Advertisement
Cell
This journal offers authors two options (open access or subscription) to publish research

The multifaceted roles of breast milk antibodies

      Summary

      Neonates are born with an immature immune system and rely on the transfer of immunity from their mothers. Maternal antibodies are transferred via the placenta and breast milk. Although the role of placentally transferred immunoglobulin G (IgG) is established, less is known about the selection of antibodies transferred via breast milk and the mechanisms by which they provide protection against neonatal disease. Evidence suggests that breast milk antibodies play multifaceted roles, preventing infection and supporting the selection of commensals and tolerizing immunity during infancy. Here, we discuss emerging data related to the importance of breast milk antibodies in neonatal immunity and development.

      Introduction

      When an infant is born, it is exposed to an expansive array of viruses, bacteria, fungi, and environmental antigens that it was shielded from in the placenta. Lacking a mature immune system, the neonate relies heavily on sources of immunity derived from its mother to distinguish commensals from pathogens. These sources of immunity are transferred to the infant via the placenta and through breast milk (BM). In the placenta, maternal immunity is transferred largely as immunoglobulin G (IgG), which passes directly into the serum of infants (
      • Simister N.E.
      Placental transport of immunoglobulin G.
      ;
      • Palmeira P.
      • Quinello C.
      • Silveira-Lessa A.L.
      • Zago C.A.
      • Carneiro-Sampaio M.
      IgG placental transfer in healthy and pathological pregnancies.
      ) and is instrumental in protection against many childhood infections, including influenza, pertussis, and tetanus (
      • Benowitz I.
      • Esposito D.B.
      • Gracey K.D.
      • Shapiro E.D.
      • Vázquez M.
      Influenza vaccine given to pregnant women reduces hospitalization due to influenza in their infants.
      ;
      • Gall S.A.
      • Myers J.
      • Pichichero M.
      Maternal immunization with tetanus-diphtheria-pertussis vaccine: effect on maternal and neonatal serum antibody levels.
      ;
      • Jackson L.A.
      • Patel S.M.
      • Swamy G.K.
      • Frey S.E.
      • Creech C.B.
      • Munoz F.M.
      • Artal R.
      • Keitel W.A.
      • Noah D.L.
      • Petrie C.R.
      • et al.
      Immunogenicity of an inactivated monovalent 2009 H1N1 influenza vaccine in pregnant women.
      ;
      • Healy C.M.
      Vaccines in pregnant women and research initiatives.
      ). Moreover, emerging studies have also suggested a role for placentally transferred IgE in the neonatal allergic response (
      • Msallam R.
      • Balla J.
      • Rathore A.P.S.
      • Kared H.
      • Malleret B.
      • Saron W.A.A.
      • Liu Z.
      • Hang J.W.
      • Dutertre C.A.
      • Larbi A.
      • et al.
      Fetal mast cells mediate postnatal allergic responses dependent on maternal IgE.
      ). Antibodies transferred through the placenta wane over the first year of life, due to an average IgG half-life of 21 days (
      • Mankarious S.
      • Lee M.
      • Fischer S.
      • Pyun K.H.
      • Ochs H.D.
      • Oxelius V.A.
      • Wedgwood R.J.
      The half-lives of IgG subclasses and specific antibodies in patients with primary immunodeficiency who are receiving intravenously administered immunoglobulin.
      ), although the kinetics of waning vary by antigen-specificity, likely driven by differences in the antibody Fc (
      • Glezen W.P.
      Effect of maternal antibodies on the infant immune response.
      ;
      • Lehmann D.
      • Pomat W.S.
      • Riley I.D.
      • Alpers M.P.
      Studies of maternal immunisation with pneumococcal polysaccharide vaccine in Papua New Guinea.
      ). However, infants continue to receive a supply of maternal immunity through breast milk.
      Unlike placentally transferred IgG, which provide largely systemic immunity, BM-antibodies play a dominant role in neonatal mucosal immunity. Although colostrum-derived antibodies can pass into serum in rodents and ungulates (
      • Guidry J.
      • Butler J.E.
      • Pearson R.E.
      • Weinland B.T.
      IgA, igG1, IgG2, IgM, and BSA in serum and mammary secretion throughout lactation.
      ;
      • Israel E.J.
      • Patel V.K.
      • Taylor S.F.
      • Marshak-Rothstein A.
      • Simister N.E.
      Requirement for a beta 2-microglobulin-associated Fc receptor for acquisition of maternal IgG by fetal and neonatal mice.
      ), the mucosal barriers close at birth in primates, including humans, preventing BM-antibodies from transferring systemic immunity. Instead, these antibodies populate the mucosal surfaces of the neonate, providing a first line of defense on this highly vulnerable surface during the early days of life.
      Nursing is associated with an improvement in a number of infant outcomes, including a reduction in the burden of diarrheal diseases, decreased respiratory infections, and decreased long-term risk of developing asthma, diabetes, and inflammatory bowel disease (
      • Bahl R.
      • Frost C.
      • Kirkwood B.R.
      • Edmond K.
      • Martines J.
      • Bhandari N.
      • Arthur P.
      Infant feeding patterns and risks of death and hospitalization in the first half of infancy: Multicentre cohort study.
      ;
      • Sankar M.J.
      • Sinha B.
      • Chowdhury R.
      • Bhandari N.
      • Taneja S.
      • Martines J.
      • Bahl R.
      Optimal breastfeeding practices and infant and child mortality: A systematic review and meta-analysis.
      ;
      • Victora C.G.
      • Bahl R.
      • Barros A.J.
      • França G.V.
      • Horton S.
      • Krasevec J.
      • Murch S.
      • Sankar M.J.
      • Walker N.
      • Rollins N.C.
      Lancet Breastfeeding Series Group
      Breastfeeding in the 21st century: epidemiology, mechanisms, and lifelong effect.
      ). Critically, nursing is especially important in low-income countries, where diarrheal diseases and malnutrition are more prominent (
      • Jones G.
      • Steketee R.W.
      • Black R.E.
      • Bhutta Z.A.
      • Morris S.S.
      Bellagio Child Survival Study Group
      How many child deaths can we prevent this year?.
      ;
      • Melese B.
      • Paulos W.
      • Astawesegn F.H.
      • Gelgelu T.B.
      Prevalence of diarrheal diseases and associated factors among under-five children in Dale District, Sidama zone, Southern Ethiopia: a cross-sectional study.
      ). Given these numerous health benefits conferred through BM, both with respect to nutritional content and immune protection, exclusive nursing is recommended during the first 6 months of life by the . BM contains human milk oligosaccharides (HMOs), cytokines, and glycoproteins that have been implicated in non-specific immune defense against pathogens encountered by the neonate (
      • Andreas N.J.
      • Kampmann B.
      • Mehring Le-Doare K.
      Human breast milk: A review on its composition and bioactivity.
      ). However, in addition, maternal secretory IgA (SIgA), secretory IgM (SIgM), and IgG in BM represent an antigen-specific form of immunity for the neonate.
      Although the presence of maternal antibodies in BM is clearly established, our understanding of the precise role for these transferred antibodies is still emerging. Accumulating data points to an enrichment of certain populations of antibodies, both at an isotypic level and with respect to unique antibody specificities and functions in BM (
      • Fouda G.G.
      • Yates N.L.
      • Pollara J.
      • Shen X.
      • Overman G.R.
      • Mahlokozera T.
      • Wilks A.B.
      • Kang H.H.
      • Salazar-Gonzalez J.F.
      • Salazar M.G.
      • et al.
      Center for HIV/AIDS Vaccine Immunology
      HIV-specific functional antibody responses in breast milk mirror those in plasma and are primarily mediated by IgG antibodies.
      ;
      • Sacha C.R.
      • Vandergrift N.
      • Jeffries Jr., T.L.
      • McGuire E.
      • Fouda G.G.
      • Liebl B.
      • Marshall D.J.
      • Gurley T.C.
      • Stiegel L.
      • Whitesides J.F.
      • et al.
      Restricted isotype, distinct variable gene usage, and high rate of gp120 specificity of HIV-1 envelope-specific B cells in colostrum compared with those in blood of HIV-1-infected, lactating African women.
      ). Here, we explore emerging data that shows a role for BM antibodies in the protection of newborns against neonatal infections, seeding the gut microbiome, and training tolerance toward mucosal antigens, pointing to antibodies as critical players in immune defense, microbial organization, and immune-education. Defining these novel roles of antibodies provides opportunities not only to define new strategies to improve health outcomes for neonates globally, but also to develop novel strategies to power the humoral immune system in reprogramming immunity throughout life.

      Origins of antibodies in BM

      BM plays a critical role in transferring immunity from mother to child, evolving throughout lactation in response to the needs of the infant (
      • Lyons K.E.
      • Ryan C.A.
      • Dempsey E.M.
      • Ross R.P.
      • Stanton C.
      Breast milk, a source of beneficial microbes and associated benefits for infant health.
      ). The first wave of fluid, colostrum, delivers immune-stimulating factors and serves as an initial food source (
      • Casey C.E.
      • Neifert M.R.
      • Seacat J.M.
      • Neville M.C.
      Nutrient intake by breast-fed infants during the first five days after birth.
      ). This first fluid is rich in proteins and immune factors, including immunoglobulins, cytokines, and leukocytes, with lower concentrations of other metabolites, such as lactose and glucose (
      • Kulski J.K.
      • Hartmann P.E.
      Changes in human milk composition during the initiation of lactation.
      ;
      • Casey C.E.
      • Neifert M.R.
      • Seacat J.M.
      • Neville M.C.
      Nutrient intake by breast-fed infants during the first five days after birth.
      ). Colostrum gives way to transitional milk, shifting to a rich food source, to support to the changing needs of the growing infant (
      • Lyons K.E.
      • Ryan C.A.
      • Dempsey E.M.
      • Ross R.P.
      • Stanton C.
      Breast milk, a source of beneficial microbes and associated benefits for infant health.
      ). A few weeks after delivery, BM matures, containing essential nutrients plus numerous bioactive components, such as hormones, growth factors, and enzymes (
      • Sundekilde U.K.
      • Downey E.
      • O’Mahony J.A.
      • O’Shea C.A.
      • Ryan C.A.
      • Kelly A.L.
      • Bertram H.C.
      The effect of gestational and lactational age on the human milk metabolome.
      ;
      • Lyons K.E.
      • Ryan C.A.
      • Dempsey E.M.
      • Ross R.P.
      • Stanton C.
      Breast milk, a source of beneficial microbes and associated benefits for infant health.
      ). The composition of mature milk during the first year of lactation differs significantly from that of colostrum, with an increased percentage of carbohydrates and lipids and a decreased percentage of proteins, including lower concentrations of antibodies (
      • Goldman A.S.
      • Garza C.
      • Nichols B.L.
      • Goldblum R.M.
      Immunologic factors in human milk during the first year of lactation.
      ;
      • Goonatilleke E.
      • Huang J.
      • Xu G.
      • Wu L.
      • Smilowitz J.T.
      • German J.B.
      • Lebrilla C.B.
      Human milk proteins and their glycosylation exhibit quantitative dynamic variations during lactation.
      ).
      Although secretory IgA (SIgA) accounts for the majority of BM antibodies, SIgM and IgG are also transferred (
      • Andreas N.J.
      • Kampmann B.
      • Mehring Le-Doare K.
      Human breast milk: A review on its composition and bioactivity.
      ). Interestingly, the immunoglobulin composition in human BM differs significantly from that in other mammals. For instance, in ungulates, the primary immunoglobulin in BM is IgG, whereas in in rodents, BM contains high levels of both IgG and SIgA (
      • Barrington G.M.
      • Parish S.M.
      Bovine neonatal immunology.
      ;
      • Hurley W.L.
      • Theil P.K.
      Perspectives on immunoglobulins in colostrum and milk.
      ). This difference in immunoglobulin composition across species reflects differences in antibody absorption. While enterocytes no longer absorb macromolecules at the time of birth in humans, preventing large macromolecules from passing through (
      • Van de Perre P.
      Transfer of antibody via mother’s milk.
      ), ungulates and rodents continue to transfer antibodies from the gut to the circulation for up to 48 h and 21 days after birth, respectively (
      • Sangild P.T.
      • Trahair J.F.
      • Loftager M.K.
      • Fowden A.L.
      Intestinal macromolecule absorption in the fetal pig after infusion of colostrum in utero.
      ;
      • Arévalo Sureda E.
      • Weström B.
      • Pierzynowski S.G.
      • Prykhodko O.
      Maturation of the intestinal epithelial barrier in neonatal rats coincides with decreased FcRn expression, replacement of vacuolated enterocytes and changed Blimp-1 expression.
      ). As an exception, gut closure occurs later after birth in preterm primate infants (
      • Weaver L.T.
      • Laker M.F.
      • Nelson R.
      Intestinal permeability in the newborn.
      ), permitting IgG from the BM to reach circulation in the first days of life. Evolutionarily, differences in BM transfer to circulation may compensate for differences in placental transfer, where ungulates and rodents experience reduced placental transfer, but benefit from BM antibodies both mucosally and systemically (
      • Guidry J.
      • Butler J.E.
      • Pearson R.E.
      • Weinland B.T.
      IgA, igG1, IgG2, IgM, and BSA in serum and mammary secretion throughout lactation.
      ;
      • Israel E.J.
      • Patel V.K.
      • Taylor S.F.
      • Marshak-Rothstein A.
      • Simister N.E.
      Requirement for a beta 2-microglobulin-associated Fc receptor for acquisition of maternal IgG by fetal and neonatal mice.
      ). Conversely, in humans, immune transfer is temporally divided, with in utero population of circulatory immunity, followed by population of mucosal immunity following birth.
      Due to the inability of antibodies in human BM to reach circulation, the primary role of these immunoglobulins is to provide barrier immunity in the human infant (
      • Brandtzaeg P.
      Induction of secretory immunity and memory at mucosal surfaces.
      ). The IgA in BM are produced by IgA plasma cells that accumulate in the lactating mammary glands (
      • Halsey J.F.
      • Mitchell C.S.
      • McKenzie S.J.
      The origins of secretory IgA in milk: a shift during lactation from a serum origin to local synthesis in the mammary gland.
      ). These CCR10+ IgA+ plasma cells are primed in the lymph nodes and the Peyer’s patches of the mucosal tissues and home to the mammary glands due to expression of the mucosal chemokine CCL28 in the lactating mammary gland, which is upregulated by the mammary gland epithelial cells during lactation (Figure 1) (
      • Wilson E.
      • Butcher E.C.
      CCL28 controls immunoglobulin (Ig)A plasma cell accumulation in the lactating mammary gland and IgA antibody transfer to the neonate.
      ). Thus, previously generated maternal mucosal plasma cells home to the mammary glands to populate the newly forming BM. The precise mechanism and selection of this recruitment remains incompletely understood. Given that the IgA originate from B cells primed in the mucosa (
      • Lindner C.
      • Thomsen I.
      • Wahl B.
      • Ugur M.
      • Sethi M.K.
      • Friedrichsen M.
      • Smoczek A.
      • Ott S.
      • Baumann U.
      • Suerbaum S.
      • et al.
      Diversification of memory B cells drives the continuous adaptation of secretory antibodies to gut microbiota.
      ), there is growing evidence that a large fraction of BM SIgA in BM are directed toward commensal, gut, and respiratory antigen specificities (
      • Nathavitharana K.A.
      • Catty D.
      • McNeish A.S.
      IgA antibodies in human milk: epidemiological markers of previous infections?.
      ;
      • Durand D.
      • Ochoa T.J.
      • Bellomo S.M.
      • Contreras C.A.
      • Bustamante V.H.
      • Ruiz J.
      • Cleary T.G.
      Detection of secretory immunoglobulin A in human colostrum as mucosal immune response against proteins of the type III secretion system of Salmonella, Shigella and enteropathogenic Escherichia coli.
      ;
      • Schlaudecker E.P.
      • Steinhoff M.C.
      • Omer S.B.
      • McNeal M.M.
      • Roy E.
      • Arifeen S.E.
      • Dodd C.N.
      • Raqib R.
      • Breiman R.F.
      • Zaman K.
      IgA and neutralizing antibodies to influenza a virus in human milk: a randomized trial of antenatal influenza immunization.
      ;
      • Gopalakrishna K.P.
      • Macadangdang B.R.
      • Rogers M.B.
      • Tometich J.T.
      • Firek B.A.
      • Baker R.
      • Ji J.
      • Burr A.H.P.
      • Ma C.
      • Good M.
      • et al.
      Maternal IgA protects against the development of necrotizing enterocolitis in preterm infants.
      ). Thus, the BM selectively empowers neonates with similar mucosal barrier activity found in the mother, drawing from her mucosal immune archive and transferring antibodies able to provide a barrier against the same antigens found in the mother’s immediate environment, which are the most likely to be encountered by the neonate.
      Figure thumbnail gr1
      Figure 1Transfer of antibodies to breast milk
      Top: plasma cells from mucosal tissues home to the mammary gland, following a CCL28 chemokine gradient generated by the evolving mammary tissue. Bottom: these plasma cells produce IgA (SIgA) and IgM, which is passed into breast milk by the polymeric Ig receptor (pIgR) on the mammary epithelium (bottom). IgG originating from the blood is transferred into the breast milk via FcRn expressed on the mammary epithelium cells.
      Antibodies are transferred to BM found in the mammary glands, a branching epithelial structure, consisting of milk-transporting lactiferous ducts and alveoli, involved in synthesizing and delivering milk to the newborn (Figure 2). The walls of the duct tissue are composed of two layers of epithelial cells: a luminal layer of cuboidal epithelial cells and a basal layer of myoepithelial cells (
      • Watson C.J.
      • Khaled W.T.
      Mammary development in the embryo and adult: a journey of morphogenesis and commitment.
      ). These ductal and alveoli epithelial cells express the polymeric Ig receptor (pIgR) on their basolateral side and express neonatal Fc receptor (FcRn) endosomally (
      • De Groot N.
      • Van Kuik-Romeijn P.
      • Lee S.H.
      • De Boer H.A.
      Increased immunoglobulin A levels in milk by over-expressing the murine polymeric immunoglobulin receptor gene in the mammary gland epithelial cells of transgenic mice.
      ;
      • Cianga P.
      • Cianga C.
      • Cozma L.
      • Ward E.S.
      • Carasevici E.
      The MHC class I related Fc receptor, FcRn, is expressed in the epithelial cells of the human mammary gland.
      ). PIgR is instrumental for the passage of SIgA and SIgM into BM (
      • De Groot N.
      • Van Kuik-Romeijn P.
      • Lee S.H.
      • De Boer H.A.
      Increased immunoglobulin A levels in milk by over-expressing the murine polymeric immunoglobulin receptor gene in the mammary gland epithelial cells of transgenic mice.
      ). pIgR binds to polymeric IgA or IgM, after which the complex undergoes endocytosis, followed by vesicular transport to the apical surface (
      • Johansen F.-E.
      • Braathen R.
      • Brandtzaeg P.
      The J chain is essential for polymeric Ig receptor-mediated epithelial transport of IgA.
      ), where pIgR is proteolytically cleaved between its external and intramembranous domains, releasing IgA or IgM still bound to the external domain of the pIgR (
      • Turula H.
      • Wobus C.E.
      The role of the polymeric immunoglobulin receptor and secretory immunoglobulins during mucosal infection and immunity.
      ). This external domain of pIgR, the secretory component (SC), plays a critical role in protecting secretory antibodies from cleavage by proteases in the gut (
      • Stadtmueller B.M.
      • Huey-Tubman K.E.
      • López C.J.
      • Yang Z.
      • Hubbell W.L.
      • Bjorkman P.J.
      The structure and dynamics of secretory component and its interactions with polymeric immunoglobulins.
      ;
      • Demers-Mathieu V.
      • Underwood M.A.
      • Beverly R.L.
      • Dallas D.C.
      Survival of Immunoglobulins from Human Milk to Preterm Infant Gastric Samples at 1, 2, and 3 h Postprandial.
      ). Whereas studies that have examined the accumulation of plasma cells in the lactating mammary gland have focused on IgA+ cells, few studies have examined the origin of IgG in BM of humans. However, it is hypothesized that FcRn plays a role in the passage of IgG into BM (
      • Cianga P.
      • Medesan C.
      • Richardson J.A.
      • Ghetie V.
      • Ward E.S.
      Identification and function of neonatal Fc receptor in mammary gland of lactating mice.
      ;
      • Adamski F.M.
      • King A.T.
      • Demmer J.
      Expression of the Fc receptor in the mammary gland during lactation in the marsupial Trichosurus vulpecula (brushtail possum).
      ). Additionally, some antibodies in BM likely arise from plasma cells that are transferred into BM itself, able to populate the neonatal immune system for a short time (
      • Tuaillon E.
      • Valea D.
      • Becquart P.
      • Al Tabaa Y.
      • Meda N.
      • Bollore K.
      • Van de Perre P.
      • Vendrell J.P.
      Human milk-derived B cells: a highly activated switched memory cell population primed to secrete antibodies.
      ).
      Figure thumbnail gr2
      Figure 2Mammary gland anatomy
      The mammary gland consists of milk ducts that terminate at lobes. During lactation, this branching ductal system expands to support milk production. The walls of the ducts of the mammary gland consist of two epithelial cell types: cuboidal ductal epithelial cells and myoepithelial cells. The lobes of the mammary gland consist of 10–20 alveoli. Milk production occurs in these alveoli by lactocytes that differentiate from the ductal epithelial cells during lactation. The epithelial cells express pIgR and FcRn, which direct the transport of maternal antibodies into breast milk.

