Lipopolysaccharide-induced interferon response networks at birth are predictive of severe viral lower respiratory infections in the first year of life.

Appropriate innate immune function is essential to limit pathogenesis and severity of severe lower respiratory infections (sLRI) during infancy, a leading cause of hospitalization and risk factor for subsequent asthma in this age group. Employing a systems biology approach to analysis of multi-omic profiles generated from a high-risk cohort (n=50), we found that the intensity of activation of an LPS-induced interferon gene network at birth was predictive of sLRI risk in infancy (AUC=0.724).

Protection against severe infant lower respiratory tract infections by immune training: Mechanistic studies.

Background: Results from recent clinical studies suggest potential efficacy of immune training (IT)-based approaches for protection against severe lower respiratory tract infections in infants, but underlying mechanisms are unclear.

Objective: We used systems-level analyses to elucidate IT mechanisms in infants in a clinical trial setting.

Methods: Pre- and posttreatment peripheral blood mononuclear cells from a placebo-controlled trial in which winter treatment with the IT agent OM85 reduced infant respiratory infection frequency and/or duration were stimulated for 24 hours with the virus/bacteria mimics polyinosinic:polycytidylic acid/lipopolysaccharide.

Cord-blood respiratory syncytial virus antibodies and respiratory health in first 5 years of life.

Objective: To determine the potential longer-term effects of maternal antenatal respiratory syncytial virus (RSV) vaccination, we examined the association between cord-blood RSV-neutralizing antibodies (RSV-NA) and RSV infections in the first 2 years of life, RSV-NA at 3 years, and respiratory health to age 5 years.

Methods: Two community-based Australian birth cohorts were combined. For children with at least one atopic parent, paired serum RSV-NA levels were compared in cord blood and at age 3 years.

Neonatal genetics of gene expression reveal potential origins of autoimmune and allergic disease risk.

Chronic immune-mediated diseases of adulthood often originate in early childhood. To investigate genetic associations between neonatal immunity and disease, we map expression quantitative trait loci (eQTLs) in resting myeloid cells and CD4 T cells from cord blood samples, as well as in response to lipopolysaccharide (LPS) or phytohemagglutinin (PHA) stimulation, respectively. Cis-eQTLs are largely specific to cell type or stimulation, and 31% and 52% of genes with cis-eQTLs have response eQTLs (reQTLs) in myeloid cells and T cells, respectively.

Rewiring of gene networks underlying mite allergen-induced CD4 + Th-cell responses during immunotherapy.

Background: Multiple regulatory mechanisms have been identified employing conventional hypothesis-driven approaches as contributing to allergen-specific immunotherapy outcomes, but understanding of how these integrate to maintain immunological homeostasis is incomplete.

Objective: To explore the potential for unbiased systems-level gene co-expression network analysis to advance understanding of immunotherapy mechanisms.

Methods: We profiled genome-wide allergen-induced Th-cell responses prospectively during 24 months subcutaneous immunotherapy (SCIT) in 25 rhinitis, documenting changes in immunoinflammatory pathways and associated co-expression networks and their relationships to symptom scores out to 36 months.

Personalized Transcriptomics Reveals Heterogeneous Immunophenotypes in Children with Viral Bronchiolitis.

A subset of infants are hypersusceptible to severe/acute viral bronchiolitis (AVB), for reasons incompletely understood. To characterize the cellular/molecular mechanisms underlying infant AVB in circulating cells/local airway tissues. Peripheral blood mononuclear cells and nasal scrapings were obtained from infants (<18 mo) and children (≥18 mo to 5 yr) during AVB and after convalescence.

Developmental regulation of type 1 and type 3 interferon production and risk for infant infections and asthma development.

Background: Virus-associated febrile lower respiratory tract infections (fLRIs) during infancy have been identified as risk factors for persistent wheeze development. We hypothesized that variations in innate immune defense capacity during this period, as exemplified by production of type 1 and 3 interferons (T1/3IFNs), might be an underlying determinant of risk.

