Physiologic delays in production of immune factors occur in mammals including Homo sapiens. This finding is counter to a basic tenet of biologic evolution, because such delays increase the risk of infections. The disadvantage is, however, offset by defense factors in milk of the species in whom the developmental delay occurs. Reciprocal relationships between the production of immune factors by the lactating mammary gland and the production of those defense agents during early infancy are found in all investigated mammalian species. Thus, the evolution of these processes is closely related. Certain immunologic components of milk are highly conserved, whereas others vary according to the species. The variations most likely evolved by genetic mutations and natural selection. In addition, the immune composition of mammalian milks is associated with developmental delays in the same immunologic agents. Furthermore, most closely related mammals, such as humans and chimpanzees, are most similar in the defense agents in their milks and the corresponding developmental delays in their immune systems. Defense factors in human milk include antimicrobial agents (secretory IgA, lactoferrin, lysozyme, glycoconjugates, oligosaccharides, and digestive products of milk lipids), antiinflammatory factors (antioxidants, epithelial growth factors, cellular protective agents, and enzymes that degrade mediators of inflammation), immunomodulators (nucleotides, cytokines, and antiidiotypic antibodies), and leukocytes (neutrophils, macrophages, and lymphocytes). Because of a lack of geographic/ethnic variation in the immunologic composition of human milk and corresponding immunologic delays in infants, these evolutionary processes seem stable. This is supported by investigations of diverse populations that indicate that this evolutionary outcome is highly beneficial to human infants.
The extrauterine development of many components of the human immune system is delayed(1–14)(Table 1), and the delays partly explain why young infants are more susceptible to many types of infections and why the susceptibility increases with the degree of prematurity. Certain immunologic agents are transmitted either through amniotic fluid or via the placenta during fetal life. The risk of infections in newborn infants is, however, further lessened by human milk feeding(15–17). Moreover, breast-feeding protects against gastrointestinal and respiratory infections well past the newborn period(18–23).
A host of investigations performed over the past 40 y indicate that the protection is mainly due to defense agents in human milk, many of which are developmentally delayed in the infant (Table 1). The defense system in human milk is comprised of antimicrobial, antiinflammatory, and immunomodulating agents that are adapted to mucosal sites, are often multifunctional, and are not well represented in other milks used in human infant feeding. The antimicrobial factors include secretory IgA, lactoferrin, lysozyme, glycoconjugates, oligosaccharides, and antiviral lipids generated by partial digestion of milk fat(24–30). The antiinflammatory agents involve some of the antimicrobial factors, enzymes that degrade inflammatory mediators, cellular protective agents, epithelial growth factors, and antioxidants(31–33). The immunomodulators include nucleotides, cytokines, and antiidiotypic antibodies(34–39).
In addition to the soluble and compartmentalized immune agents, human milk, particularly early in lactation, contains many leukocytes (≈1-3 × 106/mL)(40). About 80% of those cells are neutrophils, 15% are macrophages, and 5-10% are lymphocytes(40). The vast majority of the lymphocytes are T cells(41). Furthermore, virtually all leukocytes in human milk are activated. In that respect, the neutrophils and macrophages have an increased expression of CD11b/CD18 and a decreased expression of L-selectin(42), the macrophages are more motile than blood monocytes(43), and the T cells display the memory phenotype, CD45RO, and other phenotypic markers of activation(41, 44). The fate of these cells in the recipient is uncertain, but there is evidence from experimental animal models that milk T cells enter tissues of the neonatal animal(45–47). Furthermore, some observations suggest that cellular immunity to tuberculosis or to schistosomal antigens may be transferred to the infant by breast-feeding(48, 49). Thus, it is possible that some of these maternal cells function in the recipient infant to compensate for certain developmental delays in the T cell system(6, 12).
The discovery of reciprocal relationships between postnatal development of the human immune system and immune factors produced by the mammary gland led us to question whether the evolution of these two processes was associated. That question will be explored in the context of mammalian evolution.
CENTRAL CONCEPTS OF EVOLUTION
The basic axioms of biologic evolution are 1) all species descended from a common origin; 2) as a result of multiplication, populations of a species increase; and 3) because of environmental pressures, biologic selection occurs(50, 51). Indeed, when the environment changes sufficiently, a species may no longer be well adapted as happened during dramatic disruptions in the Ordovician, Permian, Triassic, and Cretaceous periods(52). Individuals of a species who are genetically well adapted compete successfully for newly created environmental niches. Because of natural selection and saturation of environmental sites, the overall genomic composition of a particular species stabilizes. Thus, evolutionary success is determined by the degree of reproductive capacity and ability to cope with the environment long enough to reach the reproductive period and assure the survival of offspring.
ORIGIN OF MAMMALS AND HOMO SAPIENS
Paleontologic evidence and comparisons of genetic material from living mammalian species (the molecular clock approach)(53, 54) suggest that vertebrates evolved from deuterostome ancestors approximately 500-600 million years ago (mya) and developed in a gradual manner, where many innovations were retained in their evolutionary descendants(55).
The evolutionary innovation that defines mammals was the development of the mammary gland. It is likely that the mammary gland developed in certain reptilian insectivores about 190 mya (Fig. 1) as a consequence (in the context of natural selection) of their newborns obtaining some nutrients from secretions produced by epidermal glands located on the ventral part of the mother's thorax/abdomen(56). In such a scenario, the ventral location of the mammary gland would be favored by face to face interactions between the mother and the infant. Attractant pheromones may have also played a role in the process. The mammalian placenta evolved, but there is evidence that the mammary gland appeared before the placenta. Monotremes (Prototheria), the echidna (Tachyglossus aculeatus), and the duck-billed platypus (Ornithorhynchus anatinus), are mammals that display reptilian features including egg-laying, filiform sperm, microchromosomes, and bones in the pectoral girdle found only in the fossil remains of mammalian-like reptiles (theriodonts) from which mammals probably evolved (Fig. 1). These remnants of primitive mammals have well developed mammary glands, but no placenta(57).
