Abstract
Allergies, asthma, and autoimmunity are the most prevalent immune disorders and affect millions of people worldwide. The role of prevention of these immune disorders at the level of infancy and early childhood has become an important emphasis of recent research. The proper development of the growing infant’s immune system provides a promising avenue into prevention of these disorders.
Breast milk has long been acknowledged as the optimal source of nutrition for infants, and emerging research points to its profound effect on the immune development of infants.
Breast milk has long been acknowledged as the optimal source of nutrition for infants, and emerging research points to its profound effect on the immune development of infants.
Introduction
Immune disorders like asthma, allergies, and autoimmunity have become predominant issues in both pediatric and adult healthcare. An estimated 300 million people worldwide suffer from asthma, with 250,000 annual deaths attributed to the disease.1 Allergic diseases affect as many as 40 to 50 million Americans.2 Autoimmune diseases include more than 70 different disorders and affect approximately 5 percent of the U.S. population, or an estimated 23.5 million Americans.3 Early intervention as a means of preventing immune disorders later in life has become the subject of abundant research in recent years. Special attention must be paid to the infant’s developing immune system in order for this type of prevention to be a success. The infant is born with an immature immune system that doesn’t fully develop until several years after birth.4,5 Mounting evidence shows that breast milk is not only an excellent source of nutrition, but it also has a profound influence on the development of the immune system and thus, the pathogenesis of asthma, allergies, and autoimmunity. This paper will focus on immune development in infants and the use of breast milk as a potential prevention of immune disorders. We will briefly review the workings of a healthy, mature immune system before discussing the developing immune system of an infant and how breast milk best promotes its proper development.
Although our knowledge of the system is always advancing, the immune system in healthy adults has several distinct arms: Th0, Th1, Th2, Th3, and Th17. The T helper cells 0 (Th0) refer to mature T cells that have yet to encounter an antigen. When these naïve Th0 cells encounter an antigen, they differentiate into Th1 or Th2 cells depending on the cytokine environment. The T helper cells 1 (Th1) are recruited in response to infection and are the predominant cells used against bacterial and viral infections. T helper cells 2 (Th2) are responsible for allergic responses and responses to parasites. Cytokines are secreted proteins that stimulate most of the biological effects in the immune system, such as the cell-mediated immunity seen in infections, predominately driven by Th1, and allergictype responses, predominately driven by Th2. These cytokines inhibit the opposing immune reaction, so a robust Th1 response to an infection inhibits a Th2 response and vice versa. Immune tolerance is characterized by a Th3 response, which involves T regulatory cells (Treg cells) and the cytokine, transforming growth factor-beta (TGF-beta). Treg cells play a major part in the regulation of immune responses, sustaining immunological self-tolerance and immune homeostasis.6 They also play a crucial role in the control of auto-reactive T-cells, making them a necessary combatant against autoimmune reactions.7 A Th17 immune response is associated with autoimmune conditions and the cytokine secretion of various interleukins: IL-17, IL-12 and IL-23.8 IL-17 is produced by Th17, which comes from a different lineage than Th1 and Th2 cells but can also stimulate the secretion of TNF-alpha and IL-1.9,10
Th17 and Treg cells have taken center stage in the discussion of autoimmune conditions. A new category of cells named Th22 was recently discovered. Th22 enables innate epithelial immune responses.11 Allergies, asthma, and autoimmune conditions are associated with unresolved inflammation that contributes to the pathogenesis of these conditions. The immune system contains this system of checks and balances with responses like Th3 so that the immune system stays plastic without ever becoming stuck in one particular immune response.
