The composition of mature milk remains constant after 6 weeks through the remainder of the lactation period. The amount of Igs and LF in milk decreases over the first 3—4 months, while the amount of lysozyme increases Tregoat et al. More recent published studies using proteomic analysis of human milk 16 , 64 , 89 continue to facilitate our understanding of the complex nature of human milk and its role related to immune function and intestinal development.
They describe a large percentage of milk proteins having to do with immune function including complement factors and serine protease inhibitors important in regulating the complement system. The quantities of these factors declined in transition from colostrum to mature milk.
They also identified proteins associated with the extracellular matrix including cytokines, fibronectin, tenascin, and OPN. These proteins were more prevalent in transitional milk. Glutathione and antioxidant activity-related proteins were more common in mature milk.
Overall, the quantity of immune factors and immune effects of human milk diminish over time in parallel with the developing immune system of the infant. Nevertheless, it will be essential to understand the specific roles of the various bioactive components of human milk and how the change in milk composition over time influences the evolving effects of human milk on the intestine and innate immunity. Preterm babies require additional nutrition and immune protection compared to term infants.
Interestingly, preterm breast milk has been found to contain increased nutrients such as protein 90 and higher concentrations of certain immune factors.
Preterm human milk also has higher amounts of phagocytes and secretory IgA These increased amounts may serve a protective role since premature infants have poorly functioning neutrophils, limited production of Igs, and lower levels of passively acquired Igs.
A few studies reported a difference in breast milk microbiome when comparing preterm and term milk. Some trends include more Bifidobacterium in term milk 91 and more Enterococcus in preterm milk A study looking at preterm infants, testing stool and breast milk samples, found a high proportion of antibiotic-resistant high-risk clones in both fecal and milk samples during the neonatal intensive care unit NICU admission Differences are also seen in gut microbiome between term and preterm infants.
Variations in microbiota of preterm infants have been described as predisposing to development of necrotizing enterocolitis NEC 93 — Hormones and cytokines also vary by gestational age. EGF has anti-inflammatory properties and is higher in preterm milk compared to full-term milk 24 The cytokine IL, with anti-inflammatory properties, was detected in lower amounts in breast milk for infants with increased risk of NEC Trend et al.
Castellote et al. A study by Maheshwari et al. This is particularly important in preterm infants who are at increased risk of late-onset sepsis. The hBD-1 was higher in preterm colostrum compared to term colostrum Wang et al. Armogida et al. The amount of LF in human milk does not seem to be affected by gestational age 99 but is more dependent on milk volume expressed.
There are conflicting results for concentrations of lysozyme in preterm and term milk. It has been proposed that the increased levels of immune factors in preterm milk may be a result of a compensatory mechanism whereby in the mother during preterm labor, the breast shifts the immune content of the milk to provide more protection. Another explanation suggested by Goldman et al. The mechanisms for the differences between preterm and term milk remain unknown. Interestingly, most immune factors decrease over the first month regardless of gestational age, thus term and preterm milk become more similar over time as the chronological age of the baby increases.
As Lars Bode et al. The cells, the microbes, and the bioactive factors make milk alive, and the interactions of human milk with its natural host, the infant, create a symbiotic commensal relationship. This is the challenge to explain and understand the complexity and dynamic relationship between the everchanging secretion, human breast milk and the developing, evolving human infant.
All authors have made substantial, direct, and intellectual contribution to the work and approved it for publication. NC is primarily responsible for Figure 1. The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
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Naturally acquired passive immunity occurs during pregnancy, in which certain antibodies are passed from the maternal blood into the fetal bloodstream in the form of IgG.
Antibodies are transferred from one person to another through natural means such as in prenatal and postnatal relationships between mother and child.
Some antibodies can cross the placenta and enter the fetal blood. This provides some protection for the child for a short time after birth, but eventually these deteriorate and the infant must rely on its own immune system.
Antibodies may also be transferred through breast milk. The spleen, where plasma cells responsible for antibody production reside, is the major site of specific IgM production Capolunghi et al. IgG is the main type of antibody found in blood and extracellular fluid allowing it to control infection within body tissues.
Immunoglobulin A IgA plays a crucial role in the immune function of mucous membranes. The amount of IgA produced in association with mucosal membranes is greater than all other types of antibodies combined Fagarasan and Honjo ; Holmgren and Czerkinsky ; Snoeck et al. However, recent discoveries of IgD in ancient vertebrates suggest that IgD has been preserved in evolution from fish to humans for important immunological functions Chen and Cerutt Immunoglobulin E IgE has only been identified in mammals.
IgE also has an essential role in type I hypersensitivity Gould et al. Antibodies bind antigens at the upper tips of the Y molecule. The region of antigen where binding occurs is called the epitope Fig.