Thus, immunologic activity may have been an early feature of the mammary gland. A primordial immunologic adaptation may have been to secrete antimicrobial agents such as fatty acids, oligosaccharides, lysozyme and iron-binding proteins to protect the recipient infant from the bacterial flora of the mother's skin. The fatty acids may have been similar to the those found in human sebum(58). In that respect, lysozyme, which is phylogenetically very ancient, is produced by mammalian apocrine glands(59), and melanotransferrin, an iron-binding protein found in sweat glands, has a 40% homology with lactoferrin(60). Milk produced by monotremes displays certain major features of the immune system found in milk from eutherian mammals including humans (Fig. 1). They include lysozyme(61), transferrins(61, 62), and difucosyllactose(63, 64). The oligosaccharide(63, 64) interferes with the attachment of Campylobacter jejuni(65) or Escherichia coli stable toxin(66) to epithelial cells. The protection by these and other immune components of milk against pathogens found on the nipples or areola is found in mammals as diverse as the marsupial quokka (Setonix branchyusus)(67) and humans living in primitive societies(19).
Primates appeared about 65-100 mya, the earliest hominids (the genus Australopithecus) diverged from other primates about 5-6 mya(68), our more direct Homo ancestors arose about 2.5 mya(69, 70), and H. sapiens emerged at least 100 000-200 000 y ago (Fig. 1)(71–77). The evolutionary proximity of our species to other mammals has been reconstructed from phenotypic and genotypic analyses of existing mammalian species. The genomes of humans and chimpanzees (Pan troglodytes and Pan paniscus) are remarkably similar(73, 76, 78–81), whereas far greater differences in genomic and phenotypic features are found between H. sapiens, other primates, or other mammalian orders(78–81).
These evolutionary relationships hold for the composition of milks from various species. The composition of human milk is closest to the chimpanzee and gorilla, less similar to other primates, and even more different from milks produced by more distantly related mammals. The immune system in human milk, including the type of IgA, is most similar to that found in our most closely related living primate, the chimpanzee(82). The evolutionary proximity of antibodies in milk from humans and closely related primates is also demonstrated in an antigen-binding specificity of the antibodies. A human antibody against the mammalian α-galactosyl epitope cross-reacts with enteric bacteria that display similar epitopes. This antibody specificity is common in apes and Old World monkeys, but is undetected in New World monkeys, prosimians, and other types of mammals(83) that are more distantly related to the genus Homo. IgA antibodies with that specificity are present in human milk(83). Thus, the evolutionary relationship of our species to other primates holds in respect to immune functions of the mammary gland.
Certain factors in mammalian milks are remarkably conserved in many mammalian species. They include antigenic similarities between the carboxy-terminal, intracytoplasmic regions of the Muc-1 mucins found in milks from humans and many other mammalian species(84) and structural similarities in lysozyme and α-lactalbumin in all mammalian species that have been investigated(85). In contrast, some immunologic functions of the mammary gland are not as highly conserved in certain mammalian species. Because of exposures to dissimilar environmental microorganisms, one might anticipate that certain immune responses by different orders of mammals diverged as a consequence of natural selection. Furthermore, because of major distinctions in the rate and degree of motor development, the type and extent of exposure to microorganisms by young infants of those species are not entirely alike. Thus, it would be predicted that immunologic adaptations to these different environments are also reflected in the immunologic composition of milk produced by those species. A striking example is the qualitative and quantitative immunologic differences between human and cow's milk (Table 2). The quantities and types of antimicrobial oligosaccharides and glycoconjugates(27) and the concentrations of Ig isotypes(24–26, 56, 86), lactoferrin(24–26), lysozyme(24–26), lactoperoxidase(87, 88), and complement components(31) are very different in milks from those species.
EVOLUTIONARY ASPECTS OF IMMUNE DEVELOPMENTAL DELAYS
The immune status of the newborn infant is an outcome of the development of the immune system and the maternal contributions that are received during fetal life. The production of certain components of the fetal immune system is delayed throughout pregnancy. There are two potential evolutionary reasons for these physiologic delays. The first is that the fetus is shielded from most microbial pathogens and therefore does not require the full-fledged defense system required for independent survival. Therefore, energy and nutritional factors can be directed toward developing other organ systems that will be required for immediate extrauterine life. The second reason is that the delays are adaptations to avoid untoward immunologic reactions to maternal tissues. Although the phenomenon is not unique to our species, the prevention of allograft rejection by the fetus against the mother or vice versa permits the prolonged gestation found in H. sapiens. The lag in the fetal immune system sets the stage for delays in the immunologic system that are manifest at birth.
Postnatal developmental delays in the immune system are found in every mammal that has been investigated. If such delays occurred in the earliest mammals before compensatory immune agents were present in milk, the progeny would have been at a survival disadvantage. It is more likely that the immune activities of the mammary gland permitted newborns of primitive mammals, who had evolved a slowed rate of immune development, to survive. Further development of the immune system of newborns of the immediate precursors of early mammals may have been delayed, but those developmental delays were compensated for by certain immune factors obtained from the egg yolk. This is suggested by the recent discovery of lysozyme in tortoise eggs(89). Thus, part of the evolutionary pattern may have been a switch from the immune factors provided in eggs to the immune system produced by the mammary gland.
