Infant Immune System Research Articles

Hypothesis: Conjugate vaccines may predispose children to autism spectrum disorders

The first conjugate vaccine was approved for use in the US in 1988 to protect infants and young children against the capsular bacteria Haemophilus influenzae type b (Hib). Since its introduction in the US, this vaccine has been approved in most developed countries, including Denmark and Israel where the vaccine was added to their national vaccine programs in 1993 and 1994, respectively.There have been marked increases in the reported prevalence of autism spectrum disorders (ASDs) among children in the US beginning with birth cohorts in the late 1980s and in Denmark and Israel starting approximately 4–5years later. Although these increases may partly reflect ascertainment biases, an exogenous trigger could explain a significant portion of the reported increases in ASDs. It is hypothesized here that the introduction of the Hib conjugate vaccine in the US in 1988 and its subsequent introduction in Denmark and Israel could explain a substantial portion of the initial increases in ASDs in those countries. The continuation of the trend toward increased rates of ASDs could be further explained by increased usage of the vaccine, a change in 1990 in the recommended age of vaccination in the US from 15 to 2months, increased immunogenicity of the vaccine through changes in its carrier protein, and the subsequent introduction of the conjugate vaccine for Streptococcus pneumoniae.Although conjugate vaccines have been highly effective in protecting infants and young children from the significant morbidity and mortality caused by Hib and S. pneumoniae, the potential effects of conjugate vaccines on neural development merit close examination. Conjugate vaccines fundamentally change the manner in which the immune systems of infants and young children function by deviating their immune responses to the targeted carbohydrate antigens from a state of hypo-responsiveness to a robust B2 B cell mediated response. This period of hypo-responsiveness to carbohydrate antigens coincides with the intense myelination process in infants and young children, and conjugate vaccines may have disrupted evolutionary forces that favored early brain development over the need to protect infants and young children from capsular bacteria.

Pathogen Associated Molecular Patterns, Pattern Recognition Receptors and Pediatric Sepsis

The mortality of septic shock in the pediatric population has improved over the last 2 decades with better supportive care however it still remains unacceptably high. Exaggerated inflammatory responses early in septic shock have been associated with poor outcomes. Regulation of the magnitude of the early inflammatory response is not well understood. The earliest aspect of the inflammatory response to pathogens is the innate immune response which is important to pathogen containment. Elements of the innate immune system activate the adaptive immune system in an antigen-specific way which leads to pathogen-specific protection and lasting immunologic memory to prevent subsequent infection. Pattern recognition receptors (PRRs) are evolutionarily conserved receptors on multiple types of innate immune cells and are capable of responding to highly conserved components of pathogens called pathogen associated molecular patterns (PAMPs). Numerous PRRs have been defined and are present on the cell surface as well as in the cytosol. These receptors fall into several classes called Toll-like receptors which are expressed on the cell surface or on the endosomal plasma membrane, C type lectin receptors and scavenger receptors which are only present on the cell surface. Other PRRs are present in the cytosol and including NOD-like receptors which can aggregate to form inflammasomes and RIG1 like receptors. Pathogenic microorganisms are extremely diverse however there are some common patterns repeated in components of structures such as the cell wall. PRRs can respond to PAMPs comprised of proteins, lipids, and carbohydrates, DNA and RNA. Numerous PAMPs have been described for many classes of pathogenic microorganisms such as Gram negative bacteria, Gram positive bacteria, viruses, fungi, and protozoa. The interactions between PRRs and PAMPs comprise the earliest immune responses to foreign substances and are critical for pathogen containment and amplification of the full repertoire of the immune response. There are developmental differences in the immune systems of infants and children compared to adults. The innate immune system matures much earlier than the adaptive immune response and as a result infants and young children may be more reliant on their innate immune system. For this reason it important to fully understand the key elements of the innate immune response including the many categories of PRRs and their cognate PAMPs. As these interactions are very early in the immune response, they are particularly relevant targets for therapeutic intervention. Below is a discussion of the major classes of PRRs, their expression, ligands, and signaling pathways as well as the major classes of PAMPs that activate them.

