IgA and the intestinal microbiota: the importance of being specific

Abstract

Secretory IgA has long been a divisive molecule. Some immunologists point to the mild phenotype of IgA deficiency to justify ignoring it, while some consider its abundance and evolutionary history as grounds for its importance. Further, there is extensive and growing disagreement over the relative importance of affinity-matured, T cell-dependent IgA vs. "natural" and T cell-independent IgA in both microbiota and infection control. As with all good arguments, there is good data supporting different opinions. Here we revisit longstanding questions in IgA biology. We start the discussion from the question of intestinal IgA antigen specificity and critical definitions regarding IgA induction, specificity, and function. These definitions must then be tessellated with the cellular and molecular pathways shaping IgA responses, and the mechanisms by which IgA functions. On this basis we propose how IgA may contribute to the establishment and maintenance of beneficial interactions with the microbiota.

Fig. 1

Secretory IgA is formed by the combined function of plasma cells producing multimeric IgA and epithelial cells expressing pIgR a Schematic diagrams illustrating the structure of human dimeric IgA1, human dimeric IgA2, human secretory IgA1, and the free secretory component (SC, which is a cleavage product of pIgR). Both, human IgA1 and IgA2 show the canonical antibody structure of two heavy and two light chains building Fab and Fc portions of the antibody. Human IgA1 is characterized by an extended hinge region linking the Fab and Fc part. In dimeric IgA, two antibody monomers are covalently bound through disulfide bonds to the J chain. Secretory component covalently bound to IgA differs in its conformation from free SC. Consequently, free SC and bound SC might have different microbiota binding capacity. b Transcytosis of pIgR/dIgA complexes results from initial recognition binding, conformational changes, and final binding before the complex becomes transcytosed. Following transcytosis, free SC, and SIgA are released into the gut lumen (here depicted for human IgA1). Illustrations adapted from refs.^,

Fig. 2

Secretory IgA interacts with the microbiota by canonical Fab-dependent and noncanonical glycan-dependent binding. a Schematic diagram of human IgA1 as depicted in Fig. 1. Canonical binding occurs via the Fab regions indicated by dashed boxes. Noncanonical interactions are mediated by glycans. O-Glycans (Yellow-green) are present in the IgA1 hinge region. N-gylcans (red-orange) are present in the Fc portion and the J-chain (modified from ref.) b Canonical and noncanonical interactions confer binding to the microbiota. Top panel, schematic illustration of SIgA binding single species in Fab-dependent manner. In this scenario, a given antibody will bind in a highly species-specific manner (here depicted by the antibody binding to one but not another bacterial species). Middle panel, cross-species binding, here depicted by the same antibody binding to two different bacterial species, may occur by canonical interactions if an antibody recognizes epitopes shared between different species. Such binding pattern might occur in case of identical or related shared epitopes expressed by different species. Bottom panel, cross-species reactivity might arise from a combination of canonical and noncanonical binding of antibodies to different bacterial species.

Fig. 3

Recirculating B cells coordinate IgA responses in GALT. Antigen experienced B cell are capable of re-entering germinal center (GC). Red dotted lines schematically illustrate B cell migratory routes. GALT#1 and GALT #2 are displayed to represent two different GALT structures such as Peyer’s patches or isolated lymphoid follicles. Different members of the microbiota might have been taken up into GALT and create distinct antigenic environments. We speculate that repeated rounds of selection in different GC, putatively including different antigens, might contribute to the generation of affinity matured cross-species reactive antibodies.

Fig. 4

A wide range of selective pressures can be affected by SIgA in the gut lumen. Direct negative selective effects on SIgA-bound bacteria include increased flow-mediated clearance due to enchained growth or agglutination, as well as neutralization of secreted virulence factors. We could also have direct positive effects via metabolism of abundant SIgA O- and N-linked glycans and generation of beneficial community structure by enchained growth/agglutination. Further, extensive indirect effects, i.e., also affected species that do not directly bind SIgA, are expected if the localization or abundance of a metabolic keystone species is altered, altering metabolic network interactions. We also expect major indirect effects due to alterations in the level of immune system activation in the gut due to changes in flow rates, nutrient availability, antimicrobial substances, and phage reactivation.