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The Mucosal Immune System and Its Integration with the Mammary Glands

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Mucosal immunity reduces the need for elimination of penetrating exogenous antigens by proinflammatory systemic immunity. The adult gut mucosa contains some 80% of the body's activated B cells—differentiated to plasmablasts and plasma cells (PCs). Most mucosal PCs produce dimeric immunoglobulin A (IgA), which, along with pentameric immunoglobulin M (IgM), can be exported by secretory epithelia expressing the polymeric immunoglobulin receptor. Immune exclusion of antigens is performed mainly by secretory IgA in cooperation with innate defenses, but, in newborns and in IgA deficiency, secretory IgM is important. In the gut, induction and regulation of mucosal immunity occurs primarily in gut-associated lymphoid tissue—particularly the Peyer's patches—and also in mesenteric lymph nodes. Terminal differentiation to PCs is accomplished in the lamina propria to which the activated memory/effector T and B cells home. Lactating mammary glands are part of the secretory immune system, and IgA antibodies in breast milk reflect antigenic stimulation of gut-associated lymphoid tissue and nasopharynx-associated lymphoid tissue such as the tonsils. Breast-milk antibodies are thus highly targeted against infectious agents and other exogenous antigens in the mother's environment, which are those likely to be encountered by the infant. Therefore breast-feeding represents an ingenious immunologic integration of mother and child.

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Immunologic Defense Strategies of the Mucosae

Mucosal immunity provides a first defense line that reduces the need for elimination of penetrating exogenous antigens by proinflammatory systemic immunity. The local immune system operates by 2 adaptive antiinflammatory mechanisms: (1) immune exclusion performed by SIgA (and SIgM) antibodies to inhibit surface colonization of microorganisms and dampen penetration of potentially dangerous exogenous proteins; and (2) immunosuppressive mechanisms to avoid local and peripheral hypersensitivity to

Cell Biology of Secretory Immunity

Many structural, cellular, molecular, and functional differences exist between the mucosal and the systemic immune system.18 Mucosal immunity is most abundantly expressed in the gut, and the intestinal mucosa of an adult contains at least 80% of the body's activated B cells (Figure 1, B)—terminally differentiated to plasmablasts and plasma cells (PCs).1, 10 Most mucosal PCs produce dimeric IgA, which, along with pentameric IgM that likewise contains a polypeptide called “joining” (J) chain (15

Secretory Immunity Reinforces the Epithelial Barrier

Immune exclusion is performed mainly by SIgA, and to a lesser extent SIgM, in cooperation with innate nonspecific defenses.10 Most important to this end, SIgA antibodies coat the microorganisms and inhibit colonization—and particularly invasion—of both commensals and overt pathogens (Figure 2, A). Interestingly, pIgR-transported high-affinity dimeric IgA and pentameric IgM antibodies may even inactivate viruses (eg, rotavirus and influenza virus) inside of secretory epithelial cells and carry

Activation and Homing Properties of Mucosal Immune Cells

B-cell responses that give rise to secretory antibodies are elicited mainly in organized mucosa-associated lymphoid tissue (MALT). These structures resemble lymph nodes with B-cell follicles, intervening T-cell zones and a variety of APCs such as macrophages and DCs, but there are no afferent lymphatic vessels.18 Exogenous stimuli therefore come directly from the mucosal surfaces via a follicle-associated epithelium containing specialized epithelial “membrane” (M) cells, probably aided by DCs,

Mammary Glands and the Mucosal Immune System

Lactating mammary glands are part of the integrated mucosal immune system, and milk antibodies reflect antigenic stimulation of MALT both in the gut and airways. This has been documented by showing that SIgA from breast milk exhibits specificity for an array of common intestinal, as well as respiratory pathogens,9, 25 and expression of CCR10 on both GALT- and NALT-derived B cells is important for shared homing properties (Figure 4, A). This was shown by blocking of the chemokine CCL28 that acts

Neonatal Deficiency of Mucosal and Systemic Immunity

Full-term babies growing up under privileged conditions generally show satisfactory resistance to mucosal infections, as long as their innate defense mechanisms are normal. Adequate systemic antibody protection of their mucosae is provided by placental transfer of IgG, of which at least 50% is distributed extravascularly.5 However, when most maternal IgG has been catabolized after approximately 2 months, the protective value of breast-feeding is highlighted in relation to mucosal infections,

Conclusions

Increased epithelial permeability is an important primary or secondary event in the pathogenesis of many diseases, including allergy, celiac disease, and inflammatory bowel disease. The intestinal barrier function is determined by the individual's age (eg, preterm vs term infant), genetics, mucus, interactions between mast cells, nerves and neuropeptides, concurrent infection, and the mucosa-shielding effect of SIgA provided by breast milk or produced by the infant's gut. The integrity of the

Author Disclosures

Studies by Per Brandtzaeg, PhD, were supported by the Research Council of Norway, Anders Jahre's Fund, the University of Oslo and Oslo University Hospital. Mead Johnson Nutrition sponsored the symposium and provided an honorarium for attendance, presentation, and manuscript preparation. This article is an overview of the presentation given by Dr. Brandtzaeg at the above Symposium; it has been written by Dr. Brandtzaeg. Dr. Brandtzaeg has no financial interests in the production or sales of

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