In keeping with that contention, mirror-image patterns of immunologic development and immune factors in milk are found not only in eutherians(placentarians) but also in metatherians (marsupials) (Fig. 1) that are profoundly dissimilar from eutherians because of their choriovitelline placentas and the prolonged postnatal attachment of their atricial newborns (essentially fetuses) to the nipple of the mammary gland. In that respect, newborn infants of two species of the primitive marsupial family Didelphis, the North American Virginia opossum (Didelphis virginiana) and the Brazilian gray, short-tailed opossum(Monodelphis domestica) are immunologically immature(90, 91) and acquire passive immunity via maternal antibodies in milk(91, 92).
The isotypes of Igs in human and bovine milk (Table 2) and how they relate to the immunologic development of the off-spring are striking examples of different evolutionary adaptations. The fetal or newborn calf produces very little IgG(93, 94), and very little of that Ig is transmitted across the bovine epichordial placenta(93). Consequently, the concentration of IgG in extracellular fluids in the newborn calf is very low(93, 94). IgG is, however, the dominant Ig in bovine colostrum (Table 2)(86). This ingested IgG is intestinally absorbed during the immediate newborn period. As a result, adult concentrations of IgG are achieved in the extracellular fluids of the calf after the first nursing. The human fetus also does not produce IgG, but adult levels of serum IgG are attained at birth via transport across the placenta(11). In contrast, little IgG is found in human milk(28). The dominant Ig isotype in human milk is secretory IgA, a dimeric form of IgA bound to a portion of the polymeric Ig receptor, secretory component (Table 2)(24, 26, 28). Secretory IgA antibodies act principally to protect mucosal sites by neutralizing toxins and interfering with adherence of bacterial enteric and respiratory pathogens including Vibrio cholerae, Shigella species, E. coli, and Streptococcus pneumoniae to epithelial cells(28).
ADAPTATIONS PROTECT IMMUNE FACTORS IN HUMAN MILK
Evolutionary adaptations also enhance the survival of defense factors in human milk in the recipient infant. The nature of defense agents secreted by the mammary gland, their physical state in milk, antiproteases in milk, and the diminished ability of the recipient infant to process the factors are responsible for the enhancement. 1) Defense factors in human milk such as lactoferrin, lysozyme, and secretory IgA are inherently resistant to digestion(95–97), whereas others are compartmentalized and are thus shielded from digestive enzymes or denaturing conditions(98–100). 2) Antiproteases in human milk such as α1-antichymotrypsin andα1-antitrypsin protect immune agents in human milk that are proteins from digestion(101). 3) In addition, ingested defense factors in human milk are protected during the first month of life because stimulated gastric production of HCl(102, 103), and pancreatic secretion of trypsin and chymotrypsin(104–107) are very low at that time.
MAJOR FEATURES OF DEVELOPMENTAL DELAYS IN IMMUNITY AND PROVISION OF THOSE AGENTS BY THE HUMAN MAMMARY GLAND
One advantage of a delayed development of the immune system is that less energy and nutrients are required to maintain and mobilize the immune system of the infant. Indeed, when the immune system is challenged, a great deal of cell division and differentiation occurs(108). Both processes increase nutritional demands. Spared energy/nutrients may be used for the growth and development of the CNS(109, 110) and of alveoli and vascular structures of the lung(111).
The postnatal developmental delays are evolutionary successes because of compensatory maternal defense factors that that are transmitted to the infant via breastfeeding. They include antimicrobial, antiinflammatory, and immunomodulating agents in human milk. The antimicrobial factors are common to mucosal sites and protect by noninflammatory mechanisms. The provision of a wide spectrum of agents throughout lactation effectively prevents infections that the nursling may encounter. Furthermore, it is nutritionally efficient that the bulk of antimicrobial agents as well as other defense agents in human milk are used to nurture the recipient infant.
There are two general evolutionary strategies regarding antimicrobial agents in human milk. The first is a constitutive production of protective factors that is independent of exposure to infectious or other foreign agents. They include lactoferrin, lysozyme, glucoconjugates, and oligosaccharides. The second strategy is an antigen-dependent mechanism that leads to the production of secretory IgA antibodies that protect against enteric and respiratory pathogens.
The origin, specificity, and spectrum of the secretory IgA antibodies in human milk are achieved as follows. Maternal IgM+ B cells in Peyer's patches of the small intestine or in the submucosa of the tracheobronchial tree are programmed to recognize microbial antigens by the antigen-binding specificity of their surface IgM antibodies. When B cells encounter those antigens, they switch their surface membrane Ig isotype to IgA and migrate sequentially to local lymphatics, regional lymph nodes, major lymphatic vessels, and the systemic circulation(28). Under the influence of hormones produced late in pregnancy and during lactation(112), IgA+ B cells home to the mammary gland where they transform into plasma cells and secrete large amounts of dimeric IgA antibodies that bind to the same microbial antigens encountered at the maternal mucosal sites. Thus, these antibodies protect against mucosal pathogens in the maternal environment(28). Because the production of secretory IgA is delayed in newborn infants, those who are breast-fed are more resistant to enteric and respiratory pathogens than are non-breast-fed ones.
The increasing development of the immune system, including the ability to mount mucosal secretory antibody responses and the expansion of the antigen binding repertoire of antibodies, coincides with the onset of weaning and widening exposures of the infant to environments outside of the maternal sphere. Although the mammary gland produces antimicrobial agents throughout lactation, the need for the agents slowly declines as the infant's immune system matures.
The infant is exposed to microbial immunogens while receiving protective agents in human milk. This is tantamount to an attenuated immunization, in that the pathogenicity of the microbial agent is reduced by accompanying immune factors. One example is the transmission of infectious cytomegalovirus by breast-feeding. Cytomegalovirus is commonly excreted in human milk produced by seropositive women(30). Antiviral factors in human milk(30, 113) are simultaneously transmitted to the recipient infant. The infant becomes infected, develops a systemic immune response including the formation of specific antibodies, but does not become diseased. A second possible immunization mechanism provided by breast-feeding is the transfer of antiidiotypic secretory IgA antibodies into human milk(39). In this respect, idiotypic antibodies directed against binding sites of antibodies that recognize epitopes of foreign antigens serve as surrogates for foreign immunogens such as polioviruses(39).
