Innate and acquired immunity mother infant relationship problems

Frontiers | Innate Immunity of Neonates and Infants | Immunology

Understand how immunity works, including adaptive and innate, An example of artificial active immunity is building up a resistance to a disease due to A nursing mother transfers antibodies to her baby through her milk. Immunity from disease is conferred by two cooperative defense The innate immune system provides this kind of nonspecific .. These molecules also are secreted into the mother's milk and, once they have been ingested by an infant, can When this IgM attachment occurs, it causes microorganisms to. The fetal immune system develops in a sterile and protected It is also modulated in order to coexist with the mother's immune system. depends upon components of the innate or antigen-independent immune system, Challenges in infant immunity: implications for responses to infection and vaccines.

Proteins from naturally occurring bacteria In the small and large intestines the growth of invading bacteria can be inhibited by naturally gut-dwelling bacteria that do not cause disease. These gut-dwelling microorganisms secrete a variety of proteins that enhance their own survival by inhibiting the growth of the invading bacterial species. Cellular defenses If an infectious agent is not successfully repelled by the chemical and physical barriers described above, it will encounter cells whose function is to eliminate foreign substances that enter the body.

These cells are the nonspecific effector cells of the innate immune response. They include scavenger cells—i. Some of these cells destroy infectious agents by engulfing and destroying them through the process of phagocytosiswhile other cells resort to alternative means.

As is true of other components of innate immunity, these cells interact with components of acquired immunity to fight infection. Time-lapse photography of a macrophage the light-coloured, globular structure consuming bacteria.

Scavenger cells All higher animals and many lower ones have scavenger cells—primarily leukocytes white blood cells —that destroy infectious agents.

Most vertebrates, including all birds and mammals, possess two main kinds of scavenger cells. Granulocytes Microphages are now called either granulocytesbecause of the numerous chemical-containing granules found in their cytoplasmor polymorphonuclear leukocytes, because of the oddly shaped nucleus these cells contain.

Some granules contain digestive enzymes capable of breaking down proteins, while others contain bacteriocidal bacteria-killing proteins. There are three classes of granulocytes— neutrophilseosinophilsand basophils —which are distinguished according to the shape of the nucleus and the way in which the granules in the cytoplasm are stained by dye.

The differences in staining characteristics reflect differences in the chemical makeup of the granules. Neutrophils are the most common type of granulocytemaking up about 60 to 70 percent of all white blood cells.

These granulocytes ingest and destroy microorganisms, especially bacteria. Less common are the eosinophils, which are particularly effective at damaging the cells that make up the cuticle body wall of larger parasites. Fewer still are the basophils, which release heparin a substance that inhibits blood coagulationhistamineand other substances that play a role in some allergic reactions see immune system disorder: Very similar in structure and function to basophils are the tissue cells called mast cellswhich also contribute to immune responses.

Granulocytes, which have a life span of only a few days, are continuously produced from stem i. They enter the bloodstream and circulate for a few hours, after which they leave the circulation and die.

Granulocytes are mobile and are attracted to foreign materials by chemical signals, some of which are produced by the invading microorganisms themselves, others by damaged tissues, and still others by the interaction between microbes and proteins in the blood plasma.

Some microorganisms produce toxins that poison granulocytes and thus escape phagocytosis; other microbes are indigestible and are not killed when ingested.

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By themselves, then, granulocytes are of limited effectiveness and require reinforcement by the mechanisms of specific immunity. Macrophages The other main type of scavenger cell is the macrophage, the mature form of the monocyte.

Like granulocytes, monocytes are produced by stem cells in the bone marrow and circulate through the blood, though in lesser numbers. But, unlike granulocytes, monocytes undergo differentiation, becoming macrophages that settle in many tissues, especially the lymphoid tissues e. Macrophages live longer than granulocytes and, although effective as scavengers, basically provide a different function. Compared with granulocytes, macrophages move relatively sluggishly.