      BM antibodies and seeding the infant microbiome

      Microbiome development

      Emerging research clearly illustrates that microbiome composition has a profound impact on an individual’s long-term health and development (
      • Houghteling P.D.
      • Walker W.A.
      Why is initial bacterial colonization of the intestine important to infants’ and children’s health?.
      ;
      • Lynch S.V.
      • Pedersen O.
      The Human Intestinal Microbiome in Health and Disease.
      ). Studies have suggested that proper seeding of the microbiome during infancy can prevent diarrheal diseases, inflammatory bowel disease in adulthood, asthma, allergies, and even more recently, the evolution of autoimmune diseases (
      • Gülden E.
      • Wong F.S.
      • Wen L.
      The gut microbiota and Type 1 Diabetes.
      ;
      • Johnson C.C.
      • Ownby D.R.
      The infant gut bacterial microbiota and risk of pediatric asthma and allergic diseases.
      ). Although it is still controversial if colonization occurs in utero, infants are clearly exposed to components of the mother’s microbiome that are present in amniotic fluid (
      • Aagaard K.
      • Ma J.
      • Antony K.M.
      • Ganu R.
      • Petrosino J.
      • Versalovic J.
      The placenta harbors a unique microbiome.
      ;
      • Gomez de Agüero M.
      • Ganal-Vonarburg S.C.
      • Fuhrer T.
      • Rupp S.
      • Uchimura Y.
      • Li H.
      • Steinert A.
      • Heikenwalder M.
      • Hapfelmeier S.
      • Sauer U.
      • et al.
      The maternal microbiota drives early postnatal innate immune development.
      ). Still, these studies suggesting in utero colonization are controversial (
      • Perez-Muñoz M.E.
      • Arrieta M.C.
      • Ramer-Tait A.E.
      • Walter J.
      A critical assessment of the “sterile womb” and “in utero colonization” hypotheses: implications for research on the pioneer infant microbiome.
      ;
      • de Goffau M.C.
      • Lager S.
      • Sovio U.
      • Gaccioli F.
      • Cook E.
      • Peacock S.J.
      • Parkhill J.
      • Charnock-Jones D.S.
      • Smith G.C.S.
      Human placenta has no microbiome but can contain potential pathogens.
      ). Instead, the major exposure to the microbiome occurs at birth, when the infant is exposed to a massive influx of microorganisms from the mother’s vaginal canal, skin-derived nursing microbiome, BM, and the environment (
      • Dominguez-Bello M.G.
      • Costello E.K.
      • Contreras M.
      • Magris M.
      • Hidalgo G.
      • Fierer N.
      • Knight R.
      Delivery mode shapes the acquisition and structure of the initial microbiota across multiple body habitats in newborns.
      ;
      • Bäckhed F.
      • Roswall J.
      • Peng Y.
      • Feng Q.
      • Jia H.
      • Kovatcheva-Datchary P.
      • Li Y.
      • Xia Y.
      • Xie H.
      • Zhong H.
      • et al.
      Dynamics and stabilization of the human gut microbiome during the first year of life.
      ;
      • Pannaraj P.S.
      • Li F.
      • Cerini C.
      • Bender J.M.
      • Yang S.
      • Rollie A.
      • Adisetiyo H.
      • Zabih S.
      • Lincez P.J.
      • Bittinger K.
      • et al.
      Association between breast milk bacterial communities and establishment and development of the infant gut microbiome.
      ), making the time window directly following birth crucial for the selection of microbial friends versus foes. Colonization appears to occur in a sequential and highly organized manner, with diversification occurring in a rather reproducible manner (
      • Yatsunenko T.
      • Rey F.E.
      • Manary M.J.
      • Trehan I.
      • Dominguez-Bello M.G.
      • Contreras M.
      • Magris M.
      • Hidalgo G.
      • Baldassano R.N.
      • Anokhin A.P.
      • et al.
      Human gut microbiome viewed across age and geography.
      ;
      • Avershina E.
      • Lundgård K.
      • Sekelja M.
      • Dotterud C.
      • Storrø O.
      • Øien T.
      • Johnsen R.
      • Rudi K.
      Transition from infant- to adult-like gut microbiota.
      ).
      During early infancy, a newborn’s microbiome has a low diversity, dominated particularly by Enterobacteriaceae (
      • Arboleya S.
      • Sánchez B.
      • Milani C.
      • Duranti S.
      • Solís G.
      • Fernández N.
      • de los Reyes-Gavilán C.G.
      • Ventura M.
      • Margolles A.
      • Gueimonde M.
      Intestinal microbiota development in preterm neonates and effect of perinatal antibiotics.
      ), and followed by a shift to Bifidobacterium and Bacteroides (
      • Bokulich N.A.
      • Chung J.
      • Battaglia T.
      • Henderson N.
      • Jay M.
      • Li H.
      • D Lieber A.
      • Wu F.
      • Perez-Perez G.I.
      • Chen Y.
      • et al.
      Antibiotics, birth mode, and diet shape microbiome maturation during early life.
      ;
      • Yassour M.
      • Vatanen T.
      • Siljander H.
      • Hämäläinen A.M.
      • Härkönen T.
      • Ryhänen S.J.
      • Franzosa E.A.
      • Vlamakis H.
      • Huttenhower C.
      • Gevers D.
      • et al.
      DIABIMMUNE Study Group
      Natural history of the infant gut microbiome and impact of antibiotic treatment on bacterial strain diversity and stability.
      ). However, the neonatal microbiome is highly susceptible to the introduction of new species, and several factors can significantly impact the composition of the neonatal microbiome, including mode of delivery, gestational age, maternal diet, the use of antibiotics, and formula-feeding (
      • Collado M.C.
      • Isolauri E.
      • Laitinen K.
      • Salminen S.
      Effect of mother’s weight on infant’s microbiota acquisition, composition, and activity during early infancy: a prospective follow-up study initiated in early pregnancy.
      ;
      • Dominguez-Bello M.G.
      • Costello E.K.
      • Contreras M.
      • Magris M.
      • Hidalgo G.
      • Fierer N.
      • Knight R.
      Delivery mode shapes the acquisition and structure of the initial microbiota across multiple body habitats in newborns.
      ;
      • Rougé C.
      • Goldenberg O.
      • Ferraris L.
      • Berger B.
      • Rochat F.
      • Legrand A.
      • Göbel U.B.
      • Vodovar M.
      • Voyer M.
      • Rozé J.C.
      • et al.
      Investigation of the intestinal microbiota in preterm infants using different methods.
      ;
      • Stewart C.J.
      • Ajami N.J.
      • O’Brien J.L.
      • Hutchinson D.S.
      • Smith D.P.
      • Wong M.C.
      • Ross M.C.
      • Lloyd R.E.
      • Doddapaneni H.
      • Metcalf G.A.
      • et al.
      Temporal development of the gut microbiome in early childhood from the TEDDY study.
      ). Improper seeding of the microbiome in infancy can result in dysbiosis, an altered composition of the bacterial communities in the gut that persists throughout life (
      • Walker W.A.
      The importance of appropriate initial bacterial colonization of the intestine in newborn, child, and adult health.
      ). For example, mode of delivery can result in microbiome changes that persist for several years following birth (
      • Salminen S.
      • Gibson G.R.
      • McCartney A.L.
      • Isolauri E.
      Influence of mode of delivery on gut microbiota composition in seven year old children.
      ), and infants born by C-section have an increased risk of asthma (
      • Thavagnanam S.
      • Fleming J.
      • Bromley A.
      • Shields M.D.
      • Cardwell C.R.
      A meta-analysis of the association between Caesarean section and childhood asthma.
      ), allergy (
      • Bager P.
      • Wohlfahrt J.
      • Westergaard T.
      Caesarean delivery and risk of atopy and allergic disease: meta-analyses.
      ), type I diabetes (
      • Cardwell C.R.
      • Stene L.C.
      • Joner G.
      • Cinek O.
      • Svensson J.
      • Goldacre M.J.
      • Parslow R.C.
      • Pozzilli P.
      • Brigis G.
      • Stoyanov D.
      • et al.
      Caesarean section is associated with an increased risk of childhood-onset type 1 diabetes mellitus: a meta-analysis of observational studies.
      ), and obesity (
      • Pei Z.
      • Heinrich J.
      • Fuertes E.
      • Flexeder C.
      • Hoffmann B.
      • Lehmann I.
      • Schaaf B.
      • von Berg A.
      • Koletzko S.
      Influences of Lifestyle-Related Factors on the Immune System and the Development of Allergies in Childhood plus Air Pollution and Genetics (LISAplus) Study Group
      Cesarean delivery and risk of childhood obesity.
      ), associated with an imbalanced microbiome. Fluctuations in the abundance of microbial species vary during the first few months to years of life (
      • Bäckhed F.
      • Roswall J.
      • Peng Y.
      • Feng Q.
      • Jia H.
      • Kovatcheva-Datchary P.
      • Li Y.
      • Xia Y.
      • Xie H.
      • Zhong H.
      • et al.
      Dynamics and stabilization of the human gut microbiome during the first year of life.
      ), after which microbial colonization stabilizes at ∼2–3 years of age (
      • Yatsunenko T.
      • Rey F.E.
      • Manary M.J.
      • Trehan I.
      • Dominguez-Bello M.G.
      • Contreras M.
      • Magris M.
      • Hidalgo G.
      • Baldassano R.N.
      • Anokhin A.P.
      • et al.
      Human gut microbiome viewed across age and geography.
      ;
      • Bäckhed F.
      • Roswall J.
      • Peng Y.
      • Feng Q.
      • Jia H.
      • Kovatcheva-Datchary P.
      • Li Y.
      • Xia Y.
      • Xie H.
      • Zhong H.
      • et al.
      Dynamics and stabilization of the human gut microbiome during the first year of life.
      ). After this time, the microbiome is considered mature, comprising a highly diverse microbial population that remains relatively constant throughout adulthood (
      • Lozupone C.A.
      • Stombaugh J.I.
      • Gordon J.I.
      • Jansson J.K.
      • Knight R.
      Diversity, stability and resilience of the human gut microbiota.
      ).