Objective: We sought to investigate relationships between postnatal development of innate interferon response capacity and susceptibility to early infections and persistent wheeze.

Airway Microbiota Dynamics Uncover a Critical Window for Interplay of Pathogenic Bacteria and Allergy in Childhood Respiratory Disease.

Repeated cycles of infection-associated lower airway inflammation drive the pathogenesis of persistent wheezing disease in children. In this study, the occurrence of acute respiratory tract illnesses (ARIs) and the nasopharyngeal microbiome (NPM) were characterized in 244 infants through their first five years of life. Through this analysis, we demonstrate that >80% of infectious events involve viral pathogens, but are accompanied by a shift in the NPM toward dominance by a small range of pathogenic bacterial genera.

Vitamin D over the first decade and susceptibility to childhood allergy and asthma.

Background: Vitamin D (25(OH)D) deficiency has been implicated as a possible risk factor for asthma development, but studies at selected time points measuring 25(OH)D levels during childhood have yielded conflicting findings. Prospective studies tracking 25(OH)D levels during the initiation phase of asthma in early childhood have not been reported.

Objective: We sought to elucidate relationships between 25(OH)D levels from birth to age 10 years and susceptibility to allergic sensitization, respiratory tract infections, and asthma.

Distinguishing benign from pathologic TH2 immunity in atopic children.

Background: Although most children with asthma and rhinitis are sensitized to aeroallergens, only a minority of sensitized children are symptomatic, implying the underlying operation of efficient anti-inflammatory control mechanisms.

Objective: We sought to identify endogenous control mechanisms that attenuate expression of IgE-associated responsiveness to aeroallergens in sensitized children.

Methods: In 3 independent population samples we analyzed relationships between aeroallergen-specific IgE and corresponding allergen-specific IgG (sIgG) and associated immunophenotypes in atopic children and susceptibility to asthma and rhinitis, focusing on responses to house dust mite and grass.

The infant nasopharyngeal microbiome impacts severity of lower respiratory infection and risk of asthma development.

The nasopharynx (NP) is a reservoir for microbes associated with acute respiratory infections (ARIs). Lung inflammation resulting from ARIs during infancy is linked to asthma development. We examined the NP microbiome during the critical first year of life in a prospective cohort of 234 children, capturing both the viral and bacterial communities and documenting all incidents of ARIs.

Low maternal serum vitamin D during pregnancy and the risk for postpartum depression symptoms.

Pregnancy is a time of vulnerability for vitamin D insufficiency, and there is an emerging literature associating low levels of 25(OH)-vitamin D with depressive symptoms. However, the link between 25(OH)-vitamin D status in pregnancy and altered risk of postnatal depressive symptoms has not been examined. We hypothesise that low levels of 25(OH)-vitamin D in maternal serum during pregnancy will be associated with a higher incidence of postpartum depressive symptoms.

Maternal vitamin D levels and the autism phenotype among offspring.

We tested whether maternal vitamin D insufficiency during pregnancy is related to the autism phenotype. Serum 25(OH)-vitamin D concentrations of 929 women were measured at 18 weeks' pregnancy. The mothers of the three children with a clinical diagnosis of autism spectrum disorder had 25(OH)-vitamin D concentrations above the population mean.

Maternal serum vitamin D levels during pregnancy and offspring neurocognitive development.

Objectives: To determine the association between maternal serum 25(OH)-vitamin D concentrations during a critical window of fetal neurodevelopment and behavioral, emotional, and language outcomes of offspring.

Methods: Serum 25(OH)-vitamin D concentrations of 743 Caucasian women in Perth, Western Australia (32°S) were measured at 18 weeks pregnancy and grouped into quartiles. Offspring behavior was measured with the Child Behavior Checklist at 2, 5, 8, 10, 14, and 17 years of age (n range = 412-652).

Toward improved prediction of risk for atopy and asthma among preschoolers: a prospective cohort study.

