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Background: IgE‐mediated sensitisation to egg is common in infants. In some cases, the processes leading to egg sensitisation are established in early life, even before introduction to solid foods. The underlying mechanisms remain poorly understood. Methods: We performed detailed immune cell phenotyping of peripheral blood mononuclear cells and determined in vitro cytokine responses following allergen specific and non‐specific immune stimulation. To determine if unique immune profiles were linked to early‐life egg sensitisation, we compared 92 infants at 4–6 months of age, with (EggCAP+, n = 41) and without (EggCAP−, n = 51) early egg sensitisation. Additionally, 47 cord blood samples were analysed. For a subset of participants (n = 39), matching cord blood mononuclear cells were assessed by flow cytometry to establish the impact of IgE sensitisation on immune developmental trajectories. Results: EggCAP+ infants were found to exhibit a unique immune phenotype characterised by increased levels of circulating CD4+ T regulatory cells (Treg), CD4+ effector memory (EM) Treg and increased expression of the IgE receptor, FcεR1, on basophils. The increased CD4+ EM Treg profiles were already present in cord blood samples from EggCAP+ infants. A general Th2‐skewing of the immune system was observed based on increased IL‐13 production following phytohemagglutinin stimulation and by comparing immune developmental trajectories, EggCAP+ infants displayed an expansion of basophils and reduced levels of CD4− T cells compared to EggCAP− infants. Conclusions: Immunological profiles associated with egg sensitisation are detectable in infant circulation at 4–6 months of age and at birth. Understanding the immune mechanisms underlying early‐life sensitisation could provide important insights for future food allergy prevention strategies. [ABSTRACT FROM AUTHOR]

Brown adipose tissue (BAT) may be an important metabolic regulator of whole‐body glucose. While important roles have been ascribed to macrophages in regulating metabolic functions in BAT, little is known of the roles of other immune cells subsets, particularly dendritic cells (DCs). Eating a high‐fat diet may compromise the development of hematopoietic stem and progenitor cells (HSPCs)—which give rise to DCs—in bone marrow, with less known of its effects in BAT. We have previously demonstrated that ongoing exposure to low‐dose ultraviolet radiation (UVR) significantly reduced the 'whitening' effect of eating a high‐fat diet upon interscapular (i) BAT of mice. Here, we examined whether this observation may be linked to changes in the phenotype of HSPCs and myeloid‐derived immune cells in iBAT and bone marrow of mice using 12‐colour flow cytometry. Many HSPC subsets declined in both iBAT and bone marrow with increasing metabolic dysfunction. Conversely, with rising adiposity and metabolic dysfunction, conventional DCs (cDCs) increased in both of these tissues. When compared with a low‐fat diet, consumption of a high‐fat diet significantly reduced proportions of myeloid, common myeloid and megakaryocyte–erythrocyte progenitors in iBAT, and short‐term hematopoietic stem cells in bone marrow. In mice fed the high‐fat diet, exposure to low‐dose UVR significantly reduced proportions of cDCs in iBAT, independently of nitric oxide release from irradiated skin [blocked using the scavenger 2‐(4‐carboxyphenyl)‐4,4,5,5‐tetramethylimidazoline‐1‐oxyl‐3‐oxide potassium salt (cPTIO)], but did not significantly modify HSPC subsets in either tissue. Further studies are needed to determine whether changes in these cell populations contribute towards metabolic dysfunction. [ABSTRACT FROM AUTHOR]

Objectives: Incomplete maturation of immune regulatory functions at birth is antecedent to the heightened risk for severe respiratory infections during infancy. Our forerunner animal model studies demonstrated that maternal treatment with the microbial‐derived immune training agent OM‐85 during pregnancy promotes accelerated postnatal maturation of mechanisms that regulate inflammatory processes in the offspring airways. Here, we aimed to provide proof of concept for a novel solution to reduce the burden and potential long‐term sequelae of severe early‐life respiratory viral infection through maternal oral treatment during pregnancy with OM‐85, already in widespread human clinical use. Methods: In this study, we performed flow cytometry and targeted gene expression (RT‐qPCR) analysis on lungs from neonatal offspring whose mothers received oral OM‐85 treatment during pregnancy. We next determined whether neonatal offspring from OM‐85 treated mothers demonstrate enhanced protection against lethal lower respiratory infection with mouse‐adapted rhinovirus (vMC0), and associated lung immune changes. Results: Offspring from mothers treated with OM‐85 during pregnancy display accelerated postnatal seeding of lung myeloid populations demonstrating upregulation of function‐associated markers. Offspring from OM‐85 mothers additionally exhibit enhanced expression of TLR4/7 and the IL‐1β/NLRP3 inflammasome complex within the lung. These treatment effects were associated with enhanced capacity to clear an otherwise lethal respiratory viral infection during the neonatal period, with concomitant regulation of viral‐induced IFN response intensity. Conclusion: These results demonstrate that maternal OM‐85 treatment protects offspring against lethal neonatal respiratory viral infection by accelerating development of innate immune mechanisms crucial for maintenance of local immune homeostasis in the face of pathogen challenge. [ABSTRACT FROM AUTHOR]