They are attracted by different stimuli and usually arrive at sites of invasion later than granulocytes. Macrophages recognize and ingest foreign particles by mechanisms that are basically similar to those of granulocytes, although the digestive process is slower and not as complete. This aspect is of great importance for the role that macrophages play in stimulating specific immune responses—something in which granulocytes play no part.

Scanning electron micrograph of a macrophage purple attacking a cancer cell yellow. NK cells were first recognized inwhen researchers observed cells in the blood and lymphoid tissues that were neither the scavengers described above nor ordinary lymphocytes but which nevertheless were capable of killing cells.

Although similar in outward appearance to lymphocytes, NK cells contain granules that harbour cytotoxic chemicals. NK cells recognize dividing cells by a mechanism that does not depend on specific immunity. They then bind to these dividing cells and insert their granules through the outer membrane and into the cytoplasm. This causes the dividing cells to leak and die. NK cells are the third most abundant type of lymphocyte in the body B and T lymphocytes being present in the greatest numbers.

They develop from hematopoietic stem cells and mature in the bone marrow and the liver. Nonspecific responses to infection The body has a number of nonspecific methods of fighting infection that are called early induced responses. They include the acute-phase response and the inflammation response, which can eliminate infection or hold it in check until specific, acquired immune responses have time to develop. Nonspecific immune responses occur more rapidly than acquired immune responses do, but they do not provide lasting immunity to specific pathogens.

Created and produced by QA International. These cytokines include members of the family of proteins called interleukinswhich induce fever and the acute-phase response, and tumour necrosis factor -alpha, which initiates the inflammatory response. Acute-phase response When the body is invaded by a pathogen, macrophages release the protein signals interleukin-1 IL-1 and interleukin-6 IL-6 to help fight the infection.

One of their effects is to raise the temperature of the body, causing the fever that often accompanies infection. The interleukins increase body temperature by acting on the temperature-regulating hypothalamus in the brain and by affecting energy mobilization by fat and muscle cells. Fever is believed to be helpful in eliminating infections because most bacteria grow optimally at temperatures lower than normal body temperature. But fever is only part of the more general innate defense mechanism called the acute-phase response.

In addition to raising body temperature, the interleukins stimulate liver cells to secrete increased amounts of several different proteins into the bloodstream. These proteins, collectively called acute-phase proteins, bind to bacteria and, by doing so, activate complement proteins that destroy the pathogen. The acute-phase proteins act similarly to antibodies but are more democratic—that is, they do not distinguish between pathogens as antibodies do but instead attack a wide range of microorganisms equally.

Another effect the interleukins have is to increase the number of circulating neutrophils and eosinophils, which help fight infection. Inflammatory response Infection often results in tissue damage, which may trigger an inflammatory response. The signs of inflammation include painswelling, redness, and fever, which are induced by chemicals released by macrophages.

These substances promote blood flow to the area, increase the permeability of capillariesand induce coagulation. The increased blood flow is responsible for redness, and the leakiness of the capillaries allows cells and fluids to enter tissues, causing pain and swelling. These effects bring more phagocytic cells to the area to help eliminate the pathogens. The first cells to arrive, usually within an hour, are neutrophils and eosinophils, followed a few hours later by macrophages.

Macrophages not only engulf pathogens but also help the healing process by disposing of cellular debris which accumulates from destroyed tissue cells and neutrophils that self-destruct after ingesting microorganisms.

If infection persists, components of specific immunity—antibodies and T cells —arrive at the site to fight the infection. Specific, acquired immunity It has been known for centuries that persons who contract certain diseases and survive generally do not catch those illnesses again.

Greek historian Thucydides recorded that, when the plague was raging in Athens during the 5th century bce, the sick and dying would have received no nursing at all had it not been for the devotion of those who had already recovered from the disease; it was known that no one ever caught the plague a second time.