      SIgA in microbiome homeostasis

      Over the past decade, it has become clear that SIgA play a critical role in the establishment and maintenance of the microbiome in infancy. Much of the SIgA in the mucosa is thought to be non-specific and highly cross-reactive, with broad reactivity to microbiota (
      • Bunker J.J.
      • Erickson S.A.
      • Flynn T.M.
      • Henry C.
      • Koval J.C.
      • Meisel M.
      • Jabri B.
      • Antonopoulos D.A.
      • Wilson P.C.
      • Bendelac A.
      Natural polyreactive IgA antibodies coat the intestinal microbiota.
      ). Moreover, some studies suggest that SIgA can bind antigens in a Fab-independent manner through glycans on the Fc portion of the antibody and on the SC and J-chain (
      • Mathias A.
      • Corthésy B.
      N-Glycans on secretory component: mediators of the interaction between secretory IgA and gram-positive commensals sustaining intestinal homeostasis.
      ), allowing for broad reactivity of SIgA to antigens. Emerging data suggest that these antibodies play an essential role in providing a first line of defense against environmental microorganisms (
      • Binsker U.
      • Lees J.A.
      • Hammond A.J.
      • Weiser J.N.
      Immune exclusion by naturally acquired secretory IgA against pneumococcal pilus-1.
      ). Maternally derived Igs selectively coat microorganisms in the small intestine, promoting the anchoring of bacteria and commensalization and also deliver antigens to antigen-presenting cells in the underlying tissues, required by the immune system to differentiate commensals from pathogens (
      • Palm N.W.
      • de Zoete M.R.
      • Cullen T.W.
      • Barry N.A.
      • Stefanowski J.
      • Hao L.
      • Degnan P.H.
      • Hu J.
      • Peter I.
      • Zhang W.
      • et al.
      Immunoglobulin A coating identifies colitogenic bacteria in inflammatory bowel disease.
      ;
      • Rogier E.W.
      • Frantz A.L.
      • Bruno M.E.
      • Wedlund L.
      • Cohen D.A.
      • Stromberg A.J.
      • Kaetzel C.S.
      Secretory antibodies in breast milk promote long-term intestinal homeostasis by regulating the gut microbiota and host gene expression.
      ). Through a process referred to as immune exclusion, SIgA trap microbes and prevent the translocation of both commensal and pathogenic microbes across the mucosal epithelia by slowing attachment and spatially segregating microbiota from the epithelium (
      • Harris N.L.
      • Spoerri I.
      • Schopfer J.F.
      • Nembrini C.
      • Merky P.
      • Massacand J.
      • Urban Jr., J.F.
      • Lamarre A.
      • Burki K.
      • Odermatt B.
      • et al.
      Mechanisms of neonatal mucosal antibody protection.
      ;
      • Binsker U.
      • Lees J.A.
      • Hammond A.J.
      • Weiser J.N.
      Immune exclusion by naturally acquired secretory IgA against pneumococcal pilus-1.
      ) (Figure 3). Additionally, SIgA can drive the clumping of pathogens in the lumen, through agglutination or by enchaining growth of daughter cells, (
      • Moor K.
      • Diard M.
      • Sellin M.E.
      • Felmy B.
      • Wotzka S.Y.
      • Toska A.
      • Bakkeren E.
      • Arnoldini M.
      • Bansept F.
      • Co A.D.
      • et al.
      High-avidity IgA protects the intestine by enchaining growing bacteria.
      ) or neutralize pathogens in the gut lumen (
      • Perrier C.
      • Sprenger N.
      • Corthésy B.
      Glycans on secretory component participate in innate protection against mucosal pathogens.
      ;
      • Boullier S.
      • Tanguy M.
      • Kadaoui K.A.
      • Caubet C.
      • Sansonetti P.
      • Corthésy B.
      • Phalipon A.
      Secretory IgA-mediated neutralization of Shigella flexneri prevents intestinal tissue destruction by down-regulating inflammatory circuits.
      ), resulting in the immune exclusion of viruses and bacteria from the gut epithelium. Antibody coating can further limit the motility of bacteria through the gut lumen, enabling the immune system to selectively sample complexed bacteria to generate immunity, while deliberately excluding pathogen penetration into the mesenteric lymph nodes and Peyer’s patches (
      • Forbes S.J.
      • Eschmann M.
      • Mantis N.J.
      Inhibition of Salmonella enterica serovar typhimurium motility and entry into epithelial cells by a protective antilipopolysaccharide monoclonal immunoglobulin A antibody.
      ).
      Figure thumbnail gr3
      Figure 3Breast milk antibodies recognize and segregate commensals from the gut epithelium
      Left: maternal antibodies from breast milk bind to microbes in the neonatal gut, spatially segregating microbes from the gut epithelium. These maternal antibodies prevent the penetration of bacteria through the epithelium, limiting an immune response to these microbes but also providing signals for underlying antigen-presenting cells to sample complexes of microbes targeted for tolerance. Right: in the absence of maternal antibodies, bacteria can penetrate the neonatal gut epithelium, resulting in the activation of T cells in the mesenteric lymph nodes and the induction of a T cell-dependent antibody response.
      How IgA differentiates between pathogenic antigens and commensal antigens remains unclear. The importance of SIgA in colonization has been clearly demonstrated in the setting of both IgA-deficient humans and pIgR-deficient mice, both lacking IgA in their gut. Interestingly, in both of these settings, microbiome dysbiosis is observed compared to humans with IgA or pIgR wild-type littermate controls (
      • Reikvam D.H.
      • Derrien M.
      • Islam R.
      • Erofeev A.
      • Grcic V.
      • Sandvik A.
      • Gaustad P.
      • Meza-Zepeda L.A.
      • Jahnsen F.L.
      • Smidt H.
      • Johansen F.E.
      Epithelial-microbial crosstalk in polymeric Ig receptor deficient mice.
      ;
      • Fadlallah J.
      • El Kafsi H.
      • Sterlin D.
      • Juste C.
      • Parizot C.
      • Dorgham K.
      • Autaa G.
      • Gouas D.
      • Almeida M.
      • Lepage P.
      • et al.
      Microbial ecology perturbation in human IgA deficiency.
      ). For instance, in luminal-IgA-deficient mice, an expansion of segmented filamentous bacteria was observed (
      • Suzuki K.
      • Meek B.
      • Doi Y.
      • Muramatsu M.
      • Chiba T.
      • Honjo T.
      • Fagarasan S.
      Aberrant expansion of segmented filamentous bacteria in IgA-deficient gut.
      ). In individuals with IgA-deficiency, dysbiosis manifests with a high proportion of Enterobacterieae dominating the microbiome, which is the same dominant family in the microbiome of young infants, potentially related to early selection events in infancy, prior to maternal SIgA influx, that fail to evolve over time (
      • Catanzaro J.R.
      • Strauss J.D.
      • Bielecka A.
      • Porto A.F.
      • Lobo F.M.
      • Urban A.
      • Schofield W.B.
      • Palm N.W.
      IgA-deficient humans exhibit gut microbiota dysbiosis despite secretion of compensatory IgM.
      ). While these individuals continue to generate SIgM, able to also trap and drive microbial colonization, these SIgM target a broad, less specific subset of commensals, resulting in the expansion and dysregulated colonization of the gut (
      • Catanzaro J.R.
      • Strauss J.D.
      • Bielecka A.
      • Porto A.F.
      • Lobo F.M.
      • Urban A.
      • Schofield W.B.
      • Palm N.W.
      IgA-deficient humans exhibit gut microbiota dysbiosis despite secretion of compensatory IgM.
      ). Interestingly, elevated rates of allergies and autoimmune diseases have been observed in individuals with IgA-deficiency, potentially as a result of this altered microbiota (
      • Yazdani R.
      • Azizi G.
      • Abolhassani H.
      • Aghamohammadi A.
      Selective IgA Deficiency: Epidemiology, Pathogenesis, Clinical Phenotype, Diagnosis, Prognosis and Management.
      ) Therefore, SIgA not only protects against pathogens in the gut, but also drives the development and maintenance of a healthy gut microbiota.

      SIgA in BM and microbiome colonization

      Several studies suggest that nursing is key to determining newborn microbial composition (
      • Ho N.T.
      • Li F.
      • Lee-Sarwar K.A.
      • Tun H.M.
      • Brown B.P.
      • Pannaraj P.S.
      • Bender J.M.
      • Azad M.B.
      • Thompson A.L.
      • Weiss S.T.
      • et al.
      Meta-analysis of effects of exclusive breastfeeding on infant gut microbiota across populations.
      ;
      • Stewart C.J.
      • Ajami N.J.
      • O’Brien J.L.
      • Hutchinson D.S.
      • Smith D.P.
      • Wong M.C.
      • Ross M.C.
      • Lloyd R.E.
      • Doddapaneni H.
      • Metcalf G.A.
      • et al.
      Temporal development of the gut microbiome in early childhood from the TEDDY study.
      ). BM contains many components that are vital for the proper seeding of the infant microbiota. For instance, HMOs act as a prebiotics for Bifidobacteria (
      • Ward R.E.
      • Niñonuevo M.
      • Mills D.A.
      • Lebrilla C.B.
      • German J.B.
      In vitro fermentation of breast milk oligosaccharides by Bifidobacterium infantis and Lactobacillus gasseri.
      ), likely contributing to the higher proportion of Bifidobacteria in breastfed infants compared to formula-fed infants (
      • Stewart C.J.
      • Ajami N.J.
      • O’Brien J.L.
      • Hutchinson D.S.
      • Smith D.P.
      • Wong M.C.
      • Ross M.C.
      • Lloyd R.E.
      • Doddapaneni H.
      • Metcalf G.A.
      • et al.
      Temporal development of the gut microbiome in early childhood from the TEDDY study.
      ). In contrast, formula-fed infants have higher Enterobacteriaceae and Clostridiaceae abundance and a loss of Bifidobacterium species (
      • Stewart C.J.
      • Ajami N.J.
      • O’Brien J.L.
      • Hutchinson D.S.
      • Smith D.P.
      • Wong M.C.
      • Ross M.C.
      • Lloyd R.E.
      • Doddapaneni H.
      • Metcalf G.A.
      • et al.
      Temporal development of the gut microbiome in early childhood from the TEDDY study.
      ). Besides prebiotics, the antibodies in BM play a central tolerogenic relationship with commensal bacteria (
      • Maynard C.L.
      • Elson C.O.
      • Hatton R.D.
      • Weaver C.T.
      Reciprocal interactions of the intestinal microbiota and immune system.
      ;
      • Torow N.
      • Yu K.
      • Hassani K.
      • Freitag J.
      • Schulz O.
      • Basic M.
      • Brennecke A.
      • Sparwasser T.
      • Wagner N.
      • Bleich A.
      • et al.
      Active suppression of intestinal CD4(+)TCRαβ(+) T-lymphocyte maturation during the postnatal period.
      ;
      • Koch M.A.
      • Reiner G.L.
      • Lugo K.A.
      • Kreuk L.S.
      • Stanbery A.G.
      • Ansaldo E.
      • Seher T.D.
      • Ludington W.B.
      • Barton G.M.
      Maternal IgG and IgA Antibodies Dampen Mucosal T Helper Cell Responses in Early Life.
      ), enabling the selection and seeding of the gut microbiome.
      Production of neonatal-derived SIgA begins several months after birth and does not reach adult levels until 3 years of infant age (
      • South M.A.
      • Warwick W.J.
      • Wolheim F.A.
      • Good R.A.
      The IgA system. 3. IgA levels in the serum and saliva of pediatric patients--evidence for a local immunological system.
      ;
      • Rognum T.O.
      • Thrane S.
      • Stoltenberg L.
      • Vege A.
      • Brandtzaeg P.
      Development of intestinal mucosal immunity in fetal life and the first postnatal months.
      ). Thus, maternal SIgA from BM is the only source of SIgA during early life, representing an emerging regulator of infant microbial colonization (
      • Harris N.L.
      • Spoerri I.
      • Schopfer J.F.
      • Nembrini C.
      • Merky P.
      • Massacand J.
      • Urban Jr., J.F.
      • Lamarre A.
      • Burki K.
      • Odermatt B.
      • et al.
      Mechanisms of neonatal mucosal antibody protection.
      ;
      • Ho N.T.
      • Li F.
      • Lee-Sarwar K.A.
      • Tun H.M.
      • Brown B.P.
      • Pannaraj P.S.
      • Bender J.M.
      • Azad M.B.
      • Thompson A.L.
      • Weiss S.T.
      • et al.
      Meta-analysis of effects of exclusive breastfeeding on infant gut microbiota across populations.
      ). As mentioned above, breastfed infants have a different microbiome composition compared to formula fed infants (
      • Ho N.T.
      • Li F.
      • Lee-Sarwar K.A.
      • Tun H.M.
      • Brown B.P.
      • Pannaraj P.S.
      • Bender J.M.
      • Azad M.B.
      • Thompson A.L.
      • Weiss S.T.
      • et al.
      Meta-analysis of effects of exclusive breastfeeding on infant gut microbiota across populations.
      ;
      • Stewart C.J.
      • Ajami N.J.
      • O’Brien J.L.
      • Hutchinson D.S.
      • Smith D.P.
      • Wong M.C.
      • Ross M.C.
      • Lloyd R.E.
      • Doddapaneni H.
      • Metcalf G.A.
      • et al.
      Temporal development of the gut microbiome in early childhood from the TEDDY study.
      ). Although these differences in microbial composition could be caused by other components of the BM, studies in mice have confirmed the role for BM SIgA in the development of an infant’s microbiome. For example, wild-type mice pups nursed by pIgR-deficient dams, lacking BM SIgA and SIgM, exhibited decreased epithelial barrier function, marked by an increase in the translocation of pathogenic aerobic bacteria into the mesenteric lymph nodes compared to pups that received SIgA in BM from wild-type dams (
      • Rogier E.W.
      • Frantz A.L.
      • Bruno M.E.
      • Wedlund L.
      • Cohen D.A.
      • Stromberg A.J.
      • Kaetzel C.S.
      Secretory antibodies in breast milk promote long-term intestinal homeostasis by regulating the gut microbiota and host gene expression.
      ). Moreover, mice that did not receive SIgA in BM had significantly altered microbiome communities that persisted through adulthood, with an increase in Proteobacteria in the families Pasteurellaceae and Comamonadaceae (
      • Rogier E.W.
      • Frantz A.L.
      • Bruno M.E.
      • Wedlund L.
      • Cohen D.A.
      • Stromberg A.J.
      • Kaetzel C.S.
      Secretory antibodies in breast milk promote long-term intestinal homeostasis by regulating the gut microbiota and host gene expression.
      ), both of which have also been shown to be elevated in individuals with inflammatory bowel disease (IBD) (
      • Saulnier D.M.
      • Riehle K.
      • Mistretta T.A.
      • Diaz M.A.
      • Mandal D.
      • Raza S.
      • Weidler E.M.
      • Qin X.
      • Coarfa C.
      • Milosavljevic A.
      • et al.
      Gastrointestinal microbiome signatures of pediatric patients with irritable bowel syndrome.
      ;
      • Tannock G.W.
      • Lawley B.
      • Munro K.
      • Lay C.
      • Taylor C.
      • Daynes C.
      • Baladjay L.
      • Mcleod R.
      • Thompson-Fawcett M.
      Comprehensive analysis of the bacterial content of stool from patients with chronic pouchitis, normal pouches, or familial adenomatous polyposis pouches.
      ) These studies demonstrate the importance of SIgA early in infancy in shaping the establishment of a healthy gut microbiome that profoundly influences microbiome quality into adulthood. Still, much work is needed to fully define the role of antibodies in seeding of the microbiome.

