Secretory IgA's complex roles in immunity and mucosal homeostasis in the gut

Abstract

Secretory IgA (SIgA) serves as the first line of defense in protecting the intestinal epithelium from enteric toxins and pathogenic microorganisms. Through a process known as immune exclusion, SIgA promotes the clearance of antigens and pathogenic microorganisms from the intestinal lumen by blocking their access to epithelial receptors, entrapping them in mucus, and facilitating their removal by peristaltic and mucociliary activities. In addition, SIgA functions in mucosal immunity and intestinal homeostasis through mechanisms that have only recently been revealed. In just the past several years, SIgA has been identified as having the capacity to directly quench bacterial virulence factors, influence composition of the intestinal microbiota by Fab-dependent and Fab-independent mechanisms, promote retro-transport of antigens across the intestinal epithelium to dendritic cell subsets in gut-associated lymphoid tissue, and, finally, to downregulate proinflammatory responses normally associated with the uptake of highly pathogenic bacteria and potentially allergenic antigens. This review summarizes the intrinsic biological activities now associated with SIgA and their relationships with immunity and intestinal homeostasis.

Figure 1. IgA-mediated agglutination of S Typhimurium is accompanied by gross changes in cell shape

Mid-log phase cultures of S. Typhimurium strain 14028S were exposed to Sal4 mAb (5 μg/ml) for 45 min and then subjected to scanning electron microscopy. Panels: (A) S. Typhimurium control cells not treated with Sal4; (B and C) Cells treated with Sal4 mAb at (B) low and (C) high power. Note the gross changes in cell shape and the bridging that occurs between cells in the presence of Sal4 (panels B and C) but not in the absence of Sal4 (panel A). Figure kindly provided by Dr. Steve Forbes.

Figure 2. Entry of commensal bacteria coated with SIgA in a Peyer's patch via M cells

Image acquired by laser scanning confocal microscopy. Lactobacillus rhamnosus labeled with FITC was injected in the form of SIgA-based complexes into a mouse intestinal ligated loop comprising a Peyer's patch, and in vivo incubation was performed for 2 hours. After cryosection of the tissue, M cells (blue), SIgA (red) and cell nuclei (greyish) were stained respectively, with UEA-1 lectin, anti-SC antibodies, and DAPI. Arrowheads indicate bacteria in the form of SIgA-based complexes. The appearance of SIgA-based complexes in the lumen, at the surface of M cells, and transiting through an M cell on the snapshot picture reflects the various steps in the passage from the lumen to the SED (subepithelial dome) region. Bars in insets represent 5 μm.

Figure 3. Multi-functional interactions of between SIgA and pathogenic and nonpathogenic bacteria in the intestinal mucosa

In all pathways, pathogenic and non-pathogenic bacteria are coated by SIgA (depicted as a dimer with bound SC) in a Fab-specific or in a Fab-independent, glycan-mediated manner. (A) Enhanced interaction between SIgA-coated non-pathogenic bacteria and the epithelium reinforces its barrier function via multiple mechanisms, including reinforcement of tight junctions, overproduction of pIgR, and reduction in nuclear translocation of NF-κB. (B) SIgA-based immune complexes with commensal and/or pathogenic bacteria are taken up by M cells where they are targeted to underlying myeloid DCs, possibly upon binding to DC-SIGN, resulting in the down regulation of local pro-inflammatory responses. (C) SIgA, as well as free SC, may play a role of “selection” by excluding pathogenic bacteria off the epithelial surface via anchoring within mucus and favoring biofilm formation of non-pathogenic bacteria in the space in close contact with epithelial cells. +: activatory effect; −: inhibitory effect.