In addition to the control over the bacterial enteric flora that is exerted by direct-acting antimicrobial agents in human milk, human milk provides growth factors that encourage the proliferation of a protective enteric flora. Certain glycoconjugates in human milk, particularly κ caseins(114), promote the growth of lactobacilli and bifidobacilli in the lower intestinal tract of the recipient. These bacteria produce large amounts of organic acids that inhibit the growth of bacterial enteropathogens such as Shigella and Salmonella sp. and E. coli.
Breast-feeding protects against infections without provoking inflammation(19, 22, 31). This may be explained by a paucity of inflammatory mediators in human milk and the presence of many antiinflammatory agents in milk(31–33, 115). It is likely that the inhibition of inflammation by those agents spares the functions of mucosal sites of the recipient infant. For example, platelet-activating factor-acetylhydrolase(33) and IL-10(100) in human milk may compensate for developmental delay in the production of those antiinflammatory factors(5, 6), and that may account in part for the decreased risk to necrotizing enterocolitis of newborn infants fed human milk(116).
Breast-feeding also prepares the recipient to resist certain immune-mediated diseases, such as type I diabetes mellitus(117), Crohn's disease(118), and lymphomas(119) that emerge in late childhood. The mechanisms are undetermined, but it is possible that some of the protection may be due to immunomodulators in human milk. The evolutionary consequences would be to permit the child to mature to a sexually active adult who could better cope with the environment. Further research will be required to examine that possibility.
Finally, it should be realized that some defense agents may be created after partial digestion of human milk constituents in the gastrointestinal tract of the recipient. For example, antiviral fatty acids and monglycerides liberated from milk fat by in vivo lipolysis disrupt enveloped viruses(30), and lactoferricin created by partial proteolysis of lactoferrin kills Candida albicans(120), certain enteric bacteria(121), and Giardia(122) by damaging their outer cell membranes(120–122).
Stabilization of these evolutionary processes is evidenced by a lack of geographic/ethnic variation in the immunologic development of the human infant and the composition of human milk as long as nutrient intake is not limiting(123). This suggests that those evolutionary outcomes are highly successful. Although no basic differences have been reported, subtle variations in the mammary gland immune system or the postnatal development of the immune system may have occurred in isolated populations. It is worthwhile to explore such possibilities by studying isoforms of immune agents in human milk and the definitive patterns of immune development. Such variations should be sought, but the evidence suggests that immune functions of the mammary gland and postnatal immune development are not influenced by ethnicity or geographic location.
The postnatal development of the human immune system and the immune functions of the mammary gland are related evolutionary events in all mammalian species. Consistent patterns of postnatal development of the immune system and immune functions of the mammary gland found in widely separated human populations suggest that this evolutionary embrace assisted in the dissemination of Homo sapiens from Africa to other environments(70, 71, 73, 124, 125) by enhancing infant survival. In that respect, breast-feeding protects against common infections in many populations.
Although the protection provided by breast-feeding is due mainly to defense agents in human milk that compensate for those that are not sufficiently produced by the infant, the relationships may be more complex. Delays in producing some agents may be linked to lags in appearance of others. That is suggested in a recent study that provided some evidence that the lag in IL-10 production may be secondary to a delayed TNF-α production and a reduced expression of TNF-α receptors(6). That is plausible because TNF-α is a potent stimulus for the production of IL-10(126). Furthermore, the rate of postnatal development of the production other agents such as antiadherent oligosaccharides and glycoconjugates that are well represented in human milk(27) is not established. Investigations will be needed to determine whether the production of those agents by the infant during the early postnatal period and by the mammary gland also evolved in a reciprocal pattern.
millions of years ago
tumor necrosis factor
Adderson EE, Johnston JM, Shackerford PG, Carroll WL 1992 Development of the human antibody repertoire. Pediatr Res 32: 257–263.
Boat TF, Kleinerman JI, Fanaroff AA 1977 Human tracheobronchial secretions: development of mucous glycoprotein and lysozyme-secreting systems. Pediatr Res 11: 977–980.
Cairo MS, Suen Y, Knoppel E, van de Ven C, Nguyen A, Sender L 1991 Decreased stimulated GM-CSF expression and GM-CSF gene expression but normal numbers of GM-CSF receptors in human term newborns as compared with adults. Pediatr Res 30: 362–367.
Cairo MS, Suen Y, Knoppel E, Dana R, Park L, Clark S, van de Ven C, Sender L 1992 Decreased G-CSF and IL-3 production and gene expression from mononuclear cells of newborn infants. Pediatr Res 31: 574–578.
Caplan MS, Hsueh W, Kelly A, Donovan M 1990 Serum PAF-acetylhydrolase increases during neonatal maturation. Prostaglandins 39: 705–714.
Chheda S, Palkowetz KH, Garofalo R, Rassin DK, Goldman AS 1996 Decreased interleukin-10 production by neonatal monocytes and T cells: relationship to decreased production and expression of tumor necrosis factor-α and its receptors. Pediatr Res 40: 475–483.
Hanson LA, Carlsson B, Dahlgren U 1980 The secretory IgA system in the neonatal period. Ciba Found Symp 77: 187–204.
Hanson LÅ, Soderstrom T, Brinton C, Carlsson B, Larsson P, Mellander L, Svanborg Eden C 1983 Neonatal colonization with Escherichia coli and the ontogeny of the antibody response. Prog Allergy 33: 40–52.
