Infant Immune System Research Articles

Maternal modifiers of the infant gut microbiota: metabolic consequences.

Transmission of metabolic diseases from mother to child is multifactorial and includes genetic, epigenetic and environmental influences. Evidence in rodents, humans and non-human primates support the scientific premise that exposure to maternal obesity or high-fat diet during pregnancy creates a long-lasting metabolic signature on the infant innate immune system and the juvenile microbiota, which predisposes the offspring to obesity and metabolic diseases. In neonates, gastrointestinal microbes introduced through the mother are noted for their ability to serve as direct inducers/regulators of the infant immune system. Neonates have a limited capacity to initiate an immune response. Thus, disruption of microbial colonization during the early neonatal period results in disrupted postnatal immune responses that highlight the neonatal period as a critical developmental window. Although the mechanisms are poorly understood, increasing evidence suggests that maternal obesity or poor diet influences the development and modulation of the infant liver and other end organs through direct communication via the portal system, metabolite production, alterations in gut barrier integrity and the hematopoietic immune cell axis. This review will focus on how maternal obesity and dietary intake influence the composition of the infant gut microbiota and how an imbalance or maladaptation in the microbiota, including changes in early pioneering microbes, might contribute to the programming of offspring metabolism with special emphasis on mechanisms that promote chronic inflammation in the liver. Comprehension of these pathways and mechanisms will elucidate our understanding of developmental programming and may expand the avenue of opportunities for novel therapeutics.

Outer Membrane Proteome of Veillonella parvula: A Diderm Firmicute of the Human Microbiome.

Veillonella parvula is a biofilm-forming commensal found in the lungs, vagina, mouth, and gastro-intestinal tract of humans, yet it may develop into an opportunistic pathogen. Furthermore, the presence of Veillonella has been associated with the development of a healthy immune system in infants. Veillonella belongs to the Negativicutes, a diverse clade of bacteria that represent an evolutionary enigma: they phylogenetically belong to Gram-positive (monoderm) Firmicutes yet maintain an outer membrane (OM) with lipopolysaccharide similar to classic Gram-negative (diderm) bacteria. The OMs of Negativicutes have unique characteristics including the replacement of Braun's lipoprotein by OmpM for tethering the OM to the peptidoglycan. Through phylogenomic analysis, we have recently provided bioinformatic annotation of the Negativicutes diderm cell envelope. We showed that it is a unique type of envelope that was present in the ancestor of present-day Firmicutes and lost multiple times independently in this phylum, giving rise to the monoderm architecture; however, little experimental data is presently available for any Negativicutes cell envelope. Here, we performed the first experimental proteomic characterization of the cell envelope of a diderm Firmicute, producing an OM proteome of V. parvula. We initially conducted a thorough bioinformatics analysis of all 1,844 predicted proteins from V. parvula DSM 2008's genome using 12 different localization prediction programs. These results were complemented by protein extraction with surface exposed (SE) protein tags and by subcellular fractionation, both of which were analyzed by liquid chromatography tandem mass spectrometry. The merging of proteomics and bioinformatics results allowed identification of 78 OM proteins. These include a number of receptors for TonB-dependent transport, the main component of the BAM system for OM protein biogenesis (BamA), the Lpt system component LptD, which is responsible for insertion of LPS into the OM, and several copies of the major OmpM protein. The annotation of V. parvula's OM proteome markedly extends previous inferences on the nature of the cell envelope of Negativicutes, including the experimental evidence of a BAM/TAM system for OM protein biogenesis and of a complete Lpt system for LPS transport to the OM. It also provides important information on the role of OM components in the lifestyle of Veillonella, such as a possible gene cluster for O-antigen synthesis and a large number of adhesins. Finally, many OM hypothetical proteins were identified, which are priority targets for further characterization.