      Training tolerance

      Limiting immune response toward the microbiome

      Aside from aiding in the establishment of a healthy gut microbiome (
      • Rogier E.W.
      • Frantz A.L.
      • Bruno M.E.
      • Wedlund L.
      • Cohen D.A.
      • Stromberg A.J.
      • Kaetzel C.S.
      Secretory antibodies in breast milk promote long-term intestinal homeostasis by regulating the gut microbiota and host gene expression.
      ), BM antibodies have been found to play a critical role in preventing the development of an immune response to commensal bacteria in the gut. In humans, formula-fed infants and individuals with IgA-deficiency exhibit increased gut inflammation (
      • Fadlallah J.
      • El Kafsi H.
      • Sterlin D.
      • Juste C.
      • Parizot C.
      • Dorgham K.
      • Autaa G.
      • Gouas D.
      • Almeida M.
      • Lepage P.
      • et al.
      Microbial ecology perturbation in human IgA deficiency.
      ;
      • Ossa J.C.
      • Yáñez D.
      • Valenzuela R.
      • Gallardo P.
      • Lucero Y.
      • Farfán M.J.
      Breast Milk and Its Association With Their Gut Microbiota
      Intestinal inflammation in Chilean infants fed with bovine formula vs. Breast milk and its association with their gut microbiota.
      ). Similarly, in mice, pups fed with BM lacking immunoglobulins experience early expansions of IgA-producing plasma cells in the intestinal mucosa and early appearance of plasma IgA due to increased penetration of commensal bacteria into mesenteric lymph nodes (
      • Kramer D.R.
      • Cebra J.J.
      Early appearance of “natural” mucosal IgA responses and germinal centers in suckling mice developing in the absence of maternal antibodies.
      ;
      • Harris N.L.
      • Spoerri I.
      • Schopfer J.F.
      • Nembrini C.
      • Merky P.
      • Massacand J.
      • Urban Jr., J.F.
      • Lamarre A.
      • Burki K.
      • Odermatt B.
      • et al.
      Mechanisms of neonatal mucosal antibody protection.
      ). Pups fed with BM lacking IgA also showed an increase in the expression of genes that have been associated with IBD and inflammatory diseases that persisted into adulthood (
      • Rogier E.W.
      • Frantz A.L.
      • Bruno M.E.
      • Wedlund L.
      • Cohen D.A.
      • Stromberg A.J.
      • Kaetzel C.S.
      Secretory antibodies in breast milk promote long-term intestinal homeostasis by regulating the gut microbiota and host gene expression.
      ). In addition to this inflammatory profile, a lack of both IgA and IgG in BM, but not IgG or IgA alone, resulted in an increase in the frequency of CD4 T effector cells (Teff) and activated, non-T regulatory CD69+Foxp3 T helper cells in mesenteric lymph nodes and Peyer’s patches (
      • Koch M.A.
      • Reiner G.L.
      • Lugo K.A.
      • Kreuk L.S.
      • Stanbery A.G.
      • Ansaldo E.
      • Seher T.D.
      • Ludington W.B.
      • Barton G.M.
      Maternal IgG and IgA Antibodies Dampen Mucosal T Helper Cell Responses in Early Life.
      ). Furthermore, this expansion of T cells was accompanied by an elevation in germinal center B cells (
      • Koch M.A.
      • Reiner G.L.
      • Lugo K.A.
      • Kreuk L.S.
      • Stanbery A.G.
      • Ansaldo E.
      • Seher T.D.
      • Ludington W.B.
      • Barton G.M.
      Maternal IgG and IgA Antibodies Dampen Mucosal T Helper Cell Responses in Early Life.
      ). Likewise, pups derived from IgA- and FcRn-deficient dams showed increased weight loss and inflammatory cytokine levels compared to pups from wild-type dams (
      • Koch M.A.
      • Reiner G.L.
      • Lugo K.A.
      • Kreuk L.S.
      • Stanbery A.G.
      • Ansaldo E.
      • Seher T.D.
      • Ludington W.B.
      • Barton G.M.
      Maternal IgG and IgA Antibodies Dampen Mucosal T Helper Cell Responses in Early Life.
      ). In a similar study, offspring of both B cell-deficient dams and pIgR-knockout dams showed an expansion of mature CD4+ T cells in the small intestine, pointing to an overactivation of T cells in the absence of maternal antibodies (
      • Torow N.
      • Yu K.
      • Hassani K.
      • Freitag J.
      • Schulz O.
      • Basic M.
      • Brennecke A.
      • Sparwasser T.
      • Wagner N.
      • Bleich A.
      • et al.
      Active suppression of intestinal CD4(+)TCRαβ(+) T-lymphocyte maturation during the postnatal period.
      ). These studies point to a collaborative role between milk-derived IgG and IgA in preventing immune activation against commensal bacteria, however, whether this BM-IgG and IgA also contribute to dampening inflammation in human neonates has yet to be determined.

      Allergies

      Several studies have linked nursing to a decreased risk of developing allergies, eczema, atopic dermatitis, and asthma (
      • Obihara C.C.
      • Marais B.J.
      • Gie R.P.
      • Potter P.
      • Bateman E.D.
      • Lombard C.J.
      • Beyers N.
      • Kimpen J.L.
      The association of prolonged breastfeeding and allergic disease in poor urban children.
      ;
      • Lodge C.
      • Tan D.J.
      • Lau M.X.
      • Dai X.
      • Tham R.
      • Lowe A.J.
      • Bowatte G.
      • Allen K.J.
      • Dharmage S.C.
      Breastfeeding and asthma and allergies: A systematic review and meta-analysis.
      ;
      • Oddy W.H.
      Breastfeeding, Childhood Asthma, and Allergic Disease.
      ). Importantly, BM antibodies have been associated with reduced evolution of allergies. Studies suggest that similar to the role of SIgA in preventing an immune response to commensal microbes, BM antibodies likely trap and prevent the dissemination of allergens beyond the epithelial barrier of the mucosa, thereby limiting an immune response to the allergen (
      • Ahmed T.
      • Fuchs G.J.
      Gastrointestinal allergy to food: a review.
      ;
      • Dzidic M.
      • Abrahamsson T.R.
      • Artacho A.
      • Björkstén B.
      • Collado M.C.
      • Mira A.
      • Jenmalm M.C.
      Aberrant IgA responses to the gut microbiota during infancy precede asthma and allergy development.
      ). One study showed that IgA can prevent the transcytosis of β-lactoglobulin (BLG), a whey protein from cow’s milk, into Caco-2 epithelial cells, and low levels of these antibodies in BM were associated with an increased probability of the evolution of a cow milk allergy in infants (
      • Järvinen K.M.
      • Westfall J.E.
      • Seppo M.S.
      • James A.K.
      • Tsuang A.J.
      • Feustel P.J.
      • Sampson H.A.
      • Berin C.
      Role of maternal elimination diets and human milk IgA in the development of cow’s milk allergy in the infants.
      ). In another study, it was found that infants that were exposed to peanuts during the first year and whose mothers were exposed to peanuts during nursing were the most protected against peanut sensitization (
      • Pitt T.J.
      • Becker A.B.
      • Chan-Yeung M.
      • Chan E.S.
      • Watson W.T.A.
      • Chooniedass R.
      • Azad M.B.
      Reduced risk of peanut sensitization following exposure through breast-feeding and early peanut introduction.
      ). Similarly, an inverse relationship between BM SIgA levels and risk of developing atopic dermatitis and food allergies have been noted in humans (
      • Machtinger S.
      • Moss R.
      Cow’s milk allergy in breast-fed infants: the role of allergen and maternal secretory IgA antibody.
      ;
      • Savilahti E.
      • Tainio V.M.
      • Salmenperä L.
      • Arjomaa P.
      • Kallio M.
      • Perheentupa J.
      • Siimes M.A.
      Low colostral IgA associated with cow’s milk allergy.
      ;
      • Orivuori L.
      • Loss G.
      • Roduit C.
      • Dalphin J.C.
      • Depner M.
      • Genuneit J.
      • Lauener R.
      • Pekkanen J.
      • Pfefferle P.
      • Riedler J.
      • et al.
      PASTURE Study Group
      Soluble immunoglobulin A in breast milk is inversely associated with atopic dermatitis at early age: the PASTURE cohort study.
      ). Epidemiologic studies have demonstrated lower concentrations of SIgA to the specific allergen present in the BM of allergic mothers (
      • Casas R.
      • Böttcher M.F.
      • Duchén K.
      • Björkstén B.
      Detection of IgA antibodies to cat, β-lactoglobulin, and ovalbumin allergens in human milk.
      ). These results have led to the hypothetical model that in the absence of allergen-specific antibodies, infants may be exposed to higher levels of “free” allergen, resulting in allergy. Conversely, in the presence of antibodies, allergens are complexed, providing additional signals required to attenuate immunity against these common-foreign antigens. This model postulates that allergen-specific breast milk antibodies survey the mucosa, forming immune-complexes able to act as “safe-signal” delivery vehicles for the mucosa, potentially tempering life-long immunity.
      Similarly, higher levels of allergen-specific IgG in breast milk are also associated with a lower risk of allergy in nursed infants (
      • Järvinen K.M.
      • Westfall J.E.
      • Seppo M.S.
      • James A.K.
      • Tsuang A.J.
      • Feustel P.J.
      • Sampson H.A.
      • Berin C.
      Role of maternal elimination diets and human milk IgA in the development of cow’s milk allergy in the infants.
      ;
      • Lupinek C.
      • Hochwallner H.
      • Johansson C.
      • Mie A.
      • Rigler E.
      • Scheynius A.
      • Alm J.
      • Valenta R.
      Maternal allergen-specific IgG might protect the child against allergic sensitization.
      ). In contrast to IgA, that has been suggested to reduce delivery of antigens, it has been proposed that IgG promotes tolerization by forming IgG-allergen complexes that promote the uptake of allergen through epithelial cells and aid in immune presentation of the allergen (
      • Mosconi E.
      • Rekima A.
      • Seitz-Polski B.
      • Kanda A.
      • Fleury S.
      • Tissandie E.
      • Monteiro R.
      • Dombrowicz D.D.
      • Julia V.
      • Glaichenhaus N.
      • Verhasselt V.
      Breast milk immune complexes are potent inducers of oral tolerance in neonates and prevent asthma development.
      ). A study in mice found direct evidence that IgG delivered through the BM can prevent induction of an immune response against an allergen. Specifically, ovalbumin (OVA)-specific IgG1, when delivered from lactating female mice to their offspring or directly delivered orally to the offspring, prevented allergic airway inflammation when offspring were challenged with OVA (
      • Nakata K.
      • Kobayashi K.
      • Ishikawa Y.
      • Yamamoto M.
      • Funada Y.
      • Kotani Y.
      • Blumberg R.S.
      • Karasuyama H.
      • Yoshida M.
      • Nishimura Y.
      The transfer of maternal antigen-specific IgG regulates the development of allergic airway inflammation early in life in an FcRn-dependent manner.
      ). This study directly showed that anti-allergen BM-delivered antibodies prevent the development of an allergic response. In a similar study, it was found that IgG-OVA complexes in breast milk also induced the development of FoxP3+ regulatory T cells, potentially aiding in the tolerization toward OVA (
      • Mosconi E.
      • Rekima A.
      • Seitz-Polski B.
      • Kanda A.
      • Fleury S.
      • Tissandie E.
      • Monteiro R.
      • Dombrowicz D.D.
      • Julia V.
      • Glaichenhaus N.
      • Verhasselt V.
      Breast milk immune complexes are potent inducers of oral tolerance in neonates and prevent asthma development.
      ).
      Further studies in humans need to be conducted to confirm the tolerogenic role of breast milk IgA and IgG against allergen in early life. Whether BM IgG versus SIgA temper act synergistically or independently in tolerization remains unclear (
      • Fälth-Magnusson K.
      Breast milk antibodies to foods in relation to maternal diet, maternal atopy and the development of atopic disease in the baby.
      ;
      • Ismail I.H.
      • Licciardi P.V.
      • Oppedisano F.
      • Boyle R.J.
      • Tang M.L.
      Relationship between breast milk sCD14, TGF-β1 and total IgA in the first month and development of eczema during infancy.
      ), however, defining the specific mechanism(s) by which BM-derived antibodies shape response to allergens may reveal opportunities to temper allergies and autoimmunity and engineer immunity in early life.