Maternal psychosocial factors determining the concentrations of transforming growth factor‐beta in breast milk

Cytokines in breast milk may play crucial roles in the beneficial effects of breastfeeding in protecting against allergic and infectious diseases in infants. In particular, breast milk-borne transforming growth factor-beta (TGF-β) has an important potential role in developing the mucosal immune system in infants. However, little is known about what factors influence TGF-β expression in human milk. We investigated whether the behavioral and psychosocial characteristics of mothers affect breast milk TGF-β levels. We conducted a survey of all 139 mothers who were lactating between February and October 2010 in Koshu City, Japan. Participants completed a questionnaire and provided breast milk at the health checkups for their 3-month-old child (N = 129, 93%). Breast milk was assayed for total TGF-β2 levels by ELISA. We took an exploratory approach based on linear and ordered logistic regressions to model TGF-β2 concentrations with their multiple potential determinants. Mothers with depression or poor self-rated health had higher TGF-β2 concentrations than mothers without depression (odds ratio for a higher TGF-β2 quartile: 3.11, 95% confidence intervals: 1.03-9.37) or those reporting better health (odds ratio: 2.34, 1.21-4.55). Smoking, drinking alcohol, probiotics supplementation, social support, and maternal history of allergic diseases were not associated with milk TGF-β2 levels. Milk gathered between August and October or later in the afternoon (3-4 pm vs. 12-2 pm) contained less TGF-β2. Depression, as the consequence of psychosocial stress, may be a strong determinant of TGF-β levels in breast milk. Seasonal and daily fluctuations in milk TGF-β2 concentrations warrant further study.

Non‐digestible oligosaccharides reduce immunoglobulin free light‐chain concentrations in infants at risk for allergy

Prebiotic oligosaccharides influence the intestinal microbiota and can positively modulate the infant's immune system. It was demonstrated that a special prebiotic mixture (Immunofortis(®)) of short-chain galacto-oligosaccharides (scGOS) and long-chain fructo-oligosaccharides (lcFOS) can reduce the cumulative incidence of atopic dermatitis (AD) in infants at risk for allergy as determined using the AD symptom score (SCORAD). Additionally, it was shown very recently that immunoglobulin free light-chain (Ig-fLC) might be involved in the pathophysiology of allergic disease. Increased Ig-fLC concentrations were found in patients suffering from AD, cow's milk allergy, allergic rhinitis, or asthma. In this study, the effect of supplementation of scGOS/lcFOS on the Ig-fLC plasma concentrations in infants at risk for allergy was assessed. The plasma kappa and lambda Ig-fLC concentrations were measured in a double-blind, placebo-controlled, randomized trial, in which infants at risk for developing allergic disease received a hypoallergenic whey formula containing 8 g/l of the scGOS/lcFOS mixture (n = 34) or maltodextrin as a placebo (n=40) for 6 months. After intervention, plasma samples were collected, and total plasma concentrations of lambda and kappa Ig-fLC were analyzed using ELISA. Total kappa and lambda Ig-fLC plasma concentrations were higher in infants suffering from AD when compared to infants without any sign of AD. In infants receiving the prebiotic mixture, the Ig-fLC levels were significantly lower compared to the placebo-fed infants (p<0.001). Interestingly, lambda Ig-fLC concentrations were positively correlated with total IgE (p<0.05). These data demonstrate for the first time that the specific scGOS/lcFOS mixture lowered kappa and lambda Ig-fLC plasma concentrations in infants at high risk for allergies when compared to infants receiving placebo formula. Because Ig-fLC concentrations were increased in infants suffering from AD, this may have contributed, at least in part, to the reduced incidence in AD as described previously. This suggests a possible role for Ig-fLC in the pathophysiology of AD in infants at risk for allergy development.

Booster hepatitis B vaccination not necessary for long-term protection in children immunised with hexavalent vaccines.