Innate Immunity and Breast Milk

Human milk is a dynamic source of nutrients and bioactive factors; unique in providing for the human infant’s optimal growth and development. The growing infant’s immune system has a number of developmental immune deficiencies placing the infant at increased risk of infection. This review focuses on how human milk directly contributes to the infant’s innate immunity. Remarkable new findings clarify the multifunctional nature of human milk bioactive components. New research techniques have expanded our understanding of the potential for human milk’s effect on the infant that will never be possible with milk formulas. Human milk microbiome directly shapes the infant’s intestinal microbiome, while the human milk oligosaccharides drive the growth of these microbes within the gut. New techniques such as genomics, metabolomics, proteomics, and glycomics are being used to describe this symbiotic relationship. An expanded role for antimicrobial proteins/peptides within human milk in innate immune protection is described. The unique milieu of enhanced immune protection with diminished inflammation results from a complex interaction of anti-inflammatory and antioxidative factors provided by human milk to the intestine. New data support the concept of mucosal-associated lymphoid tissue and its contribution to the cellular content of human milk. Human milk stem cells (hMSCs) have recently been discovered. Their direct role in the infant for repair and regeneration is being investigated. The existence of these hMSCs could prove to be an easily harvested source of multilineage stem cells for the study of cancer and tissue regeneration. As the infant’s gastrointestinal tract and immune system develop, there is a comparable transition in human milk over time to provide fewer immune factors and more calories and nutrients for growth. Each of these new findings opens the door to future studies of human milk and its effect on the innate immune system and the developing infant.

Effect of probiotics on digestibility and immunity in infants: A study protocol for a randomized controlled trial.

The gastrointestinal (GI) tract of a fetus in utero is sterile but it becomes colonized with environmental microorganisms shortly after birth. Since the gut microbiota undergoes substantial changes in early life, healthy gut microflora is essential to an infant's gut health and immune system and probably also has an effect on overall health status in later life. Probiotics, defined as viable microbial preparations that have a beneficial effect on the health of the host, represent a rapidly expanding field. Although randomized controlled trials using probiotics in infants have shown promising results in the prevention and treatment of common diseases such as diarrhea and allergy, little is known about whether probiotics could offer benefits to healthy infants. We have designed a randomized controlled trial to test the hypothesis that an oral preparation of probiotics is superior to placebo in improving digestive and immune function in healthy infants.The trial will be a randomized, double-blind, placebo-controlled, 2-parallel-group study in Shanghai, China. After a 2-week run-in period, 200 exclusively formula-fed healthy infants aged 4 to 6 months will be randomly allocated to receive either a probiotic product containing Bifidobacterium infantis R0033, Bifidobacterium bifidum R0071, and Lactobacillus helveticus R0052 or an identical placebo once daily for 4 weeks and will be followed up for 8 weeks. The duration of the subject's participation will be 14 weeks, with a total of 5 visits: inclusion (Visit 1, Day 1), start of intervention (V2, D15), end of intervention (V3, D44), and follow-up (V4 and V5, D72 and D100). Stool and saliva samples will be collected at the first 3 visits to measure microbial populations and secretory immunoglobulin A (SIgA), respectively. Physical examination will be performed at each visit, and tolerance records will be completed 1 day prior to each visit. The primary endpoints will be the changes in the composition of fecal microbiota, particularly the Bifidobacterium bifidum population. The secondary endpoints will include the change in salivary SIgA level, growth parameters, digestive tolerance, and adverse events.An effective, practical, and acceptable probiotic intervention in manipulating the gut microbiota and boosting the immune system in formula-fed infants would represent a major clinical advance. The administration of probiotic supplementation or follow-on formula to infant may be associated with some clinic benefits.

A Neonatal Murine Model of MRSA Pneumonia.

Pneumonia due to methicillin-resistant Staphylococcus aureus (MRSA) is a significant cause of morbidity and mortality in infants particularly following lower respiratory tract viral infections such as Respiratory Syncytial Virus (RSV). However, the mechanisms by which co-infection of infants by MRSA and RSV cause increased lung pathology are unknown. Because the infant immune system is qualitatively and quantitatively different from adults we developed a model of infant MRSA pneumonia which will allow us to investigate the effects of RSV co-infection on disease severity. We infected neonatal and adult mice with increasing doses of MRSA and demonstrate that neonatal mice have delayed kinetics in clearing the bacteria in comparison to adult mice. There were differences in recruitment of immune cells into the lung following infection. Adult mice exhibited an increase in neutrophil recruitment that coincided with reduced bacterial titers followed by an increase in macrophages. Neonatal mice, however, exhibited an early increase in neutrophils that did not persist despite continued presence of the bacteria. Unlike the adult mice, neonatal mice failed to exhibit an increase in macrophages. Neonates exhibited a decrease in phagocytosis of MRSA suggesting that the decrease in clearance was partially due to deficient phagocytosis of the bacteria. Both neonates and adults responded with an increase in pro-inflammatory cytokines following infection. However, in contrast to the adult mice, neonates did not express constitutive levels of the anti-microbial peptide Reg3γ in the lung. Infection of neonates did not stimulate expression of the co-stimulatory molecule CD86 by dendritic cells and neonates exhibited a diminished T cell response compared to adult mice. Overall, we have developed a neonatal model of MRSA pneumonia that displays a similar delay in bacterial clearance as is observed in the neonatal intensive care unit and will be useful for performing co-infection studies.

