Abstract
Mucosal immunoglobulins comprise mainly secretory IgA antibodies (SIgAs), which are the major contributor to pathogen-specific immune responses in mucosal tissues. These SIgAs are highly heterogeneous in terms of their quaternary structure. A recent report shows that the polymerization status of SIgA defines their functionality in the human upper respiratory mucosa. Higher order polymerization of SIgA (i.e., tetramers) leads to a marked increase in neutralizing activity against influenza viruses. However, the precise molecular mechanisms underlying the effects of SIgA polymerization remain elusive. Here, we developed a method for generating recombinant tetrameric monoclonal SIgAs. We then compared the anti-viral activities of these tetrameric SIgAs, which possessed variable regions identical to that of a broadly neutralizing anti-influenza antibody F045-092 against influenza A viruses, with that of monomeric IgG or IgA. The tetrameric SIgA showed anti-viral inhibitory activity superior to that of other forms only when the antibody exhibits low-affinity binding to the target. By contrast, SIgA tetramerization did not substantially modify anti-viral activity against targets with high-affinity binding. Taken together, the data suggest that tetramerization of SIgA improved target breadth, but not peak potency of antiviral functions of the broadly neutralizing anti-influenza antibody. This phenomenon presumably represents one of the mechanisms by which SIgAs present in human respiratory mucosa prevent infection by antigen-drifted influenza viruses. Understanding the mechanisms involved in cross neutralization of viruses by SIgAs might facilitate the development of vaccine strategies against viral infection of mucosal tissues.
Highlights
Secretory IgA antibodies (SIgAs) play an important role as a first line of defense by inactivating pathogens on mucosal surfaces; this is especially true in the case of viruses such as influenza [1, 2]
We describe a means of generating a recombinant tetrameric monoclonal SIgA to enable exhaustive characterization of tetrameric SIgAs
To generate polymeric IgA antibodies in secretory form, the secretory component (SC) was coexpressed in mammalian cells along with human α1 heavy (A1), L, and J chains
Summary
Secretory IgA antibodies (SIgAs) play an important role as a first line of defense by inactivating pathogens on mucosal surfaces; this is especially true in the case of viruses such as influenza [1, 2]. IgA present in external secretions is highly heterogeneous, the majority is present in the form of polymers in which the heavy chains are covalently linked by a J chain These polymeric IgA antibodies are associated with the extracellular portion of the polymeric immunoglobulin receptor (pIgR), called the secretory component (SC), resulting in SIgA [5]. SIgA is composed primarily of dimers, some larger polymeric forms, tetramers, are present at low levels [5,6,7,8,9,10] These tetrameric SIgA antibodies display greater neutralizing activity against influenza A viruses in the nasal mucosa than monomers or dimers [8, 9]. No one has yet developed a method of generating trimeric or tetrameric IgA molecules
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