ORCID Profile
0000-0001-6823-4696
Current Organisations
Telethon Kids Institute
,
University of Western Australia
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Publisher: Cold Spring Harbor Laboratory
Date: 15-01-2023
DOI: 10.1101/2023.01.13.523912
Abstract: Experimental studies suggest that exposures may impact respiratory health across generations via epigenetic changes transmitted specifically through male germ cells. Studies in humans are however limited. We aim to identify epigenetic marks in offspring associated with father’s preconception smoking. We conducted epigenome-wide association studies (EWAS) in the RHINESSA cohort on father’s any preconception smoking (N=875 offspring) and father’s pubertal onset smoking years (N=304), using Infinium MethylationEPIC Beadchip arrays, adjusting for offspring age, maternal smoking and personal smoking. EWAS of maternal and offspring personal smoking were performed for replication. Father’s smoking commencing preconception was associated with methylation of blood DNA in offspring at two Cytosine-phosphate-Guanine sites (CpGs) (False Discovery Rate (FDR) .05) in PRR5 and CENPP . Father’s pubertal onset smoking was associated with 19 CpGs (FDR .05) mapped to 14 genes ( TLR9, DNTT, FAM53B, NCAPG2, PSTPIP2, MBIP, C2orf39, NTRK2, DNAJC14, CDO1, PRAP1, TPCN1, IRS1 and CSF1R ). These differentially methylated sites were hypermethylated and associated with promoter regions capable of gene silencing. Some of these sites were associated with offspring outcomes in this cohort including ever-asthma (NTRK2), ever-wheezing (DNAJC14, TPCN1), weight (FAM53B, NTRK2) and BMI (FAM53B, NTRK2) (P 0.05). Pathway analysis showed enrichment for gene ontology pathways including regulation of gene expression, inflammation and innate immune responses. Father’s preconception smoking, particularly in puberty, is associated with offspring DNA methylation, providing evidence that epigenetic mechanisms may underly epidemiological observations that pubertal paternal smoking increases risk of offspring asthma, low lung function and obesity.
Publisher: Wiley
Date: 11-2022
DOI: 10.1111/PAI.13890
Abstract: IgE‐mediated food allergies have been linked to suboptimal naïve CD4 T (nCD4T) cell activation in infancy, underlined by epigenetic and transcriptomic variation. Similar attenuated nCD4T cell activation in adolescents with food allergy have also been reported, but these are yet to be linked to specific epigenetic or transcriptional changes. We generated genome‐wide DNA methylation data in purified nCD4 T cells at quiescence and following activation in a cohort of adolescents (aged 10–15 years old) with peanut allergy (peanut only or peanut + ≥1 additional food allergy) (FA, n = 29), and age‐matched non‐food allergic controls (NA, n = 18). Additionally, we assessed transcriptome‐wide gene expression and cytokine production in these cells following activation. We found widespread changes in DNA methylation in both NA and FA nCD4T cells in response to activation, associated with the T cell receptor signaling pathway. Adolescents with FA exhibit unique DNA methylation signatures at quiescence and post‐activation at key genes involved in Th1/Th2 differentiation ( RUNX3 , RXRA , NFKB1A , IL4R) , including a differentially methylated region (DMR) at the TNFRSF6B promoter, linked to Th1 proliferation. Combined analysis of DNA methylation, transcriptomic data and cytokine output in the same s les identified an attenuated interferon response in nCD4T cells from FA in iduals following activation, with decreased expression of several interferon genes, including IFN‐γ and a DMR at a key downstream gene, BST2 . We find that attenuated nCD4T cell responses from adolescents with food allergy are associated with specific epigenetic variation, including disruption of interferon responses, indicating dysregulation of key immune pathways that may contribute to a persistent FA phenotype. However, we recognize the small s le size, and the consequent restraint on reporting adjusted p ‐value statistics as limitations of the study. Further study is required to validate these findings.
