Ever since the late 20th century, it has been accepted that the lactating human mammary gland elaborates a complex immunological system uniquely adapted to protect the recipient infant. It is not well appreciated, however, that many basic discoveries concerning these matters were made long before the era of molecular biology. Observations during the eighteenth and nineteenth centuries in Europe suggested that mortality was lower in breastfed than in non-breastfed infants. The basis of this protection was unknown. Although similar but more structured observations were made in the first part of the twentieth century (Westergaard, 1901; Groth and Hahn, 1910; Davis, 1913; Woodbury, 1922, 1925; Gruleeet al.1934, 1935) there was little scientific information concerning the immunology of human milk or of milk obtained from other species. This was partly because most of the immune system was not uncovered until the latter part of the twentieth century. However, discoveries concerning the protective properties of milk from humans and other mammalian species that were made during the nineteenth and early twentieth centuries provided the foundation for the molecular research that came thereafter. Furthermore, it is striking that these discoveries were made by individuals eminent in the history of immunology and medicine. Then in the mid-twentieth century, critical information was that led to the paradigm of an immune system in human milk and to the reslization that the system comprises not only antimicrobial factors but also anti-inflammatory and immunomodulating agents. Parallel investigations indicated that immune systems were in other mammalian milks. Because of many differences in the immune systems were in other from the various mammalian species, the scope of the information in this review will be limited to limited to key discoveries concerning the immunological aspects of human milk.
Breast milk transmission of maternal viral infection is well established for CMV and HIV-1. In the case of CMV, this usually does not pose a risk to the infant since serious disease is prevented by placentally transferred maternal antibody. However, in HIV infection, breast-feeding increases the risk of maternal-fetal transmission by about 25% with late breast-feeding (after six months of age) constituting a particular risk. In other maternal viral diseases, e.g., other herpes viruses, parvovirus, hepatitis A, B and C, and rubella, the virus is often demonstrated in the breast milk, but transmission is very rare. The highest risk is during an acute viral infection at the time of birth, since the breast milk has a high titer of virus, and a lack of antibody to neutralize the organism.
Newborn mammals emerge from the clean, stable and sterile uterus into a world where they are immediately exposed to an enormous variety of microorganisms. If they are to survive, newborns therefore must be able to control microbial invasion. The immune system, however, may not be ready for this defensive role. In mammals with a short gestation period such as the marsupials, the immune system may not have developed fully. In mammals with a long gestation period such as the domestic herbivores, although the immune system is structurally complete at birth, it cannot function fully for several weeks. The complete development of immune capability depends on antigenic stimulation. The development of adequate numbers of antigen-sensitive lymphocytes depends on clonal selection and antigen-driven cell multiplication. The first immune responses mounted by a newborn animal must be primary responses with a prolonged lag period and low concentrations of antibodies produced. Thus newborn mammals are highly vulnerable to microbial invasion for the first few weeks of life and unless immunological assistance is provided, they may be killed by microorganisms that present little threat to an adult. This "immunological assistance" is provided by antibodies and other proteins transferred from the mother to her offspring through the placenta and/or by antibodies and lymphocytes transferred through colostrum and milk.
Milk contains a multitude of components that can, or may, provide immune protection to the suckling offspring and that also may promote development of neonatal immune competence. In addition, these specialized factors are essential for the protection of the mammary gland, the offspring's food source, from pathogen colonization and lactation failure. Breast milk also facilitates the establishment of a gut flora that inhibits colonization by many pathogens and stimulates the growth of beneficial microorganisms. Maternal immunity can be transferred to the infant via antibodies, primarily of the sIgA type in humans, as well as by leukocytes including effector and memory T lymphocytes. In this way, protection is provided passively against the pathogens to which the mother has been exposed. Currently, there is much interest in determining the protective efficacy of oral supplementation with immunoglobulins from the milk of lactating animals hyperimmunized against specific pathogens. An array of immunostimulatory components in milk, notably cytokines, may be protected against intestinal proteolysis, thereby providing the offspring with a prepackaged immune response system. These components may help to boost the infant's immature immune system. At the same time, anti-inflammatory factors in breast milk help to modulate cytokine responses to infection, thereby facilitating defense while minimizing tissue damage such as that which occurs in infants with necrotizing enterocolitis. Undoubtedly, the many components constituting the repertoire of immune and immunomodulating agents in milk interact synergistically to protect both the mammary gland and the offspring from invading pathogenic microorganisms.