The same applies, with rare exceptions, to many other diseases, such as smallpoxchicken poxmeaslesand mumps. Yet having had measles does not prevent a child from contracting chicken pox or vice versa. The protection acquired by experiencing one of these infections is specific to that infection; in other words, it is due to specific, acquired immunity, also called adaptive immunity.

Acquired immunity depends on the activities of T and B lymphocytes T and B cells. One part of acquired immunity, humoral immunity, involves the production of antibodies by B cells.

The other part, cell-mediated immunity, involves the actions of T cells. When an antigen such as a bacterium enters the body, it is attacked and engulfed by macrophages, which process and display parts of it on their cell surface. A helper T cell, recognizing the antigen displayed, initiates maturation and proliferation of other T cells.

Cytotoxic killer T cells develop and attack foreign and infected cells. B cells stimulated by the presence of antigen are activated by helper T cells to divide and form antibody-producing cells plasma cells. Released antibody binds to antigen, marking the cell for destruction. Helper T cells also induce the development of memory T and B cells needed to mount future immune responses on reinfection with the same pathogen.

There are other infectious conditions, such as the common coldinfluenzapneumoniaand diarrheal diseases, that can be caught again and again; these seem to contradict the notion of specific immunity. But the reason such illnesses can recur is that many different infectious agents produce similar symptoms and thus the same disease.

For example, more than viruses can cause the cluster of symptoms known as the common cold. Consequently, even though infection with a particular agent does protect against reinfection by that same pathogen, it does not confer protection from other pathogens that have not been encountered.

Acquired immunity is dependent on the specialized white blood cells known as lymphocytes. This section describes the various ways in which lymphocytes operate to confer specific immunity. Although pioneer studies were begun in the late 19th century, most of the knowledge of specific immunity has been gained since the s, and new insights are continually being obtained.

Lymphocytes are mainly a dormant population, awaiting the appropriate signals to be stirred to action. The inactive lymphocytes are small, round cells filled largely by a nucleus. Although they have only a small amount of cytoplasm compared with other cells, each lymphocyte has sufficient cytoplasmic organelles small functional units such as mitochondriathe endoplasmic reticulumand a Golgi apparatus to keep the cell alive. Lymphocytes move only sluggishly on their own, but they can travel swiftly around the body when carried along in the blood or lymph.

The majority are concentrated in various tissues scattered throughout the body, particularly the bone marrowspleenthymuslymph nodestonsilsand lining of the intestines, which make up the lymphatic system.

Organs or tissues containing such concentrations of lymphocytes are described as lymphoid. The lymphocytes in lymphoid structures are free to move, although they are not lying loose; rather, they are confined within a delicate network of lymph capillaries located in connective tissues that channel the lymphocytes so that they come into contact with other cells, especially macrophages, that line the meshes of the network.

This ensures that the lymphocytes interact with each other and with foreign materials trapped by the macrophages in an ordered manner. The human lymphatic system, showing the lymphatic vessels and lymphoid organs. T and B cells Lymphocytes originate from stem cells in the bone marrow ; these stem cells divide continuously, releasing immature lymphocytes into the bloodstream.

Some of these cells travel to the thymuswhere they multiply and differentiate into T lymphocytes, or T cells. The T stands for thymus-derived, referring to the fact that these cells mature in the thymus. Once they have left the thymus, T cells enter the bloodstream and circulate to and within the rest of the lymphoid organs, where they can multiply further in response to appropriate stimulation.

About half of all lymphocytes are T cells. NIAID Some lymphocytes remain in the bone marrow, where they differentiate and then pass directly to the lymphoid organs. They are termed B lymphocytes, or B cellsand they, like T cells, can mature and multiply further in the lymphoid organs when suitably stimulated.

Although it is appropriate to refer to them as B cells in humans and other mammals, because they are bone-marrow derived, the B actually stands for the bursa of Fabriciusa lymphoid organ found only in birds, the organisms in which B cells were first discovered.