Superantigens and adhesins of infant gut commensal Staphylococcus aureus strains and association with subsequent development of atopic eczema.

According to the hygiene hypothesis, insufficient immune activation by microbes increases the risk of allergy development. Staphylococcus aureus, which is part of the skin and gut microbiota of infants in Western countries, produces a variety of T-cell-activating enterotoxins, called superantigens. To investigate whether early (0-2 months of age) gut colonization by S. aureus strains that carry specific superantigens and adhesins was related to subsequent development of atopic eczema in a Swedish birth cohort. Staphylococcus aureus was isolated from rectal swabs and cultured quantitatively from faecal samples, with individual strains being tested for carriage of genes for superantigens and adhesins. Atopic eczema was diagnosed at onset of symptoms and at 18 months of age. Although the frequency of early gut colonization by S. aureus was not related to subsequent eczema development, the S. aureus strains that were found to colonize those infants who developed atopic eczema were less likely to carry the gene encoding the superantigen SElM (P = 0·008) and the gene for elastin-binding protein (P = 0·03), compared with strains that were isolated from infants who had not developed atopic eczema by 18 months of age. Gut colonization by S. aureus strains carrying a certain combination of superantigen and adhesin genes was negatively associated with subsequent development of atopic eczema. Such strains may provide stimulation and promote maturation of the infant immune system.

Increased rates of cesarean sections and large families: a potentially dangerous combination.

Rates of cesarean sections have been on the rise over the past three decades all over the world, despite the ideal rate of 10-15% that had been set by the World Health Organization (WHO) in 1985, in Fortaleza, Brazil. This epidemic increase in the rate of cesarean delivery is due to many factors which include, cesarean delivery on request, advanced maternal age at first pregnancy, decrease in number of patients who are willing to try vaginal birth after cesarean delivery, virtual disappearance of vaginal breech delivery, perceived increase in the weight of the fetus and increase in the number of women with chronic medical conditions such as Diabetes Mellitus and congenital heart disease in the reproductive age. There is no doubt that cesarean delivery is a safe procedure and it is getting safer and safer for many reasons. However, like all other surgical procedures it is not without risks both to the mother and the new born. There is a substantial increase in the incidence of morbidly adherent placenta and the risk of scar pregnancy. In the Middle East and many African and Asian countries women tend to have large families. The number of previous cesarean section deliveries is directly proportional to the risk of developing morbidly adherent placenta. Morbidly adherent placenta is the most common cause of emergency postpartum hysterectomy, which is often associated with multiple surgical complications, severe maternal morbidity and mortality. The increased rates of cesarean sections lead to increased rates of scar pregnancies, which can have lethal consequences. Cesarean delivery has a negative impact on the infant immune system. This effect on the infant led to the introduction of a new concept called "Vaginal seeding". This refers to the practice of transferring some maternal vaginal fluid to the infant born via cesarean section in an effort to enhance its immune system.

BCG vaccination at birth and early childhood hospitalisation: a randomised clinical multicentre trial

BackgroundThe BCG vaccine is administered to protect against tuberculosis, but studies suggest there may also be non-specific beneficial effects upon the infant immune system, reducing early non-targeted infections and atopic...

The microbiome in early life: implications for health outcomes.

Recent studies have characterized how host genetics, prenatal environment and delivery mode can shape the newborn microbiome at birth. Following this, postnatal factors, such as antibiotic treatment, diet or environmental exposure, further modulate the development of the infant's microbiome and immune system, and exposure to a variety of microbial organisms during early life has long been hypothesized to exert a protective effect in the newborn. Furthermore, epidemiological studies have shown that factors that alter bacterial communities in infants during childhood increase the risk for several diseases, highlighting the importance of understanding early-life microbiome composition. In this review, we describe how prenatal and postnatal factors shape the development of both the microbiome and the immune system. We also discuss the prospects of microbiome-mediated therapeutics and the need for more effective approaches that can reconfigure bacterial communities from pathogenic to homeostatic configurations.

Obesity and overweight: Impact on maternal and milk microbiome and their role for infant health and nutrition.