Milk lipids serve not only as nutrients but as antimicrobial agents that constitute a defense system against microbial infections that occur at mucosal surfaces. The lipid fraction of milk develops antimicrobial activity in the gastrointestinal tract of suckling neonates as a result of lipolytic activity which converts milk triglycerides to antimicrobial fatty acids and monoglycerides. Antimicrobial milk lipids may be particularly important in protecting infants with an inadequate secretory immune response from infection. The lipid-dependent antimicrobial activity of milk is due to medium-chain saturated and long-chain unsaturated fatty acids and their respective monoglycerides released by lipases in the gastrointestinal tract. The antimicrobial activity of fatty acids and monoglycerides is additive and consequently it is their combined concentration that determines the lipid-dependent antimicrobial activity of milk. Microbial inactivation occurs rapidly by membrane destabilization. The antimicrobial activity of milk lipids can be duplicated using purified fatty acids and monoglycerides. It should be possible, therefore, to supplement banked human milk to provide lipid-dependent antimicrobial activity from the moment of ingestion (Schanler et al., 1986). This could reduce the risk of viral transmission from mother to infant through milk. Milk lipids also could be adapted for use at mucosal surfaces other than those in the gastrointestinal tract to reduce vertical transmission of pathogens during birth.
The immunoprotective constituents of human milk are stable when stored at room temperature for 8 hours, when stored at 0 degree-4 degrees C for three days, or when frozen at -20 degrees C for 12 months. They are also stable during pasteurization at 56 degrees C for 30 minutes. Sonification may reduce levels of sIgA and lysozyme and the ability of milk to inhibit growth of E coli. The number of cells in human milk is reduced by storage, freezing, pasteurizing, microwaving and sonification, and the functional capacity of surviving cells is also reduced.
The ability of highly developed organisms to defend themselves against invading microorganisms depends on recognizing and destroying dangerous substances such as microbes and their toxins. Recognition and destruction are tasks of the immune system, primarily of the leukocytes. Subpopulations of leukocytes variously release antimicrobial substances such as immunoglobulins, lysozyme, complement factors and reactive oxygen metabolites into the cellular environment upon exposure to an antigenic stimulus, and they also ingest foreign materials or secrete cytokines which regulate the immune response. During lactation a mother can pass immunogenic substances to her offspring through her mammary secretions. These compounds in colostrum and milk are an important, if not decisive, part of the adoptive transfer of immunity from mother to offspring in many species. Most scientific investigations into the adoptive transfer of immunity through milk have focused on immunoglobulins rather than on leukocytes. However, adoptive transfer of the cells in milk also appears to occur. It is important to explain how immunocompetent maternal leukocytes can modulate immune responses in the newborn without recognizing and destroying the neonate’s leukocytes and tissues as nonself elements that bear different, paternally-derived major histocompatibility complex (MHC) antigens. Conversely, why don’t the immunocompetent leukocytes of the newborn attack and eliminate milk-derived cells that bear a maternal MHC? An important purpose of this chapter is to address these intriguing questions to the extent that current data permit. Another important question is whether mammary leukocytes have any protective role or whether the milk is simply a convenient route of excretion for these cells. A full understand-ing of the anti-microbial action of mammary gland leukocytes for all mammalian species must await more exhaustive study.
Hip fracture incidence seems to be lower in Japan than in many Western countries, but the difference is apparently becoming smaller with progressive Westernization of the Japanese lifestyle and nutritional habits. Nutrition cannot explain the lower incidence of hip fracture. A lower calcium intake prevails in Japan. Genetic differences in body build, including a lower center of gravity, better motor function and agility, well developed hip musculature and small but more fracture-resistant bones secondary to a difference in life- and work-style may contribute to fewer falls and a lower fracture rate among Japanese than among their Western counterparts. Such traditional lifestyle habits as sitting directly on the floor are rapidly decreasing, and time will tell how much of the low incidence of hip fracture in Japan can be explained by lifestyle and how much by genetic and other factors. The Japanese women who now enjoy a low hip fracture incidence led a hard physical life when they were young. This may be a lesson to the young of future generations in how to avoid bone fractures when they are old. Bone health may be achieved by enjoying life through sports or even the tea ceremony in place of the hard physical work of their ancestors, which is gradually disappearing.