Publisher: MyJove Corporation
Date: 21-06-2018
DOI: 10.3791/57601
Publisher: MDPI AG
Date: 30-09-2021
DOI: 10.3390/MICROORGANISMS9102066
Abstract: Dysbiosis refers to a reduction in microbial ersity, combined with a loss of beneficial taxa, and an increase in pathogenic microorganisms. Dysbiosis of the intestinal microbiota can have a substantial effect on the nervous and immune systems, contributing to the onset of several inflammatory diseases. Epidemiological studies provided insight in how changes in the living environment have contributed to an overall loss of ersity and key taxa in the gut microbiome, coinciding with increased reports of atopy and allergic diseases. The gut microbiome begins development at birth, with major transition periods occurring around the commencement of breastfeeding, and the introduction of solid foods. As such, the development of the gut microbiome remains highly plastic and easily influenced by environmental factors until around three years of age. Developing a erse and rich gut microbiome during this sensitive period is crucial to setting up a stable gut microbiome into adulthood and to prevent gut dysbiosis. Currently, the delivery route, antibiotic exposure, and diet are the best studied drivers of gut microbiome development, as well as risk factors of gut dysbiosis during infancy. This review focuses on recent evidence regarding key environmental factors that contribute to promoting gut dysbiosis.
Publisher: Elsevier BV
Date: 2010
Publisher: Elsevier BV
Date: 05-2018
Publisher: Wiley
Date: 19-11-2019
DOI: 10.1111/ALL.13572
Abstract: IgE-mediated egg allergy presents as one of the most common food allergies in children. Measurement of egg white specific IgE (sIgE) levels in serum or skin prick test has been shown to be a poor predictor of clinical allergy to raw egg white, and also to baked or cooked egg. Recent developments in component resolved diagnostic (CRD) technology have enabled us to improve the way in which we diagnose and predict peanut allergy by examining IgE specificity to in idual peptides. We aimed to investigate whether egg CRD could improve current methods to diagnose various egg allergy phenotypes as well as predict the development of tolerance to egg. Using the HealthNuts cohort of food challenge-proven egg allergic and egg-sensitized and egg-tolerant, age-matched 12-month infants with longitudinal follow-up at 2 and 4 years (n = 451), we measured serum egg white, Gal d 1, 2, 3 and 5 sIgE using ImmunoCAP. Gal d 1 sensitization increased the risk of persistent egg allergy by 2.5-fold. The production of sIgE to all four egg allergens (Gal d 1, 2, 3 or 5) increased the risk of having persistent raw egg allergy fourfold (OR 4.19 (95% CI: 1.25-14.07). We did not find any improvements of using Gal d 1, 2, 3 or 5 to diagnose current egg allergy compared to egg white sIgE. Sensitization to multiple egg allergens Gal d 1, 2, 3 or 5 may be a prognostic marker that could be useful for patient management and identifying in iduals at risk of developing persistent egg allergy.
Publisher: Springer Science and Business Media LLC
Date: 21-01-2022
DOI: 10.1186/S13148-022-01231-9
Abstract: Prenatal alcohol exposure (PAE) is associated with a range of adverse offspring neurodevelopmental outcomes. Several studies suggest that PAE modifies DNA methylation in offspring cells and tissues, providing evidence for a potential mechanistic link to Fetal Alcohol Spectrum Disorder (FASD). We systematically reviewed existing evidence on the extent to which maternal alcohol use during pregnancy is associated with offspring DNA methylation. A systematic literature search was conducted across five online databases according to Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. PubMed, Web of Science, EMBASE, Google Scholar and CINAHL Databases were searched for articles relating to PAE in placental mammals. Data were extracted from each study and the Risk of Bias in Non-Randomized Studies of Interventions (ROBINS-I) was used to assess the potential for bias in human studies. Forty-three articles were identified for inclusion. Twenty-six animal studies and 16 human studies measured offspring DNA methylation in various tissues using candidate gene analysis, methylome-wide association studies (MWAS), or total nuclear DNA methylation content. PAE dose and timing varied between studies. Risk of bias was deemed high in nearly all human studies. There was insufficient evidence in human and animal studies to support global disruption of DNA methylation from PAE. Inconclusive evidence was found for hypomethylation at IGF2/H19 regions within somatic tissues. MWAS assessing PAE effects on offspring DNA methylation showed inconsistent evidence. There was some consistency in the relatively small number of MWAS conducted in populations with FASD. Meta-analyses could not be conducted due to significant heterogeneity between studies. Considering heterogeneity in study design and potential for bias, evidence for an association between PAE and offspring DNA methylation was inconclusive. Some reproducible associations were observed in populations with FASD although the limited number of these studies warrants further research. Trail Registration : This review is registered with PROSPERO (registration number: CRD42020167686).