Obesity, particularly in infants, is becoming a significant public health problem that has reached "epidemic" status worldwide. Obese children have an increased risk of developing obesity-related diseases, such as metabolic syndromes and diabetes, as well as increased risk of mortality and adverse health outcomes later in life. Experimental data show that maternal obesity has negative effects on the offspring's health in the short and long term. Increasing evidence suggests a key role for microbiota in host metabolism and energy harvest, providing novel tools for obesity prevention and management. The maternal environment, including nutrition and microbes, influences the likelihood of developing childhood diseases, which may persist and be exacerbated in adulthood. Maternal obesity and weight gain also influence microbiota composition and activity during pregnancy and lactation. They affect microbial diversity in the gut and breast milk. Such microbial changes may be transferred to the offspring during delivery and also during lactation, affecting infant microbial colonisation and immune system maturation. Thus, an adequate nutritional and microbial environment during the peri-natal period may provide a window of opportunity to reduce the risk of obesity and overweight in our infants using targeted strategies aimed at modulating the microbiota during early life.

Breastfeeding and Risk of Kawasaki Disease: A Nationwide Longitudinal Survey in Japan.

Kawasaki disease (KD) is the most common cause of childhood-acquired heart disease in developed countries. However, the etiology of KD is not known. Aberrant immune responses are considered to play key roles in disease initiation and breastfeeding can mature immune system in infants. We thus examined the association between breastfeeding and the development of KD. We used a nationwide population-based longitudinal survey ongoing since 2010 and restricted participants to a total of 37 630 children who had data on their feeding during infancy. Infant feeding practice was queried at 6 to 7 months of age, and responses to questions about hospital admission for KD during the period from 6 to 30 months of age were used as outcome. We conducted logistic regression analyses controlling for child and maternal factors with formula feeding without colostrum as our reference group. A total of 232 hospital admissions were observed. Children who were breastfed exclusively or partially were less likely to be hospitalized for KD compared with those who were formula fed without colostrum; odds ratios for hospitalization were 0.26 (95% confidence interval: 0.12-0.55) for exclusive breastfeeding and 0.27 (95% confidence interval: 0.13-0.55) for partial breastfeeding. Although the risk reduction was not statistically significant, feeding colostrum only also provided a protective effect. We observed protective effects of breastfeeding on the development of KD during the period from 6 to 30 months of age in a nationwide, population-based, longitudinal survey in Japan, the country in which KD is most common.

Breastfeeding and perinatal exposure, and the risk of asthma and allergies.

Exposures during the perinatal period, a phase of rapid development, may have a profound and sustained effect on disease risk. In particular, perinatal exposures may influence the development and maturation of the infant immune system and the risk of allergic disease. We aimed to summarize the current literature on perinatal exposures and the risk of asthma and allergic disease Increased risk of offspring wheeze or asthma was found for: maternal obesity and hypertension during pregnancy; febrile illness, gynaecological, and viral respiratory infections in pregnancy; exposure to bisphenol A and phthalates in pregnancy and childhood; exposure to smoking in utero; low birth weight; caesarean section and neonatal hyperbilirubinaemia. Reduced risk of offspring atopic eczema was found for hookworm infection in pregnancy and reduced risk of offspring wheeze was associated with increased pregnancy dietary intake of vitamin E and zinc. Higher levels of selenium in pregnancy were associated with less risk of asthma in genetically susceptible offspring. Early life pet ownership was associated with a decrease in atopic asthma but an increase in nonatopic asthma risk. A diverse range of exposures were associated with allergic disease risk, highlighting the susceptibility of children during the perinatal period. Clinicians should reinforce public health messages concerning maternal obesity, smoking, and breastfeeding. The infant gut microbiome is emerging as an important hypothesis, which may mediate the relationship between many perinatal exposures and allergic disease.

Redistribution of T follicular helper cells to the lungs of neonatal mice infected with influenza

Abstract The infant immune system responds poorly to both infection and vaccination, however the mechanisms responsible for impaired immune responses in neonates are incompletely understood. Here we analyzed T and B cell responses to influenza infection in neonatal mice. We found that neonatal mice were much more susceptible to primary influenza infection and cleared virus with delayed kinetics. Although CD8 T cell responses were slightly delayed in neonates compared to adults, neonates ultimately generated robust CD8 T cell responses. Following resolution of infection, however, the accumulation of tissue-resident memory (Trm) CD8 T cell responses was impaired in mice infected as neonates. In contrast, the appearance of influenza-specific CD4 T cells, including T follicular helper (Tfh) cells, was not delayed. Surprisingly, Tfh cells appeared in the lungs of neonatal mice, but not the lungs of adult mice. Tfh cells in the lungs of neonates correlated with the appearance of germinal center (GC) B cells and the formation of inducible bronchus-associated lymphoid tissue (iBALT) in the lungs. However, despite the appearance of local Tfh and GC B cells, the production of influenza-specific antibody was severely impaired in neonatal mice. Thus, despite the differentiation of influenza-specific Tfh in both lymphoid organs and lungs of neonatal mice, B cell-mediated immunity was still profoundly impaired. Nevertheless, while mice given a primary influenza infection as neonates had diminished Trm CD8 T cell responses and impaired B cell-mediated immunity, they were able to survive lethal rechallenge as adults, indicating that protective immunity could be generated in neonates.

