CNS viral infection diverts homing of antibody-secreting cells from lymphoid organs to the CNS
Department of Pathology, University of Southern California, Keck School of Medicine, Los Angeles, CA, USA. European Journal of Immunology
(Impact Factor: 4.03).
04/2006; 36(3):603-12. DOI: 10.1002/eji.200535123
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 ASC-supporting environment, even after resolution of viral infection and in the absence of chronic ongoing inflammation.
Available from: Jason G Weinger
- "Notably, CCL5 neutralization abrogates both CD4þ and CD8þ T cell accumulation during chronic infection (Glass et al., 2004), indicating differential chemokine usage between the T cell subsets (Stiles et al., 2009). More recently, Bergmann and colleagues have provided compelling evidence that CXCR3 ligands CXCL9 and CXCL10 are crucial for allowing plasmablast migration into the CNS of MHV-infected mice via signaling through CXCR3 expressed on these cells (Marques et al., 2011; Phares et al., 2011; Tschen et al., 2006). These findings highlight a previously unappreciated role for these chemokines in host defense by attracting activated antibody secreting cells into the CNS of mice persistently infected with a neurotropic virus. "
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ABSTRACT: Inoculation with the neurotropic JHM strain of mouse hepatitis virus (MHV) into the central nervous system (CNS) of susceptible strains of mice results in an acute encephalomyelitis in which virus preferentially replicates within glial cells while excluding neurons. Control of viral replication during acute disease is mediated by infiltrating virus-specific T cells via cytokine secretion and cytolytic activity, however sterile immunity is not achieved and virus persists resulting in chronic neuroinflammation associated with demyelination. CXCR2 is a chemokine receptor that upon binding to specific ligands promotes host defense through recruitment of myeloid cells to the CNS as well as protecting oligodendroglia from cytokine-mediated death in response to MHV infection. These findings highlight growing evidence of the diverse and important role of CXCR2 in regulating neuroinflammatory diseases.
Available from: Kristen A Bernard
- "The trafficking and persistence of ASC in the CNS also occurs in other viral models. We observed that antiviral IgM and IgG ASC in the spleen preceded the detection of ASC in the brain, suggesting that B cells from the periphery are activated and subsequently traffic to the CNS where they differentiate into ASC, as occurs for mouse hepatitis virus . Similar to our results, virus-specific ASC are detected in mouse brains for one year after infection with Sindbis virus  and for 90 days after infection with mouse hepatitis virus [29,31]. "
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ABSTRACT: West Nile virus (WNV) persists in humans and several animal models. We previously demonstrated that WNV persists in the central nervous system (CNS) of mice for up to 6 months post-inoculation. We hypothesized that the CNS immune response is ineffective in clearing the virus.
Immunocompetent, adult mice were inoculated subcutaneously with WNV, and the CNS immune response was examined at 1, 2, 4, 8, 12 and 16 weeks post-inoculation (wpi). Characterization of lymphocyte phenotypes in the CNS revealed elevation of CD19+ B cells for 4 wpi, CD138 plasma cells at 12 wpi, and CD4+ and CD8+ T cells for at least 12 wpi. T cells recruited to the brain were activated, and regulatory T cells (Tregs) were present for at least 12 wpi. WNV-specific antibody secreting cells were detected in the brain from 2 to 16 wpi, and virus-specific CD8+ T cells directed against an immunodominant WNV epitope were detected in the brain from 1 to 16 wpi. Furthermore, these WNV-specific immune responses occurred in mice with and without acute clinical disease.
Virus-specific immune cells persist in the CNS of mice after WNV infection for up to 16 wpi.
Available from: Stephen Lalor
- "By comparison to other viral encephalitis models, CXCL13 was not induced in the CNS during experimental coronavirus encephalomyelitis despite prominent accumulation of virus-specific antibody-secreting cells in the target tissue (Tschen et al., 2006). Here, CXCL9 and CXCL10, both acting on plasmablasts through CXCR3, were implicated in CNS B cell recruitment (Tschen et al., 2006). Our data would suggest that neither CXCL9 nor CXCL10 are likely responsible for B cell recruitment to the CNS of SVinfected animals, since one mediator (CXCL9) is simply not induced by infection and the other (CXCL10) only goes up transiently and then declines as B cell influx begins in earnest (Fig. 1C and 1D). "
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ABSTRACT: Cases of progressive multifocal leukoencephalopathy can occur in patients treated with the B cell depleting anti-CD20 antibody, rituximab, highlighting the importance of B cell surveillance of the central nervous system (CNS). The lymphoid chemokine, CXCL13, is critical for B cell recruitment and functional organization of peripheral lymphoid tissues, and CXCL13 levels are often elevated in the inflamed CNS. To more directly investigate the role of CXCL13 in CNS B cell migration, its role in animal models of infectious and inflammatory demyelinating disease was examined. During acute alphavirus encephalitis where viral clearance depends on the local actions of anti-viral antibodies, CXCL13 levels and B cell numbers increased in brain tissue over time. Surprisingly, however, CXCL13-deficient animals showed normal CNS B cell recruitment, unaltered CNS virus replication and clearance, and intact peripheral anti-viral antibody responses. During experimental autoimmune encephalomyelitis (EAE), CNS levels of CXCL13 increased as symptoms emerged and equivalent numbers of B cells were identified among the CNS infiltrates of CXCL13-deficient mice compared to control animals. However, CXCL13-deficient mice did not sustain pathogenic anti-myelin T cell responses, consistent with their known propensity to develop more self-limited EAE. These data show that CXCL13 is dispensable for CNS B cell recruitment in both models. The disease course is unaffected by CXCL13 in a CNS infection paradigm that depends on a pathogen-specific B cell response, while it is heightened and prolonged by CXCL13 when myelin-specific CD4+ T cells drive CNS pathology. Thus, CXCL13 could be a therapeutic target in certain neuroinflammatory diseases, but not by blocking B cell recruitment to the CNS.
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