Antibodies can bind to a wide range of chemical structures and can discriminate among related compounds. How well the antibody binds to an antigen is known as affinity.
This affinity can range from low to high. Mammals are born without a fully functional adaptive immune system even though the basic elements are present. When a mammal is born, it emerges from the sterile uterus into an environment where it is immediately exposed to a host of microorganisms. The gastrointestinal tract GIT acquires a complex microbial flora within hours. If it is to survive, the newborn animal must be able to control this microbial invasion. In practice, the adaptive immune system takes some time to become fully functional, and innate mechanisms are responsible for the initial resistance to infection.
In some species with a short gestation period, such as mice, the adaptive immune system may not even be fully developed at birth. In animals with a long gestation period, such as domestic mammals, the adaptive immune system is fully developed at birth but cannot function at adult levels for several weeks. The complete development of active immunity depends on antigenic stimulation.
The proper development of B cells and B-cell receptor diversity requires clonal selection and antigen-driven cell multiplication. Thus, newborn mammals are vulnerable to infection for the first few weeks of life. They need assistance in defending themselves at this juncture. Temporary help is provided by the mother in the form of colostrum, which contains antibodies.
The passive transfer of immunity from mother to newborn is essential for survival. Calves are born without an active immune system and rely on the consumption of antibodies for protection from disease such as scours and pneumonia. The cow provides its calf with nutrients for growth and development during gestation, but the cow cannot directly provide the calf with antibodies to protect it from diseases.
Fortunately, immunoglobulins form an important component of the immunological activity found in milk and colostrum. While humans have a large amount of IgA in their colostrum, the colostrum from most other animals contains a high percentage of IgG Hurley and Theil Fig. Immunoglobulins found in mammary secretions arise from systemic and local sources.
In the case of IgG in milk, the major portion comes from the serum Mayer et al. While plasma cells producing IgG may occur within the mammary tissue, their contribution to the IgG in colostrum is minor compared with the IgG derived from serum.
The other major classes of immunoglobulins transported into colostrum and milk are IgA and IgM. Immunoglobulin A IgA is the major immunoglobulin in human colostrum and milk; however, it is also present in milk of most other species. Much of this is produced by plasma cells in the mammary tissue.
GALT is a part of the mucosa-associated lymphoid tissue and works in the immune system to protect animals from invasion of pathogens in the gut. One of the physiological functions of the mucosa in the gut is for food absorption. This provides a rationale for the observations that bovine colostrum from nonimmunized cows may also afford passive immune protection against human pathogens in both humans and animals Li-Chan et al.
Antibodies must be obtained by drinking colostrum within the first couple of hours after birth as part of the passive immunization system in order to maximize antibody absorption Pakkanen and Aalto Like other animals, antibodies are generated by healthy cows as a result of every day exposure to infectious agents.
Antibodies can also be the result of specific vaccination programs. The level of antibodies transmitted from the cow through the colostrum can be elevated by a pre-calving vaccination program Thomas Some of the immunoglobulins also remain in the gut where they can neutralize pathogenic bacteria and help prevent the development of diarrhea.
The absorption of antibodies from the GIT into the bloodstream is called passive transfer. Calves that experience FPT are more likely to become sick or die in the first 2 months of life than calves with adequate immunity. Many factors can contribute to FPT, but colostrum and the management of colostrum feeding are often involved.
To successfully obtain passive transfer and provide the calf with protection from diseases, it is thought that the calf needs to consume a minimum of — g of immunoglobulins Meganck et al. The pathway between the gastrointestinal tract and the bloodstream is only open for a short window of time. It has therefore been recommended to feed calves as much colostrum as they want by bottle within 1—4 h after birth and at 12 h of age to substantially reduce the probability of FPT Chigerwe et al.
Colostrum also provides the calf with protein, energy in the form of fat and sugar, and vitamins Quigley and Drewry Some vitamins do not cross the placental barrier, and colostrum is the primary source of these nutrients for the calf after birth. Energy is required for all metabolic functions including maintenance of body temperature.
One of the leading causes of death in dairy calves is failure to initiate breathing and metabolic processes in the first hours of life. The newborn calf only has a few hours of energy reserves in stored fat and therefore needs the energy from colostrum.
Research also confirms that the sooner a calf consumes colostrum, the more maternal antibodies it can utilize. The quality of colostrum is a major issue that the dairy industry faces on a regular basis. Generally speaking, quality of colostrum is related to the amount of antibody that is present.
Colostral IgG concentration is an important factor that affects whether calves receive sufficient passive immunity Godden et al. Colostral quality is difficult to estimate by the farmer based on produced volume or appearance of the colostrum. There are many variables that impact colostrum quality, including nutrition, the time the cow is milked, heat stress, and stage of lactation.