Publisher: Cold Spring Harbor Laboratory
Date: 18-06-2023
DOI: 10.1101/2023.06.15.544516
Abstract: Alcohol consumption in pregnancy can affect genome regulation in the developing offspring but results have been contradictory. We employed a physiologically relevant murine model of short-term moderate prenatal alcohol exposure (PAE) resembling common patterns of alcohol consumption in pregnancy. Moderate early PAE was sufficient to affect site-specific DNA methylation in new-born pups without altering behavioural outcomes in adult littermates. Whole genome-bisulphite sequencing of neonatal brain and liver revealed stochastic influence on DNA methylation that was mostly tissue-specific, with some perturbations likely originating as early as gastrulation. Methylation changes were enriched in non-coding genomic regions with regulatory potential indicative of broad effects of alcohol on genome regulation. Replication studies in human cohorts with fetal alcohol spectrum disorder suggested some effects were metastable at genes linked to disease-relevant traits including facial morphology, intelligence, educational attainment, autism, and schizophrenia. A maternal diet high in folate and choline protected against some of the damaging effects of PAE on DNA methylation. Our studies demonstrate that moderate early exposure is sufficient to affect fetal genome regulation even in the absence of overt phenotypic changes and highlight a role for preventative maternal dietary interventions.
Publisher: Elsevier BV
Date: 10-2015
DOI: 10.1016/J.PLEFA.2015.07.003
Abstract: Recent evidence suggests that the effects of n-3LCPUFA might be mediated through epigenetic mechanisms, especially DNA-methylation, during pregnancy and early life. A randomized trial was conducted in 133 9-mo-old, infants who received 3.8g/day of fish oil (FO) or sunflower oil (SO) for 9 mo. In a subset of 12 children, buffy-coat DNA was extracted before and after intervention and analyzed on Illumina-Human-Methylation 450-arrays to explore genome-wide differences between the FO and SO groups. Genome-wide-methylation analysis did not reveal significant differences between groups after adjustment for multiple testing. However, analysis of the top-ranked CpG-sites revealed 43 CpG׳s that appear modified with an absolute difference in methylation of ≥10%. Methylation levels at these sites were associated with phenotypic changes mainly in blood pressure. In conclusion, our analyses suggest potential epigenome effects that might be associated with functional outcomes, yet the effect sizes were small and should be verified by additional investigation.
Publisher: MDPI AG
Date: 12-10-2020
Abstract: The regulation of innate immunity is substantially more ‘plastic’ than previously appreciated. Innate immune memory (manifested through trained immunity and tolerance) is a recently described epigenetic phenomenon that is a model ex le, with broad implications for infectious disease, allergy and autoimmunity. Training the innate immune system to combat infections and temper inappropriate responses in non-communicable diseases will likely be an area of intense research. Innate immunity is influenced by short chain fatty acids, which are the natural products of digestion by the intestinal microbiota that possess inherent histone deacetylase inhibitory properties. It therefore stands to reason that a healthy gut microbiome may well influence mucosal and systemic trained immunity via short chain fatty acids. There is a lack of data on this specific topic, and we discuss potential relationships based on available and preliminary evidence. Understanding the link between intestinal microbiome composition, capacity for short chain fatty acid production and downstream effects on innate immune memory in early life will have important implications for host immunobiology. In this review we explore the intersection between the gut microbiota, short chain fatty acids and epigenetic regulation of innate immunity with a focus on early life.
