Intracellular neutralization of virus by immunoglobulin A antibodies.

Abstract

IgA is thought to neutralize viruses at the epithelial surface of mucous membranes by preventing their attachment. Since IgA, a polymeric immunoglobulin, is transported through the lining of epithelial cells by the polymeric-immunoglobulin receptor and since viruses are obligate intracellular parasites, we hypothesized that IgA antibodies may also interfere with viral replication by binding to newly synthesized viral proteins within infected cells. Polarized monolayers of Madin-Darby canine kidney epithelial cells expressing the polymeric-immunoglobulin receptor were infected on the apical surface with Sendai virus. Anti-Sendai virus IgA monoclonal antibody delivered from the basolateral surface colocalized with viral protein within the cell, as documented by immunofluorescence. More importantly, anti-viral IgA reduced virus titers greater than 1000-fold (P less than 0.0001) in apical supernatants and greater than 10-fold (P less than 0.0001) in cell lysates from monolayers treated with anti-viral IgA compared with those treated with either anti-viral IgG or an irrelevant IgA monoclonal antibody. We believe that the differences in viral titers between cell layers treated with specific IgA, which enters the epithelial cell by binding to the polymeric-immunoglobulin receptor, and those treated with specific IgG, which does not enter the cells, or irrelevant IgA indicate that specific intracellular IgA antibodies can inhibit viral replication. Thus, in addition to the classical role of humoral antibodies in extracellular defense, IgA antibody may be able to neutralize microbial pathogens intracellularly, giving IgA a role in host defense that has traditionally been reserved for cell-mediated immunity.

Intraepithelial Cell Neutralization of HIV-1 Replication by IgA

“…These results suggest that although Ab transcytosed to the apical side can neutralize virus in the apical supernatant, virus neutralization can also be mediated by IgA inside epithelial cells. In the current study, CM 1 reduced apical virus to a greater extent than in previous reports with other viruses (19,20,22). This is probably due to the smaller amount of HIV reaching the apical surface (6% of cells infected) compared with the previous reports, where most of the cells were infected.…”

“…During transport of IgA through mucosal epithelial cells, after polymeric Ig receptor (pIgR) 4 -mediated endocytosis, IgA Abs may also be able to interact intracellularly with viral proteins to inhibit viral replication. Evidence for such intraepithelial cell neutralization has been demonstrated in vitro with IgA mAbs against Sendai and measles viruses (paramyxoviruses), influenza virus (an orthomyxovirus), and rotavirus (a reovirus) (17)(18)(19)(20)(21)(22)37), but not yet with Abs to HIV (a retrovirus). In addition, neutralization (presumably intracellular) was shown in mice by an IgA mAb against a rotavirus internal protein, which was able both to prevent infection and cure persistent infection (17).…”

Cross-protection against influenza virus infection by intranasal administration of nucleoprotein-based vaccine with compound 48/80 adjuvant

“…The level of mucosal IgA might be correlated with the potential against the viral challenge. 16,17 Tamura et al confirmed that mice immunized intranasally with rNP from A/PR/8/34 expressed in insect cells could accelerate the clearing of the homologous virus in the nasal site of the mice, promoting recovery from infection. 18 Our study also confirmed that the protection immunity in mice was associated with the level of anti-NP IgA.…”

Immunoprophylaxie des infections respiratoires

“…Ce mécanisme de neutralisation est efficace contre les pathogènes extracellulaires ou la dissémination intercellulaire des pathogènes intracellulaires, mais est inefficace contre les virus intracellulaires [20,21]. Expérimentalement, la demi-vie des IVIG dans les fluides pulmonaires non inflammatoires de la souris est de 48 heures contre 7jours dans le sang après injection intraveineuse, et les IVIG administrées par voie intranasale ne sont pas détectables dans le sang [16].…”

“…Des anticorps monoclonaux de classe IgA sont capables de neutraliser le virus Sendai [21] et le virus respiratoire syncytial (RSV) [27] par des mécanismes limités à l'agglutination et la neutralisation de l'attachement du pathogène à ses récepteurs, car les IgA n'activent pas le complément et ne se fixent pas aux récepteurs Fcγ des phagocytes. Ils seraient cependant capables de neutraliser des pathogènes intracellulaires, par un mécanisme impliquant leur internalisation via leur attachement au récepteur pour les Ig polymé-riques [21]. Deux IgG1 monoclonales humanisées reconnaissant la protéine de fusion du RSV neutralisent les deux sous-types du virus dans le modèle d'infection respiratoire chez le rat cotonnier [28].…”