< 0.0001). Geometric mean concentration (GMC) was lower among children primed with Hexavac than among those primed with Infanrix Hexa (p < 0.0001). In the multivariate analysis the type of hexavalent vaccine given was the only determinant of anti-HBs concentration after adjustment. However, children in both groups who received a booster hepatitis B vaccination had a similar rapid anamnestic response, and the proportion of children who responded to the booster were similar between groups. 92.1% of children originally given Hexavac and 94.3% of children originally given Infanrix Hexa showed protective levels of antibodies after the booster vaccination, thus showing the presence of specific immune memory. Side-effects were infrequent, mild, and did not differ between the two booster groups. No serious adverse events were reported. These results suggest that infant immune systems are able to recall responding to hepatitis B more than 5 years after primary immunisation with hexavalent vaccines, thereby providing effective protection even in children showing low (< 10 mIU/ml) or undetectable levels of antibodies. Together, these findings suggest that in healthy children the immunological memory for hepatitis B surface antigen (HBsAg) may outlast the presence of antibody. In other words, children who have lost preventive antibody concentrations might still maintain T-cell memory that is able to trigger anti-HBs production by B cells when activated by revaccination

Understanding the Inflammatory Response of the Neonate: Clinical Implications for Caregivers in the Neonatal Intensive Care Unit

Nurses who care for preterm infants within the neonatal intensive care unit (NICU) face a multitude of challenges. An issue of major importance is supporting the immature immune response that when left unchecked makes young and preterm infants especially vulnerable to infection. Research has shown that the neonate's inflammatory response is moderately effective yet not well differentiated, which can lead to additional tissue destruction. This article examines the pathophysiology of the inflammatory process and discusses the influence that inflammation has on the infant before and after birth. Links between neonatal sepsis and neurologic insults such as intraventricular hemorrhage and periventricular leukomalacia are discussed. These insults have been associated with poor neurodevelopmental outcomes. Nursing interventions and management strategies are provided to best support the infant during this critical process. An understanding of the infant's immune system and the inflammation process will enhance the neonatal caregiver's ability to consider and provide preventative measures in routine care practices.

Early life: gut microbiota and immune development in infancy

The immune system of infants is actively downregulated during pregnancy and therefore the first months of life represent a period of heightened susceptibility to infection. After birth, there is an age-dependent maturation of the immune system. Exposure to environmental microbial components is suggested to play an important role in the maturation process. The gastrointestinal tract is the major site of interaction between the host immune system and microorganisms, both commensal as well as potentially pathogenic. It is well established that the mammalian immune system is designed to help protect the host from invading microorganisms and other danger signals. However, recent research is emerging in the field of host-microbe interactions showing that commensal microorganisms (microbiota) are most likely one of the drivers of immune development and, in turn the immune system shapes the composition of the microbiota. Specific early microbial exposure of the gut is thought to dramatically reduce the incidence of inflammatory, autoimmune and atopic diseases further fuelling the scientific view that microbial colonisation plays an important role in regulating and fine-tuning the immune system throughout life. Therefore, the use of pre-, pro- and synbiotics may result in a beneficial microbiota composition that might have a pivotal role on the prevention of several important diseases that develop in early life such as necrotizing enterocolitis and atopic eczema.

The challenge of assessing infant vaccine responses in resource-poor settings

Newborns and infants are highly susceptible to infectious diseases, resulting in high mortality and morbidity, particularly in resource-poor settings. Many vaccines require several booster doses, resulting in an extensive vaccine schedule, and yet there is still inadequate protection from some of these diseases. This is partly due to the immaturity of the neonate and infant immune system. Little is known about the specific modifications to immunological assessment protocols in early life but increasing knowledge of infant immunology has helped provide better recommendations for assessing these responses. Since most new vaccines will eventually be deployed in low-income settings such as Africa, the logistics and resources of assessing immunity in such settings also need to be understood. In this article, we will review immunity to vaccines in early life, discuss the many challenges associated with assessing immunogenicity and provide practical tips.