      BM antibodies provide protection against early diseases

      Enteric diseases

      In developing countries, infants are highly susceptible to frequent diarrheal diseases, resulting in 700,000 deaths annually in children under 5 (
      • Lanata C.F.
      • Fischer-Walker C.L.
      • Olascoaga A.C.
      • Torres C.X.
      • Aryee M.J.
      • Black R.E.
      Child Health Epidemiology Reference Group of the World Health Organization and UNICEF
      Global causes of diarrheal disease mortality in children <5 years of age: a systematic review.
      ). In particular, enterotoxigenic Escherichia coli (ETEC), rotavirus, Shigella, and Vibrio cholerae account for high mortality rates among infants in these countries, underscoring the need to develop tools to protect this at-risk population (
      • Lanata C.F.
      • Fischer-Walker C.L.
      • Olascoaga A.C.
      • Torres C.X.
      • Aryee M.J.
      • Black R.E.
      Child Health Epidemiology Reference Group of the World Health Organization and UNICEF
      Global causes of diarrheal disease mortality in children <5 years of age: a systematic review.
      ). Many studies have clearly shown that exclusive nursing during the first months of life is associated with lower incidence of gastrointestinal illness for up to the first year of life (
      • Lamberti L.M.
      • Fischer Walker C.L.
      • Noiman A.
      • Victora C.
      • Black R.E.
      Breastfeeding and the risk for diarrhea morbidity and mortality.
      ), with an up to 10-fold decrease in the risk of infant death from diarrheal diseases with nursing (
      • Ozsoyla S.
      Warm chain for breastfeeding.
      ). Importantly, high titers of SIgA in the gut against enteric infections, including rotavirus, poliovirus, etc. (
      • Cheuvart B.
      • Neuzil K.M.
      • Steele A.D.
      • Cunliffe N.
      • Madhi S.A.
      • Karkada N.
      • Han H.H.
      • Vinals C.
      Association of serum anti-rotavirus immunoglobulin A antibody seropositivity and protection against severe rotavirus gastroenteritis: analysis of clinical trials of human rotavirus vaccine.
      ;
      • Wright P.F.
      • Wieland-Alter W.
      • Ilyushina N.A.
      • Hoen A.G.
      • Arita M.
      • Boesch A.W.
      • Ackerman M.E.
      • van der Avoort H.
      • Oberste M.S.
      • Pallansch M.A.
      • et al.
      Intestinal immunity is a determinant of clearance of poliovirus after oral vaccination.
      ) are correlated with protection following both vaccination and natural infection. BM is rich in antibodies that target enteric pathogens (
      • Brandtzaeg P.
      Mucosal immunity: Integration between mother and the breast-fed infant.
      ), and antibodies against enteric pathogens can be detected in the stool of breastfed infants but not formula-fed infants (
      • Maruyama K.
      • Hida M.
      • Kohgo T.
      • Fukunaga Y.
      Changes in salivary and fecal secretory IgA in infants under different feeding regimens.
      ;
      • Bridgman S.L.
      • Konya T.
      • Azad M.B.
      • Sears M.R.
      • Becker A.B.
      • Turvey S.E.
      • Mandhane P.J.
      • Subbarao P.
      • Scott J.A.
      • Field C.J.
      • Kozyrskyj A.L.
      CHILD Study Investigators
      Infant gut immunity: a preliminary study of IgA associations with breastfeeding.
      ). For example, IgA titers are tightly linked to rotavirus vaccine efficacy, pointing to IgA-mediated immune mechanisms in protection (
      • Patel M.
      • Glass R.I.
      • Jiang B.
      • Santosham M.
      • Lopman B.
      • Parashar U.
      A systematic review of anti-rotavirus serum IgA antibody titer as a potential correlate of rotavirus vaccine efficacy.
      ). Likewise, pathogen-specific SIgA titers in BM are also linked to natural protection against Shigella and cholera (
      • Glass R.I.
      • Svennerholm A.M.
      • Stoll B.J.
      • Khan M.R.
      • Hossain K.M.
      • Huq M.I.
      • Holmgren J.
      Protection against cholera in breast-fed children by antibodies in breast milk.
      ;
      • Durand D.
      • Ochoa T.J.
      • Bellomo S.M.
      • Contreras C.A.
      • Bustamante V.H.
      • Ruiz J.
      • Cleary T.G.
      Detection of secretory immunoglobulin A in human colostrum as mucosal immune response against proteins of the type III secretion system of Salmonella, Shigella and enteropathogenic Escherichia coli.
      ). Yet, whether these IgA responses provide strict protection via neutralization, or through additional IgA mediated immune mechanisms, remains poorly defined.
      Necrotizing enterocolitis (NEC) is a devastating common disease that affects preterm infants, resulting in high morbidity and mortality in this vulnerable population (
      • Lin P.W.
      • Stoll B.J.
      Necrotising enterocolitis.
      ). NEC is marked by dysbiosis in the gut microbiome, with increases in Proteobacteria, including Enterobacteriaceae, and decreased levels of Firmicutes and Bacteroidetes (
      • Brower-Sinning R.
      • Zhong D.
      • Good M.
      • Firek B.
      • Baker R.
      • Sodhi C.P.
      • Hackam D.J.
      • Morowitz M.J.
      Mucosa-associated bacterial diversity in necrotizing enterocolitis.
      ;
      • Pammi M.
      • Cope J.
      • Tarr P.I.
      • Warner B.B.
      • Morrow A.L.
      • Mai V.
      • Gregory K.E.
      • Kroll J.S.
      • McMurtry V.
      • Ferris M.J.
      • et al.
      Intestinal dysbiosis in preterm infants preceding necrotizing enterocolitis: a systematic review and meta-analysis.
      ). Several studies have found that BM reduces the risk of developing NEC, particularly among preterm infants (
      • Quigley M.
      • Embleton N.D.
      • McGuire W.
      Formula versus donor breast milk for feeding preterm or low birth weight infants.
      ). One prospective study of 926 infants demonstrated that formula-fed preterm infants were 6–10 times more likely to develop NEC compared to preterm infants that are fed BM (
      • Lucas A.
      • Cole T.J.
      Breast milk and neonatal necrotising enterocolitis.
      ). Notably, a recent study analyzed fecal bacteria from preterm infants and found that the development of NEC was associated with a decrease in IgA-bound bacteria. Unbound bacteria were predominantly Enterobacteriaceae, which dominated the microbiome (
      • Gopalakrishna K.P.
      • Macadangdang B.R.
      • Rogers M.B.
      • Tometich J.T.
      • Firek B.A.
      • Baker R.
      • Ji J.
      • Burr A.H.P.
      • Ma C.
      • Good M.
      • et al.
      Maternal IgA protects against the development of necrotizing enterocolitis in preterm infants.
      ). In the same study, the authors also showed that mice pups reared by IgA-deficient dams were more susceptible and exhibited increased mortality and intestinal damage upon exposure to Enterobacter spp., pointing to the critical role of SIgA from the BM in providing protection against NEC-like disease in mice (
      • Gopalakrishna K.P.
      • Macadangdang B.R.
      • Rogers M.B.
      • Tometich J.T.
      • Firek B.A.
      • Baker R.
      • Ji J.
      • Burr A.H.P.
      • Ma C.
      • Good M.
      • et al.
      Maternal IgA protects against the development of necrotizing enterocolitis in preterm infants.
      ). Therefore, IgA-coating plays a key role in regulating penetration, inflammation, and intestinal damage in early life.
      Several studies have shown that BM-derived antibodies can supply passive immunity and protection against enteric infection in mice (
      • Shope S.R.
      • Schiemann D.A.
      Passive secretory immunity against Salmonella typhimurium demonstrated with foster mouse pups.
      ;
      • Lasaro M.O.
      • Luiz W.B.
      • Sbrogio-Almeida M.E.
      • Ferreira L.C.
      Prime-boost vaccine regimen confers protective immunity to human-derived enterotoxigenic Escherichia coli.
      ). However, the mechanism by which these antibodies provide protection is just beginning to be elucidated. One mechanistic study showed that maternal infection or immunization with the enteric pathogen Citrobacter rodentium, which is a model for Enteropathogenic Escherichia coli (EPEC), resulted in lower pathogen loads in the feces, liver, and spleen and decreased intestinal damage in breastfed pups (
      • Caballero-Flores G.
      • Sakamoto K.
      • Zeng M.Y.
      • Wang Y.
      • Hakim J.
      • Matus-Acuña V.
      • Inohara N.
      • Núñez G.
      Maternal Immunization Confers Protection to the Offspring against an Attaching and Effacing Pathogen through Delivery of IgG in Breast Milk.
      ). Interestingly, this protection was found to be mediated by maternal IgG in BM, not IgA, which coat the pathogen and activate neutrophil phagocytosis, ultimately reducing pathogen colonization in the gut of the mice pups (
      • Caballero-Flores G.
      • Sakamoto K.
      • Zeng M.Y.
      • Wang Y.
      • Hakim J.
      • Matus-Acuña V.
      • Inohara N.
      • Núñez G.
      Maternal Immunization Confers Protection to the Offspring against an Attaching and Effacing Pathogen through Delivery of IgG in Breast Milk.
      ). By cross-fostering pups born from naive mothers to dams that were immunized, the authors confirmed that this protection was conferred by IgG delivered through BM. Moreover, using mutant mice lacking IgA, FcRn, or pIgR, the study verified that protection was mediated through IgG, as pups of FcRn-deficient dams were most vulnerable to C. rodentium challenge. Pups of immunized dams but reared by non-immunized dams showed increased intestinal pathogen IgG-coating, increased intracellular bacterial load in peritoneal neutrophils, and decreased bacteria loads, supporting the role of BM-IgG in aiding in the immunity against C. rodentium infection in neonatal pups.
      Similarly, in another study, infection of dams with the enteric pathogen enterotoxigenic Escherichia coli (ETEC) resulted in protection of pups by maternally transferred IgG (
      • Zheng W.
      • Zhao W.
      • Wu M.
      • Song X.
      • Caro F.
      • Sun X.
      • Gazzaniga F.
      • Stefanetti G.
      • Oh S.
      • Mekalanos J.J.
      • Kasper D.L.
      Microbiota-targeted maternal antibodies protect neonates from enteric infection.
      ). By challenging pups fostered by antibody-deficient or antibody-sufficient dams, the authors showed that this protective maternal antibody transfer occurred through BM. To understand whether antibodies against commensal bacteria could also provide protection to ETEC, germ-free mice were immunized with formalin-dead Pantoea, a commensal species closely related to ETEC. Interestingly, pups fostered by Pantoea-immunized dams were also protected against ETEC challenge by Pantoea-specific maternal IgG transferred through BM, highlighting the cross-reactive nature of mucosal antibodies. This data supports the hypothesis that maternal antibodies transferred through BM can protect against pathogenic gut microorganisms and suggests that this protection may even exist in the absence of maternal infection, via the generation of cross-reactive antibodies. These papers therefore directly demonstrate that maternally derived antibodies in BM provide an essential barrier against pathogens that infants may encounter in early life. Interestingly, unlike antibodies positioned to promote colonization, which is largely directed by IgA (
      • Ohashi Y.
      • Hiraguchi M.
      • Sunaba C.
      • Tanaka C.
      • Fujisawa T.
      • Ushida K.
      Colonization of segmented filamentous bacteria and its interaction with the luminal IgA level in conventional mice.
      ;
      • Mirpuri J.
      • Raetz M.
      • Sturge C.R.
      • Wilhelm C.L.
      • Benson A.
      • Savani R.C.
      • Hooper L.V.
      • Yarovinsky F.
      Proteobacteria-specific IgA regulates maturation of the intestinal microbiota.
      ), pathogenic bacteria are controlled via IgG. Whether IgG/IgA redundancies can be programmed into the system, via vaccination, remains unclear, however, studies of NEC provide compelling arguments for broadly programmable roles of multiple antibody isotypes in the control of human neonatal infection.

      HIV

      In the absence of therapeutic interventions, ∼30% of infants born to HIV-positive mothers acquire HIV (
      • Coovadia H.
      Antiretroviral agents--how best to protect infants from HIV and save their mothers from AIDS.
      ;
      • Milligan C.
      • Slyker J.A.
      • Overbaugh J.
      The Role of Immune Responses in HIV Mother-to-Child Transmission.
      ). However, these rates have been drastically reduced with anti-retroviral therapy (ART), with less than 5% vertical transmission occurring in pregnant women receiving antiretroviral treatment followed by a short course of antiretroviral drugs for the baby (
      • Coovadia H.
      Antiretroviral agents--how best to protect infants from HIV and save their mothers from AIDS.
      ;
      • Shapiro R.L.
      • Hughes M.D.
      • Ogwu A.
      • Kitch D.
      • Lockman S.
      • Moffat C.
      • Makhema J.
      • Moyo S.
      • Thior I.
      • McIntosh K.
      • et al.
      Antiretroviral regimens in pregnancy and breast-feeding in Botswana.
      ). In addition to a potential risk in utero and during delivery (
      • Ehrnst A.
      • Lindgren S.
      • Dictor M.
      • Johansson B.
      • Sönnerborg A.
      • Czajkowski J.
      • Sundin G.
      • Bohlin A.B.
      HIV in pregnant women and their offspring: evidence for late transmission.
      ;
      • Rouzioux C.
      • Costagliola D.
      • Burgard M.
      • Blanche S.
      • Mayaux M.J.
      • Griscelli C.
      • Valleron A.J.
      The HIV Infection in Newborns French Collaborative Study Group
      Estimated timing of mother-to-child human immunodeficiency virus type 1 (HIV-1) transmission by use of a Markov model.
      ), BM is a vehicle for transmission of HIV to a neonate (
      • Richardson B.A.
      • John-Stewart G.C.
      • Hughes J.P.
      • Nduati R.
      • Mbori-Ngacha D.
      • Overbaugh J.
      • Kreiss J.K.
      Breast-milk infectivity in human immunodeficiency virus type 1-infected mothers.
      ;
      • Van de Perre P.
      • Rubbo P.A.
      • Viljoen J.
      • Nagot N.
      • Tylleskär T.
      • Lepage P.
      • Vendrell J.P.
      • Tuaillon E.
      HIV-1 reservoirs in breast milk and challenges to elimination of breast-feeding transmission of HIV-1.
      ). However, despite the risk of transmission of HIV through nursing, the benefits of BM, including prevention of diarrheal diseases, outweigh the risk of vertical transmission of HIV through BM in many low-income countries (
      • Kuhn L.
      • Aldrovandi G.M.
      • Sinkala M.
      • Kankasa C.
      • Semrau K.
      • Mwiya M.
      • Kasonde P.
      • Scott N.
      • Vwalika C.
      • Walter J.
      • et al.
      Zambia Exclusive Breastfeeding Study
      Effects of early, abrupt weaning on HIV-free survival of children in Zambia.
      ;
      • Kafulafula G.
      • Hoover D.R.
      • Taha T.E.
      • Thigpen M.
      • Li Q.
      • Fowler M.G.
      • Kumwenda N.I.
      • Nkanaunena K.
      • Mipando L.
      • Mofenson L.M.
      Frequency of gastroenteritis and gastroenteritis-associated mortality with early weaning in HIV-1-uninfected children born to HIV-infected women in Malawi.
      ). Several factors have been associated with mother-to-child transmission (MTCT) of HIV through BM in the absence of ART, including high milk levels of viral RNA, the transfer of infected cells via BM, as well as mastitis resulting in blood product transfer to the infant (
      • Fawzi W.
      • Msamanga G.
      • Spiegelman D.
      • Renjifo B.
      • Bang H.
      • Kapiga S.
      • Coley J.
      • Hertzmark E.
      • Essex M.
      • Hunter D.
      Transmission of HIV-1 through breastfeeding among women in Dar es Salaam, Tanzania.
      ;
      • Richardson B.A.
      • John-Stewart G.C.
      • Hughes J.P.
      • Nduati R.
      • Mbori-Ngacha D.
      • Overbaugh J.
      • Kreiss J.K.
      Breast-milk infectivity in human immunodeficiency virus type 1-infected mothers.
      ). The presence of anti-HIV antibodies, however, has been correlated with a decreased risk of MTCT. Interestingly, most studies have found an association between a decrease in MTCT and anti-HIV IgG antibody titers (
      • Becquart P.
      • Hocini H.
      • Lévy M.
      • Sépou A.
      • Kazatchkine M.D.
      • Bélec L.
      Secretory anti-human immunodeficiency virus (HIV) antibodies in colostrum and breast milk are not a major determinant of the protection of early postnatal transmission of HIV.
      ;
      • Kuhn L.
      • Trabattoni D.
      • Kankasa C.
      • Sinkala M.
      • Lissoni F.
      • Ghosh M.
      • Aldrovandi G.
      • Thea D.
      • Clerici M.
      Hiv-specific secretory IgA in breast milk of HIV-positive mothers is not associated with protection against HIV transmission among breast-fed infants.
      ), although some studies have also noted a role for anti-HIV IgA in preventing MTCT through BM (
      • Pollara J.
      • McGuire E.
      • Fouda G.G.
      • Rountree W.
      • Eudailey J.
      • Overman R.G.
      • Seaton K.E.
      • Deal A.
      • Edwards R.W.
      • Tegha G.
      • et al.
      Association of HIV-1 Envelope-Specific Breast Milk IgA Responses with Reduced Risk of Postnatal Mother-to-Child Transmission of HIV-1.
      ). These antibodies have been found to decrease HIV transmission through multiple mechanisms, including neutralization (
      • Wu X.
      • Parast A.B.
      • Richardson B.A.
      • Nduati R.
      • John-Stewart G.
      • Mbori-Ngacha D.
      • Rainwater S.M.
      • Overbaugh J.
      Neutralization escape variants of human immunodeficiency virus type 1 are transmitted from mother to infant.
      ;
      • Fouda G.G.
      • Yates N.L.
      • Pollara J.
      • Shen X.
      • Overman G.R.
      • Mahlokozera T.
      • Wilks A.B.
      • Kang H.H.
      • Salazar-Gonzalez J.F.
      • Salazar M.G.
      • et al.
      Center for HIV/AIDS Vaccine Immunology
      HIV-specific functional antibody responses in breast milk mirror those in plasma and are primarily mediated by IgG antibodies.
      ), the induction of antibody-dependent cellular cytotoxicity (ADCC) (
      • Fouda G.G.
      • Yates N.L.
      • Pollara J.
      • Shen X.
      • Overman G.R.
      • Mahlokozera T.
      • Wilks A.B.
      • Kang H.H.
      • Salazar-Gonzalez J.F.
      • Salazar M.G.
      • et al.
      Center for HIV/AIDS Vaccine Immunology
      HIV-specific functional antibody responses in breast milk mirror those in plasma and are primarily mediated by IgG antibodies.
      ;
      • Mabuka J.
      • Nduati R.
      • Odem-Davis K.
      • Peterson D.
      • Overbaugh J.
      HIV-specific antibodies capable of ADCC are common in breastmilk and are associated with reduced risk of transmission in women with high viral loads.
      ;
      • Himes J.E.
      • Goswami R.
      • Mangan R.J.
      • Kumar A.
      • Jeffries Jr., T.L.
      • Eudailey J.A.
      • Heimsath H.
      • Nguyen Q.N.
      • Pollara J.
      • LaBranche C.
      • et al.
      Polyclonal HIV envelope-specific breast milk antibodies limit founder SHIV acquisition and cell-associated virus loads in infant rhesus monkeys.
      ), or by preventing penetration of the virus via the tight human epithelial barrier of gut (
      • Hocini H.
      • Bomsel M.
      Infectious human immunodeficiency virus can rapidly penetrate a tight human epithelial barrier by transcytosis in a process impaired by mucosal immunoglobulins.
      ). Thus, given the fact that HIV is transmitted in BM, IgG in BM may be able to play a significant role in preventing neonatal HIV infection by inactivating the virus in BM through neutralization or ADCC prior to the virus reaching mucosal surfaces in the infant. However, the different mechanisms, as well as opportunities to induce both IgG and IgA in BM against HIV, require further investigation.

      Respiratory infections

      Lower respiratory infections are the number one cause of death during the first year of life (
      • Lozano R.
      • Naghavi M.
      • Foreman K.
      • Lim S.
      • Shibuya K.
      • Aboyans V.
      • Abraham J.
      • Adair T.
      • Aggarwal R.
      • Ahn S.Y.
      • et al.
      Global and regional mortality from 235 causes of death for 20 age groups in 1990 and 2010: a systematic analysis for the Global Burden of Disease Study 2010.
      ), resulting in nearly 1 million deaths per year in children under 5 (
      • Liu L.
      • Oza S.
      • Hogan D.
      • Chu Y.
      • Perin J.
      • Zhu J.
      • Lawn J.E.
      • Cousens S.
      • Mathers C.
      • Black R.E.
      Global, regional, and national causes of under-5 mortality in 2000-15: an updated systematic analysis with implications for the Sustainable Development Goals.
      ). These deaths are caused primarily by respiratory syncytial virus (RSV), Haemophilus influenzae type B (Hib), Streptococcus pneumoniae, and influenza. BM has been clearly and repeatedly associated with a decreased risk of both upper and lower respiratory tract infections in neonates (
      • Henkle E.
      • Steinhoff M.C.
      • Omer S.B.
      • Roy E.
      • Arifeen S.E.
      • Raqib R.
      • Breiman R.F.
      • Caulfield L.E.
      • Moss W.J.
      • Zaman K.
      The effect of exclusive breast-feeding on respiratory illness in young infants in a maternal immunization trial in Bangladesh.
      ;
      • Nunes M.C.
      • Cutland C.L.
      • Jones S.
      • Downs S.
      • Weinberg A.
      • Ortiz J.R.
      • Neuzil K.M.
      • Simões E.A.F.
      • Klugman K.P.
      • Madhi S.A.
      Efficacy of Maternal Influenza Vaccination Against All-Cause Lower Respiratory Tract Infection Hospitalizations in Young Infants: Results From a Randomized Controlled Trial.
      ;
      • Oddy W.H.
      Breastfeeding, Childhood Asthma, and Allergic Disease.
      ;
      • Tromp I.
      • Kiefte-de Jong J.
      • Raat H.
      • Jaddoe V.
      • Franco O.
      • Hofman A.
      • de Jongste J.
      • Moll H.
      Breastfeeding and the risk of respiratory tract infections after infancy: The Generation R Study.
      ). Specifically, nursing has been associated with a lower risk of respiratory syncytial virus (RSV) and influenza infection, (
      • Downham M.A.P.S.
      • Scott R.
      • Sims D.G.
      • Webb J.K.
      • Gardner P.S.
      Breast-feeding protects against respiratory syncytial virus infections.
      ;
      • Bulkow L.R.
      • Singleton R.J.
      • Karron R.A.
      • Harrison L.H.
      Alaska RSV Study Group
      Risk factors for severe respiratory syncytial virus infection among Alaska native children.
      ), suggesting that oral supplementation of antibodies, beyond those transferred placentally at birth, may provide protection in early life. Although the transfer of pathogen-specific antibodies appears to be key to BM-mediated protective immunity, it is also plausible that like the gut, antibody-mediated regulation of the commensalization of the respiratory tract could contribute to protective immunity against these pathogens (
      • Unger S.A.
      • Bogaert D.
      The respiratory microbiome and respiratory infections.
      ).

