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Relationship of the quaternary structure of human secretory IgA to neutralization of influenza virus

Significance Preexisting secretory IgA (S-IgA) antibodies can provide immediate immunity via their unique capability to eliminate a pathogen before it passes the mucosal barrier. Several clinical trials have reported that S-IgA against influenza virus was induced by intranasal administration of an inactivated influenza vaccine. S-IgA in mucosa consists predominantly of dimers rather than tetramers, as revealed by ultracentrifugation almost 50 years ago. However, direct evidence concerning the quaternary architectures and the physiological function of polymers larger than dimers has not been reported in healthy humans. The present study revealed, for the first time to our knowledge, the existence of large polymeric IgA in the healthy human upper respiratory mucosa, as well as the physiological functions of these molecules in protecting against viral infection in humans. Secretory IgA (S-IgA) antibodies, the major contributors to humoral mucosal immunity to influenza virus infection, are polymeric Igs present in many external secretions. In the present study, the quaternary structures of human S-IgA induced in nasal mucosa after administration of intranasal inactivated influenza vaccines were characterized in relation to neutralization potency against influenza A viruses. Human nasal IgA antibodies have been shown to contain at least five quaternary structures. Direct and real-time visualization of S-IgA using high-speed atomic force microscopy (AFM) demonstrated that trimeric and tetrameric S-IgA had six and eight antigen-binding sites, respectively, and that these structures exhibited large-scale asynchronous conformational changes while capturing influenza HA antigens in solution. Furthermore, trimeric, tetrameric, and larger polymeric structures, which are minor fractions in human nasal IgA, displayed increased neutralizing potency against influenza A viruses compared with dimeric S-IgA, suggesting that the larger polymeric than dimeric forms of S-IgA play some important roles in protection against influenza A virus infection in the human upper respiratory tract.