Current controversies in the USA regarding vaccine safety

As a result of the vaccines discovered in the 20th Century, parents and many healthcare providers of the 21st Century have limited or no experience with the devastating effects of diseases such as polio, smallpox or measles. Fear of disease has shifted to concerns regarding vaccine safety. Scientific evidence has refuted many of the misconceptions regarding vaccine safety; however, parental refusal of vaccines is increasing. Here we review six of the most prevalent controversies surrounding vaccine safety: the proposed causal relationship between receipt of the measles–mumps–rubella vaccine and autism; thimerosal as a potential trigger for autism; religious objection based on some vaccine viruses being grown in cell lines from aborted fetal tissues; parental worries that use of the human papillomavirus vaccine may lead to youth promiscuity; fears regarding the purported association between pertussis vaccination and adverse neurological outcomes; and concerns regarding too many vaccines overloading or weakening the infant immune system. Healthcare providers are ideally positioned to correct these misconceptions, but they must recognize and acknowledge parents’ concerns, educate themselves on the latest scientific research that addresses these, and dedicate sufficient time to discuss vaccine safety with worried parents.

MicroRNA as a new immune-regulatory agent in breast milk

BackgroundBreast milk is a complex liquid that provides nutrition to the infant and facilitates the maturation of the infant's immune system. Recent studies indicated that microRNA (miRNA) exists in human body fluid. Because miRNAs are known to regulate various immune systems, we hypothesized that human breast milk contains miRNAs that may be important for the development of the infant's immune system.FindingsWe profiled miRNA expression in human breast milk and detected high expression levels of immune-related miRNAs in the first 6 months of lactation. Furthermore, these miRNA molecules are stable even in very acidic conditions, indicating that breast milk allows dietary intake of miRNAs by infants.ConclusionsOur findings provide new insight into how breast milk can modulate the development of the infant's immune system. This study suggests the transfer of genetic material as miRNA from human to human occurs by means other than through sexual reproduction.

Respiratory viral infections in infants: causes, clinical symptoms, virology, and immunology.

In global terms, respiratory viral infection is a major cause of morbidity and mortality. Infancy, in particular, is a time of increased disease susceptibility and severity. Early-life viral infection causes acute illness and can be associated with the development of wheezing and asthma in later life. The most commonly detected viruses are respiratory syncytial virus (RSV), rhinovirus (RV), and influenza virus. In this review we explore the complete picture from epidemiology and virology to clinical impact and immunology. Three striking aspects emerge. The first is the degree of similarity: although the infecting viruses are all different, the clinical outcome, viral evasion strategies, immune response, and long-term sequelae share many common features. The second is the interplay between the infant immune system and viral infection: the immaturity of the infant immune system alters the outcome of viral infection, but at the same time, viral infection shapes the development of the infant immune system and its future responses. Finally, both the virus and the immune response contribute to damage to the lungs and subsequent disease, and therefore, any prevention or treatment needs to address both of these factors.

Th1 and Th2 Chemokines, Vaccine-Induced Immunity, and Allergic Disease in Infants After Maternal ω-3 Fatty Acid Supplementation During Pregnancy and Lactation

We investigated whether the previously reported preventive effect of maternal ω-3 fatty acid supplementation on IgE-associated allergic disease in infancy may be mediated by facilitating a balanced circulating Th2/Th1 chemokine profile in the infant. Vaccine-induced immune responses at 2 y of age were also evaluated. Pregnant women, at risk of having an allergic infant, were randomized to daily supplementation with 1.6 g eicosapentaenoic acid and 1.1 g docosahexaenoic acid or placebo from the 25th gestational week through 3.5 mo of breastfeeding. Infant plasma was analyzed for chemokines (cord blood, 3, 12, 24 mo) and anti-tetanus and anti-diphtheria IgG (24 mo). High Th2-associated CC-chemokine ligand 17 (CCL17) levels were associated with infant allergic disease (p < 0.05). In infants without, but not with, maternal history of allergy, the ω-3 supplementation was related to lower CCL17/CXC-chemokine ligand 11 (CXCL11) (Th2/Th1) ratios (p < 0.05). Furthermore, in nonallergic, but not in allergic infants, ω-3 supplementation was linked with higher Th1-associated CXCL11 levels (p < 0.05), as well as increased IgG titers to diphtheria (p = 0.01) and tetanus (p = 0.05) toxins. Thus, the prospect of balancing the infant immune system toward a less Th2-dominated response, by maternal ω-3 fatty acid supplementation, seems to be influenced by allergic status.