Other production mammals such as piglets face the same issues as calves for colostrum quality. Giving spray-dried bovine colostrum to other animals such piglets has been shown Sty et al. It may be possible that using bovine colostrum for piglets could help supplement sow colostrum. Research has also been done in foals with an enhanced bovine colostrum supplementation Fenger et al. High-quality maternal colostrum is still the gold standard for feeding newborn calves. However, colostrum supplement and replacer products can be valuable tools to increase calf immunity when colostrum supplies are limited or disease eradication is desired.
Supplements do not contain sufficient quantities of antibodies to raise the blood IgG level in calves beyond what average quality colostrum will do. Colostrum replacer contains greater levels of IgG and other nutrients and provides an effective, convenient method of providing passive immunity to calves when maternal colostrum is not available. The fat content of these products ranges from 0. Spray-dried colostrum with high concentrations of immunoglobulin may be produced economically and used as an effective and convenient colostrum replacer in newborn calves Chelack et al.
Numerous products designed to replace colostrum are now on the market. These products are made from bovine colostrum or serum and contain — g of IgG per dose.
These products also provide fat, protein, vitamins, and minerals needed by the newborn calf, although the amount varies between products. It has been recognized that while antibodies found in colostrum can certainly reduce diseases in animals via passive immunity when given to a newborn, they will only work if the colostrum donor animal has been exposed either naturally to the disease or given a vaccine to the disease, in order to have specific antibodies produced. Bovine colostrum that is typically spray-dried for supplements or replacer will contain only the antibodies that the cow may have encountered naturally.
Therefore, the colostrum used may not have specific antibodies against particular diseases that a producer might be interested in. The animal industry has recognized this issue and has developed methods to produce specific antibodies in high titer against specific diseases that can be delivered in colostrum products. This is achieved by hyperimmunizing animals such as cows against specific animal diseases, collecting colostrum and processing it into powders such as by freeze-drying methods and then giving to a newborn animal in gels or boluses.
A number of diseases including bacterial diseases like E. The hyperimmunized colostrum is collected, processed, and given to newborn calves. To varying degrees of success, these hyperimmunized colostrum antibodies have been proven to be successful in providing passive immunization. Besides calves, research has been done in a variety of production animals using bovine or other sources of colostrum.
For example, lambs have been supplemented with ewe colostrum as well as hyperimmunized serum from sheep against E. Other research has examined vaccination of cows with clostridial antigens and passive transfer of clostridial antibodies from bovine colostrum to lambs Clarkson et al. Piglets have also been given passive protection against porcine epidemic diarrhea by hyperimmune bovine colostrum Shibata et al. Specific antibodies in a hyperimmunized colostrum-derived product can be used while complementing early colostrum feeding and can be delivered at the same time as colostrum.
There are some advantages to this strategy as specific immunoglobulins immediately fight at the gut level to protect against diseases that destroy the intestinal lining while also allowing for antibodies to be absorbed into the bloodstream. Besides the quality of the colostrum itself, researchers first believed that calves could not be vaccinated effectively while they had circulating maternal antibodies from the colostrum in their system.
Preweaning calves can respond to vaccination stimulation as early as 1 month of age. The maternal antibodies absorbed from colostrum, however, cannot distinguish between the antigens of a natural challenge and the antigens in a vaccine. Therefore, colostrum antibodies can interfere with the immune response to a vaccination Niewiesk Work continues to be done to develop ways to circumvent maternal antibody interference.
Vaccination of calves in the face of maternal antibodies IFOMA often does not result in seroconversion as maternally derived immunity interferes with the activation of adequate antibody responses to vaccination. However, it can prime T- and B-cell memory responses that protect calves against clinical disease when maternal immunity has decayed.
The activation of B- and T-cell memory responses in calves vaccinated IFOMA varies and is affected by several factors, including age, level of maternal immunity, type of vaccine, and route of administration.
These factors influence the adequate priming of humoral and cell-mediated immune responses and the outcome of vaccination. There is obviously some controversy about whether newborn calves should be vaccinated Cook et al. It is thought that the process of the calf mounting an immune response to a vaccine requires energy that could better be used to fight off disease and gain weight and the response could actually be detrimental to the early health of that calf.
On the other hand, while maternal antibodies can block response to vaccination, sometimes they do not Woolums The exact immunologic outcome in calves vaccinated IFOMA can vary, and this variation likely depends on many factors.
These factors are not well characterized but likely include the nature of the vaccine administered, number of doses administered, age of the calf and level of maternal antibody present in the calf, and the means by which a protective response is defined.
Guidelines for vaccinating newborn animals such as calves require additional research to clarify the IFOMA vaccination reactions. Fortunately, producers also have the option of using antibody products in order to generate immediate protection in situations where colostrum quality is poor. Antibody products complement colostrum feeding because they can be fed at the same time.