Background: Low vitamin D levels have been associated with allergic diseases. Vitamin D has potent immunomodulatory properties, but the mechanisms remain unclear. We have investigated the effect of oral vitamin D supplementation on circulating immune cell phenotypes in infants. Method: A double‐blinded randomised controlled trial was conducted to investigate the effect of oral vitamin D supplementation (400 IU/d) on eczema and immune development. A subset of 78 infants was included in this analysis. Phenotypic analysis of immune cell subsets was performed using flow cytometry. Results: Vitamin D supplementation resulted in median 25(OH)D levels of 80.5 vs 59.5 nmol/L in the placebo group at 3 months of age (P =.002) and 87.5 vs 77 nmol/L at 6 months of age (P =.08). We observed significant changes in immune cell composition from birth (cord blood) to 6 months of age. Vitamin D supplementation did not impact these changes, nor did immune cell composition correlate with plasma 25(OH)D levels. Through exploratory analysis, we identified possible associations with eczema development and increased abundance of naïve CD4‐ T cells at birth, as well as associations with basophils, iNKT and central memory CD4+ T cells, and altered expression patterns of IgE receptor (FcεR1) on monocytes and dendritic cells with eczema at 6 months. Conclusions: Vitamin D supplementation in infants who were vitamin D sufficient at birth did not affect developmental changes in immune cells during the first 6 months of life. However, immune cell profiles at birth and at 6 months of age were associated with early life eczema. [ABSTRACT FROM AUTHOR]

Background: The prevalence and severity of asthma, particularly the most common (atopic) form of the disease, increase amongst females but not males after puberty, and asthma activity also changes throughout the menstrual cycle and during pregnancy. The contribution of female sex hormones to asthma pathogenesis is incompletely understood. Objective: To obtain insight into the role of oestrogen (E2) in experimental atopic asthma, and guide future research on sex‐related variations in atopic asthma susceptibility/intensity in humans. Methods: We utilized an experimental model comprising rat strains expressing dichotomous Th2‐high vs Th2‐low immunophenotypes exemplified by eosinophilia, mirroring differences between human atopics/non‐atopics. We compared the efficiency of Th2‐associated immunoinflammatory mechanisms, which differed markedly between the two strains, and between sexes in the Th2‐high strain, and determined the effects of E2 administration on these differences. Results: Unique to the Th2‐high strain, eosinophil: neutrophil ratios in the airways at baseline and following sensitization/aeroallergen challenge were logfold higher in females relative to males, and this was reflected by higher baseline blood eosinophil numbers in females. Pretreatment of Th2‐high males with E2 abrogated this sex difference by selectively boosting Th2‐associated genes in the airways and eosinophilia, but was without corresponding effect in the Th2‐low strain. In contrast, parallel E2 effects on myeloid and lymphoid cell populations were relatively modest. Conclusions and Clinical Relevance: E2 acts to amplify the eosinophilic component of pre‐existing Th2‐high immunophenotype, possibly acting at the level of the common eosinophil/neutrophil precursor in bone marrow to preferentially drive eosinophil differentiation. Constitutive granulocyte profiles in which the balance between eosinophils and neutrophils is skewed towards eosinophils have been identified in independent cohort studies as markers of asthma risk, and these findings suggest that more detailed studies on the role of E2 in this context, and in relation to asthma pathogenesis in post‐pubertal females in particular, appear warranted. [ABSTRACT FROM AUTHOR]

Background: Antigen‐specific IgE binds the Fcε receptor I (FcεRI) expressed on several types of immune cells, including dendritic cells (DCs). Activation of FcεRI on DCs in atopics has been shown to modulate immune responses that potentially contribute to asthma development. However, the extent to which DC subsets differ in FcεRI expression between atopic children with or without asthma is currently not clear. This study aimed to analyse the expression of FcεRI on peripheral blood mononuclear cells (PBMCs) from atopic children with and without asthma, and non‐atopic/non‐asthmatic age‐matched healthy controls. Methods: We performed multiparameter flow cytometry on PBMC from 391 children across three community cohorts and one clinical cohort based in Western Australia. Results: We confirmed expression of FcεRI on basophils, monocytes, plasmacytoid and conventional DCs, with higher proportions of all cell populations expressing FcεRI in atopic compared to non‐atopic children. Further, we observed that levels of FcεRI expression were elevated across plasmacytoid and conventional DC as well as basophils in atopic asthmatic compared to atopic non‐asthmatic children also after adjusting for serum IgE levels. Conclusion: Our data suggest that the expression pattern of FcεRI on DC and basophils differentiates asthmatic from non‐asthmatic atopic children. Given the significant immune modulatory effects observed as a consequence of FcεRI expression, this altered expression pattern is likely to contribute to asthma pathology in children. [ABSTRACT FROM AUTHOR]

