The structures of tetrameric avian immunoglobulin A are uniquely structured to support mucosal immunity

Birds and mammals assemble polymeric (p) forms of immunoglobulin (Ig) A, which are transported to mucosal surfaces and released as secretory (S) IgA, the predominant mucosal antibody. Mammalian SIgA, which is typically dimeric, is well characterized; however, avian IgA structure-function relationships and how they compare to those in mammals remains unclear. Here we report the cryo-electron microscopy structures of mallard duck pIgA and SIgA at 3.76-Å and 3.21-Å resolution, respectively. Both structures revealed four IgA monomers linked through one joining chain (JC) and adopted a non-planar conformation; a heavy chain domain absent in mammals, extended the tetramer’s non-planar geometry toward antigen binding sites. The SIgA structure revealed four secretory component (SC) domains binding IgA and JC analogous to four of the five mammalian SC domains; however, SC and JC N-terminal extensions, absent in mammals, mediated additional interfaces between complex components. Experiments comparing mammalian and avian SC binding to cognate and non-cognate IgA ligands demonstrated that species-specific structural differences correlated with differences in SC binding and that adding an N-terminal extension to mammalian SC enhanced binding to avian pIgA. Together, results and comparison to published structures indicate that avian IgA components co-evolved unique elements compared to mammalian IgA, including a predominantly tetrameric state, and suggest that birds may employ different IgA effector mechanisms to combat mucosal pathogens compared to mammals. These findings are broadly relevant to understanding IgA evolution and function and combating zoonotic disease such as avian influenza A virus.