Publisher: Wiley
Date: 07-04-2021
DOI: 10.1111/ALL.14823
Abstract: In Western countries, Asian children have higher food allergy risk than Caucasian children. The early‐life environmental exposures for this discrepancy are unclear. We aimed to compare prevalence of food allergy and associated risk factors between Asian children in Singapore and Australia. We studied children in the Growing Up in Singapore Towards healthy Outcomes (GUSTO) birth cohort (n = 878) and children of Asian ancestry in the HealthNuts cohort (n = 314). Food allergy was defined as a positive SPT ≥3 mm to egg or peanut AND either a convincing history of IgE‐mediated reaction at 18 months (GUSTO) or a positive oral food challenge at 14‐18 months (HealthNuts). Eczema was defined as parent‐reported doctor diagnosis. Food allergy prevalence was 1.1% in Singapore and 15.0% in Australia ( P .001). Egg introduction was more often delayed ( months) in Singapore (63.5%) than Australia (16.3% P .001). Prevalence of early‐onset eczema ( months) was lower in Singapore (8.4%) than Australia (30.5%) ( P .001). Children with early‐onset eczema were more likely to have food allergy than those without eczema in Australia [aOR 5.11 (2.34‐11.14) P .001] and Singapore [aOR4.00 (0.62‐25.8) P = 0.145]. Among Asian children, prevalence of early‐onset eczema and food allergy was higher in Australia than Singapore. Further research with larger s le sizes and harmonized definitions of food allergy between cohorts is required to confirm and extend these findings. Research on environmental factors influencing eczema onset in Australia and Singapore may aid understanding of food allergy pathogenesis in different parts of the world.
Publisher: Elsevier BV
Date: 02-2016
DOI: 10.1016/J.JACI.2015.05.051
Abstract: There is evolving evidence that vitamin D insufficiency may contribute to food allergy, but findings vary between populations. Lower vitamin D-binding protein (DBP) levels increase the biological availability of serum vitamin D. Genetic polymorphisms explain almost 80% of the variation in binding protein levels. We sought to investigate whether polymorphisms that lower the DBP could compensate for adverse effects of low serum vitamin D on food allergy risk. From a population-based cohort study (n = 5276) we investigated the association between serum 25-hydroxyvitamin D3 (25[OH]D3) levels and food allergy at age 1 year (338 challenge-proven food-allergic and 269 control participants) and age 2 years (55 participants with persistent and 50 participants with resolved food allergy). 25(OH)D3 levels were measured using liquid chromatography-tandem mass spectrometry and adjusted for season of blood draw. Analyses were stratified by genotype at rs7041 as a proxy marker of DBP levels (low, the GT/TT genotype high, the GG genotype). Low serum 25(OH)D3 level (≤50 nM/L) at age 1 years was associated with food allergy, particularly among infants with the GG genotype (odds ratio [OR], 6.0 95% CI, 0.9-38.9) but not in those with GT/TT genotypes (OR, 0.7 95% CI, 0.2-2.0 P interaction = .014). Maternal antenatal vitamin D supplementation was associated with less food allergy, particularly in infants with the GT/TT genotype (OR, 0.10 95% CI, 0.03-0.41). Persistent vitamin D insufficiency increased the likelihood of persistent food allergy (OR, 12.6 95% CI, 1.5-106.6), particularly in those with the GG genotype. Polymorphisms associated with lower DBP level attenuated the association between low serum 25(OH)D3 level and food allergy, consistent with greater vitamin D bioavailability in those with a lower DBP level. This increases the biological plausibility of a role for vitamin D in the development of food allergy.