Diet and asthma: looking back, moving forward

Asthma is an increasing global health burden, especially in the western world. Public health interventions are sought to lessen its prevalence or severity, and diet and nutrition have been identified as potential factors. With rapid changes in diet being one of the hallmarks of westernization, nutrition may play a key role in affecting the complex genetics and developmental pathophysiology of asthma. The present review investigates hypotheses about hygiene, antioxidants, lipids and other nutrients, food types and dietary patterns, breastfeeding, probiotics and intestinal microbiota, vitamin D, maternal diet, and genetics. Early hypotheses analyzed population level trends and focused on major dietary factors such as antioxidants and lipids. More recently, larger dietary patterns beyond individual nutrients have been investigated such as obesity, fast foods, and the Mediterranean diet. Despite some promising hypotheses and findings, there has been no conclusive evidence about the role of specific nutrients, food types, or dietary patterns past early childhood on asthma prevalence. However, diet has been linked to the development of the fetus and child. Breastfeeding provides immunological protection when the infant's immune system is immature and a modest protective effect against wheeze in early childhood. Moreover, maternal diet may be a significant factor in the development of the fetal airway and immune system. As asthma is a complex disease of gene-environment interactions, maternal diet may play an epigenetic role in sensitizing fetal airways to respond abnormally to environmental insults. Recent hypotheses show promise in a biological approach in which the effects of dietary factors on individual physiology and immunology are analyzed before expansion into larger population studies. Thus, collaboration is required by various groups in studying this enigma from epidemiologists to geneticists to immunologists. It is now apparent that this multidisciplinary approach is required to move forward and understand the complexity of the interaction of dietary factors and asthma.

A specific mixture of short‐chain galacto‐oligosaccharides and long‐chain fructo‐oligosaccharides induces a beneficial immunoglobulin profile in infants at high risk for allergy

It has been suggested that human breast milk oligosaccharides play a role in the development of the immune system in infants, and may consequently inhibit the onset of allergy. A specific prebiotic mixture of short-chain galacto-oligosaccharides and long-chain fructo-oligosaccharides (GOS/FOS) has been shown to reduce the incidence of atopic dermatitis (AD) at 6 months of age in infants at risk for allergy. This study was aimed to analyze the effect of GOS/FOS on the immune response in these infants. In a double-blind randomized placebo-controlled study, infants received a hypoallergenic whey formula with either 8 g/l GOS/FOS in a 9 : 1 ratio (IMMUNOFORTIS) or 8 g/l maltodextrine (placebo) for 6 months. At 3 months of age, children were vaccinated with Hexavac against a.o. diphteria, tetanus, polio (DTP). At 6 months of age, plasma samples were collected from 84 infants (verum group n = 41, placebo group n = 43). Levels of total immunoglobulins (Ig) and of cow's milk protein (CMP-) and DTP-specific Ig were measured. GOS/FOS supplementation led to a significant reduction in the plasma level of total IgE, IgG1, IgG2 and IgG3, whereas no effect on IgG4 was observed. CMP-specific IgG1 was significantly decreased. DTP-specific Ig levels were not affected. This study shows that GOS/FOS supplementation induces a beneficial antibody profile. GOS/FOS reduces the total Ig response and modulates the immune response towards CMP, while leaving the response to vaccination intact. This suggests that oral GOS/FOS supplementation is a safe method to restrain the atopic march.

Breast-Feeding and Its Role in Early Development of the Immune System in Infants: Consequences for Health Later in Life1,

Respiratory tract infections and gastrointestinal tract infections of both bacterial and viral origin cause the highest mortality and morbidity in neonates and infants. This is true not only for developing countries but also for industrialized countries (1). Increased susceptibility to infections and decreased immune responsiveness to these infectious agents continue to be present significantly in y 2 of life. However, it should be realized that the induction of an immune response against nonharmful common environmental antigens, such as food antigens and particular commensals (bacteria), has to be inhibited lest it give rise to undesirable, excessive, and destructive inflammatory and allergic reactions (2,3). It appears that the development of the immune system in neonates and young infants is reflected in the enhancement of ‘‘specific’’ immune responses to danger signals and in the induction of tolerance toward common nonharmful environmental antigens such as food components as well as the microbiota of the infant gut. It should be realized that the human immune system can be modulated easily during the first months of life (4), when it can be affected not only positively but, unfortunately, also negatively. This dichotomy is illustrated by, e.g., survival advantage after surgery early in life and survival postsurgery health consequences later on (5). This article provides a brief overview of the current knowledge of the development of the infant immune system and possibilities for intervention and immunomodulation.