Towards a functional hypothesis relating anti-islet cell autoimmunity to the dietary impact on microbial communities and butyrate production.

BackgroundThe development of anti-islet cell autoimmunity precedes clinical type 1 diabetes and occurs very early in life. During this early period, dietary factors strongly impact on the composition of the gut microbiome. At the same time, the gut microbiome plays a central role in the development of the infant immune system. A functional model of the association between diet, microbial communities, and the development of anti-islet cell autoimmunity can provide important new insights regarding the role of the gut microbiome in the pathogenesis of type 1 diabetes.ResultsA novel approach was developed to enable the analysis of the microbiome on an aggregation level between a single microbial taxon and classical ecological measures analyzing the whole microbial population. Microbial co-occurrence networks were estimated at age 6 months to identify candidates for functional microbial communities prior to islet autoantibody development. Stratification of children based on these communities revealed functional associations between diet, gut microbiome, and islet autoantibody development. Two communities were strongly associated with breast-feeding and solid food introduction, respectively. The third community revealed a subgroup of children that was dominated by Bacteroides abundances compared to two subgroups with low Bacteroides and increased Akkermansia abundances. The Bacteroides-dominated subgroup was characterized by early introduction of non-milk diet, increased risk for early autoantibody development, and by lower abundances of genes for the production of butyrate via co-fermentation of acetate. By combining our results with information from the literature, we provide a refined functional hypothesis for a protective role of butyrate in the pathogenesis of type 1 diabetes.ConclusionsBased on functional traits of microbial communities estimated from co-occurrence networks, we provide evidence that alterations in the composition of mucin degrading bacteria associate with early development of anti-islet cell autoimmunity. We hypothesize that lower levels of Bacteroides in favor of increased levels of Akkermansia lead to a competitive advantage of acetogens compared to sulfate reducing bacteria, resulting in increased butyrate production via co-fermentation of acetate. This hypothesis suggests that butyrate has a protective effect on the development of anti-islet cell autoantibodies.Electronic supplementary materialThe online version of this article (doi:10.1186/s40168-016-0163-4) contains supplementary material, which is available to authorized users.

Lymphocyte subpopulations in premature infants: an observational study

Background and objectivesThe infant's immune system evolves over the first months and years of life. Strong correlation exists between lymphocyte count, lymphocyte subpopulations and gestational age at birth. Associations with...

Microbiome: Baby steps towards the microbiome.

Two new studies show that the maternal microbiota affects the development of the infant's immune system and identified colonization by uropathogenicE. colilineages as a risk factor for the development of necrotizing enterocolitis and infant death.

Changes over lactation in breast milk serum proteins involved in the maturation of immune and digestive system of the infant

To objective of this study was to better understand the biological functions of breast milk proteins in relation to the growth and development of infants over the first six months of life. Breast milk samples from four individual women collected at seven time points in the first six months after delivery were analyzed by filter aided sample preparation and dimethyl labeling combined with liquid chromatography tandem mass spectrometry. A total of 247 and 200 milk serum proteins were identified and quantified, respectively. The milk serum proteome showed a high similarity (80% overlap) on the qualitative level between women and over lactation. The quantitative changes in milk serum proteins were mainly caused by three groups of proteins, enzymes, and transport and immunity proteins. Of these 21 significantly changed proteins, 30% were transport proteins, such as serum albumin and fatty acid binding protein, which are both involved in transporting nutrients to the infant. The decrease of the enzyme bile salt-activated lipase as well as the immunity proteins immunoglobulins and lactoferrin coincide with the gradual maturation of the digestive and immune system of infants. The human milk serum proteome didn't differ qualitatively but it did quantitatively, both between mothers and as lactation advanced. The changes of the breast milk serum proteome over lactation corresponded with the development of the digestive and immune system of infants. Biological significanceBreast milk proteins provide nutrition, but also contribute to healthy development of infants. Despite the previously reported large number of identified breast milk proteins and their changes over lactation, less is known on the changes of these proteins in individual mothers. This study is the first to determine the qualitative and quantitative changes of milk proteome over lactation between individual mothers. The results indicate that the differences in the milk proteome between individual mothers are more related to the quantitative level than qualitative level. The correlation between the changes of milk proteins and the gradual maturation of the gastrointestinal tract and immune system in infants, contributes to a better understanding of the biological functions of human milk proteins for the growth and development of infants.

