Abstract
IgA is the predominant immunoglobulin isotype in mucosal tissues and external secretions, playing important roles both in defense against pathogens and in maintenance of commensal microbiota. Considering the complexity of its interactions with the surrounding environment, IgA is a likely target for diversifying or positive selection. To investigate this possibility, the action of natural selection on IgA was examined in depth with six different methods: CODEML from the PAML package and the SLAC, FEL, REL, MEME and FUBAR methods implemented in the Datamonkey webserver. In considering just primate IgA, these analyses show that diversifying selection targeted five positions of the Cα1 and Cα2 domains of IgA. Extending the analysis to include other mammals identified 18 positively selected sites: ten in Cα1, five in Cα2 and three in Cα3. All but one of these positions display variation in polarity and charge. Their structural locations suggest they indirectly influence the conformation of sites on IgA that are critical for interaction with host IgA receptors and also with proteins produced by mucosal pathogens that prevent their elimination by IgA-mediated effector mechanisms. Demonstrating the plasticity of IgA in the evolution of different groups of mammals, only two of the eighteen selected positions in all mammals are included in the five selected positions in primates. That IgA residues subject to positive selection impact sites targeted both by host receptors and subversive pathogen ligands highlights the evolutionary arms race playing out between mammals and pathogens, and further emphasizes the importance of IgA in protection against mucosal pathogens.
Highlights
Immunoglobulin A (IgA), in the form of dimers or higher polymers tetramers, is the predominant immunoglobulin isotype in mucosal tissues and external secretions, where it provides a major line of defense against pathogens
IgA is present as secretory IgA (S-IgA), a complex of dIgA or pIgA with another polypeptide chain, the secretory component (SC) [3], which confers some protection from proteolytic cleavage
Using the maximum likelihood (ML) approach of PAML [23], [24], evidence for positive diversifying selection was obtained in primates for two of the three IgA constant domains, Ca1 and Ca2, with the model allowing sites to evolve under positive selection (M8) showing a significantly better fit than the model that did not (M7) (a = 0.01– 0.05; Table 1)
Summary
Immunoglobulin A (IgA), in the form of dimers or higher polymers (pIgA) tetramers, is the predominant immunoglobulin isotype in mucosal tissues and external secretions, where it provides a major line of defense against pathogens. It plays a major role in the maintenance of the commensal microbiota in the intestinal tract, where interplay between commensal microorganisms and IgA promotes a mutually beneficial co-existence [1]. Linking the Fab and Fc regions is a flexible hinge region This basic IgA unit can exist as monomers or be arranged into dimers (dIgA) and higher order multimers in which the monomers are linked by a J (joining) chain. IgA is present as secretory IgA (S-IgA), a complex of dIgA or pIgA with another polypeptide chain, the secretory component (SC) [3], which confers some protection from proteolytic cleavage
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