Publisher: Springer Science and Business Media LLC
Date: 03-10-2012
DOI: 10.1007/S11882-012-0312-1
Abstract: The profile of allergic disease worldwide continues to change as the number of severe IgE-mediated allergies increases. This phenomenon is thought to reflect the outcome of combined genetic/environmental/developmental/stochastic effects on immune development, but understanding this remains a challenge. Epigenetic disruption at key immune genes during development has been proposed as a potential explanation for how environmental exposures may alter immune cell development and function. This represents an emerging area of research with the potential to yield new understanding of how disease risk is modified. Here, we examine recent developments in this field that are defining new epigenetic paradigms of allergic disease.
Publisher: Elsevier BV
Date: 05-2014
DOI: 10.1016/J.JSBMB.2014.01.018
Abstract: It is well-established that vitamin D impacts gene regulation via vitamin D response elements (VDREs) across the genome. Recent evidence, primarily at a locus-specific level, suggests that alterations to DNA methylation may also be a relevant mechanism through which vitamin D regulates gene expression. Given the intense interest in vitamin D, particularly as an immune modifier, we sought to examine the impact of vitamin D exposure on the immune cell methylome in vitro. We exposed primary human blood mononuclear cells with up to 100nM calcitriol for up to 120h, and measured genome-scale DNA methylation response using the Illumina Infinium HumanMethylation450 beadchip array. We observed that, while the expression of known vitamin D responsive genes was clearly altered by calcitriol exposure, substantial genome-scale changes to DNA methylation were not induced. Our data suggests that, over the exposure period measured, changes to DNA methylation may not be a predominant mechanism through which vitamin D impacts gene expression in human immune cells.
Publisher: Informa UK Limited
Date: 10-09-2015
DOI: 10.1586/17474124.2015.1084873
Abstract: The rates of IgE-mediated food allergy have increased globally, particularly in developed countries. The rising incidence is occurring more rapidly than changes to the genome sequence would allow, suggesting that environmental exposures that alter the immune response play an important role. Genetic factors may also be used to predict an increased predisposition to these environmental risk factors, giving rise to the concept of gene-environment interactions, whereby differential risk of environmental exposures is mediated through the genome. Increasing evidence also suggests a role for epigenetic mechanisms, which are sensitive to environmental exposures, in the development of food allergy. This paper discusses the current state of knowledge regarding the environmental and genetic risk factors for food allergy and how environmental exposures may interact with immune genes to modify disease risk or outcome.
Publisher: Wiley
Date: 11-12-2009
DOI: 10.1111/J.1398-9995.2009.02186.X
Abstract: Epigenetic mechanisms provide new insights into how environmental changes may mediate the increasing propensity for complex immune diseases such as allergic disease. There is now strong evidence that early environmental exposures play a key role in activating or silencing genes by altering DNA and histone methylation, histone acetylation and chromatin structure. These modifications determine the degree of DNA compaction and accessibility for gene transcription, altering gene expression, phenotype and disease susceptibility. While there is already evidence that a number of early environmental exposures are associated with an increased risk of allergic disease, several new studies indicate in utero microbial and dietary exposures can modify gene expression and allergic disease propensity through epigenetic modification. This review explores the evidence that immune development is under clear epigenetic regulation, including the pattern of T helper (Th)1 and Th2 cell differentiation, regulatory T cell differentiation, and more recently, Th17 development. It also considers the mechanisms of epigenetic regulation and early immune defects in allergy prone neonates. The inherent plasticity conferred by epigenetic mechanisms clearly also provides opportunities for environmental strategies that can re-programme gene expression for disease prevention. Identifying genes that are differentially silenced or activated in relation to subsequent disease will not only assist in identifying causal pathways, but may also help identify the contributing environmental factors.
