted either to areas of infection or inflammation. The spatial relationship between viral and MHC expression supports our hypothesis that a soluble mediator is involved in the mechanism of the increase in MHC levels. The fact that MHC induction occurs in vivo as well as in vitro suggests MHC may be important in the mechanism of MHV-induced disease.

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Experimental Neuropathology of Chronic Demyelination Induced by a JHM Virus Variant (DS)

Cited by 26 publications

References 23 publications

CNS viral infection diverts homing of antibody‐secreting cells from lymphoid organs to the CNS

CNS viral infection diverts homing of antibody‐secreting cells from lymphoid organs to the CNS

Mouse hepatitis virus A59-induced demyelination can occur in the absence of CD8+ T cells

Mouse hepatitis virus A59 increases steady-state levels of MHC mRNAs in primary glial cell cultures and in the murine central nervous system

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