B and T cells both recognize and help eliminate foreign molecules antigenssuch as those that are part of invading organisms, but they do so in different ways.

Adaptive immune system

B cells secrete antibodiesproteins that bind to antigens. Since antibodies circulate through the humours i. T cells, in contrast, do not produce antibodies but instead directly attack invaders. Because this second type of acquired immunity depends on the direct involvement of cells rather than antibodies, it is called cell-mediated immunity.

These two types of specific, acquired immunity, however, are not as distinct as might be inferred from this description, since T cells also play a major role in regulating the function of B cells.

In many cases an immune response involves both humoral and cell-mediated assaults on the foreign substance. Furthermore, both classes of lymphocytes can activate or enhance a variety of nonspecific immune responses. Ability to recognize foreign molecules Receptor molecules Lymphocytes are distinguished from other cells by their capacity to recognize foreign molecules.

Recognition is accomplished by means of receptor molecules. A receptor molecule is a special protein whose shape is complementary to a portion of a foreign molecule. This complementarity of shape allows the receptor and the foreign molecule to conform to each other in a fashion roughly analogous to the way a key fits into a lock.

Receptor molecules are either attached to the surface of the lymphocyte or secreted into fluids of the body. B and T lymphocytes both have receptor molecules on their cell surfaces, but only B cells manufacture and secrete large numbers of unattached receptor molecules, called antibodies.

Antibodies correspond in structure to the receptor molecules on the surface of the B cell. Antigens Any foreign material—usually of a complex nature and often a protein—that binds specifically to a receptor molecule made by lymphocytes is called an antigen. Antigens include molecules found on invading microorganisms, such as virusesbacteriaprotozoansand fungias well as molecules located on the surface of foreign substances, such as pollendust, or transplanted tissue.

When an antigen binds to a receptor molecule, it may or may not evoke an immune response. Antigens that induce such a response are called immunogens. Thus, it can be said that all immunogens are antigens, but not all antigens are immunogens.

For example, a simple chemical group that can combine with a lymphocyte receptor i. Although haptens cannot evoke an immune response by themselves, they can become immunogenic when joined to a larger, more complex molecule such as a protein, a feature that is useful in the study of immune responses.

Many antigens have a variety of distinct three-dimensional patterns on different areas of their surfaces. Each pattern is called an antigenic determinant, or epitopeand each epitope is capable of reacting with a different lymphocyte receptor. Some antigenic determinants are better than others at effecting an immune response, presumably because a greater number of responsive lymphocytes are present. It is possible for two or more different substances to have an epitope in common.

In these cases, immune components induced by one antigen are able to react with all other antigens carrying the same epitope. Such antigens are known as cross-reacting antigens. T cells and B cells differ in the form of the antigen they recognize, and this affects which antigens they can detect. B cells bind to antigen on invaders that are found in circulation outside the cells of the body, while T cells detect only invaders that have somehow entered the cells of the body.

Thus foreign materials that have been ingested by cells of the body or microorganisms such as viruses that penetrate cells and multiply within them are out of reach of antibodies but can be eliminated by T cells. Diversity of lymphocytes The specific immune system in other words, the sum total of all the lymphocytes can recognize virtually any complex molecule that nature or science has devised.

This remarkable ability results from the trillions of different antigen receptors that are produced by the B and T lymphocytes.

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Each lymphocyte produces its own specific receptor, which is structurally organized so that it responds to a different antigen. After a cell encounters an antigen that it recognizes, it is stimulated to multiply, and the population of lymphocytes bearing that particular receptor increases.

How is it that the body has such an incredible diversity of receptors that are always ready to respond to invading molecules? To understand this, a quick review of genes and proteins will be helpful. Antigen receptor molecules are proteinswhich are composed of a few polypeptide chains i. The sequence in which the amino acids are assembled to form a particular polypeptide chain is specified by a discrete region of DNAcalled a gene.