      Influenza

      Infants are at particular risk for influenza infection and the development of severe disease (
      • Neuzil K.M.
      • Mellen B.G.
      • Wright P.F.
      • Mitchel Jr., E.F.
      • Griffin M.R.
      The effect of influenza on hospitalizations, outpatient visits, and courses of antibiotics in children.
      ;
      • Nair H.
      • Brooks W.A.
      • Katz M.
      • Roca A.
      • Berkley J.A.
      • Madhi S.A.
      • Simmerman J.M.
      • Gordon A.
      • Sato M.
      • Howie S.
      • et al.
      Global burden of respiratory infections due to seasonal influenza in young children: a systematic review and meta-analysis.
      ). The critical role of maternally transferred influenza-specific antibodies has been clearly noted across many cohorts (
      • Zaman K.
      • Roy E.
      • Arifeen S.E.
      • Rahman M.
      • Raqib R.
      • Wilson E.
      • Omer S.B.
      • Shahid N.S.
      • Breiman R.F.
      • Steinhoff M.C.
      Effectiveness of maternal influenza immunization in mothers and infants.
      ;
      • Eick A.A.
      • Uyeki T.M.
      • Klimov A.
      • Hall H.
      • Reid R.
      • Santosham M.
      • O’Brien K.L.
      Maternal influenza vaccination and effect on influenza virus infection in young infants.
      ;
      • Tapia M.D.
      • Sow S.O.
      • Tamboura B.
      • Tégueté I.
      • Pasetti M.F.
      • Kodio M.
      • Onwuchekwa U.
      • Tennant S.M.
      • Blackwelder W.C.
      • Coulibaly F.
      • et al.
      Maternal immunisation with trivalent inactivated influenza vaccine for prevention of influenza in infants in Mali: a prospective, active-controlled, observer-blind, randomised phase 4 trial.
      ), however, whether the protection is mediated by placentally transferred IgG or by IgA and IgG transferred in BM has been more difficult to dissect in human cohorts. Cross-fostering experiments in ferrets and mice have outlined the importance of BM in protection against influenza (
      • Husseini R.H.
      • Sweet C.
      • Overton H.
      • Smith H.
      Role of maternal immunity in the protection of newborn ferrets against infection with a virulent influenza virus.
      ;
      • Sweet C.
      • Bird R.A.
      • Jakeman K.
      • Coates D.M.
      • Smith H.
      Production of passive immunity in neonatal ferrets following maternal vaccination with killed influenza A virus vaccines.
      ). Specifically, in one study, ferret pups born to immune mothers but breastfed by non-immune mothers were protected on influenza challenge, however, they exhibited detectable virus in the nasal turbinates (
      • Husseini R.H.
      • Sweet C.
      • Overton H.
      • Smith H.
      Role of maternal immunity in the protection of newborn ferrets against infection with a virulent influenza virus.
      ). In contrast, pups born to non-immune mothers but breastfed by immune mothers were both protected and did not have detectable virus in the nasal turbinates after challenge (
      • Husseini R.H.
      • Sweet C.
      • Overton H.
      • Smith H.
      Role of maternal immunity in the protection of newborn ferrets against infection with a virulent influenza virus.
      ). Thus, BM-derived antibodies appear to confer protection in the highly susceptible ferret model of influenza.
      Along these lines, emerging data in humans illustrates that both total influenza-specific IgA and neutralizing IgA antibodies are effectively transferred in BM for at least 6 months postpartum following maternal vaccination (
      • Schlaudecker E.P.
      • Steinhoff M.C.
      • Omer S.B.
      • McNeal M.M.
      • Roy E.
      • Arifeen S.E.
      • Dodd C.N.
      • Raqib R.
      • Breiman R.F.
      • Zaman K.
      IgA and neutralizing antibodies to influenza a virus in human milk: a randomized trial of antenatal influenza immunization.
      ). This same study found that infants of mothers who had received the influenza vaccine antepartum and were exclusively breastfed were less likely to develop respiratory disease than infants whose mothers did not receive an influenza vaccine (
      • Schlaudecker E.P.
      • Steinhoff M.C.
      • Omer S.B.
      • McNeal M.M.
      • Roy E.
      • Arifeen S.E.
      • Dodd C.N.
      • Raqib R.
      • Breiman R.F.
      • Zaman K.
      IgA and neutralizing antibodies to influenza a virus in human milk: a randomized trial of antenatal influenza immunization.
      ). These data clearly suggest that augmented anti-influenza IgA levels after birth, delivered via BM, play an essential role in increasing resistance to infection during this vulnerable window of early life. Less is understood about the role of IgG in BM-mediated protection against influenza, despite the transfer of copious influenza-specific IgG in BM (
      • Renegar K.B.
      • Small Jr., P.A.
      • Boykins L.G.
      • Wright P.F.
      Role of IgA versus IgG in the control of influenza viral infection in the murine respiratory tract.
      ;
      • Järvinen K.M.
      • Wang J.
      • Seppo A.E.
      • Zand M.
      Novel multiplex assay for profiling influenza antibodies in breast milk and serum of mother-infant pairs.
      ). Thus, further studies aimed at exploring the coordinated role across-isotypes are likely to provide enhanced resolution on the landscape of protective mechanisms explored in early life to restrict respiratory infection.

      Respiratory syncytial virus (RSV)

      As mentioned above, breastfed infants have a lower risk of severe disease on RSV infection and experience lower hospitalization rates following RSV infection when compared to non-breastfed infants (
      • Downham M.A.P.S.
      • Scott R.
      • Sims D.G.
      • Webb J.K.
      • Gardner P.S.
      Breast-feeding protects against respiratory syncytial virus infections.
      ;
      • Bulkow L.R.
      • Singleton R.J.
      • Karron R.A.
      • Harrison L.H.
      Alaska RSV Study Group
      Risk factors for severe respiratory syncytial virus infection among Alaska native children.
      ;
      • Shi T.
      • Balsells E.
      • Wastnedge E.
      • Singleton R.
      • Rasmussen Z.A.
      • Zar H.J.
      • Rath B.A.
      • Madhi S.A.
      • Campbell S.
      • Vaccari L.C.
      • et al.
      Risk factors for respiratory syncytial virus associated with acute lower respiratory infection in children under five years: Systematic review and meta-analysis.
      ). Importantly, in contrast to the anticipated role of mucosal IgA in respiratory viral control, a recent study found that levels of IgG against the prefusion RSV fusion protein (preF) in BM was correlated with a decreased risk of RSV-induced acute respiratory infection (ARI) in breastfed infants (
      • Mazur N.I.
      • Horsley N.M.
      • Englund J.A.
      • Nederend M.
      • Magaret A.
      • Kumar A.
      • Jacobino S.R.
      • de Haan C.A.M.
      • Khatry S.K.
      • LeClerq S.C.
      • et al.
      Breast milk prefusion F immunoglobulin g as a correlate of protection against respiratory syncytial virus acute respiratory illness.
      ). Despite the robust transfer of RSV-specific IgA, these data point again to the importance of IgG, rather than IgA, in natural protection against RSV infection in neonates. Given that preterm infants are at the highest risk for severe RSV, and they are able to absorb IgG from BM into the serum (
      • Weaver L.T.
      • Laker M.F.
      • Nelson R.
      Intestinal permeability in the newborn.
      ;
      • Brandtzaeg P.
      Mucosal immunity: Integration between mother and the breast-fed infant.
      ;
      • Demers-Mathieu V.
      • Underwood M.A.
      • Beverly R.L.
      • Nielsen S.D.
      • Dallas D.C.
      Comparison of human milk immunoglobulin survival during gastric digestion between preterm and term infants.
      ), this result points to the possibility that vaccines able to enhance the induction of anti-preF IgG, such as through maternal immunization, could be a potential way to improve outcomes in infants, particularly among preterm infants. Whether enhanced placentally transferred IgG could compensate and drive protection, or whether protective antibodies must be administered via BM remains unclear but points to novel opportunities to enhance immunity in infants.

      SARS-CoV-2

      Among the pediatric population, infants 0–2 months of age are among the most susceptible to severe Coronavirus Disease 2019 (COVID-19) and hospitalization on infection with SARS-CoV-2 (
      • Dong Y.
      • Mo X.
      • Hu Y.
      • Qi X.
      • Jiang F.
      • Jiang Z.
      • Tong S.
      Epidemiology of COVID-19 among children in China.
      ;
      • Liguoro I.
      • Pilotto C.
      • Bonanni M.
      • Ferrari M.E.
      • Pusiol A.
      • Nocerino A.
      • Vidal E.
      • Cogo P.
      SARS-COV-2 infection in children and newborns: a systematic review.
      ). Yet, newborns and pregnant women are excluded from vaccine trials and will likely be among the last to be vaccinated on vaccine licensure (
      • Whitehead C.L.
      • Walker S.P.
      Consider pregnancy in COVID-19 therapeutic drug and vaccine trials.
      ). Emerging data point to inefficient FcRn-mediated transfer of SARS-CoV-2-specific antibodies through the placenta when the mothers are infected during the third trimester, but efficient transfer of antibodies if mothers are infected earlier in gestation (
      • Atyeo C.
      • Pullen K.M.
      • Bordt E.A.
      • Fischinger S.
      • Burke J.
      • Michell A.
      • Slein M.D.
      • Loos C.
      • Shook L.L.
      • Boatin A.A.
      • et al.
      Compromised SARS-CoV-2-specific placental antibody transfer.
      ). These data suggest that time is required to accrue sufficient antibodies for robust antibody transfer to the neonate. However, whether similar defects in antibody transfer will be observed in the BM remains unclear. IgA antibodies have been observed in the BM of previously SARS-CoV-2 infected mothers (
      • Fox A.
      • Marino J.
      • Amanat F.
      • Krammer F.
      • Hahn-Holbrook J.
      • Zolla-Pazner S.
      • Powell R.L.
      Robust and specific secretory IgA against SARS-CoV-2 detected in human milk.
      ; ), and current recommendations suggest that mothers with suspected or confirmed SARS-CoV-2 infection should continue to nurse (). However, given the emerging appreciation for SARS-CoV-2 rapid-antibody waning (
      • Ibarrondo F.J.
      • Fulcher J.A.
      • Goodman-Meza D.
      • Elliott J.
      • Hofmann C.
      • Hausner M.A.
      • Ferbas K.G.
      • Tobin N.H.
      • Aldrovandi G.M.
      • Yang O.O.
      Rapid Decay of Anti-SARS-CoV-2 Antibodies in Persons with Mild Covid-19.
      ), as well as the lack of information related to the thresholds of antibodies required to confer protection, it is unclear whether maternally transferred antibodies will be of a sufficient titer to provide protection to the neonate. However, synergistic delivery of both placentally derived IgG and BM delivered IgG and IgA may be key to protection against this novel pathogen.

      Maternal BM antibodies on neonatal vaccine responses

      Several lines of evidence suggest that maternal antibodies transferred via the placenta can limit vaccine responses in infants by capturing vaccine antigens, thereby neutralizing the induction of a de novo immune response as is proposed to occur for the tetanus, poliovirus, and measles vaccines (
      • Osterhaus A.
      • van Amerongen G.
      • van Binnendijk R.
      Vaccine strategies to overcome maternal antibody mediated inhibition of measles vaccine.
      ;
      • Jones C.
      • Pollock L.
      • Barnett S.M.
      • Battersby A.
      • Kampmann B.
      The relationship between concentration of specific antibody at birth and subsequent response to primary immunization.
      ;
      • Tang R.
      • Chu K.
      • Hu Y.
      • Chen L.
      • Zhang M.
      • Liu S.
      • Ma H.
      • Wang J.
      • Zhu F.
      • Hu Y.
      • Gao Q.
      Effect of maternal antibody on the infant immune response to inactivated poliovirus vaccines made from Sabin strains.
      ). Mechanistically, it is proposed that maternally derived antibodies specifically opsonize vaccine antigens, driving enhanced clearance via the inhibitory receptor, FcgRIIB, resulting in an overall dampened immune response (
      • Karlsson M.C.I.
      • Getahun A.
      • Heyman B.
      FcgammaRIIB in IgG-mediated suppression of antibody responses: different impact in vivo and in vitro.
      ). However, whether BM antibodies are also able to inhibit vaccine induced immunity remains unclear. In particular, the role of maternal antibodies on the responsiveness to infant rotavirus vaccination has been widely explored. Interestingly, rotavirus vaccines have a lower efficacy and immunogenicity in low income countries (
      • De Mol P.
      • Zissis G.
      • Butzler J.P.
      • Mutwewingabo A.
      • André F.E.
      Failure of live, attenuated oral rotavirus vaccine.
      ;
      • Georges-Courbot M.C.
      • Monges J.
      • Siopathis M.R.
      • Roungou J.B.
      • Gresenguet G.
      • Bellec L.
      • Bouquety J.C.
      • Lanckriet C.
      • Cadoz M.
      • Hessel L.
      • et al.
      Evaluation of the efficacy of a low-passage bovine rotavirus (strain WC3) vaccine in children in Central Africa.
      ). Several studies have found that women in low-income countries have higher IgA titers against rotavirus in BM compared to women in developed countries (
      • Chilengi R.
      • Simuyandi M.
      • Beach L.
      • Mwila K.
      • Becker-Dreps S.
      • Emperador D.M.
      • Velasquez D.E.
      • Bosomprah S.
      • Jiang B.
      Association of maternal immunity with rotavirus vaccine immunogenicity in Zambian Infants.
      ;
      • Moon S.S.
      • Groome M.J.
      • Velasquez D.E.
      • Parashar U.D.
      • Jones S.
      • Koen A.
      • van Niekerk N.
      • Jiang B.
      • Madhi S.A.
      Prevaccination Rotavirus Serum IgG and IgA Are Associated With Lower Immunogenicity of Live, Oral Human Rotavirus Vaccine in South African Infants.
      ), but the role of BM in stunting seroconversion upon infant vaccination is controversial (
      • Becker-Dreps S.
      • Vilchez S.
      • Velasquez D.
      • Moon S.S.
      • Hudgens M.G.
      • Zambrana L.E.
      • Jiang B.
      Rotavirus-specific IgG antibodies from mothers’ serum may inhibit infant immune responses to the pentavalent rotavirus vaccine.
      ;
      • Moon S.S.
      • Groome M.J.
      • Velasquez D.E.
      • Parashar U.D.
      • Jones S.
      • Koen A.
      • van Niekerk N.
      • Jiang B.
      • Madhi S.A.
      Prevaccination Rotavirus Serum IgG and IgA Are Associated With Lower Immunogenicity of Live, Oral Human Rotavirus Vaccine in South African Infants.
      ). A cross-fostering study in mice found that both placentally transferred and BM-delivered antibodies prevented neonate responsiveness to a live-attenuated, orally delivered vaccine (
      • Yang H.
      • Luo G.
      • Zeng Y.
      • Li Y.
      • Yu S.
      • Zhao B.
      • An R.
      • Zhang S.
      • Wang Y.
      • Li T.
      • et al.
      The distinct impact of maternal antibodies on the immunogenicity of live and recombinant rotavirus vaccines.
      ), suggesting that both mucosal and serum antibodies can have negative effects on vaccine immunogenicity in early life. Still, further studies need to be undertaken to understand the mechanism of BM antibody-induced restriction of vaccine response in neonates. Given our emerging appreciation for the differential role of BM-derived IgG and IgA in immunity and microbe control (Figure 4), next generation analyses may reveal novel nuances on how BM-antibodies may be leveraged as potential adjuvants, rather than tolerogenic signals, to promote enhanced vaccine immunity in neonates.
      Figure thumbnail gr4
      Figure 4IgG-mediated protection against infection versus IgA-mediated tolerization
      Left: maternal IgG originating from breast milk recognize and bind to pathogens to which the mother has been exposed in the lumen, triggering an antipathogen response in the lumen or lamina propria of the infant gut, able to recruit innate immune mechanisms aimed at eliminating the foreign invader. Right: IgAs from breast milk spatially segregate commensal bacteria, preventing their dissemination and reducing their pathogenic functions. Additionally, IgAs complex-bacterial antigens and allergens providing “safe” signals to the immune system limiting the activation of T cells in the lamina propria, via dendritic cell sampling of immune complex material.