Lewis DB, Yu CC, Meyer J, English BK, Kahn SJ, Wilson CB 1991 Cellular and molecular mechanisms for reduced interleukin 4 and interferon-γ production by neonatal T cells. J Clin Invest 87: 194–202.
Miller LC, Isa S, LoPreste G, Schaller JG, Dinarello CA 1990 Neonatal interleukin-1β, interleukin-6, and tumor necrosis factor: cord blood levels and cellular production. J Pediatr 117: 961–965.
Toivanen P, Rossi T, Hirvonen T 1969 Immunoglobulins in human fetal sera at different stages of gestation. Experientia 25: 527–528.
Wilson CB, Westfall J, Johson L, Lewis DB, Dower SK, Alpert AR 1986 Decreased production of interferon-γ by human neonatal cells. Intrinsic and regulatory deficiencies. J Clin Invest 77: 860–867.
Yachie A, Takano N, Ohta K, Uehara T, Fujita S, Myawaki T, Taniguchi N 1992 Defective production of interleukin-6 in very small premature infants in response to bacterial pathogens. Infect Immun 60: 749–753.
Rowen JL, Smith CW, Edwards MS 1995 Group B streptococci elicit leukotriene B4 and interleukin-8 from monocytes: neonates exhibit a diminished response. J Infect Dis 172: 420–426.
Narayanan I, Prakash K, Bala S, Verma RK, Gujral VV 1980 Partial supplementation with expressed breast-milk for prevention of infection in low-birth-weight infants. Lancet 2: 561–563.
Winberg J, Wessner G 1971 Does breast milk protect against septicaemia in the newborn?. Lancet 2: 1091–1094.
Yu VYH, Jamieson J, Bajuk B 1981 Breast milk feeding in very low birthweight infants. Aust Paediatr J 17: 186–190.
Glass RI, Svennerholm AM, Stoll BJ, Khan MR, Hossain KM, Huq MI, Holmgren J 1983 Protection against Cholera in breast-fed children by antibodies in breast milk. N Engl J Med 308: 1389–1392.
Mata LJ, Urrutia JJ 1971 Intestinal colonization of breast-fed children in rural area of low socioeconomic level. Ann NY Acad Sci 176: 93–109.
Hayani KC, Guerrero ML, Morrow AL, Gomez HF, Winsor DK, Ruiz-Palacios GM, Cleary TG 1992 Concentration of milk secretory immunoglobulin A against Shigella virulence plasmid-associated antigens as a predictor of symptom status in Shigella-infected breast-fed infants. J Pediatr 121: 852–856.
Mata LJ, Urrutia JJ, García B, Fernández R, Behar M 1969 Shigella infection in breast-fed Guatemalan Indian neonates. Am J Dis Child 117: 142–146.
Duffy LC, Riepenhoff-Talty M, Byers TE, La Scolea LJ, Zielezny MA, Dryja DM, Ogra PL 1986 Modulation of rotavirus enteritis during breastfeeding. Am J Dis Child 140: 1164–1168.
Pullan CR, Toms GL, Martin AJ, Gardner PS, Webb JKG, Appleton DR 1980 Breast-feeding and respiratory syncytial virus infection. BMJ 281: 1034–1036.
Goldman AS, Garza C, Johnson CA, Nichols BL, Goldblum RM 1982 Immunologic factors in human milk during the first year of lactation. J Pediatr 100: 563–567.
Goldman AS, Garza C, Goldblum RM 1983 Immunologic components in human milk during the second year of lactation. Acta Paediatr Scand 72: 461–462.
Butte NF, Goldblum RM, Fehl LM, Loftin K, Smith EO, Garza C, Goldman AS 1984 Daily ingestion of immunologic components in human milk during the first four months of life. Acta Paediatr Scand 73: 296–301.
Newburg D 1996 Oligosaccharides and glycoconjugates in human milk. J Mammary Gland Biol Neopl 1: 271–283.
Telemo E, Hanson LÅ 1996 Antibodies in milk. J Mammary Gland Biol Neopl 1: 243–249.
Yolken RH, Peterson JA, Vonderfecht SL, Fouts ET, Midthun K, Newburg DS 1992 Human milk mucin inhibits rotavirus replication and prevents experimental gastroenteritis. J Clin Invest 90: 1984–1991.
May JT 1994 Antimicrobial factors and microbial contaminants in human milk: recent studies. J Paediatr Child Health 30: 470–475.
Goldman AS, Thorpe LW, Goldblum RM, Hanson LÅ 1986 Anti-inflammatory properties of human milk. Acta Paediatr Scand 75: 689–695.
Buescher SE, McIlheran SM 1992 Colostral antioxidants: separation and characterization of two activities in human colostrum. J Pediatr Gastroenterol Nutr 14: 47–56.
Furukawa M, Narahara H, Yasuda K, Johnston JM 1993 Presence of plateletactivating factor-acetylhydrolase in milk. J Lipid Res 34: 1603–1609.
Leach JL, Baxter JH, Moliter BE, Ramstack MB, Masor ML 1995 Total potentially available nucleosides of human milk by stage of lactation. Am J Clin Nutr 61: 1224–1230.
Eglinton BA, Roberton DM, Cummin AG 1994 Phenotype of T cells, their soluble receptor levels, and cytokine profile of human breast milk. Immunol Cell Biol 72: 306–313.
Goldman AS, Chheda S, Garofalo R, Schmalstieg FC 1996 Cytokines in human milk: properties and potential effects upon the mammary gland and the neonate. J Mammary Gland Biol Neopl 1: 251–258.