The Infant Immune System
We must first look at the immune system of an infant and the necessity of its proper development in the prevention of immune disorders. The infant’s immune system differs from that of an adult. During gestation, the immune system of the fetus is actively down-regulated to avoid immunological reactions that would end in termination of the pregnancy. This adaptation is demonstrated by high levels of Treg cells, by the down-regulation of antigen-specific T-cell proliferation, and by removal of activated T cells via FasL-induced apoptosis.12,13,14,15,16 The immune system remains in this state through birth and doesn’t fully develop until several years after birth.17,18 Th1 cytokines, such as interleukin-2 (IL-2), interferon-g (IFN-gamma) and Th2 cytokines, mainly interleukin-4 (IL-4), are seen at different levels in infants versus adults. Infants have more IL-2 and IL-4, with less IFN-gamma than seen in adults, giving them a predominately Th2-driven immune system.19 Infants have less Th1 memory effector function compared to adults.20 Even though infants produce ample amounts of IL-2, it does not induce the increase in IFN-gamma necessary to incite a Th1 response.21 When looking at the immunological cytokine response in infants, we see the production of Th1 cytokines tumor necrosis factoralpha (TNF-alpha), IFN-gamma, IL-12, and IL-1 are downregulated, whereas the cytokines IL-6, IL-8, IL-10, and IL-23 that are associated with inflammation and autoimmunity are up-regulated.22 All of these contribute to a down-regulation of the Th1 immune response in infants.
The immune response of tolerance, which modulates rampant Th1 or Th2 reactions, is vital to the immune development and health of the infant. A study that examined children with no clinical or pathological diagnosis, children with multiple food allergies, children with celiac disease, and children with inflammatory enteropathies showed that the deciding factor in the allergic group was the reduction of a Th3 response with a corresponding reduction in TGF-beta.23 The celiac and inflammatory enteropathies groups showed a dominance of the Th1 response, typical of inflammatory autoimmune diseases in which the control of the Th3 Treg cells is a necessity. The production of IL-10, a cytokine released by Treg cells, was lower in infants of atopic mothers compared with non-atopic mothers.24 Oral TGF-beta has demonstrated a preventive role for allergic diseases in infants, again highlighting the importance of immune tolerance in the prevention of immune disorders.25
Research into the etiology of necrotizing enterocolitis (NEC) has found another difference in the immunological state of adults and infants. The immature enterocytes that line the infant’s intestine react with an excessive pro-inflammatory cytokine production after inflammatory stimulation. This reaction leaves infants vulnerable to the influence of excessive inflammation. 26 Another difference in the infants’ mucosa is the variety of glycoproteins as compared to adults. Lining the gastrointestinal and respiratory tracts are glycoproteins, such as mucins, which cover the entire epithelial layer with protective mucus. These glycoproteins play an important role in inflammatory and antigen control in these mucosal tracts. The composition and glycosylation of the mucus layer differs significantly between infants and adults.27 An infant’s gastrointestinal tract not only has low levels of mucus, but it also has increased permeability and low levels of secretory immunoglobulin A.28
Although much is known, more studies are needed to complete our understanding of the immunological workings of infants. Research highlights the infant’s need for Th1 support to protect against infection and the damage that can ensue, a refined and effective Th3 response that can control rampant immune responses, and a healthy mucosal lining to ensure proper immune development and potentially prevent allergy, asthma, and autoimmune disorders.
Immunological Advantages of Breast Milk
Breast milk provides optimal nutrition to the developing infant, and that has prompted both the American Academy of Pediatrics and the World Health Organization to increase the recommendation for exclusive breastfeeding to age 6 months. As a part of the diet, the AAP recommends breast milk for at least 1 year, while the WHO advises continuing for 2 years or more.29,30 Breast milk provides nutrition with polyunsaturated fatty acids that have also been shown to help prevent allergies. In susceptible infants, the development of allergic symptoms was modified by the intake of n-3 long-chain polyunsaturated fatty acids through breast milk.31 Another study demonstrated the substantial reduction in risk of childhood asthma as assessed at age 6 years, if exclusive breastfeeding is continued for at least the first 4 months of life.32 Breast milk protects against the infant’s susceptibility to infections as well as against future development of allergic diseases, in part due to its fatty acid content.33
Breast milk not only provides nutrition that helps to balance immunity in infants, it also directly impacts the development of the Th1 response. Evidence points toward the importance of breast milk in the maturation of the infant’s immune system, helping with immature Th1 function. During the education of the immune system in infancy, maternal milk provides signals to the immune system that generate appropriate response and memory.34 Although infants’ Th1 response is somewhat inefficient, breast milk compensates for this relative inefficiency by providing considerable amounts of secretory IgA antibodies and lactoferrin. These secretory IgA antibodies bind the microbes at the infant’s mucosal membranes, preventing activation of the pro-inflammatory defenses while lactoferrin both destroys microbes and reduces inflammatory responses.35 Breast milk also contains various cytokines, including IL-1, IL-6, IL-12, TNF-alpha, IFN-gamma, and IL-8, that help defend against gastrointestinal and respiratory infections.36,37,38,39,40,41 A recent study found high levels of immune-related miRNAs that were stable under acidic environments in breast milk for the first 6 months of lactation. The dietary intake of miRNAs by infants can have a profound impact on the development of the infant’s immune system.42 Breast milk clearly imparts important factors for the proper maturation of the infant’s immune system.