Fostering of advanced mutualism with gut microbiota by Immunoglobulin A.

Immunoglobulin A (IgA), the most abundantly secreted antibody isotype in mammals, not only provides direct immune protection to neonates via maternal milk but also helps program the infant immune system by regulating the microbiota. IgA continues to maintain dynamic interactions with the gut microbiota throughout life and this influences immune system homeostasis as well as other physiological processes. The secretory IgA produced independently of T-cell selection are commonly referred to as natural or innate antibodies. Our studies have shown that innate-IgA, while effective at excluding microorganisms from the gut, does not promote mutualism with the microbiota in the same way as adaptive-IgA that is selected in T cell-dependent germinal center reactions. Adaptive-IgA fosters more advanced mutualism with the microbiota than innate-IgA by selecting and diversifying beneficial microbial communities. In this review, we suggest that the diversified microbiota resulting from adaptive-IgA pressure was pivotal in promoting ecological adaptability and speciation potential of mammals.

Best practice in the prevention and management of paediatric respiratory syncytial virus infection.

Respiratory syncytial virus (RSV) infection is ubiquitous with almost all infants having been infected by 2 years of age and lifelong repeated infections common. It is the second largest cause of mortality, after malaria, in infants outside the neonatal period and causes up to 200,000 deaths per year worldwide. RSV results in clinical syndromes that include upper respiratory tract infections, otitis media, bronchiolitis (up to 80% of cases) and lower respiratory tract disease including pneumonia and exacerbations of asthma or viral-induced wheeze. For the purposes of this review we will focus on RSV bronchiolitis in infants in whom the greatest disease burden lies. For infants requiring hospital admission, the identification of the causative respiratory virus is used to direct cohorting or isolation and infection control procedures to minimize nosocomial transmission. Nosocomial RSV infections are associated with poorer clinical outcomes, including increased mortality, the need for mechanical ventilation and longer length of hospital stay. Numerous clinical guidelines for the management of infants with bronchiolitis have been published, although none are specific for RSV bronchiolitis. Ribavirin is the only licensed drug for the specific treatment of RSV infection but due to drug toxicity and minimal clinical benefit it has not been recommended for routine clinical use. There is currently no licensed vaccine to prevent RSV infection but passive immunoprophylaxis using a monoclonal antibody, palivizumab, reduces the risk of hospitalization due to RSV infection by 39-78% in various high-risk infants predisposed to developing severe RSV disease. The current management of RSV bronchiolitis is purely supportive, with feeding support and oxygen supplementation until the infant immune system mounts a response capable of controlling the disease. The development of a successful treatment or prophylactic agent has the potential to revolutionize the care and outcome for severe RSV infections in the world's most vulnerable infants.

Evidence for the essentiality of arachidonic and docosahexaenoic acid in the postnatal maternal and infant diet for the development of the infant's immune system early in life.

Long-chain polyunsaturated fatty acids (LCPUFA), especially the balance between arachidonic (AA) and docosahexaenoic (DHA) acids are known to have important immunomodulatory roles during the postnatal period when the immune system is rapidly developing. AA and DHA are required in infant formula in many countries but are optional in North America. The rationale for adding these LCPUFA to full-term formula is based on their presence in breast milk and randomized controlled studies that suggest improved cognitive function in preterm infants, but results are more variable in full-term infants. Recently, the European Food Safety Authority has proposed, based on a lack of functional evidence, that AA is not required in infant formula for full-term infants during the first year of life but DHA should remain mandatory. The purpose of this review is to review the evidence from epidemiological and intervention studies regarding the essentiality of AA and DHA in the postnatal infant and maternal diet (breast-feeding) for the immune system development early in life. Although studies support the essentiality of DHA for the immune system development, more research is needed to rule out the essentiality of AA. Nevertheless, intervention studies have demonstrated improvement in many markers of immune function in infants fed formula supplemented with AA and DHA compared with unsupplemented formula, which appears to consistently result in beneficial health outcomes including reduction in the risk of developing allergic and atopic disease early in life.