Gasparoni A, Chirico G, De Amici M, Ravagni-Probizer M, Ciardelli L, Marchesi ME, Rondini G 1996 Granulocyte-macrophage colony-stimulating factor in human milk [letter]. Eur J Pediatr 155: 69
Goldman AS, Chheda S, Garofalo R 1997 Spectrum of immunomodulating agents in human milk. Int J Pediatr Hematol/Oncol 4: 491–497.
Hahn-Zoric M, Carlsson B, Jeansson O, Ekre O, Osterhaus AD, Roberton DM, Hanson LÅ 1993 Anti-idiotypic antibodies to polio virus in commercial immunoglobulin preparations, human serum, and milk. Pediatr Res 33: 475–480.
Goldman AS, Goldblum RM 1996 Transfer of maternal leukocytes to the infant by human milk. In: Olding L (ed). Reproductive Immunology/Current Topics in Microbiology and Immunology. Springer-Verlag, Heidelberg, pp 205–213.
Wirt DP, Adkins LT, Palkowetz KH, Schmalstieg FC, Goldman AS 1992 Activatedmemory T lymphocytes in human milk. Cytometry 13: 282–290.
Keeney SE, Schmalstieg FC, Palkowetz KH, Rudloff HE, Goldman AS 1993 Activated neutrophils and neutrophil activators in human milk. Increased expression of CD11b and decreased expression of L-selectin. J Leukoc Biol 54: 97–104.
Ozkaragoz F, Rudloff HE, Rajaraman S, Mushtaha AA, Schmalstieg FC, Goldman AS 1988 The motility of human milk macrophages in collagen gels. Pediatr Res 23: 449–452.
Bertotto A, Gerli R, Fabietti G, Crupi S, Arcangeli C, Scalise F, Vaccaro R 1990 Human breast milk T cells display the phenotype and functional characteristics of memory T cells. Eur J Immunol 20: 1877–1880.
Head JR, Beer AE, Billingham RE 1977 Significance of the cellular component of the maternal immunologic endowment in milk. Transplant Proc 9: 1465–1471.
Schnorr KL, Pearson LD 1983 Intestinal absorption of maternal leukocytes by newborn lambs. J Reprod Immunol 6: 329–337.
Jain L, Vidyasagar D, Xanthou M, Ghai V, Shimada S, Blend M 1989 In vivo distribution of human milk leucocytes after ingestion by newborn baboons. Arch Dis Child 64: 930–933.
Pabst HF, Godel J, Grace M, Cho H, Spady DW 1989 Effect of breast-feeding on immune response to BCG vaccination. Lancet 1: 295–297.
Eissa AM, Saad MA, Ghaffar AK, el-Sharkaway IM, Kamal KA 1989 Transmission of lymphocyte responsiveness to schistosomal antigens by breast feeding. Trop Geogr Med 41: 208–212.
Darwin C 1859 On the Origin of Species by Means of Natural Selection, or the Preservation of Favoured Races in the Struggle for Life, 1st Ed. John Murray, London
Mayr E 1991 One Long Argument. Charles Darwin and the Genesis of Modern Evolutionary Thought. Harvard University Press, Cambridge, MA
Gould SJ 1994 The evolution of life on the earth. Sci Am 271: 84–91.
Nei M, Stephens JC, Saitou N 1985 Methods for computing the standard errors of branching points in an evolutionary tree and their application to molecular data from humans and apes. Mol Biol Evol 2: 66–85.
Templeton AR 1985 The phylogeny of the hominoid primates: a statistical analysis of the DNA-DNA hybridization data. Mol Biol Evol 2: 420–433.
Smith LC, Davidson EH 1994 The echinoderm immune system. Characters shared with vertebrate immune systems and characters arising later in deuterostome phylogeny. Ann NY Acad Sci 712: 213–226.
Blackburn DG 1993 Lactation: historical patterns and potential for manipulation. J Dairy Sci 76: 3195–3212.
Griffiths M 1988 The platypus. Sci Am 258: 84–91.
Stewart ME 1992 Sebaceous gland lipids. Semin Dermatol 11: 100–105.
Anasi S, Koseki S, Hozum Y, Kondo S 1995 An immunohistochemical study of lysozyme, CD-15 (Leu M1), and gross cystic disease fluid protein-15 in various skin tumors. Assessment of the specificity and sensitivity of markers of apocrine differentiation. Am J Dermatopathol 17: 249–255.
Alemany R, Vila MR, Franci C, Egea G, Real FX, Thomson TM 1993 Glycosyl phosphatidylinositol membrane anchoring of melanotransferrin(p97): apical compartmentalization in intestinal epithelial cells. J Cell Sci 104: 1155–1162.
Tehan CG, McKenzie HA, Griffiths M 1991 Some monotreme milk “whey” and blood proteins. Comp Biochem Physiol 99B: 99–118.
Tehan CG, McKenzie HA 1990 Iron(III) binding proteins of echidna (Tachyglossus aculeatus) and platypus(Ornithorhynchus anatinus). Biochem Int 22: 321–328.
Messer M, Gadiel PA, Ralston GB, Griffiths M 1983 Carbohydrates of the milk of the platypus. Aust J Biol Sci 36: 129–137.
Jenkins GA, Bradbury JH, Messer M, Trifonoff E 1984 Determination of the structures of fucosyl-lactose and difucosyl-lactose from the milk of monotremes, using 13C-nmr spectroscopy. Carbohydr Res 126: 157–161.
Cervantes LE, Newburg DS, Ruiz-Palacios GM 1995 α1-2-Fucosylated chains (H-2 and Lewisb) are the main human milk receptor analogs for Campylobacter. Pediatr Res 37: 171A
Crane JK, Azar SS, Stam A, Newburg DS 1994 Oligosaccharides from human milk block binding and activity of the Escherichia coli heat-stable enterotoxin (Sta) in T84 intestinal cells. J Nutr 124: 2358–2364.