      Other immunomodulatory components of BM

      Beyond antibodies, several other bioactive factors exist in BM that could contribute to immunity in the neonate. For instance, little is known about the interactions between antibodies and HMOs, glycoproteins such as lactoferrin and lactadherin (
      • Ballard O.
      • Morrow A.L.
      Human milk composition: nutrients and bioactive factors.
      ), extracellular vesicles (
      • Zempleni J.
      • Aguilar-Lozano A.
      • Sadri M.
      • Sukreet S.
      • Manca S.
      • Wu D.
      • Zhou F.
      • Mutai E.
      Biological activities of extracellular vesicles and their cargos from bovine and human milk in humans and implications for infants.
      ), leukocytes (
      • Hassiotou F.
      • Geddes D.T.
      • Hartmann P.E.
      Cells in human milk: state of the science.
      ), or cytokines. It is possible that the collective composition of the BM may act synergistically to drive colonization, restrict pathogens, as well as shape allergy/autoimmunity. With our emerging appreciation for the immunomodulating role of many other bioactive components in BM, additional mechanisms of antibodies may be uncovered providing additional new opportunities to shift neonatal immunity.

      Conclusions

      Emerging data clearly highlight the critical role of maternal antibody transfer via BM to both confer immediate protection against pathogens and shape life-long immunity. The delicate balance appears to be orchestrated by different classes of antibodies, with a central critical role for IgA in regulating the microbiome and a dominant role for IgG in fighting pathogens. However, this observation is likely a gross oversimplification, because subpopulations of BM-derived IgA, IgG, and other isotypes, subclasses, and post-translationally modified antibodies are likely to synergistically shape neonatal immunity. Defining the precise mechanism by which particular antibodies gain access to BM and how the composition of BM can be actively shaped offers thrilling prospects to engineer life-long immunity to curb infections, reduce allergies, and prevent the evolution of autoimmune disease.

      Acknowledgments

      We thank Nancy Zimmerman, Mark and Lisa Schwartz, an anonymous donor (financial support), Terry and Susan Ragon, and the SAMANA Kay MGH Research Scholars award for their support. We would also like to thank the NIH and Gates Foundation for their ongoing support.

      Declaration of interests

      G.A. is the founder of Seromyx.

