The dominant class of antibody in the mucosal immune system is IgA, which is produced locally by plasma cells in the mucosal wall. The nature of IgA differs between the two main compartments in which it is found—the blood and mucosal secretions. IgA in the blood is mainly in the form of a monomer (mIgA) that is produced in the bone marrow by plasma cells derived from B cells activated in lymph nodes. In mucosal tissues, IgA is produced almost exclusively as a polymer, usually as a dimer, in which the two immunoglobulin monomers are linked by a J chain (see Section 5-16).
The naive B-cell precursors of the IgA-secreting mucosal plasma cells are activated in Peyer’s patches and mesenteric lymph nodes. Class switching of activated B cells to IgA is controlled by the cytokine TGF-β. In the human gut, this class switching is entirely T-cell dependent and occurs only in organized lymphoid tissues, where follicular helper T cells (TFH) instruct B cells by the same mechanisms as described in Chapter 10. The subsequent expansion and differentiation of IgA-switched B cells are driven by IL-5, IL-6, IL-10, and IL-21. Upward of 75,000 IgA-producing plasma cells are present in the normal human intestine, and 3–4 g of IgA is secreted by the mucosal tissues each day, and is the major immunoglobulin class produced there. This continuous production of large quantities of IgA occurs in the absence of pathogenic invasion and is driven almost entirely by recognition of the commensal microbiota.
In humans, monomeric and dimeric IgA are both found as two isotypes, IgA1 and IgA2. The ratio of IgA1 to IgA2 varies markedly depending on the tissue, being about 10:1 in the blood and upper respiratory tract, about 3:2 in the small intestine, and 2:3 in the colon. Some common pathogens of the respiratory mucosa (such as Haemophilus influenzae) and the genital mucosa (such as Neisseria gonorrhoeae) produce proteolytic enzymes that can cleave IgA1, whereas IgA2 is resistant to cleavage. The higher proportion of plasma cells secreting IgA2 in the large intestine might result because the high density of commensal microorganisms at this site drives the production of cytokines that cause selective class switching. In mice, only one IgA isotype is found, and it is most closely similar to IgA2 in humans.
After activation and differentiation, the resulting IgA-expressing B lymphoblasts express the mucosal homing integrin α4:β7, as well as the chemokine receptors CCR9 and CCR10, and localize to mucosal tissues by the mechanisms discussed above. Once in the lamina propria, the B cells undergo final differentiation into plasma cells, which synthesize IgA dimers and secrete them into the subepithelial space (Fig. 12.11). To reach its target antigen in the gut lumen, the IgA has to be transported across the epithelium by the polymeric immunoglobulin receptor (pIgR), which we introduced in Section 10-16. pIgR is expressed constitutively on the basolateral surfaces of the immature epithelial cells located at the base of the intestinal crypts and binds covalently to the Fc portion of J-chain-linked polymeric immunoglobulins such as dimeric IgA and pentameric IgM, and it transports the antibody by transcytosis to the luminal surface of the epithelium, where it is released by proteolytic cleavage of the extracellular domain of the receptor. Part of the cleaved pIgR remains associated with the IgA and is known as secretory component (frequently abbreviated to SC). The resulting antibody is protected from proteolytic cleavage and is referred to as secretory IgA (SIgA).