Breast milk also provides a significant amount of Th3 tolerance factors and anti-inflammatory compounds that help regulate immune responses and inflammation. Breast milk is rich in TGF-beta, IL-10, erythropoietin, and lactoferrin, which can help reduce the excessive inflammatory response to stimuli in the infant’s intestine.43,44 In research conducted with mice, the presence of TGF-beta and an allergen conveyed protection from allergic asthma.45 Some studies suggest that breast milk may even protect against type 1 diabetes, multiple sclerosis, and rheumatoid arthritis.46
Immune system development in infants is closely tied to gastrointestinal maturation. The immunological factors found in breast milk are key instigators in the maturation of the gastrointestinal tract, as well as the gut-associated and systemic immune systems.47 Microflora such as Bifidobacterium have been identified in studies of infant fecal composition in association with maternal breast milk composition. Maternal breast milk Bifidobacterial counts dramatically impacted the infants’ fecal Bifidobacterium levels, demonstrating that breast milk is a powerful modifier of infantile gastrointestinal microflora and thus immune status.48 Breast milk–fed infants showed high levels of fecal calprotectin, indicating a low level of gastrointestinal inflammation.49 The excessive inflammation seen in NEC is less severe with a lower incidence when infants are given their mothers breast milk, in part due to the influence breast milk has on the intestinal flora.50 Recent research shows that the mucosal microflora acquired in early infancy determines the production of mucosal inflammation and the consequent development of mucosal disease, autoimmunity, and allergic disorders later in life.51 The non-absorbed milk oligosaccharides found in breast milk block attachment of microbes to the infant’s gastrointestinal mucosal membranes, thus preventing infections.52
Although oligosaccharides are major components of breast milk, the milk is also rich in other glycans, including glycoproteins, mucins, glycosaminoglycans, and glycolipids.53 Glycans protect the infant primarily by inhibiting pathogens’ binding to their host cell’s target ligands. At the same time, human milk oligosaccharides strongly attenuate inflammatory processes in the intestinal mucosa.54 Undigested glycans stimulate colonization by probiotic organisms through a prebiotic effect, modulating mucosal immunity and protecting against pathogens. Interactions between breast milk glycans, intestinal microflora, and intestinal mucosal surface glycans assist in the development of the innate mucosal immunity, protecting infants from infection and autoimmune inflammatory bowel diseases.55
Conclusion
There is a need for more extensive research into the development of the immune system in infants so that we have a more complete understanding of how to target and prevent immune disorders. Our current understanding points to 4 main areas in the ontogeny of the infant’s immune system as potential early intervention points for the prevention of immune disorders. First, nutritional support that aids in the prevention of immune disorders must be provided for infants. Second, the infant requires Th1 support so that he has protection from infections and the inflammatory damage they can incite. Third, immune tolerance and anti-inflammatory measures must be encouraged so inflammatory reactions and the corresponding immune disorders can be prevented. Fourth, the gastrointestinal health of the infant plays such a foundational role in immune status that it must be supported as well. The research demonstrates how breast milk targets all 4 of these areas and has the potential to be a powerful tool in the prevention of immune disorders. More research is necessary to confirm breast milk as a preventative treatment for asthma, allergies, and autoimmune disorders, but the current evidence is promising.
