Polyclonal B lymphocyte activation induced by mouse hepatitis virus A59 infection (original) (raw)
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Mouse hepatitis virus infection suppresses modulation of mouse spleen T-cell activation
Immunology, 1992
Natural infection by mouse hepatitis virus (MHV) can affect interpretation of immunological studies in mice. MHV, a collective term describing a group of corona viruses, is found in natural infections in over 70% of laboratory mouse populations in the U.S.A. and Canada. Natural outbreaks of MHV in our animal colony afforded us the opportunity to study MHV-induced immunosuppression as well as the effects of MHV infection on neurotransmitter immunomodulation. Concanavalin A (Con A)-stimulated DNA synthesis by spleen T lymphocytes from MHV-infected mice was 20-50% that of non-infected mice. The MHV infection also altered neurotransmitter modulation of spleen T-lymphocyte activation. In contrast to noradrenaline ablation of Con A-activated DNA synthesis by spleen lymphocytes from non-infected mice, DNA synthesis by the infected group was not inhibited by noradrenaline or dibutyryl-cAMP. These effects of MHV infection were specific for spleen T lymphocytes since MHV infection did not alt...
Journal of Virology
Viruses such as lactate dehydrogenase-elevating virus and adenovirus induce in vivo a polyclonal activation of murine B lymphocytes, followed by a marked increase in the production of immunoglobulin G2a (IgG2a). The role of T lymphocytes in this phenomenon was studied by injection of an anti-CD4 monoclonal antibody able to inhibit the T-helper function. This treatment profoundly depressed the production of IgG2a, whereas it had no effect on the proliferation of B cells. Activated B cells obtained from such infected and treated mice remained able to produce various immunoglobulin isotypes after exposure to an appropriate stimulus. In particular, gamma interferon, which is known to be secreted after viral infection, induced the production of IgG2a. These observations support the hypothesis that the influence of viruses on the switch of immunoglobulins is mediated by T-helper lymphocytes.
Immunology, 1997
Owing to their scavenging and phagocytic functions, spleen macrophages are regarded to be important in the induction and maintenance of both innate and acquired immune defence mechanisms. In this study, we investigated the role of spleen macrophages in immunity against mouse hepatitis virus strain A59 (MHV-A59). Previous studies showed that spleen and liver macrophages are the first target cells for infection by MHV-A59 in vivo, suggesting that they could be involved in the induction of immune responses against MHV-A59. We used a macrophage depletion technique to deplete macrophages in vivo and studied the induction of virus-specific antibody and cytotoxic T-cell (CTL) responses and non-immune resistance against MHV-A59 in normal and macrophage-depleted mice. Virus titres in spleen and liver increased rapidly in macrophage-depleted mice, resulting in death of mice within 4 days after infection. Elimination of macrophages before immunization with MHV-A59 resulted in increased virus-specific humoral and T-cell proliferative responses. However, virus-specific CTL responses were not altered in macrophage-depleted mice. Our results show that spleen macrophages are of major importance as scavenger cells during MHV-A59 infection and are involved in clearance of virus from the host. In addition, macrophages may be involved in the regulation of acquired immune responses. In the absence of macrophages, increased virus-specific T-cell and antibody responses are detectable, suggesting that macrophages suppress MHV-A59-specific T-and B-cell responses and that other cells serve as antigen-presenting cells.
Virology, 1999
Mutations in an immunodominant CD8 CTL epitope (S-510-518) are selected in mice persistently infected with the neurotropic JHM strain of mouse hepatitis virus. These mutations abrogate recognition by T cells harvested from the infected CNS in direct ex vivo cytotoxicity assays. Previous reports have suggested that, in general, an oligoclonal, monospecific T cell response contributes to the selection of CTL escape mutants. Herein, we show that, in MHV-JHM-infected mice, the CD8 T cell response after intraperitoneal infection is polyclonal and diverse. This diverse response was shown to include both polyclonal and oligoclonal components. The polyclonal data were shown to fit a logarithmic distribution. With regard to specificity, we used a panel of peptide analogues of epitope S-510-518 and spleen-derived CD8 T cell lines to determine why only a subset of possible mutations was selected in persistently infected mice. At a given position in the epitope, the mutations identified in in vivo isolates were among those that resulted in the greatest loss of recognition. However, not all such mutations were selected, suggesting that additional factors must contribute to selection in vivo. By extrapolation of these results to the persistently infected CNS, they suggest that the selection of CTL escape mutants requires the presence of a monospecific T cell response but also show that this response need not be oligoclonal.