But if every polypeptide region of every antigen receptor were encoded by a different gene, the human genome all the genetic information encoded in the DNA that is carried on the chromosomes of cells would need to devote trillions of genes to code just for these immune system proteins.

Since the entire human genome contains approximately 25, genes, individuals cannot inherit a gene for each particular antigen receptor component. Instead, a mechanism exists that generates an enormous variety of receptors from a limited number of genes. What is inherited is a pool of gene segments for each type of polypeptide chain. As each lymphocyte matures, these gene segments are pieced together to form one gene for each polypeptide that makes up a specific antigen receptor.

This rearrangement of alternative gene segments occurs predominantly, though not entirely, at random, so that an enormous number of combinations can result. Additional diversity is generated from the imprecise recombination of gene segments—a process called junctional diversification—through which the ends of the gene segments can be shortened or lengthened. The genetic rearrangement takes place at the stage when the lymphocytes generated from stem cells first become functional, so that each mature lymphocyte is able to make only one type of receptor.

Thus, from a pool of only hundreds of genes, an unlimited variety of diverse antigen receptors can be created. Still other mechanisms contribute to receptor diversity. Superimposed on the mechanism outlined in simplified terms above is another process, called somatic mutation. Mutation is the spontaneous occurrence of small changes in the DNA during the process of cell division. Although somatic mutation can be a chance event in any body cell, it occurs regularly in the DNA that codes for antigen receptors in lymphocytes.

Thus, when a lymphocyte is stimulated by an antigen to divide, new variants of its antigen receptor can be present on its descendant cells, and some of these variants may provide an even better fit for the antigen that was responsible for the original stimulation.

B-cell antigen receptors and antibodies The antigen receptors on B lymphocytes are identical to the binding sites of antibodies that these lymphocytes manufacture once stimulated, except that the receptor molecules have an extra tail that penetrates the cell membrane and anchors them to the cell surface. Thus, a description of the structure and properties of antibodies, which are well studied, will suffice for both.

Basic structure of the immunoglobulin molecule Antibodies belong to the class of proteins called globulins, so named for their globular structure.

Collectively, antibodies are known as immunoglobulins abbreviated Ig. All immunoglobulins have the same basic molecular structure, consisting of four polypeptide chains. Two of the chains, which are identical in any given immunoglobulin molecule, are heavy H chains; the other two are identical light L chains. The terms heavy and light simply mean larger and smaller. Each chain is manufactured separately and is encoded by different genes.

The four chains are joined in the final immunoglobulin molecule to form a flexible Y shape, which is the simplest form an antibody can take. The four-chain structure of an antibody, or immunoglobulin, moleculeThe basic unit is composed of two identical light L chains and two identical heavy H chains, which are held together by disulfide bonds to form a flexible Y shape.

Each chain is composed of a variable V region and a constant C region. At the tip of each arm of the Y-shaped molecule is an area called the antigen-bindingor antibody-combining, site, which is formed by a portion of the heavy and light chains. Every immunoglobulin molecule has at least two of these sites, which are identical to one another. The antigen-binding site is what allows the antibody to recognize a specific part of the antigen the epitopeor antigenic determinant.

Chemical bonds called weak bonds then form to hold the antigen within the binding site. The heavy and light chains that make up each arm of the antibody are composed of two regions, called constant C and variable V. These regions are distinguished on the basis of amino acid similarity—that is, constant regions have essentially the same amino acid sequence in all antibody molecules of the same class IgG, IgM, IgA, IgD, or IgEbut the amino acid sequences of the variable regions differ quite a lot from antibody to antibody.

This makes sense, because the variable regions determine the unique shape of the antibody-binding site. The tail of the molecule, which does not bind to antigens, is composed entirely of the constant regions of heavy chains. Relative to breast-fed infants, artificially fed infants had 3. The discovery soon thereafter of secretory antibodies in human milk seemed to provide a facile explanation for this phenomenon, at least for gastrointestinal disease: We now know that this is only one of many types of protection that human milk can provide to the infant, which includes elements of both an acquired immune system and an innate immune system.

