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Mucosal immunology and secretory immunoglobulin A: General concepts. Blaise CORTHESY
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In the gastrointestinal tract, the mucosal surfaces facing the lumen form a highly integrated network of host cells and factors essential to preserve the tight barrier keeping in control the translocation of various infectious and non-pathogenic microorganisms. Epithelial cells, the gut-associated lymphoid tissue (GALT), immunoreactive cells distributed within the mucosal tissue, and antibodies (Ab) act in concert to promote induction of an immunological barrier comprising innate, inflammatory and adaptive components. Non-immunological factors comprise mucus, glycocalyx, peristaltism and innate humoral factors including lactoferrin, lactoperoxidase, trefoil peptides and defensins. This physiological barrier is backed-up by specialized areas named follicle-associated epithelium (FAE) overlying the GALT in organized structures referred to as Peyer’s patch (PP), whose function is to sample and transport selectively antigens (Ag) from the lumen across the epithelium. This is accomplished by a specialized type of highly invaginated enterocyte in PP, the M (microfold) cell, whose presence might extend in intestinal villosity. Cognate interactions among underlying Ag presenting cells [APC; dendritic cells (DC) and macrophages] in the subepithelial dome (SED) region, naïve T cells residing in the interfollicular region (IFR) and B cells in the corona lead to the ultimate differentiation in the germinal center of IgA-secreting plasma cells. |
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An important activity of the MALT is the production of the special type of Ab referred to as secretory IgA (SIgA). The classical view is that SIgA serves as the first line of defense against microorganisms by agglutinating potential invaders and facilitating their clearance by peristaltic and mucociliary movements. The complex nature of the molecule is instrumental to fulfill its biological role: while the importance of the IgA moiety comprising the Ag specificity is expected, the associated secretory component (SC) possesses intrinsic, “innate-like” properties including SIgA anchoring to mucosal surfaces, binding to pathogen Ag, scavenger ability, and trapping of cytokine. Recently, the demonstration that uptake of SIgA by PP targets this class of Ab to DC in the SED region and T cells in the IFR has raised the question of the function of SIgA in modulating ongoing mucosal immune responses and/or control of local homeostasis. PP-derived DC have been shown to play a central role in the induction of local responses or tolerance regulated by Th2- or Th3-type cells. The protective and homeostatic mechanisms of mucosal IgA offer a variety of still unknown facets, whose deciphering and understanding need further studies. |
Antigen processing and induction of immune responses in the intestine. In GALT, microorganisms transported by M cells are captured by immature DC in the subepithelial dome (SED) region. This triggers DC maturation and migration to the T cell zone (IFR: interfollicular region) and into draining mesenteric lymph nodes (MLN), two sites of antigen presentation to naïve T cells. (2) By extending dendrites directly in the lumen, DC in the epithelium layer capture antigens and present them to naïve T cells in proximal draining lymph nodes. It is not yet clear how these different DC subsets are associated. (3) The degree of activation and migratory properties of DC depend on the nature of the signals/motifs associated with the antigen (food, pathogenic or commensal bacteria, virus, toxin), the local microenvironment, and possibly conditioning by epithelial cells. This results in the production of different cytokine patterns that control tolerance, inflammation, lymphocyte differentiation and homing to effector sites. The delicate tuning of these non-exclusive mechanisms guarantees intestinal homeostasis. (4) In lamina propria (LP), plasma cells produce polymeric IgA that are exported as SIgA; T cells mainly end up in the epithelium. TSLP, thymic stromal lymphopoietin; PGE-2, prostaglandin E2.
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