Virus specificity and isotype expression of intraparenchymal antibody-secreting cells during Sindbis virus encephalitis in mice.
ABSTRACT To study the generation of specific antibody responses within the central nervous system (CNS), we have utilized a murine model of acute viral encephalitis. When Sindbis virus (SV) is injected intracerebrally into weanling mice it causes an acute non-fatal encephalitis and recovery is primarily dependent on the development of antiviral antibody. We used a modified enzyme-linked immunoassay to determine the number of antibody-secreting cells (ASC) specific for SV and their Ig isotype in brain, spleen and cervical lymph nodes over the course of the acute encephalitis. The numbers of SV-specific ASC peak early in spleen and lymph nodes and then begin to increase in brain, suggesting that initial stimulation of B cells occurs primarily in peripheral lymphoid tissue followed by B cell entry into the circulation and appearance in the brain. The pattern for each individual isotype was similar with peak numbers of SV-specific cells present in the spleen 5-7 days after infection, while numbers in the brain continue to rise through day 20 when most ASC were secreting IgG2a or IgA SV-specific antibody. The data suggest therefore that most isotype switching from IgM to IgG and IgA occurs in peripheral lymphoid tissue. An exception to this pattern is IgG1, where numbers of ASC producing IgG1 do not show a peak in spleen and continue to rise in brain through the course of acute encephalitis. The data also indicate that early in infection a large proportion of ASC in the brain are not specific for SV and demonstrate that recruitment of ASC into the CNS is non-specific.(ABSTRACT TRUNCATED AT 250 WORDS)
Article: Antibody-mediated protection against cytotoxic T-cell escape in coronavirus-induced demyelination.[show abstract] [hide abstract]
ABSTRACT: C57BL/6 (B6) mice infected with mouse hepatitis virus (MHV) strain JHM develop a clinically evident, demyelinating encephalomyelitis. Infectious virus can be isolated from the spinal cords of these mice and is invariably mutated in the immunodominant CD8 T-cell epitope recognized in this strain. We showed previously that these persistently infected mice did not mount a measurable serum anti-MHV neutralizing antibody response. Here we show that cytotoxic T-lymphocyte (CTL) escape was not detected in MHV-infected BALB/b mice (H-2(b) haplotype), even though the same CD8 T-cell epitopes were recognized as in B6 mice. BALB/b mice had 25-fold more MHV-specific antibody-secreting cells in the central nervous system, the site of infection, than B6 mice, suggesting that local production of anti-MHV antibody contributed to this absence of CTL escape. Additionally, administration of anti-MHV neutralizing antibody to infected B6 mice suppressed the development of CTL escape mutants. These findings indicate a key role for the anti-MHV antibody response in suppressing virus replication, thereby minimizing the emergence and competitive advantage of CTL escape mutants.Journal of Virology 12/2003; 77(22):11867-74. · 5.40 Impact Factor
Article: Roles of immunoglobulin valency and the heavy-chain constant domain in antibody-mediated downregulation of Sindbis virus replication in persistently infected neurons.[show abstract] [hide abstract]
ABSTRACT: Clearance of infectious Sindbis virus from neurons is mediated by antibody to the E2 glycoprotein. Properties of the antibody important for downregulation of Sindbis virus replication are unknown. Immunoglobulin isotypes and valency determine many biological properties of antibodies. An immunoglobulin G1 (IgG1) isotype switch mutant and F(ab')2 and Fab fragments of IgG3 monoclonal antibody 209 were prepared and tested for clearance of infectious virus from persistently infected rat dorsal root ganglion neurons in vitro. IgG1, IgG3, and IgG3-derived F(ab')2 fragments were similarly efficacious, while IgG3-derived Fab fragments had no effect on virus replication. Cross-linking of Fab with secondary antibodies restored antiviral activity. Therefore, we found no evidence that IgG subclass plays a role in control of intracellular Sindbis virus replication. However, bivalency appears to be crucial for the ability of E2-specific IgG molecules to mediate clearance of infectious virus from neuron cells, suggesting that cross-linking of E2 molecules is essential.Journal of Virology 04/1995; 69(3):1990-3. · 5.40 Impact Factor