The burgeoning list of protective components in milk is impressive but not totally unexpected. Based on these considerations alone, it was reasonable to predict that infants need exogenous protection and that human milk might contain protective agents.

These and other considerations have lead to research over the last few decades that have resulted in an impressive array of factors in milk that are bioactive, with most of the activity being antipathogenic or immunomodulatory. With the growth of this list of bioactive components in human milk that have the potential to protect infants, some complexities have emerged.

Some of these milk factors inhibit specific pathogens, some inhibit families of pathogens, and some inhibit a very broad array of pathogens. Some function with a direct mechanism, such as inhibiting the binding of a pathogen to its receptor, and some function indirectly, such as by modifying the resident microflora of the gut.

More recent data, such as those represented in the accompanying articles of this symposium, suggest that the mechanisms of inhibition may be further confounded by additional considerations. For example, the matrix in which the inhibitor is present may contain synergistic inhibitors, such that inhibitors thought to be weakly active may become highly effective inhibitors, such as with fatty acids. The location at which an inhibitor is produced and the location at which it is effective may result in a spatial specificity that would cause an inhibitor to act entirely differently in vitro from its role in vivo, such as with biocidal peptides.

Differences in resident microflora among individuals may influence the efficacy of a probiotic. Different states of inflammation may determine if specific immunomodulators are beneficial under a specific set of circumstances.

Individual differences in glycan expression determine to which pathogens an individual is susceptible and which human-milk oligosaccharides would be protective; expression of glycans in gut also differs at different stages of development. Also, different strains of pathogens may have different binding specificities, again, determining which glycans would be effective inhibitors of these strains.

Finally, all of these factors may interact. Thus, spatial and temporal specificity, synergy, individual differences and stages of development, and immunological states and context all must be taken into account when defining the protective agents in human milk that participate in the mucosal immunity of the infant. Because this was the only major protective component recognized for some time, whose discovery coincided with the increasing recognition of the central role of antibodies in human defense, and the lower incidence of disease in breast-fed infants, the sIgA in milk was widely thought to account for the protection afforded to the nursing infant against pathogens.

The mechanism for this protection is shown in Figure 1. When the mother—infant nursing dyad is exposed to a novel enteric pathogen, the Peyer's patch in the maternal intestinal mucosa acquires the pathogen in a sample of luminal contents. The M cell presents the antigens of the pathogen to circulating B cells, priming the cell for antibody production. When the B cell is in the proximity to the basolateral side of the mammary epithelial cell, the IgA that is produced is transported into the acinar cell on the basolateral side, and, as the IgA is transported to the apical side of the cell, the IgA acquires its carbohydrate chain to become sIgA that is excreted from the apical membrane into the milk.

The sIgA in milk enters the alimentary canal of the infant where it binds to the enteric pathogen, inhibiting disease. After the mother is exposed to a pathogen, many days elapse before the induction of protective antibody and its secretion into the milk and the gut of the infant.

Assuming that both the mother and her infant are exposed to the pathogen simultaneously, this would leave the infant vulnerable to the pathogen were it not for other protective mechanisms.

Other forms of infant mucosal protection were the topic of this series of reports and include protective components that are intrinsic constituents of human milk, which we define as components of an innate immune system of human milk, and probiotics, which are food-borne bacteria that confer some positive activity toward protecting the infant.

When the nursing dyad is exposed to an enteric pathogen, the Peyer's patch of the mother acquires the pathogen from the lumen of the gut, whereupon the M cell presents its antigen on the serosal side to the B cell, which migrates to the serosal side of the mammary epithelial cell and secretes IgA. As the IgA moves from the serosal to the luminal side of the mammary epithelial cell, it is glycosylated to form secretory IgA, which is secreted into the milk.