Long-Chain Polyunsaturated Fatty Acids Influence the Immune System of Infants1,2,

Several events occur during the first months of life that allow the immune system to become competent and functional. The aim of this article is to review the rationale and evidence of an influence of (n-3) long-chain PUFA (LCPUFA) on the immune system of infants. The (n-3) LCPUFA exert their immunomodulatory activities at different levels. The (n-3) LCPUFA metabolites induce eicosanoid production, alter gene expression, and modify lipid raft composition, altering T-cell signaling; all contribute to immunological functional changes. However, the roles of these mechanisms and the types of T or other immunological cells involved remain unclear at present. Moreover, the effect of (n-3) LCPUFA on the immune system of infants may vary according to dose, time of exposure, and profile of the immune system (T-helper, Th1/Th2). Most of the interventional studies in infancy have been performed for the prevention of allergy. They all confirmed influence on T-cell function and cytokine profiles, but clinically beneficial effects are more conflicting. Supplementation of the maternal diet in pregnancy or early childhood with (n-3) LCPUFA is potentially a noninvasive intervention strategy to prevent the development of allergy, infection, and possibly other immune-mediated diseases. However, any long-term in vivo effects on (n-3) LCPUFA early in life for immunomodulatory defense in infants and later on immune status and health remain to be assessed.

Inefficient phagosome maturation in infant macrophages

The quantitative and qualitative differences between the immune systems of infants and adults have been extensively investigated in the context of adaptive immunity. Here, we demonstrate that the infantile innate immune system is immature and weak against bacterial infections. Upon infection by Escherichia coli, macrophages from infantile mice showed a lower performance in killing the bacteria. In infant macrophages, bacteria were taken up relatively normally and delivered into lysosomal compartments, but not efficiently digested. The inefficient bacterial killing in infant macrophages was correlated with impaired acidification of the lysosomal compartments and reduced lysosomal recruitment of Rab7, an essential component of the acidification process. The acidification defect was not intrinsic to the cells, and was rescued by pretreatment with interferon-γ. Thus, we propose that the limited capacity of phagosome maturation is one of the major causes of the high sensitivity to infectious microorganisms during infancy and that the specific cytokine milieu shapes the nature of infantile innate immunity.

Nutritional Support for the Infant's Immune System

Newborn babies possess a functional but immature immune system as a defense against a world teeming with microorganisms. Breast milk contains a number of biological, active compounds that support the infant's immune system. These include secretory immu-noglobulin A (IgA), which confers specific protection against enteric pathogens, as well as numerous other immunological, active ingredients. A number of these ingredients can be used as supplements for infant formulas based on cow's milk. Here, the strength of evidence regarding the immune-stimulating effects of selected minerals, vitamins, fatty acids, pre- andpro-biotics, and nucleotides is reviewed. An assessment of how these ingredients are used in infant-formula products currently available on the market is also presented.

Breastfeeding and the Infant's Immune System

Breastfeeding and the Infant's Immune System

Daily Variations in Oligosaccharides of Human Milk Determined by Microfluidic Chips and Mass Spectrometry

Human milk is a complex biological fluid that provides not only primary nourishment for infants but also protection against pathogens and influences their metabolic, immunologic, and even cognitive development. The presence of oligosaccharides in remarkable abundance in human milk has been associated to provide diverse biological functions including directing the development of an infant's intestinal microflora and immune system. Recent advances in analytical tools offer invaluable insights in understanding the specific functions and health benefits these biomolecules impart to infants. Oligosaccharides in human milk samples obtained from five different individual donors over the course of a 3 month lactation period were isolated and analyzed using HPLC-Chip/TOF-MS technology. The levels and compositions of oligosaccharides in human milk were investigated from five individual donors. Comparison of HPLC-Chip/TOF-MS oligosaccharides profiles revealed heterogeneity among multiple individuals with no significant variations at different stages of lactation within individual donors.