      References

        • Aagaard K.
        • Ma J.
        • Antony K.M.
        • Ganu R.
        • Petrosino J.
        • Versalovic J.
        The placenta harbors a unique microbiome.
        Sci. Transl. Med. 2014; 6: 237ra65
        • Adamski F.M.
        • King A.T.
        • Demmer J.
        Expression of the Fc receptor in the mammary gland during lactation in the marsupial Trichosurus vulpecula (brushtail possum).
        Mol. Immunol. 2000; 37: 435-444
        • Ahmed T.
        • Fuchs G.J.
        Gastrointestinal allergy to food: a review.
        J. Diarrhoeal Dis. Res. 1997; 15: 211-223
        • Andreas N.J.
        • Kampmann B.
        • Mehring Le-Doare K.
        Human breast milk: A review on its composition and bioactivity.
        Early Hum. Dev. 2015; 91: 629-635
        • Arboleya S.
        • Sánchez B.
        • Milani C.
        • Duranti S.
        • Solís G.
        • Fernández N.
        • de los Reyes-Gavilán C.G.
        • Ventura M.
        • Margolles A.
        • Gueimonde M.
        Intestinal microbiota development in preterm neonates and effect of perinatal antibiotics.
        J. Pediatr. 2015; 166: 538-544
        • Arévalo Sureda E.
        • Weström B.
        • Pierzynowski S.G.
        • Prykhodko O.
        Maturation of the intestinal epithelial barrier in neonatal rats coincides with decreased FcRn expression, replacement of vacuolated enterocytes and changed Blimp-1 expression.
        PLoS ONE. 2016; 11: e0164775
        • Atyeo C.
        • Pullen K.M.
        • Bordt E.A.
        • Fischinger S.
        • Burke J.
        • Michell A.
        • Slein M.D.
        • Loos C.
        • Shook L.L.
        • Boatin A.A.
        • et al.
        Compromised SARS-CoV-2-specific placental antibody transfer.
        Cell. 2021; 184: 628-642.e10
        • Avershina E.
        • Lundgård K.
        • Sekelja M.
        • Dotterud C.
        • Storrø O.
        • Øien T.
        • Johnsen R.
        • Rudi K.
        Transition from infant- to adult-like gut microbiota.
        Environ. Microbiol. 2016; 18: 2226-2236
        • Bäckhed F.
        • Roswall J.
        • Peng Y.
        • Feng Q.
        • Jia H.
        • Kovatcheva-Datchary P.
        • Li Y.
        • Xia Y.
        • Xie H.
        • Zhong H.
        • et al.
        Dynamics and stabilization of the human gut microbiome during the first year of life.
        Cell Host Microbe. 2015; 17: 690-703
        • Bager P.
        • Wohlfahrt J.
        • Westergaard T.
        Caesarean delivery and risk of atopy and allergic disease: meta-analyses.
        Clin. Exp. Allergy. 2008; 38: 634-642
        • Bahl R.
        • Frost C.
        • Kirkwood B.R.
        • Edmond K.
        • Martines J.
        • Bhandari N.
        • Arthur P.
        Infant feeding patterns and risks of death and hospitalization in the first half of infancy: Multicentre cohort study.
        Bull. World Health Organ. 2005; 83: 418-426
        • Ballard O.
        • Morrow A.L.
        Human milk composition: nutrients and bioactive factors.
        Pediatr. Clin. North Am. 2013; 60: 49-74
        • Barrington G.M.
        • Parish S.M.
        Bovine neonatal immunology.
        Vet. Clin. North Am. Food Anim. Pract. 2001; 17: 463-476
        • Becker-Dreps S.
        • Vilchez S.
        • Velasquez D.
        • Moon S.S.
        • Hudgens M.G.
        • Zambrana L.E.
        • Jiang B.
        Rotavirus-specific IgG antibodies from mothers’ serum may inhibit infant immune responses to the pentavalent rotavirus vaccine.
        Pediatr. Infect. Dis. J. 2015; 34: 115-116
        • Becquart P.
        • Hocini H.
        • Lévy M.
        • Sépou A.
        • Kazatchkine M.D.
        • Bélec L.
        Secretory anti-human immunodeficiency virus (HIV) antibodies in colostrum and breast milk are not a major determinant of the protection of early postnatal transmission of HIV.
        J. Infect. Dis. 2000; 181: 532-539
        • Benowitz I.
        • Esposito D.B.
        • Gracey K.D.
        • Shapiro E.D.
        • Vázquez M.
        Influenza vaccine given to pregnant women reduces hospitalization due to influenza in their infants.
        Clin. Infect. Dis. 2010; 51: 1355-1361
        • Binsker U.
        • Lees J.A.
        • Hammond A.J.
        • Weiser J.N.
        Immune exclusion by naturally acquired secretory IgA against pneumococcal pilus-1.
        J. Clin. Invest. 2020; 130: 927-941
        • Bokulich N.A.
        • Chung J.
        • Battaglia T.
        • Henderson N.
        • Jay M.
        • Li H.
        • D Lieber A.
        • Wu F.
        • Perez-Perez G.I.
        • Chen Y.
        • et al.
        Antibiotics, birth mode, and diet shape microbiome maturation during early life.
        Sci. Transl. Med. 2016; 8: 343ra82
        • Boullier S.
        • Tanguy M.
        • Kadaoui K.A.
        • Caubet C.
        • Sansonetti P.
        • Corthésy B.
        • Phalipon A.
        Secretory IgA-mediated neutralization of Shigella flexneri prevents intestinal tissue destruction by down-regulating inflammatory circuits.
        J. Immunol. 2009; 183: 5879-5885
        • Brandtzaeg P.
        Mucosal immunity: Integration between mother and the breast-fed infant.
        Vaccine. 2003; 21: 3382-3388
        • Brandtzaeg P.
        Induction of secretory immunity and memory at mucosal surfaces.
        Vaccine. 2007; 25: 5467-5484
        • Bridgman S.L.
        • Konya T.
        • Azad M.B.
        • Sears M.R.
        • Becker A.B.
        • Turvey S.E.
        • Mandhane P.J.
        • Subbarao P.
        • Scott J.A.
        • Field C.J.
        • Kozyrskyj A.L.
        • CHILD Study Investigators
        Infant gut immunity: a preliminary study of IgA associations with breastfeeding.
        J. Dev. Orig. Health Dis. 2016; 7: 68-72
        • Brower-Sinning R.
        • Zhong D.
        • Good M.
        • Firek B.
        • Baker R.
        • Sodhi C.P.
        • Hackam D.J.
        • Morowitz M.J.
        Mucosa-associated bacterial diversity in necrotizing enterocolitis.
        PLoS ONE. 2014; 9: e105046
        • Bulkow L.R.
        • Singleton R.J.
        • Karron R.A.
        • Harrison L.H.
        • Alaska RSV Study Group
        Risk factors for severe respiratory syncytial virus infection among Alaska native children.
        Pediatrics. 2002; 109: 210-216
        • Bunker J.J.
        • Erickson S.A.
        • Flynn T.M.
        • Henry C.
        • Koval J.C.
        • Meisel M.
        • Jabri B.
        • Antonopoulos D.A.
        • Wilson P.C.
        • Bendelac A.
        Natural polyreactive IgA antibodies coat the intestinal microbiota.
        Science. 2017; 358: eaan6619
        • Caballero-Flores G.
        • Sakamoto K.
        • Zeng M.Y.
        • Wang Y.
        • Hakim J.
        • Matus-Acuña V.
        • Inohara N.
        • Núñez G.
        Maternal Immunization Confers Protection to the Offspring against an Attaching and Effacing Pathogen through Delivery of IgG in Breast Milk.
        Cell Host Microbe. 2019; 25: 313-323.e4
        • Cardwell C.R.
        • Stene L.C.
        • Joner G.
        • Cinek O.
        • Svensson J.
        • Goldacre M.J.
        • Parslow R.C.
        • Pozzilli P.
        • Brigis G.
        • Stoyanov D.
        • et al.
        Caesarean section is associated with an increased risk of childhood-onset type 1 diabetes mellitus: a meta-analysis of observational studies.
        Diabetologia. 2008; 51: 726-735
        • Casas R.
        • Böttcher M.F.
        • Duchén K.
        • Björkstén B.
        Detection of IgA antibodies to cat, β-lactoglobulin, and ovalbumin allergens in human milk.
        J. Allergy Clin. Immunol. 2000; 105: 1236-1240
        • Casey C.E.
        • Neifert M.R.
        • Seacat J.M.
        • Neville M.C.
        Nutrient intake by breast-fed infants during the first five days after birth.
        Am. J. Dis. Child. 1986; 140: 933-936
        • Catanzaro J.R.
        • Strauss J.D.
        • Bielecka A.
        • Porto A.F.
        • Lobo F.M.
        • Urban A.
        • Schofield W.B.
        • Palm N.W.
        IgA-deficient humans exhibit gut microbiota dysbiosis despite secretion of compensatory IgM.
        Sci. Rep. 2019; 9: 13574
        • Cheuvart B.
        • Neuzil K.M.
        • Steele A.D.
        • Cunliffe N.
        • Madhi S.A.
        • Karkada N.
        • Han H.H.
        • Vinals C.
        Association of serum anti-rotavirus immunoglobulin A antibody seropositivity and protection against severe rotavirus gastroenteritis: analysis of clinical trials of human rotavirus vaccine.
        Hum. Vaccin. Immunother. 2014; 10: 505-511
        • Chilengi R.
        • Simuyandi M.
        • Beach L.
        • Mwila K.
        • Becker-Dreps S.
        • Emperador D.M.
        • Velasquez D.E.
        • Bosomprah S.
        • Jiang B.
        Association of maternal immunity with rotavirus vaccine immunogenicity in Zambian Infants.
        PLoS ONE. 2016; 11: e0150100
        • Cianga P.
        • Medesan C.
        • Richardson J.A.
        • Ghetie V.
        • Ward E.S.
        Identification and function of neonatal Fc receptor in mammary gland of lactating mice.
        Eur. J. Immunol. 1999; 29: 2515-2523
        • Cianga P.
        • Cianga C.
        • Cozma L.
        • Ward E.S.
        • Carasevici E.
        The MHC class I related Fc receptor, FcRn, is expressed in the epithelial cells of the human mammary gland.
        Hum. Immunol. 2003; 64: 1152-1159
        • Collado M.C.
        • Isolauri E.
        • Laitinen K.
        • Salminen S.
        Effect of mother’s weight on infant’s microbiota acquisition, composition, and activity during early infancy: a prospective follow-up study initiated in early pregnancy.
        Am. J. Clin. Nutr. 2010; 92: 1023-1030
        • Coovadia H.
        Antiretroviral agents--how best to protect infants from HIV and save their mothers from AIDS.
        N. Engl. J. Med. 2004; 351: 289-292
        • de Goffau M.C.
        • Lager S.
        • Sovio U.
        • Gaccioli F.
        • Cook E.
        • Peacock S.J.
        • Parkhill J.
        • Charnock-Jones D.S.
        • Smith G.C.S.
        Human placenta has no microbiome but can contain potential pathogens.
        Nature. 2019; 572: 329-334
        • De Groot N.
        • Van Kuik-Romeijn P.
        • Lee S.H.
        • De Boer H.A.
        Increased immunoglobulin A levels in milk by over-expressing the murine polymeric immunoglobulin receptor gene in the mammary gland epithelial cells of transgenic mice.
        Immunology. 2000; 101: 218-224
        • De Mol P.
        • Zissis G.
        • Butzler J.P.
        • Mutwewingabo A.
        • André F.E.
        Failure of live, attenuated oral rotavirus vaccine.
        Lancet. 1986; 2: 108
        • Demers-Mathieu V.
        • Underwood M.A.
        • Beverly R.L.
        • Nielsen S.D.
        • Dallas D.C.
        Comparison of human milk immunoglobulin survival during gastric digestion between preterm and term infants.
        Nutrients. 2018; 10: E631
        • Demers-Mathieu V.
        • Underwood M.A.
        • Beverly R.L.
        • Dallas D.C.
        Survival of Immunoglobulins from Human Milk to Preterm Infant Gastric Samples at 1, 2, and 3 h Postprandial.
        Neonatology. 2018; 114: 242-250
        • Dominguez-Bello M.G.
        • Costello E.K.
        • Contreras M.
        • Magris M.
        • Hidalgo G.
        • Fierer N.
        • Knight R.
        Delivery mode shapes the acquisition and structure of the initial microbiota across multiple body habitats in newborns.
        Proc. Natl. Acad. Sci. USA. 2010; 107: 11971-11975
        • Dong Y.
        • Mo X.
        • Hu Y.
        • Qi X.
        • Jiang F.
        • Jiang Z.
        • Tong S.
        Epidemiology of COVID-19 among children in China.
        Pediatrics. 2020; 145: e20200702
        • Downham M.A.P.S.
        • Scott R.
        • Sims D.G.
        • Webb J.K.
        • Gardner P.S.
        Breast-feeding protects against respiratory syncytial virus infections.
        BMJ. 1976; 2: 274-276
        • Durand D.
        • Ochoa T.J.
        • Bellomo S.M.
        • Contreras C.A.
        • Bustamante V.H.
        • Ruiz J.
        • Cleary T.G.
        Detection of secretory immunoglobulin A in human colostrum as mucosal immune response against proteins of the type III secretion system of Salmonella, Shigella and enteropathogenic Escherichia coli.
        Pediatr. Infect. Dis. J. 2013; 32: 1122-1126
        • Dzidic M.
        • Abrahamsson T.R.
        • Artacho A.
        • Björkstén B.
        • Collado M.C.
        • Mira A.
        • Jenmalm M.C.
        Aberrant IgA responses to the gut microbiota during infancy precede asthma and allergy development.
        J. Allergy Clin. Immunol. 2017; 139: 1017-1025.e14
        • Ehrnst A.
        • Lindgren S.
        • Dictor M.
        • Johansson B.
        • Sönnerborg A.
        • Czajkowski J.
        • Sundin G.
        • Bohlin A.B.
        HIV in pregnant women and their offspring: evidence for late transmission.
        Lancet. 1991; 338: 203-207
        • Eick A.A.
        • Uyeki T.M.
        • Klimov A.
        • Hall H.
        • Reid R.
        • Santosham M.
        • O’Brien K.L.
        Maternal influenza vaccination and effect on influenza virus infection in young infants.
        Arch. Pediatr. Adolesc. Med. 2011; 165: 104-111
        • Fadlallah J.
        • El Kafsi H.
        • Sterlin D.
        • Juste C.
        • Parizot C.
        • Dorgham K.
        • Autaa G.
        • Gouas D.
        • Almeida M.
        • Lepage P.
        • et al.
        Microbial ecology perturbation in human IgA deficiency.
        Sci. Transl. Med. 2018; 10: eaan1217
        • Fälth-Magnusson K.
        Breast milk antibodies to foods in relation to maternal diet, maternal atopy and the development of atopic disease in the baby.
        Int. Arch. Allergy Appl. Immunol. 1989; 90: 297-300
        • Fawzi W.
        • Msamanga G.
        • Spiegelman D.
        • Renjifo B.
        • Bang H.
        • Kapiga S.
        • Coley J.
        • Hertzmark E.
        • Essex M.
        • Hunter D.
        Transmission of HIV-1 through breastfeeding among women in Dar es Salaam, Tanzania.
        J. Acquir. Immune Defic. Syndr. 2002; 31: 331-338
        • Forbes S.J.
        • Eschmann M.
        • Mantis N.J.
        Inhibition of Salmonella enterica serovar typhimurium motility and entry into epithelial cells by a protective antilipopolysaccharide monoclonal immunoglobulin A antibody.
        Infect. Immun. 2008; 76: 4137-4144
        • Fouda G.G.
        • Yates N.L.
        • Pollara J.
        • Shen X.
        • Overman G.R.
        • Mahlokozera T.
        • Wilks A.B.
        • Kang H.H.
        • Salazar-Gonzalez J.F.
        • Salazar M.G.
        • et al.
        • Center for HIV/AIDS Vaccine Immunology
        HIV-specific functional antibody responses in breast milk mirror those in plasma and are primarily mediated by IgG antibodies.
        J. Virol. 2011; 85: 9555-9567
        • Fox A.
        • Marino J.
        • Amanat F.
        • Krammer F.
        • Hahn-Holbrook J.
        • Zolla-Pazner S.
        • Powell R.L.
        Robust and specific secretory IgA against SARS-CoV-2 detected in human milk.
        iScience. 2020; 23: 101735
        • Gall S.A.
        • Myers J.
        • Pichichero M.
        Maternal immunization with tetanus-diphtheria-pertussis vaccine: effect on maternal and neonatal serum antibody levels.
        Am. J. Obstet. Gynecol. 2011; 204: 334.e1-334.e5
        • Georges-Courbot M.C.
        • Monges J.
        • Siopathis M.R.
        • Roungou J.B.
        • Gresenguet G.
        • Bellec L.
        • Bouquety J.C.
        • Lanckriet C.
        • Cadoz M.
        • Hessel L.
        • et al.
        Evaluation of the efficacy of a low-passage bovine rotavirus (strain WC3) vaccine in children in Central Africa.
        Res. Virol. 1991; 142: 405-411
        • Glass R.I.
        • Svennerholm A.M.
        • Stoll B.J.
        • Khan M.R.
        • Hossain K.M.
        • Huq M.I.
        • Holmgren J.
        Protection against cholera in breast-fed children by antibodies in breast milk.
        N. Engl. J. Med. 1983; 308: 1389-1392
        • Glezen W.P.
        Effect of maternal antibodies on the infant immune response.
        Vaccine. 2003; 21: 3389-3392
        • Goldman A.S.
        • Garza C.
        • Nichols B.L.
        • Goldblum R.M.
        Immunologic factors in human milk during the first year of lactation.
        J. Pediatr. 1982; 100: 563-567
        • Gomez de Agüero M.
        • Ganal-Vonarburg S.C.
        • Fuhrer T.
        • Rupp S.
        • Uchimura Y.
        • Li H.
        • Steinert A.
        • Heikenwalder M.
        • Hapfelmeier S.
        • Sauer U.
        • et al.
        The maternal microbiota drives early postnatal innate immune development.
        Science. 2016; 351: 1296-1302
        • Goonatilleke E.
        • Huang J.
        • Xu G.
        • Wu L.
        • Smilowitz J.T.
        • German J.B.
        • Lebrilla C.B.
        Human milk proteins and their glycosylation exhibit quantitative dynamic variations during lactation.
        J. Nutr. 2019; 149: 1317-1325
        • Gopalakrishna K.P.
        • Macadangdang B.R.
        • Rogers M.B.
        • Tometich J.T.
        • Firek B.A.
        • Baker R.
        • Ji J.
        • Burr A.H.P.
        • Ma C.
        • Good M.
        • et al.
        Maternal IgA protects against the development of necrotizing enterocolitis in preterm infants.
        Nat. Med. 2019; 25: 1110-1115
        • Guidry J.
        • Butler J.E.
        • Pearson R.E.
        • Weinland B.T.
        IgA, igG1, IgG2, IgM, and BSA in serum and mammary secretion throughout lactation.
        Vet. Immunol. Immunopathol. 1980; 1: 329-341
        • Gülden E.
        • Wong F.S.
        • Wen L.
        The gut microbiota and Type 1 Diabetes.
        Clin. Immunol. 2015; 159: 143-153
        • Halsey J.F.
        • Mitchell C.S.
        • McKenzie S.J.
        The origins of secretory IgA in milk: a shift during lactation from a serum origin to local synthesis in the mammary gland.
        Ann. N Y Acad. Sci. 1983; 409: 452-460
        • Harris N.L.
        • Spoerri I.
        • Schopfer J.F.
        • Nembrini C.
        • Merky P.
        • Massacand J.
        • Urban Jr., J.F.
        • Lamarre A.
        • Burki K.
        • Odermatt B.
        • et al.
        Mechanisms of neonatal mucosal antibody protection.
        J. Immunol. 2006; 177: 6256-6262
        • Hassiotou F.
        • Geddes D.T.
        • Hartmann P.E.
        Cells in human milk: state of the science.
        J. Hum. Lact. 2013; 29: 171-182
        • Healy C.M.
        Vaccines in pregnant women and research initiatives.
        Clin. Obstet. Gynecol. 2012; 55: 474-486
        • Henkle E.
        • Steinhoff M.C.
        • Omer S.B.
        • Roy E.
        • Arifeen S.E.
        • Raqib R.
        • Breiman R.F.
        • Caulfield L.E.
        • Moss W.J.
        • Zaman K.
        The effect of exclusive breast-feeding on respiratory illness in young infants in a maternal immunization trial in Bangladesh.
        Pediatr. Infect. Dis. J. 2013; 32: 431-435
        • Himes J.E.
        • Goswami R.
        • Mangan R.J.
        • Kumar A.
        • Jeffries Jr., T.L.
        • Eudailey J.A.
        • Heimsath H.
        • Nguyen Q.N.
        • Pollara J.
        • LaBranche C.
        • et al.
        Polyclonal HIV envelope-specific breast milk antibodies limit founder SHIV acquisition and cell-associated virus loads in infant rhesus monkeys.
        Mucosal Immunol. 2018; 11: 1716-1726
        • Ho N.T.
        • Li F.
        • Lee-Sarwar K.A.
        • Tun H.M.
        • Brown B.P.
        • Pannaraj P.S.
        • Bender J.M.
        • Azad M.B.
        • Thompson A.L.
        • Weiss S.T.
        • et al.
        Meta-analysis of effects of exclusive breastfeeding on infant gut microbiota across populations.
        Nat. Commun. 2018; 9: 4169
        • Hocini H.
        • Bomsel M.
        Infectious human immunodeficiency virus can rapidly penetrate a tight human epithelial barrier by transcytosis in a process impaired by mucosal immunoglobulins.
        J. Infect. Dis. 1999; 179: S448-S453
        • Houghteling P.D.
        • Walker W.A.
        Why is initial bacterial colonization of the intestine important to infants’ and children’s health?.
        J. Pediatr. Gastroenterol. Nutr. 2015; 60: 294-307
        • Hurley W.L.
        • Theil P.K.
        Perspectives on immunoglobulins in colostrum and milk.
        Nutrients. 2011; 3: 442-474
        • Husseini R.H.
        • Sweet C.
        • Overton H.
        • Smith H.
        Role of maternal immunity in the protection of newborn ferrets against infection with a virulent influenza virus.
        Immunology. 1984; 52: 389-394
        • Ibarrondo F.J.
        • Fulcher J.A.
        • Goodman-Meza D.
        • Elliott J.
        • Hofmann C.
        • Hausner M.A.
        • Ferbas K.G.
        • Tobin N.H.
        • Aldrovandi G.M.
        • Yang O.O.
        Rapid Decay of Anti-SARS-CoV-2 Antibodies in Persons with Mild Covid-19.
        N. Engl. J. Med. 2020; 383: 1085-1087
        • Ismail I.H.
        • Licciardi P.V.
        • Oppedisano F.
        • Boyle R.J.
        • Tang M.L.
        Relationship between breast milk sCD14, TGF-β1 and total IgA in the first month and development of eczema during infancy.
        Pediatr. Allergy Immunol. 2013; 24: 352-360
        • Israel E.J.
        • Patel V.K.
        • Taylor S.F.
        • Marshak-Rothstein A.
        • Simister N.E.
        Requirement for a beta 2-microglobulin-associated Fc receptor for acquisition of maternal IgG by fetal and neonatal mice.
        J. Immunol. 1995; 154: 6246-6251
        • Jackson L.A.
        • Patel S.M.
        • Swamy G.K.
        • Frey S.E.
        • Creech C.B.
        • Munoz F.M.
        • Artal R.
        • Keitel W.A.
        • Noah D.L.
        • Petrie C.R.
        • et al.
        Immunogenicity of an inactivated monovalent 2009 H1N1 influenza vaccine in pregnant women.
        J. Infect. Dis. 2011; 204: 854-863
        • Järvinen K.M.
        • Westfall J.E.
        • Seppo M.S.
        • James A.K.
        • Tsuang A.J.
        • Feustel P.J.
        • Sampson H.A.
        • Berin C.
        Role of maternal elimination diets and human milk IgA in the development of cow’s milk allergy in the infants.
        Clin. Exp. Allergy. 2014; 44: 69-78
        • Järvinen K.M.
        • Wang J.
        • Seppo A.E.
        • Zand M.
        Novel multiplex assay for profiling influenza antibodies in breast milk and serum of mother-infant pairs.
        F1000Res. 2018; 7: 1822
        • Johansen F.-E.
        • Braathen R.
        • Brandtzaeg P.
        The J chain is essential for polymeric Ig receptor-mediated epithelial transport of IgA.
        J. Immunol. 2001; 167: 5185-5192
        • Johnson C.C.
        • Ownby D.R.
        The infant gut bacterial microbiota and risk of pediatric asthma and allergic diseases.
        Transl. Res. 2017; 179: 60-70
        • Jones G.
        • Steketee R.W.
        • Black R.E.
        • Bhutta Z.A.
        • Morris S.S.
        • Bellagio Child Survival Study Group
        How many child deaths can we prevent this year?.
        Lancet. 2003; 362: 65-71
        • Jones C.
        • Pollock L.
        • Barnett S.M.
        • Battersby A.
        • Kampmann B.
        The relationship between concentration of specific antibody at birth and subsequent response to primary immunization.
        Vaccine. 2014; 32: 996-1002
        • Kafulafula G.
        • Hoover D.R.
        • Taha T.E.
        • Thigpen M.
        • Li Q.
        • Fowler M.G.
        • Kumwenda N.I.
        • Nkanaunena K.
        • Mipando L.
        • Mofenson L.M.
        Frequency of gastroenteritis and gastroenteritis-associated mortality with early weaning in HIV-1-uninfected children born to HIV-infected women in Malawi.
        J. Acquir. Immune Defic. Syndr. 2010; 53: 6-13
        • Karlsson M.C.I.
        • Getahun A.
        • Heyman B.
        FcgammaRIIB in IgG-mediated suppression of antibody responses: different impact in vivo and in vitro.
        J. Immunol. 2001; 167: 5558-5564
        • Koch M.A.
        • Reiner G.L.
        • Lugo K.A.
        • Kreuk L.S.
        • Stanbery A.G.
        • Ansaldo E.
        • Seher T.D.
        • Ludington W.B.
        • Barton G.M.
        Maternal IgG and IgA Antibodies Dampen Mucosal T Helper Cell Responses in Early Life.
        Cell. 2016; 165: 827-841
        • Kramer D.R.
        • Cebra J.J.
        Early appearance of “natural” mucosal IgA responses and germinal centers in suckling mice developing in the absence of maternal antibodies.
        J. Immunol. 1995; 154: 2051-2062
        • Kuhn L.
        • Trabattoni D.
        • Kankasa C.
        • Sinkala M.
        • Lissoni F.
        • Ghosh M.
        • Aldrovandi G.
        • Thea D.
        • Clerici M.
        Hiv-specific secretory IgA in breast milk of HIV-positive mothers is not associated with protection against HIV transmission among breast-fed infants.
        J. Pediatr. 2006; 149: 611-616
        • Kuhn L.
        • Aldrovandi G.M.
        • Sinkala M.
        • Kankasa C.
        • Semrau K.
        • Mwiya M.
        • Kasonde P.
        • Scott N.
        • Vwalika C.
        • Walter J.
        • et al.
        • Zambia Exclusive Breastfeeding Study
        Effects of early, abrupt weaning on HIV-free survival of children in Zambia.
        N. Engl. J. Med. 2008; 359: 130-141
        • Kulski J.K.
        • Hartmann P.E.
        Changes in human milk composition during the initiation of lactation.
        Aust. J. Exp. Biol. Med. Sci. 1981; 59: 101-114
        • Lamberti L.M.
        • Fischer Walker C.L.
        • Noiman A.
        • Victora C.
        • Black R.E.
        Breastfeeding and the risk for diarrhea morbidity and mortality.
        BMC Public Health. 2011; 11: S15
        • Lanata C.F.
        • Fischer-Walker C.L.
        • Olascoaga A.C.
        • Torres C.X.
        • Aryee M.J.
        • Black R.E.
        • Child Health Epidemiology Reference Group of the World Health Organization and UNICEF
        Global causes of diarrheal disease mortality in children <5 years of age: a systematic review.
        PLoS ONE. 2013; 8: e72788
        • Lasaro M.O.
        • Luiz W.B.
        • Sbrogio-Almeida M.E.
        • Ferreira L.C.
        Prime-boost vaccine regimen confers protective immunity to human-derived enterotoxigenic Escherichia coli.
        Vaccine. 2005; 23: 2430-2438
        • Lehmann D.
        • Pomat W.S.
        • Riley I.D.
        • Alpers M.P.
        Studies of maternal immunisation with pneumococcal polysaccharide vaccine in Papua New Guinea.
        Vaccine. 2003; 21: 3446-3450
        • Liguoro I.
        • Pilotto C.
        • Bonanni M.
        • Ferrari M.E.
        • Pusiol A.
        • Nocerino A.
        • Vidal E.
        • Cogo P.
        SARS-COV-2 infection in children and newborns: a systematic review.
        Eur. J. Pediatr. 2020; 179: 1029-1046
        • Lin P.W.
        • Stoll B.J.
        Necrotising enterocolitis.
        Lancet. 2006; 368: 1271-1283