The IgA antibodies produced in these T-cell-independent responses are of limited diversity and of generally low affinity, with little evidence of somatic hypermutation. They are nevertheless an important source of ‘natural’ antibodies directed at commensal bacteria. As yet, there is little evidence for this source of IgA in humans, in whom all secretory IgA responses involve somatic hypermutation and seem to be T-cell dependent. The enzyme activation-induced cytidine deaminase (AID), which is required for class switching (see Chapter 5), cannot be detected in human intestinal lamina propria, indicating that class switching is unlikely to occur there. Nevertheless, its occurrence in lamina propria B cells in mice may offer a glimpse into the evolutionary history of specific antibody responses in the mucosa, and might indicate pathways that could be activated when T-cell-dependent IgA production is compromised in humans, as it is in AIDS. Nonetheless, it is likely that secondary reactivation of IgA-committed B lymphoblasts occurs in the lamina propria for full differentiation of plasma cells, which likely involves production by myeloid and epithelial cells of APRIL, BAFF, and other mediators 12-12 IgA deficiency is relatively common in humans but may be compensated for by secretory IgM.
Selective deficiency of IgA production is the commonest primary immune deficiency in humans, occurring in about 1 in 500 to 700 individuals in populations of Caucasian origin, although it is somewhat rarer in other ethnic groups. The most frequent genetic mutation that has been identified in this condition is in the TACI receptor for BAFF. A slightly higher incidence of respiratory infections, atopy (a tendency for allergic reactions to harmless environmental antigens), and autoimmune disease has been reported in older people with IgA deficiency. However, most individuals with IgA deficiency are not overly susceptible to infections unless there is also a deficiency in IgG2 production. The dispensability of IgA probably reflects the ability of IgM to replace IgA as the predominant antibody in secretions, and increased numbers of IgM-producing plasma cells are indeed found in the intestinal mucosa of IgA-deficient people. Because IgM is a J-chain-linked polymer, IgM produced in the gut mucosa is bound efficiently by the pIgR and is transported across epithelial cells into the gut lumen as secretory IgM. The importance of this backup mechanism has been shown in knockout mice. Animals lacking IgA alone have a normal phenotype, but those lacking the pIgR are susceptible to mucosal infections. They also show increased penetration of commensal bacteria into tissues and a consequent systemic immune response to these bacteria. Genetic absence of the pIgR has never been reported in humans, suggesting that such a defect is lethal.
12-13 The intestinal lamina propria contains antigen-experienced T cells and populations of unusual innate lymphoid cells.
Most of the T cells in the healthy lamina propria have been activated by dendritic cells and express markers of effector or memory T cells, such as CD45RO in humans, and express gut-homing markers such as CCR9 and α4:β7 integrin, as well as receptors for pro-inflammatory chemokines such as CCL5 (RANTES). The T-cell population of the lamina propria has a ratio of CD4 to CD8 T cells of 3:1 or more, similar to that in systemic lymphoid tissues.