When the infant consumes the milk, the sIgA, which is resistant to digestion, binds to the pathogen, inhibiting its ability to infect the infant. Probiotics One of the early documented differences between breast-fed and artificially fed infants was the microflora of their gut.

Breast-fed infants have a higher percentage of lactobacilli, especially Lactobacillus bifidus now Bifidobacterium bifidumwhereas artificially fed infant microflora has a composition that more closely resembles that of the adult gut.

A human-milk component, a glycan, was found to stimulate the growth of, and colonization by, L. Another more direct mechanism for altering intestinal microflora is to feed beneficial bacteria, probiotics, in the diet to benefit from their presence in the gut.

From the use of lactobacilli commonly found in traditional yogurts, the selection of probiotics that protect the recipient from diseases has advanced in the past several years to the highly popular and more effective Lactobacillus GG, an isolate with origins in the human gut. Much work on Lactobacillus GG, and the continued search for other probiotics, was and is still being performed in Finland; Salminen and colleagues 2 describe the basis for the multiple criteria being used for the selection of new probiotics.

Each probiotic has a specific target based on its specificity of binding to host cell receptors, which are usually glycans expressed on the cell surface of intestinal mucosa. Likewise, specific probiotics are able to protect against specific pathogens. For a probiotic to be able to colonize the host, thereby extending its useful duration, the interdependence of microbiota must be considered.

Administration of probiotics early in development has a greater chance of coinciding with a critical period of gut colonization and thus of producing lasting consequences. Ultimately, we would like to be able to choose probiotics with long-term sequelae for prophylaxis against chronic conditions; for example, evidence is presented that specific probiotics early in life may attenuate or prevent the development of manifestations of allergy in later life. Thus, the search for effective probiotics has moved from looking for one or a few probiotics for treating acute infections by any intestinal pathogen to looking for complex combinations of probiotics that would balance the indigenous microflora in a way that has lifelong benefits to the recipient.

The innate immune system of human milk Several milk components have been found that are important nutrients but that have, or whose partial digestion products have, antipathogenic activity. These can be classified as multifunctional agents, and, because these are intrinsic components of milk, we will consider them as part of the innate immune system of human milk. Two of the most widely recognized have been the FFAs, and especially the monoglycerides, that are released as human-milk triglycerides are digested in the infant stomach, and lactoferrin, a major protein of human milk that has been reported to have several inhibitory mechanisms, including the sequestering of iron, which may be bacteriostatic, a direct antibacterial effect by the whole protein, and the release of peptides during its digestion.

These peptides inhibit many distinct pathogenic bacteria, most commonly through local disruption of the membrane, causing it to become leaky. Recent research is not only adding more recognized components to this category of multifunctional protective agents in milk but is also defining the conditions under which they are most active.

The examples in the accompanying articles are the FFAs and monoglycerides, the antibacterial peptides, and a protein structural conformer. Fatty acids and monoglycerides. In the adult, triglyceride is digested slowly, but, in nursing infants, as milk is entering the stomach, it is already releasing FFAs from the digestion of the milk triglycerides by lingual and gastric lipases.

Thus, gastric contents of nursing infants already have appreciable fatty acids and monoglycerides, and these have been shown to be antiviral, antibacterial, and antiprotozoal. This activity may augment the ability of the stomach to act as a barrier against ingested pathogens.

An illustration of the ability of linoleate, at concentrations typical of the nursling's stomach, to destroy vesicular stomatitis virus is found in Figure 2 3. In earlier studies, the Isaacs laboratory had defined oleic and linoleic acid as having very high activity at killing enveloped viruses and found that monoglycerides had the highest activity. Of these, oleic acid is released from milk in the highest concentration, making it a primary source of protection to the breast-fed infant.

However, when fatty acids are tested in combination, even those that show no inhibitory activity at the concentrations found in stomach aspirates may display potent activity when tested in combination.