Abstract: Respiratory IgE‐sensitization to innocuous antigens increases the risk for developing diseases such as allergic asthma. Dendritic cells (DC) residing in the airways orchestrate the immune response following antigen exposure and their ability to sample and present antigens to naïve T cells in airway draining lymph nodes contributes to allergen‐specific IgE‐sensitization. In order to characterize inhaled antigen capture and presentation by DC subtypes in vivo, we used an adjuvant‐free respiratory sensitization model using two genetically distinct rat strains, one of which is naturally resistant and the other naturally susceptible to allergic sensitization. Upon multiple exposures to ovalbumin (OVA), the susceptible strain developed OVA‐specific IgE and airway inflammation, whereas the resistant strain did not. Using fluorescently tagged OVA and flow cytometry, we demonstrated significant differences in antigen uptake efficiency and presentation associated with either IgE‐sensitization or resistance to allergen exposures in respective strains. We further identified CD4+ conventional DC (cDC) as the subset involved in airway antigen sampling in both strains, however, CD4+ cDC in the susceptible strain were less efficient in OVA sampling and displayed increased MHC‐II expression compared with the resistant strain. This was associated with generation of an exaggerated Th2 response and a deficiency of airway regulatory T cells in the susceptible strain. These data suggest that subsets of cDC are able to induce either sensitization or resistance to inhaled antigens as determined by genetic background, which may provide an underlying basis for genetically determined susceptibility to respiratory allergic sensitization and IgE production in susceptible individuals. [ABSTRACT FROM AUTHOR]

Folate intake during pregnancy may affect the regulation of DNA methylation during fetal development. The genomic regions in the offspring that may be sensitive to folate exposure during in utero development have not been characterized. Using genome-scale profiling, we investigated DNA methylation in 2 immune cell types (CD4+ and antigen-presenting cells) isolated from neonatal cord blood, selected on the basis of in utero folate exposure. High-folate (HF; n=11) and low-folate (LF; n=12) groups were selected from opposite extremes of maternal serum folate levels measured in the last trimester of pregnancy. A comparison of these groups revealed differential methylation at 7 regions across the genome. By far, the biggest effect observed was hypomethylation of a 923 bp region 3 kb upstream of the ZFP57 transcript, a regulator of DNA methylation during development, observed in both cell types. Levels of H3/H4 acetylation at ZFP57 promoter and ZFP57 mRNA expression were higher in CD4+ cells in the HF group relative to the LF group. Hypomethylation at this region was replicated in an independent sample set. These data suggest that exposure to folate has effects on the regulation of DNA methylation during fetal development, and this may be important for health and disease. [ABSTRACT FROM AUTHOR]

To cite this article: Lisciandro JG, Prescott SL, Nadal-Sims MG, Devitt CJ, Pomat W, Siba PM., Holt PG, Strickland D, van den Biggelaar AHJ. Comparison of neonatal T regulatory cell function in Papua New Guinean and Australian newborns. Pediatr Allergy Immunol 2011: Doi: 10.1111/j.1399-3038.2011.01242.x. Abstract Background: Environmental changes, including declining microbial exposure, have been linked with the rising incidence of allergic and autoimmune diseases in 'western' populations. This potentially occurs by altering early development of immuno-regulatory pathways including T regulatory cells (Treg). There is now increasing evidence that such conditioning begins in utero. Methods: We compared neonatal Treg from children born under typical western conditions (Australia, AUS) with those of neonates born under more traditional conditions of high microbial burden (Papua New Guinea, PNG). Results: The frequency of neonatal Treg, defined as CD4+ Foxp3+ CD127− CD25+/high was found to be higher in the cord blood of AUS compared to PNG newborns. However, cord Treg suppressive function in a small subset of children was qualitatively similar between PNG and AUS newborns in both a Treg depletion assay and a Treg supplementation assay. Conclusions: These findings do not support the hypothesis that living in a 'western' versus more traditional environment leads to poor induction or suppressive function of neonatal Treg. However, environmentally-induced immuno-regulation may potentially occur via alternative mechanisms in PNG newborns that should now be investigated further. [ABSTRACT FROM AUTHOR]