Yadav M, Stanley NF, Waring HC 1972 The microbial flora of the gut of the pouch young and the pouch of a marsupial, Setonix brachyurus. J Gen Microbiol 70: 437–442.
White TD, Suwa G, Asfaw B 1994 Australopithecus ramidus, a new species of early hominid from Aramis, Ethiopia. Nature 371: 306–312.
Hill A, Ward S, Deino A, Curtis A, Drake R 1992 Earliest Homo. Nature 355: 719–722.
Larick R, Ciochon RL 1996 The African emergence and early Asian dispersals of the genus Homo. Am Sci 84: 538–551.
Ayala FJ 1995 The myth of Eve: molecular biology and human origins. Science 270: 1930–1936.
Collura RV, Stewart C-B 1995 Insertions and duplications of mtDNA in the nuclear genomes of Old World monkeys and hominoids. Nature 378: 485–489.
Hammer M. F. 1995 A recent common ancestry for human Y chromosomes. Nature 378: 376–378.
Schrenk F, Bromage T, Betzler G, Ring U, Juwayeyi YM 1995 Oldest Homo and Pliocene biogeography of the Malawi rift. Nature 365: 833–836.
Stringer CB, Andrews P 1988 Genetic and fossil evidence for the origin of modern humans. Science 239: 1263–1268.
Takahata N, Satta Y, Klein J 1995 Divergence time and population size in the lineage leading to modern humans. Theor Popul Biol 48: 198–221.
Wood B 1992 Origin and evolution of the genusHomo. Nature 355: 783–790.
Edwards JH 1994 Comparative genome mapping in mammals. Curr Opin Genet Dev 4: 861–867.
Goodman M, Bailey WJ, Hayasaka K, Stanhope MU, Slightom J, Czelusniak J 1994 Molecular evidence on primate phylogeny from DNA sequences. Am J Phys Anthropol 94: 3–24.
Shoshani J, Groves CP, Simons EL, Gunnell GF 1996 Primate phylogeny: morphological vs. molecular results. Mol Phylogenet Evol 5: 102–154.
Watkins DI 1995 The evolution of major histocompatibility class I genes in primates. Crit Rev Immunol 15: 1–29.
Cole MF, Hale CA, Shurzenegger S 1992 Identification of two subclasses of IgA in the chimpanzee (Pan troglodytes). J Med Primatol 21: 275–278.
Galili U 1993 Evolution and pathophysiology of the human natural anti-α-galactosyl IgG (anti-Gal) antibody. Springer Semin Immunopathol 15: 155–171.
Pemberton L, Taylor-Papadimitriou J, Gendler SJ 1992 Antibodies to the cytoplasmic domain of the MUC1 mucin show conservation throughout mammals. Biochem Biophys Res Commun 185: 167–175.
Acharya KR, Stuart DI, Phillips DC, McKenzie HA, Teahan CG 1994 Models of the three-dimensional structures of echidna, horse, and pigeon lysozymes: calcium-binding lysozymes and their relationship withα-lactalbumins. J Protein Chem 13: 569–584.
Norcross NL 1982 Secretion and composition of colostrum and milk. J Am Vet Med Assoc 181: 1057–1060.
Gothefors, L., Marklund S 1975 Lactoperoxidase activity in human milk and in saliva of newborn infants. Infect Immun 11: 1210–1215.
Reiter B 1985 The lactoperoxidase system of bovine milk. In: Pritt RM, Tenovuo J (eds) The Lactoperoxidase System: Chemistry and Biologic Significance. Marcel Dekker, New York, pp 123–144.
Aschaffenburg R, Blake CCF, Dickie HM, Gayen SK, Keegan R, Sen A 1980 The crystal structure of tortoise egg-white lysozyme at 6Å resolution. Biochim Biophys Acta 625: 64–71.
Rowlands DT Jr, Blakeslee D, Lin H 1972 The early immune response and immunoglobulins of opossum embryos. J Immunol 108: 941–946.
Samples NK, Vanderberg JL, Stone WH 1986 Passively acquired immunity in the newborn of a marsupial (Monodelphis domestica). Am J Reprod Immunol Microbiol 11: 94–97.
Hindes RD, Mizell M 1976 The origin of immunoglobulins in opossum “embryos”. Dev Biol 53: 49–61.
Banks KL 1982 Host defenses of the newborn infant. J Am Vet Med Assoc 181: 1053–1055.
Osburn BI, MacLachan NJ, Terrell TG 1982 Ontogeny of the immune system. J Am Vet Med Assoc 181: 1053–1055.
Brines RD, Brock JH 1983 The effect of trypsin and chymotrypsin on the in vitro antimicrobial and iron-binding properties of lactoferrin in human milk and bovine colostrum. Unusual resistance of human apolactoferrin to proteolytic digestion. Biochim Biophys Acta 795: 229–235.
Lindh E 1985 Increased resistance of immunoglobulin dimers to proteolytic degradation after binding of secretory component. J Immunol 113: 284–286.
Schanler RJ, Goldblum RM, Garza C, Goldman AS 1986 Enhanced fecal excretion of selected immune factors in very low birth weight infants fed fortified human milk. Pediatr Res 20: 711–714.
Rudloff HE, Schmalstieg FC, Mushtaha AA, Palkowetz KH, Liu SK, Goldman AS 1992 Tumor necrosis factor-α in human milk. Pediatr Res 31: 29–33.
Rudloff HE, Schmalstieg FC, Palkowetz KH, Paszkiewicz EJ, Goldman AS 1993 Interleukin-6 in human milk. J Reprod Immunol 23: 13–20.