Modulation of the immunological response to hepatitis b virus by antibodies
Hepatology, 1987
Antibodies to HBsAg of IgG class enhanced the helper activity of a human T cell clone to promote the in vitro synthesis of immunoglobulins by autologous B lymphocytes. Using two different assay systems, the effect of antigen-epecific antibodies on the helper function of a EBsAg-reactive T cell clone was studied. The monoclonal antibody to HBsAg ASC3 (IgG) increased significantly the T cell-dependent production of immunoglobulins by Staphyloccocus aureus-stimulated autologous B lymphocytee. Furthermore, the results obtained with a different type of assay showed that ASC3 also increased the synthesis of antibody to HBsAg by the autologous B cells in the presence of HBsAg and the helper T cell clone. On the other hand, when the monoclonal antibody to EBsAg of IgM class, H5D3 or the F(ab% fragment of A5C3 were tested, no significant enhancement of the
Hepatology, 1995
The T helper (Th) cell response to hepatitis B core antigen (HBcAg) was analyzed in 76 chronic hepatitis B virus (HBV) carriers with varying degrees of hepatic inflammation and HBV replication. Fifty-five patients had active viral replication, 28 with minimal histological changes and normal alanine transaminase (ALT) and 27 with active hepatic inflammation and elevated ALT. The remaining 21 chronic hepatitis B surface antigen (HBsAg) carriers had undetectable HBV replication, minimal histological activity, and normal ALT. In addition, 34 chronic HBV carriers were studied prospectively during treatment with a-interferon. The HBcAg-specific Th cell response was evaluated by a proliferative assay using 3H-thymidine uptake and y-interferon production by peripheral blood mononuclear cells. The proliferative response and y-interferon production of patients with active hepatic inflammation were significantly higher than in patients with minimal histological changes and in controls. In the longitudinal analysis during a-interferon treatment, 22 of 34 patients sustained an ALT flare accompanied by a parallel, significant Th cell response, which preceded or coincided with the ALT flare. The elevation in the Th cell response and the ALT flare were followed by a significant rise in the serum immunoglobulin (Ig) M anti-HBc index. Ten of twenty-two patients with an enhanced Th cell response and an ALT flare seroconverted after a-interferon treatment. The Th cell activity in the 10 responders rapidly subsided after hepatitis B e antigen (HBeAg) to anti-HBe seroconversion,
PLoS Pathogens, 2014
The mechanisms of chronic HBV infection and immunopathogenesis are poorly understood due to a lack of a robust small animal model. Here we report the development of a humanized mouse model with both human immune system and human liver cells by reconstituting the immunodeficient A2/NSG (NOD.Cg-Prkdc scid Il2rg tm1Wjl /SzJ mice with human HLA-A2 transgene) with human hematopoietic stem cells and liver progenitor cells (A2/NSG-hu HSC/Hep mice). The A2/NSG-hu HSC/Hep mouse supported HBV infection and approximately 75% of HBV infected mice established persistent infection for at least 4 months. We detected human immune responses, albeit impaired in the liver, chronic liver inflammation and liver fibrosis in infected animals. An HBV neutralizing antibody efficiently inhibited HBV infection and associated liver diseases in humanized mice. In addition, we found that the HBV mediated liver disease was associated with high level of infiltrated human macrophages with M2-like activation phenotype. Importantly, similar M2-like macrophage accumulation was confirmed in chronic hepatitis B patients with liver diseases. Furthermore, gene expression analysis showed that induction of M2-like macrophage in the liver is associated with accelerated liver fibrosis and necrosis in patients with acute HBVinduced liver failure. Lastly, we demonstrate that HBV promotes M2-like activation in both M1 and M2 macrophages in cell culture studies. Our study demonstrates that the A2/NSG-hu HSC/Hep mouse model is valuable in studying HBV infection, human immune responses and associated liver diseases. Furthermore, results from this study suggest a critical role for macrophage polarization in hepatitis B virus-induced immune impairment and liver pathology.