title: Antibody response to influenza infection of mice: different patterns for glycoprotein and nucleocapsid antigens.
abstract: Our previous studies of C57BL/6 mice intranasally infected with influenza virus (A/PR8) revealed a spike of virus-specific immunoglobulin A (IgA)-secreting antibody-forming cells (AFC) in the mediastinal lymph node (MLN) 7 days post-infection. Here we show that these AFC are directed only against viral glycoprotein, and not nucleocapsid antigens. The early IgA spike associates with a decline in glycoprotein-specific AFC during week 2 post-infection. In contrast to the glycoprotein-specific AFC, nucleocapsid-specific, IgA-secreting AFC develop gradually in the MLN and persist for more than 3 weeks post-infection. As peripheral lymph node reactions wane, the nucleocapsid-specific AFC appear as long-sustained populations in the bone marrow. Microanatomical examination of the respiratory tract in infected mice shows foci of infection established in the lung 2 days post-infection, from which virus spreads to infect the entire lining of the trachea by day 3. At this time, viral haemagglutinin can be seen within the MLN, probably on projections from infected dendritic cells. This feature disappears within a day, though viral antigen expression continues to spread throughout the respiratory tract. Total IgA- and IgG-secreting AFC appear histologically in large numbers during the first week post-infection, significantly preceding the appearance of germinal centres (revealed by peanut agglutinin staining in week 2). To explain these results, we suggest that the initial immunogenic encounter of B cells with viral antigens occurs about 3 days post-infection in the MLN, with antigens transported by dendritic cells from airway mucosa, the only site of viral replication. Viral glycoproteins expressed as integral membrane components on the surface of infected dendritic cells [probably in the absence of cognate T helper (Th) cells] promote members of expanding relevant B-cell clones to undergo an IgA switch and terminal local plasmacytoid differentiation. Anti-glycoprotein specificities are thus selectively depleted from progeny of activated B-cell clones which are channelled to participate in germinal centre formation (perhaps by cognate T helper cells when they become sufficiently frequent). One product of the germinal centre reaction is the long-sustained, bone marrow-resident population, which is accordingly rich in anti-nucleoprotein, but not anti-glycoprotein specificities. Of note, we find that AFC responses toward influenza virus and Sendai virus differ, even though viral replication is limited to the airway mucosa in each case. The response towards Sendai virus exhibits neither the early appearance of anti-glycoprotein AFC expressing IgA in draining lymph nodes, nor the subsequent relative deficit of this specificity from bone marrow AFC populations.
authors.affiliation: Department of Immunology, St Jude Children's Research Hospital, Memphis, TN, USA.
authors.forename: Robert
authors.initials: R
authors.lastname: Sealy
authors.forename: Sherri
authors.initials: S
authors.lastname: Surman
authors.forename: Julia L
authors.initials: JL
authors.lastname: Hurwitz
authors.forename: Christopher
authors.initials: C
authors.lastname: Coleclough
mesh_terms: D000818:Animals; D000914:Antibodies, Viral / Q000096:biosynthesis*; D000918:Antibody Specificity; D000921:Antibody-Producing Cells / Q000276:immunology; D000956:Antigens, Viral / Q000276:immunology* / Q000378:metabolism; D001853:Bone Marrow / Q000276:immunology; D005260:Female; D018858:Germinal Center / Q000276:immunology; D006023:Glycoproteins / Q000276:immunology; D007124:Immunoenzyme Techniques; D007070:Immunoglobulin A / Q000096:biosynthesis; D009980:Influenza A virus / Q000276:immunology*; D008198:Lymph Nodes / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D019251:Nucleocapsid / Q000276:immunology; D009976:Orthomyxoviridae Infections / Q000276:immunology*
chemical_list: D000914:Antibodies, Viral; D000956:Antigens, Viral; D006023:Glycoproteins; D007070:Immunoglobulin A