In addition to its activities in the lumen, IgA can neutralize bacterial lipopolysaccharide and viruses it encounters within endosomes inside epithelial cells, as well as across the epithelial barrier in the lamina propria after bacteria and viruses have penetrated there. The resulting IgA:antigen complexes are then reexported into the gut lumen, from where they are excreted from the body (see Fig. 12.12). Complexes containing dimeric IgA formed in the lamina propria can also be excreted via the hepatobiliary route described above. In addition to enabling the elimination of antigens, the formation of IgA:antigen complexes can enhance the uptake of luminal antigen by M cells and local dendritic cells, via binding of carbohydrate residues on IgA to lectin receptors such as Dectin-1 and DC-SIGN. As well as these antigen-specific effects, secretory IgA can restrict the entry of bacteria in a nonspecific manner. This is because the high carbohydrate content of the Fc part of the IgA heavy chain allows it to act as a decoy for receptors that bacteria use to bind carbohydrates on the epithelial surface. Secretory IgA has little capacity to activate the classical pathway of complement or to act as an opsonin, and so does not induce inflammation. Uptake of IgA:antigen complexes by dendritic cells also induces these cells to produce anti-inflammatory IL-10. Together these properties mean that IgA can limit the penetration of microbes into the mucosa without risking inflammatory damage to these fragile tissues, something that would be potentially harmful in the intestine. For the same reasons, secretory IgA is crucial to the beneficial symbiosis between an individual and gut commensal bacteria (see Section 12-20).
12-11 T-independent processes can contribute to IgA production in some species.
In mice, unlike humans, a significant proportion of intestinal IgA is derived from T-cell-independent B-cell activation and class switching. This depends on activation of the innate immune system by the products of commensal microbes and may result from the direct interaction of B cells with conventional dendritic cells and follicular dendritic cells in solitary lymphoid follicles. This antibody production seems to involve lymphocytes of the B-1 subset (see Section 8-9), which arise from precursor B cells in the peritoneal cavity and migrate to the intestinal wall in response to microbial constituents such as lipopolysaccharide. Once in the mucosa, TGF-β-dependent class switching to IgA occurs under the influence of local factors, including IL-6, retinoic acid, and BAFF and APRIL (see Fig. 10.6), which bind to TACI on B cells substituting for signals otherwise supplied by CD4 helper T cells (see Section 10-1). Intestinal epithelial cells can produce BAFF and APRIL, while local eosinophils may contribute by producing APRIL, IL-6, and TGF-β. Other myeloid cells may produce nitric oxide (NO) and TNF-α, both of which assist in the processing and activation of TGF-β.