Multi-faceted functions of secretory IgA at mucosal surfaces

Abstract

Secretory IgA (SIgA) plays an important role in the protection and homeostatic regulation of intestinal, respiratory, and urogenital mucosal epithelia separating the outside environment from the inside of the body. This primary function of SIgA is referred to as immune exclusion, a process that limits the access of numerous microorganisms and mucosal antigens to these thin and vulnerable mucosal barriers. SIgA has been shown to be involved in avoiding opportunistic pathogens to enter and disseminate in the systemic compartment, as well as tightly controlling the necessary symbiotic relationship existing between commensals and the host. Clearance by peristalsis appears thus as one of the numerous mechanisms whereby SIgA fulfills its function at mucosal surfaces. Sampling of antigen-SIgA complexes by microfold (M) cells, intimate contact occurring with Peyer's patch dendritic cells (DC), down-regulation of inflammatory processes, modulation of epithelial, and DC responsiveness are some of the recently identified processes to which the contribution of SIgA has been underscored. This review aims at presenting, with emphasis at the biochemical level, how the molecular complexity of SIgA can serve these multiple and non-redundant modes of action.

Keywords: antibody; commensal bacteria; epithelium; infectious agents; mucosal homeostasis; secretory IgA.

Figure 1

Schematic representation of the identified levels by which polymeric IgA, SIgA, or SC may contribute to protection of mucosal surfaces, as defined in various in vivo and in vitro models. (1) Polymeric IgA produced by local plasma cells in the lamina propria is transported across epithelial cells (a process referred to as transcytosis) by the polymeric Ig receptor (pIgR), and released in luminal secretions in the form of SIgA performing immune exclusion via interaction with environmental antigens (bacteria, viruses, toxins, etc). (2) Polymeric IgA on their way to pIgR-mediated secretions can intercept incoming viruses intracellularly, and excrete them in the form of non-virulent immune complexes. (3) Polymeric IgA may neutralize in the lamina propria invading infectious agents that have penetrated through breaches occurring in the inflamed epithelium; subsequent transport by pIgR will favor clearance of immune complexes. (4) Via glycans abundantly found on its surface, free SC released in secretions neutralizes pathogen-derived products, and contributes to protection of epithelial surfaces as well; this property is conserved when SC is bound to polymeric IgA in SIgA. (5) Sampling of SIgA by M cells in Peyer’s patches (PP) leads to specific targeting of the antibody to dendritic cells (DC) in the subepithelial dome region. In the form of immune complexes with noxious antigens, presentation to naïve T cells in the PP and draining mesenteric lymph nodes (not drawn) results in the onset of attenuated, Th2-biased mucosal immune responses with concomitant quenching of inflammatory circuits. (6) Remarkably, the same SIgA-mediated retro-transport is achieved with commensal bacteria, leading to the shaping of the mucosal immune system toward a non-inflammatory, tolerogenic pattern that takes place through the induction of regulatory T cells. (7) Neutralization of Gram-negative bacterial lipopolysaccharide (LPS) in apical recycling endosomes by transcytosing polymeric IgA abrogates NF-κB-mediated activation of pro-inflammatory gene products, thus preserving the epithelial barrier’s integrity. (8) Cross-talk between the probiotic bacteria and the intestinal mucosa is enhanced by SIgA, with various consequences extending from increased expression of epithelial pIgR and tight junction proteins to production of thymic stromal lymphopoietin (TSLP) involved in priming of mucosal DCs. Brown ellipses depict pathogen bacteria; gray ellipses depict commensal bacteria; purple spiky spheres depict virus; polymeric IgA are drawn in green; Free secretory component and polymeric Ig receptor (pIgR) are drawn in red; TSLP, thymic stromal lymphopoietin.