These products are available in bolus, gel, and powder form. They also are included in some colostrum replacer and supplement formulas for added value. Typically, the antibody products are from hyperimmunized cows, and the specific antibody is found in the colostrum.
The colostrum is processed and typically fractionated into a semi-purified preparation of antibody that is freeze-dried and put into capsules or boluses. Because antibody boluses can be fed in conjunction with colostrum, they can be a tool to help the calf not only achieve adequate passive transfer but also provide enough specific antibodies to protect against the most common early calf hood diseases. Antibody products do not require the calf to react to a vaccine in order to develop antibodies.
Rather specific antibodies against various diseases are already present, measured, and verified to be at a high enough level to protect the calf from scour-related diseases, and they can be fed as close to birth as possible.
United States Department of Agriculture USDA -approved antibody products are available on the market that can be fed in conjunction with colostrum and provide the calf with immediate immunity. These antibodies go to the gut to immediately bind and neutralize diarrhea antigens while also being absorbed into the blood stream for extended protection Combs et al.
Another advantage of this approach is that providing specific antibody can potentially avoid vaccine stimulation. Avoiding vaccine stimulation can allow a calf to conserve its minimal supply of fat and nutrients that are critical to get the calf through its first few days of life. Cows pass their immunity to their offspring by colostrum, and various colostrum products are on the market to achieve passive immunity. Additional sources of antibody products can be utilized in a similar manner to achieve passive immunity.
These are from avian sources such as chickens. In birds, passive transfer of immunity occurs through the egg. By hyperimmunizing chickens over a period of time with inactivated multivalent bacterial or viral vaccines, this procedure results in the production of polyclonal immunoglobulins of the IgY class specific to avians directed against the stimulating organisms.
Unfortunately, the eggs really cannot be cooked since heat dentures the antibodies found in the eggs. Other physical parameters such as an acidic pH will also destroy the antibodies to a certain extent.
However, enough orally administrated IgY may survive passage through the GIT and, after excretion, still retain a great deal of its antigen-binding ability indicating that orally administrated IgYs are useful for passive immunity. Just as immune protection is transferred in utero in mammals or passively by a lactating mother via colostrum, hens passively transfer protection to their young by secreting immunoglobulin and other immune factors into their eggs for use by the hatching chick.
IgY Y stands for yolk is an immunoglobulin class specific to avians and analogous in function to that of mammalian immunoglobulins. IgY has a similar structure as mammalian IgG with some minor differences in the heavy chains Fig. Both eggs and milk including breast milk contain naturally occurring antibodies, and there are reports of immunomodulatory factors in milk as well Li et al.
However, immunoglobulin levels in eggs can be significantly higher than levels found in serum or milk Woolley and Landon This may not be surprising since mammals have a considerably longer time of weeks or months during which they may passively transfer immunoglobulin and immune factors, while the hen has a single opportunity the egg to transfer all necessary survival components to its offspring.
All the aspects that the chick needs to survive must be in the egg. Because egg products are a common source of protein in human diets and eggs contain antibodies and immune factors, it was obvious to utilize egg antibodies to provide passive immunity to animals.
As such, this has resulted in a number of commercial egg antibody products on the market for production animals as well as companion animals to prevent various diseases. With few exceptions, oral consumption of specific antibodies has been reported Diraviyam et al.
Furthermore, in vitro studies with specific IgY antibodies have been found to inhibit processes associated with bacterial growth, adhesion to intestinal cells, and toxin production Sugita-Konishi et al. Meta-analysis has demonstrated the beneficial effects of IgY Diraviyam et al. This analysis supports the opinion that IgY is useful for prophylaxis and treatment.
Currently, the oral passive immunization using chicken IgY has been focused as an alternative to antibiotics for the treatment and control of diarrhea. IgY has been demonstrated to be effective in controlling and preventing diarrhea in humans and in animals including piglets Cui et al.
Most commercially available chickens are immunized at birth to protect them from avian diseases. A wide range of bacteria, viruses, and coccidia have been used in vaccines for producing commercial IgY products. A partial list includes Shigella dysenteriae , Staphylococcus epidermidis , Escherichia coli , E. Only the chicken not the egg is exposed to inactivated pathogens.
Immunoglobulins and other immune factors are passively transferred to the egg from the serum for use by the chick and, more importantly, for passive immunity for other animals.
After appropriate times following vaccination, eggs are collected from the specially designated chicken flocks, washed and broken, and the yolk and egg white are typically dried to a fine proteinaceous powder.
Various processes have been developed to help minimize heat damage to egg antibodies and immunoregulatory factors during the spray-drying procedure. However, spray-drying eggs can denature the IgY to an extent, due to at least some heating during the process.
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