Mechanisms of induction of mucosal IgA and their protective role at mucosal surfaces. (A) pIgA and SIgA. pIgA Abs are made of two monomers of IgA linked by a junction chain (J chain), and bind to the pIgR at the basolateral membrane of epithelial cells. After transepithelial transport, they are released into the lumen as SIgA containing the SCs, a portion of the pIgR, which confers resistance to proteolysis. (B) Induction of IgA class switching and acquisition of mucosal homing capabilities. IgA class switching and production of mucosal IgA can occur in a T-independent or T-dependent fashion. In response to luminal stimulation by microbes, vaccines, or allergen, epithelial cells and conventional APCs in the PP, cryptopatches, isolated lymph follicles, or lamina propria will produce cytokines (IL-1β, IL-10, TGF-β), NO, and the B cell–stimulating factors BAFF and APRIL. IgA class switching and production of IgA promoted through the help of cytokines derived from Th cells and NKT cells (T-dependent) will yield high-affinity IgA. In contrast, cytokine help from ILCs and other innate cells such as plasmacytoid DCs (T-independent) will result in low-affinity IgA. The presence of RA imprints IgA-producing cells with homing receptors and chemokine receptors for homing to the GI tract. (C) Mechanisms of protection by SIgA in mucosal surfaces.

T-independent induction

A number of studies have now shown that Ig CSR (Ig class switch recombination) and production of IgA can be induced in a T-independent manner in lymphoid structures of the GALT (i.e., PP, isolated lymphoid follicles, cryptopatches, and mesenteric lymph nodes) (7, 25, 26). It was also suggested that IgA production could take place in the intestinal lamina propria independently of cognate T cell help after interactions of APRIL with the transmembrane activator and CALM interactor on B cells (27, 28). It is important to indicate that a major difference between T-dependent and T-independent production of IgA is the source of cytokines that provide help to B cells. ILCs, which are present in high number in mucosal tissues, can produce the same pattern of cytokines as Th cells, and thus may play a central role in the T-independent production of mucosal IgA (29). The plasmacytoid DCs are a source of APRIL, BAFF, IL-10, and IL-6 (30), and thus could be key players in this process. In addition to soluble cytokines, membrane-bound lymphotoxin β (LTα1β2) produced by RORγt⁺ ILCs was shown to be critical for T cell–independent IgA induction in the lamina propria (31). The list of cells potentially involved in the T-independent production of IgA continues to grow and now includes eosinophils, which are widely considered as proinflammatory and associated with allergy and eosinophilic GI disorders (32). Eosinophils promote CSR and production of IgA by providing active TGF-β (32).

T-dependent IgA responses predominantly involve B2 cells, whereas T-independent IgA responses involve both follicular B2 cells and innate B1 cells that reside in the peritoneal cavity. A study that addressed the relative contribution of the B cell subsets to IgA responses toward commensal microbes has shown that most commensals elicit T-independent IgA responses by the orphan B1b and B2 cells, whereas only atypical commensal such as segmented filamentous bacteria elicits T-dependent IgA responses (33).