Antigens can be taken up across the epithelial linings of various mucosal tissues, and many of these tissues then generate robust sIgA responses. Most of our knowledge about this response has been gained from studies of gut-associated lymphoid tissue in rodents and of human tonsils. The major inductive sites of the mucosal immune system are follicles and organized aggregates of follicles, exemplified by Peyer's patches in the intestine and referred to generically as mucosa-associated lymphoid tissue (MALT). Antigens are often efficiently absorbed by specialized cells in the epithelium overlaying the MALT, the morphologically distinct M cells (37,38). In some cases dendritic cells extend processes between neighboring epithelial cells to sample antigens in the external milieu (39). Despite the well-developed conjunctival lymphoid follicles, however, most of the IgA+ plasma cells that populate the lacrimal glands appear to be generated in the gut or upper respiratory system, rather than in the eye-associated lymphoid tissues (40,41).'
The space subjacent to the M cells contains relatively few dendritic cells but large numbers of immature B cells recently emerged from the follicle. Free antigen and antigen-IgM immune complexes in the extra-follicular region can be taken up by dendritic cells for processing and presentation to the CD4+ T lymphocytes that provide help for activation of naïve B cells. However, most antigen presentation in this region is mediated by activated, MHC Class II+ B cells that have internalized antigen via surface IgM, which also generates a signal for B-cell survival.
As in the lymph nodes, follicular dendritic cells in the MALT primarily use Fcy receptors to take up antigen-IgM immune complexes. Complement C3 binds to adsorbed immune complexes at the dendritic cell surface and is recognized by CD21 on both the dendritic cells and on B cells, generating additional activation signals. Activated follicular B cells and dendritic cells express CD40, which interacts with CD40L on CD4+ T cells and sustains their activation and production of the TH2 cytokines, IL-2, IL-4, and IL-10 (42,43). The cumulative signals generated through CD40, cytokine receptors, and surface IgM maintain B-cell activation and stimulate Ig hypermutation (38). Generally, IL-2, IL-4, IL-10, and CD40L together stimulate generation of memory B cells (44). In contrast, IL-2 and IL-10 in the absence of CD40L stimulate B cells to differentiate as plasmablasts (45,46).
A characteristic phenomenon in the MALT germinal centers is upregulation of B cell J chain expression. In most cases this is accompanied by isotype switching from IgM to IgA, although in the tonsils the switch is preferentially to IgG. The signals responsible for isotype switching to IgA include TGF-^ (47-51), IL-10 (52), and vasoactive intestinal polypeptide (VIP) (53,54). It appears that these signals exert a persistent influence on the dendritic cells, since dendritic cells isolated from either Peyer's patch or spleen stimulate antigen-specific T-cell-cognate B-cell monocultures to generate IgA and, secondarily, IgG2 (55).
As B cells mature to the plasmablast stage, they downregulate CXR5 and CCR7, homing receptors that favor retention in the organized tissue, and they upregulate receptors that will favor entry and retention in the effector sites (56). The partially mature plasmablasts exit via efferent lymph vessels, pass through the draining lymph nodes, enter the circulation, and extravasate into the various effector sites of the mucosal immune system: the gastrointestinal tract, respiratory tract, urogenital tract, conjunctiva, and lacrimal drainage system, as well as to various glands: the liver, prostate, salivary glands, lacrimal glands, and, during pregnancy and lactation, the mammary glands.
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