Garofalo R, Chheda S, Mei F, Palkowetz KH, Rudloff HE, Schmalstieg FC Jr, Goldman AS 1995 Interleukin-10 in human milk. Pediatr Res 37: 444–449.
Lindberg T, Ohlsson K, Westrom B 1982 Protease inhibitors and their relation to protease activity in human milk. Pediatr Res 16: 479–483.
Euler AR, Byrne WJ, Meis PJ, Leake RD, Ament ME 1979 Basal and pentagastrin-stimulated acid secretion in newborn human infants. Pediatr Res 13: 36–37.
Agunod M, Yamaguchi N, Lopez R, Luhby AL, Glass GB 1969 Correlative study of hydrochloric acid, pepsin, and intrinsin factor secretion in newborns and infants. Am J Dig Dis 14: 400–414.
Lebenthal E, Lee PC 1980 Development of functional response in human exocrine pancreas. Pediatrics 66: 556–560.
Bujanover Y, Harel A, Geter R, Blau H, Yahav J, Spirer Z 1988 The development of the chymotryptic activity during postnatal life using the bentiromide test. Int J Pancreatol 3: 53–58.
Lindberg T 1974 Proteolytic activity in duodenal juice in infants, children, and adults. Acta Paediatr Scand 63: 805–808.
Boehm G, Bierbach U, Del Santo A, Moro G, Minoli I 1995 Activities of trypsin and lipase in duodenal aspirates of healthy preterm infants: effects of gestational and postnatal age. Biol Neonate 67: 248–253.
Goldman AS, Prabhakar B 1996 Immunology. In: Baron SB(ed) Medical Microbiology, 4th Ed. The University of Texas Medical Branch Press, Galveston TX, pp 1–34.
Dobbing J, Sands J 1973 Quantitative growth and development of human brain. Arch Dis Child 48: 757–767.
Winick M, Rosso P, Waterlow J 1970 Cellular growth of cerebrum, cerebellum, and brain stem in normal and marasmic children. Exp Neurol 26: 393–400.
Tschanz SA, Damke BM, Burri PH 1995 Influence of postnatally administered glucocorticoids on rat lung growth. Biol Neonate 68: 229–245.
Weisz-Carrington P, Roux ME, McWilliams M, Phillips-Quaglita JM, Lamm ME 1978 Hormonal induction of the secretory immune system in the mammary gland. Proc Natl Acad Sci USA 75: 2928–2932.
Harmsen MC, Swart PJ, de Bethune MP, Pauwels De Clercq E, The TH, Meijer DK 1995 Antiviral effects of plasma and milk proteins: lactoferrin shows potent activity against both human immunodeficiency virus and human cytomegalovirus in vitro. J Infect Dis 172: 380–388.
Bezkorovainy A, Topouzian N 1981 Bifidobacterium bifidus var. Pennsylvanicus growth promoting activity of human milk casein and its derivatives. Int J Biochem 13: 585–590.
Park PW, Biedermann K, Mecham L, Bissett DL, Mecham RP 1996 Lysozyme binds to elastin and protects elastin from elastase-mediated degradation. J Invest Dermatol 106: 1075–1080.
Lucas A, Cole TJ 1990 Breast milk and neonatal necrotising enterocolitis. Lancet 336: 1519–1523.
Mayer EJ, Hamman RF, Gay EC, Lezotte DC, Savitz DA, Klingensmith GJ 1988 Reduced risk of IDDM among breast fed children. The Colorado IDDM Registry. Diabetes 37: 1625–1632.
Koletzko S, Sherman P, Corey M, Griffiths A, Smith C 1989 Role of infant feeding practices in development of Crohn's disease in childhood. BMJ 298: 1617–1618.
Davis MK, Savitz DA, Grauford B 1988 Infant feeding in childhood cancer. Lancet 2: 365–368.
Bellamy W, Wakabayashi H, Takase M, Kawase K, Shimamura S, Tomita M 1993 Killing of Candida albicans by lactoferricin B, a potent antimicrobial peptide derived from the N-terminal region of bovine lactoferrin. Med Microbiol Immunol 182: 97–105.
Yamauchi K, Tomita M, Giehl TJ, Ellison RT 1993 Antibacterial activity of lactoferrin and a pepsin-derived lactoferrin peptide fragment. Infect Immun 61: 719–728.
Turchany JM, Aley SB, Gillin FD 1995 Giardicidal activity of lactoferrin and N-terminal peptides. Infect Immun 63: 4550–4552.
Hamosh M, Dewey KG, Garza C, Goldman AS, Lawrence RA, Picciano MF, Quandt SA, Rasmussen KM, Rush D 1991 Nutrition During Lactation. National Academy of Sciences Press, Washington DC
Ayala FJ, Escalante AA 1996 The evolution of human populations: a molecular perspective. Mol Phylogenet Evol 5: 188–201.
Waddle DM 1994 Matrix correlation tests support a single origin for modern humans. Nature 368: 452–454.
Wanidworanun C, Strober W 1993 Predominant role of tumor necrosis factor-α in human monocyte IL-10 synthesis. J Immunol 151: 6853–6861.
The authors thank Samuel Baron (University of Texas Medical Branch). Cutberto Garza (Cornell), Daniel Goldman (Austin, TX), Ernst Mayr (Harvard), David Rassin (University of Texas Medical Branch), and the editors and reviewers of this journal for their thoughtful suggestions, and Robert Goldman (Houston, TX) and Susan Kovacevich for their assistance in the preparation of this manuscript.
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Goldman, A., Chheda, S. & Garofalo, R. Evolution of Immunologic Functions of the Mammary Gland and the Postnatal Development of Immunity. Pediatr Res 43, 155–162 (1998). https://doi.org/10.1203/00006450-199802000-00001
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