Breast Milk: Proactive Immunomodulation and Mucosal Protection Against Viruses and Other Pathogens

Chiara Cerini; Grace M Aldrovandi

Disclosures

Future Virology. 2013;8(11):1127-1134. 

In This Article

Mechanisms of Infant Protection

Passive Protection

Secretory antibodies in milk exert their protection via multiple mechanisms.[30] First, sIgA acts as a barrier limiting access of microbes and noxious antigens to the intestinal epithelium. This is accomplished by a combination of agglutination, mucus entrapment and mucociliary clearance, and has been termed immune exclusion. Second, sIgA binds via its carbohydrate moieties to lectin-like bacterial adhesins, thereby blocking bacterial adhesion to receptors on epithelial cells. sIgA also appears to provide an internal mucosal barrier beneath the mucosal lining; incoming pathogens may be intercepted within epithelial cell vesicular compartments through the polymeric immunoglobulin receptor-mediated transport, translocated through the epithelium and thereby excreted.[31,32] Alternatively, sIgA may mediate export of pathogens back into the gut lumen.[27,33] Singularly or in combination, these mechanisms appear to mediate protection against a variety of gastrointestinal pathogens, including bacteria (Shigella, Salmonella, Campylobacter, Vibrio cholerae and Clostridium botulinum), as well as many parasites and fungi.[26,34] sIgA directly neutralizes enteroviruses,[35] respiratory syncytial virus,[36] rubella[37] and rotavirus.[14] In addition, sIgA can modify virulence factors, such as toxins of enterotoxigenic Escherichia coli,[38] the surface protein A (SpsA) of Streptococcus pneumoniae[39] and Clostridium difficile toxin A.[39] Given its opsonizing properties, sIgA favors cytotoxic pathways through interaction with FcαRI (primarily expressed on immune effector cells) and triggers antibody-dependent cellular cytotoxicity (ADCC), promoting antigen presentation to dendritic cells.[40,41] Furthermore, sIgA in the intestine is critically important for regulating bacterial communities in the gut lumen by both Fab-dependent and Fab-independent mechanisms.[42] These microbial communities are key regulators of immune activation of intestine cells. Indeed, recent studies have defined a trialogue between IgA, intestinal epithelial cells and the microbiota.[43] The net effect of these interactions determines host immune responsiveness to antigens.

Active Stimulation & Modulation of Infant Response

Breast milk represents the immunological integration of mother and child, not only by providing passive transfer of antibodies and other immune factors, but also by priming the infant immune system, facilitating the development of tolerance, regulating the inflammatory response, and promoting the humoral and cellular response to vaccines. The positive effects of breastfeeding – including its nutritional value – during the development of the infant's immune system apparently persist in the long term.[44,45] Data from European and US studies show that breastfed infants have higher antibody levels than formula-fed infants after receiving oral and parenteral vaccines.[46,47] Following MMR immunization, Pabst et al. documented a Th1-type response in breastfed children, which was not evident in the formula-fed group.[9]

Murine studies have clearly identified the microbiota as a fundamental force priming immune responses.[48] As noted above, breastfeeding profoundly shapes infant stool composition. In addition to sIgA, other factors in milk regulate the establishment of microbial communities. Breast milk is not sterile and contains many bacteria, particularly bifidobacteria and lactobacilli. Oligosaccharides are the third most abundant component in human milk. These human milk oligosaccharides act as prebiotics –that is, nondigestible components that promote the growth of commensal bacteria.[49,50] Indeed, mother's milk fosters the growth of healthy bacteria in the newborn's intestinal tract, which not only aids nutrient absorption, but also boosts the immune system. In addition, these factors constituting the human milk glycobiome can inhibit pathogen adhesion and directly influence intestinal maturation and integrity.[51] Notably, higher levels of non-3'-sialyllactose human milk oligosaccharides appear to play a role in HIV breast milk transmission.[52]

Numerous milk constituents have been implicated in modulating infant immunity and facilitating the development of tolerance.[53] Nucleotides and growth factors such as granulocyte colony-stimulating factor and macrophage colony-stimulating factor enhance the activity of T cells, natural killer cells and macrophages. Milk is enriched with antigen-specific T cells, which can survive passage through the GI tract.[54] In animal models, these cells can traverse the suckling's intestinal tract and are functional, but human studies in this regard are controversial. Nevertheless, in humans maternal–fetal microchimerism in tolerance has been implicated.[54] A variety of anti-inflammatory factors in breast milk aid to promote tolerance, including immunosuppressive cytokines (i.e., TGF-β and IL-10)[44] and long-chain polyunsaturated fatty acids.[55] Among other innate immunoregulatory factors in breast milk, soluble CD14 should be mentioned.[56] Innate sensing molecules such as TLR2 are also present in high concentrations in breast milk. TLR2 appears to inhibit the production of proinflammatory cytokines during bacterial ligand exposure.[57] In addition, breast milk contains naturally occurring anti-idiotypic antibodies, which display specificity against other autologous antibodies and thereby modulate the response to the antigen the idiotype is directed against.[58]

The tolerogenic state induced by breastfeeding is supported by evidence from both human and animal data. In large epidemiologic studies, breastfed infants have a lower incidence of several autoimmune diseases[53] and are more tolerant to renal transplants.[59–61] Intriguingly, the beneficial immunomodulatory effects of breastfeeding both on humoral and cellular responses appear to extend well beyond weaning. In rodent models, perinatal antigen exposure via mother's milk has been shown to prime the suckling animal's immune responses in a manner so profound that the effects can still be detected two generations later.[58,62] Compared with formula-fed pairs, breastfed children show enhanced antibody response to Haemophilus influenzae type b polysaccharide, diphtheria and tetanus toxoids, oral poliovirus, and pneumococcal serotypes 6B and 14 conjugate vaccines.[63,64] Enhanced Th1 responses, as well as significant changes in CD8+ T cells, natural killer cells and mitogen-induced IFN-γ production, have been documented in breastfed but not in formula-fed children who received MMR vaccination.[9]

Enhanced infant T- and B-cell development in breastfed infants has been associated with a number of cytokines, including IL-7, IL-8, IFN-γ and thymic stromal lymphoprotein.[57,65,66]

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