Background: Atopy and asthma are commonly initiated during early life, and there is increasing interest in the development of preventive treatments for at-risk children. However, effective methods for assessing the level of risk in individual children are lacking.

Objective: We sought to identify clinical and laboratory biomarkers in 2-year-olds that are predictive of the risk for persistent atopy and wheeze at age 5 years.

Elucidation of asthma phenotypes in atopic teenagers through parallel immunophenotypic and clinical profiling.

Background: Current treatment strategies for asthma in teenagers derive primarily from information on chronic disease in adults. More detailed understanding of risk factors related to teenage asthma might aid in the development of improved preventive and treatment strategies for this age group.

Objective: We sought to identify biomarkers associated with asthma phenotypes in teenagers, particularly atopic asthma, and to identify markers that aid in discriminating between atopic subjects at high versus low risk of asthma.

Cord blood hemopoietic progenitor profiles predict acute respiratory symptoms in infancy.

Atopy is characterized by eosinophilic inflammation associated with recruitment of eosinophil/basophil (Eo/B) progenitors. We have previously shown that Eo/B progenitor phenotypes are altered in cord blood (CB) in infants at high risk of atopy/asthma, and respond to maternal dietary intervention during pregnancy. As respiratory tract viral infections have been shown to induce wheeze in infancy, we investigated the relationship between CB progenitor function and phenotype and acute respiratory illness (ARI), specifically wheeze and fever.

Prenatal versus postnatal sensitization to environmental allergens in a high-risk birth cohort.

Background: The timing of allergen sensitization is controversial, with conflicting evidence suggesting transplacental priming versus exclusively postnatal priming. Resolution of this question is important in relation to rational design of allergy prevention strategies, particularly the issue of allergen avoidance during pregnancy.

Objective: To elucidate the kinetics of sensitization in high-risk children during their first 2 years of life.

CpG methylation patterns in the IFNgamma promoter in naive T cells: variations during Th1 and Th2 differentiation and between atopics and non-atopics.

Interferon-gamma (IFNgamma) gene expression is tightly regulated in early life, and exaggerated negative control of IFNgamma production in CD4(+) T cells has been associated with risk for subsequent development of atopy. Recent studies have demonstrated hypermethylation of CpG sites in the IFNgamma promoter in neonates, a mechanism which in mice leads to strong suppression of IFNgamma gene transcription. In the present study, the methylation status of six CpG sites in the proximal promoter of the human IFNgamma gene was determined by bisulphite sequencing.

Functional maturation of CD4+CD25+CTLA4+CD45RA+ T regulatory cells in human neonatal T cell responses to environmental antigens/allergens.

A number of laboratories have reported cord blood T cell responses to ubiquitous environmental Ags, including allergens, by proliferation and cytokine secretion. Moreover, the magnitude of these responses has been linked with risk for subsequent expression of allergy. These findings have been widely interpreted as evidence for transplacental priming and the development of fetal T memory cells against Ags present in the maternal environment.

High IFN-gamma production by CD8+ T cells and early sensitization among infants at high risk of atopy.

Background: High genetic risk (HR) of atopy among unstratified populations of infants is associated with attenuated IFN-gamma responses. However, the role of IFN-gamma in progression from HR status to active disease is less clear.

Objective: To identify immune function markers in neonates with HR that are associated with positive atopic outcomes at 2 years.

Development of interleukin-12-producing capacity throughout childhood.

Increasing evidence indicates that the capacity to induce protective Th1 immune responses is impaired in early childhood, an observation that can be partially attributed to deficiencies in antigen-presenting-cell function. Synthesis of interleukin 12 (IL-12), a key Th1-trophic cytokine, is markedly reduced in the neonatal period, though there is a paucity of knowledge concerning the ontogeny of IL-12-synthetic capacity throughout the childhood years. Hence, we examined the production of bioactive IL-12 p70 by circulating mononuclear cells in a population of healthy individuals.