Publisher: S. Karger AG
Date: 2015
DOI: 10.1159/000442158
Abstract: b i Introduction: /i /b Chronic inflammatory diseases including allergies and asthma are the result of complex interactions between genes and environmental factors. Epigenetic mechanisms comprise a set of biochemical reactions that regulate gene expression. In order to understand the cause-effect relationship between environmental exposures and disease development, methods capable of assessing epigenetic regulation (also) in large cohorts are needed. b i Methods: /i /b For this purpose, we developed and evaluated a miniaturized chromatin immunoprecipitation (ChIP) assay allowing for a cost-effective assessment of histone acetylation of candidate genes in a quantitative fashion. This method was then applied to assess H3 and H4 histone acetylation changes in cord blood (CB) s les from an established cohort of Australian children exposed in the fetal period to either very low or very high levels of maternal folate. b i Results: /i /b Our ChIP assay was validated for a minimum requirement of 1 × 10 sup /sup target cells (e.g. CD4+ T cells). Very high levels of maternal folate were significantly associated with increased H3/H4 acetylation at i GATA3 /i and/or i IL9 /i promoter regions in CD4+ T cells in CB. b i Conclusion: /i /b We developed a ChIP method allowing reliable assessment of H3/H4 acetylation using 1 × 10 sup /sup cells only. Practical application of this assay demonstrated an association between high maternal folate exposure and increased histone acetylation, corresponding to a more transcriptionally permissive chromatin status in the promoter regions of some Th2-related genes.
Publisher: Cold Spring Harbor Laboratory
Date: 25-11-2015
DOI: 10.1101/032862
Abstract: Understanding the relationship between variations in DNA methylation and gene expression has been challenging. Evidence suggests the function of DNA methylation may vary with genomic context, and few consistent rules linking methylation to expression have been noted. For array-based studies, the content of current DNA methylation array platforms provide broad coverage of the genome but target only a fraction of the potentially methylated CG dinucleotides. A better understanding of the interplay between DNA methylation and gene expression is beneficial for users of these platforms, and may aid with candidate prioritization in epigenome-wide association studies (EWAS). To address this we examined the relationship between DNA methylation levels and gene expression in primary T-lymphocytes at discreet genomic regions around the transcriptional unit (Promoters, gene body, untranslated regions) and at CpG island-associated regions (islands, shores and shelves), stratifying by high and low expressed genes. As anticipated we found evidence that DNA methylation at CpG sites near promoter regions are tightly correlated with gene expression in both the stably expressed and developmentally regulated genes, however this is dependent on CpG density. DNA methylation within the gene body was not consistently associated with changes in gene expression. CpG islands and island shores exhibited strong correlations with gene expression, but this was not true for island shelves. We found these relationships were generally preserved at both dynamic and steady state genes, with some notable exceptions. In combination these insights may be useful for prioritising candidates identified in epigenome-wide association studies for subsequent functional studies.
Publisher: Informa UK Limited
Date: 09-2011
Abstract: Environment induced epigenetic effects on gene expression in early life are likely to play important roles in mediating the risk of several immune-related diseases. In order to investigate this fully, it is essential to first document temporal changes in epigenetic profile in disease-free in iduals as a prelude to defining environmentally mediated changes. Mononuclear cells (MC) were collected longitudinally from a small number of females at birth, 1 year, 2.5 years and 5 years of age and examined for changes in genome-scale DNA methylation profiles using the Illumina Infinium HumanMethylation27 BeadChip array platform. MC from two males were included for comparative purposes. Flow cytometry was used to define MC cell populations in each s le in order to exclude this as the major driver of epigenetic change. The data underwent quality control and normalization within the R programming environment. Unsupervised hierarchical clustering of s les clearly delineated neonatal MC from all other ages. A further clear distinction was observed between 1 year and 5 year s les, with 2.5 year s les showing a mixed distribution between the 1 and 5 year groups. Gene ontology of probes significantly variable over the neonatal period revealed methylation changes in genes associated with cell surface receptor and signal transduction events. In the postnatal period, methylation changes were mostly associated with the development of effector immune responses and homeostasis. Unlike all other chromosomes tested, a predominantly genetic effect was identified as controlling maintenance of X-chromosome methylation profile in females, largely refractory to change over time. This data suggests that the primary driver of neonatal epigenome is determined in utero, whilst postnatally, multiple genetic and environmental factors are implicated in the development of MC epigenetic profile, particularly between the ages of 1-5 years, when the highest level of inter in idual variation is apparent. This supports a model for differential sensitivity of specific in iduals to disruption in the developing epigenome during the first years of life. Further studies are now needed to examine evolving epigenetic variations in specific cell populations in relation to environmental exposures, immune phenotype and subsequent disease susceptibility.