Mechanisms of Neonatal Mucosal Antibody

Following an abrupt transition at birth from the sterile uterus to an environment with abundant commensal and pathogenic microbes, neonatal mammals are protected by maternal Abs at mucosal surfaces. We show in mice that different Ab isotypes work in distinct ways to protect the neonatal mucosal surface. Secretory IgA acts to limit penetration of commensal intestinal bacteria through the neonatal intestinal epithelium: an apparently primitive process that does not require diversification of the primary natural Ab repertoire. In contrast, neonatal protection against the exclusively luminal parasite Heligmosomoides polygyrus required IgG from primed females. This immune IgG could either be delivered directly in milk or retrotransported via neonatal Fc receptor from the neonatal serum into the intestinal lumen to exert its protective effect. T he neonate acquires Igs from two routes: IgG passed transplacentally before birth and IgM, IgA, and IgG delivered via the milk (1). Indeed, breastfeeding is acknowledged to have immense power to avoid unnecessary human infant mortality, especially from diarrheal disease (2, 3). In rodents, IgG is also passed from the milk into the serum via the neonatal Fc receptor (FcRn) 3 present in the duodenum (4). FcRn can also transport IgG back from the serum into the intestinal lumen, in both rodents and humans (5–9), although the functional consequences of this process for neonates are unknown. Neonates are inoculated at birth with a commensal microbiota in the lower intestine and other body surfaces. These commensals successively increase in density, and within weeks the microbes in the lower intestine outnumber the host's own cells (10). These commensals compete with pathogens and stimulate mucosal and immune development, but they share many surface molecules with pathogens including potentially damaging immunostimulatory compounds. Milk contains secretory Ig (S-Ig)A and S-IgM Abs that bind enteric pathogens or their toxins, which are partly induced in the maternal intestinal lymphoid follicles. Milk IgA and IgM are not absorbed significantly in any species and act locally in the intestinal lumen (11). Whether these secretory Abs need to undergo germinal center selection and somatic hypermutation for a neutralizing function against commensals or pathogens, or whether natural germline specificities suffice to provide a primitive exclusion mechanism has not been shown. Although plasma IgG can contribute to protection from mucosal infection, it is present at lower concentrations in the milk of humans (12), and studies have mainly focused on uptake of milk IgG into the neonatal plasma as a …