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 06-2015
Publisher: Elsevier BV
Date: 09-2018
DOI: 10.1016/J.JACI.2017.10.024
Abstract: Food allergy naturally resolves in a proportion of food-allergic children without intervention however the underlying mechanisms governing the persistence or resolution of food allergy in childhood are not understood. This study aimed to define the innate immune profiles associated with egg allergy at age 1 year, determine the phenotypic changes that occur with the development of natural tolerance in childhood, and explore the relationship between early life innate immune function and serum vitamin D. This study used longitudinally collected PBMC s les from a population-based cohort of challenge-confirmed egg-allergic infants with either persistent or transient egg allergy outcomes in childhood to phenotype and quantify the functional innate immune response associated with clinical phenotypes of egg allergy. We show that infants with persistent egg allergy exhibit a unique innate immune signature, characterized by increased numbers of circulating monocytes and dendritic cells that produce more inflammatory cytokines both at baseline and following endotoxin exposure when compared with infants with transient egg allergy. Follow-up analysis revealed that this unique innate immune signature continues into childhood in those with persistent egg allergy and that increased serum vitamin D levels correlate with changes in innate immune profiles observed in children who developed natural tolerance to egg. Early life innate immune dysfunction may represent a key immunological driver and predictor of persistent food allergy in childhood. Serum vitamin D may play an immune-modulatory role in the development of natural tolerance.
Publisher: Elsevier BV
Date: 2018
DOI: 10.1016/J.JAUT.2017.09.010
Abstract: Juvenile idiopathic arthritis (JIA) is presumed to be driven by an adverse combination of genes and environment. Epigenetic processes, including DNA methylation, act as a conduit through which the environment can regulate gene activity. Altered DNA methylation has been associated with adult autoimmune rheumatic diseases such as rheumatoid arthritis, but studies are lacking for paediatric autoimmune rheumatic diseases including JIA. Here, we performed a genome-scale case-control analysis of CD4
Publisher: Wiley
Date: 11-01-2017
DOI: 10.1111/CEA.12863
Abstract: Genetic variants for IgE-mediated peanut allergy are yet to be fully characterized and to date only one genomewide association study (GWAS) has been published. To identify genetic variants associated with challenge-proven peanut allergy. We carried out a GWAS comparing 73 infants with challenge-proven IgE-mediated peanut allergy against 148 non-allergic infants (all ~ 1 year old). We tested a total of 3.8 million single nucleotide polymorphisms, as well as imputed HLA alleles and amino acids. Replication was assessed by de novo genotyping in a panel of additional 117 cases and 380 controls, and in silico testing in two independent GWAS cohorts. We identified 21 independent associations at P ≤ 5 × 10 Genetic determinants for challenge-proven peanut allergy include alleles at the HLA-DRB1 locus.
Publisher: Elsevier BV
Date: 09-2015
DOI: 10.1016/J.JIM.2015.04.016
Abstract: Data is now emerging that many human diseases not previously considered immune diseases have an immunological basis. As such human immunology is in need of more standardized systems-wide methods for monitoring immune regulation. Despite significant advances in basic immunology research, thousands of patients visiting health practitioners daily still have no reliable immunological metrics by which to assess the status of their immune health beyond the standard blood count. Further investigations are costly, time consuming and often don't offer significant insights into the mechanics of immune deviation or regulation. The immune system meets many criteria of complex biological networks and therefore systems-wide approaches are highly suitable to determining the emergent properties of immune responses. Standardization of immune monitoring, the development of new technology and integrated informatics approaches are needed in order to identify useful hematological and serological markers that are informative for immune health. This brief review outlines some of the more promising developments in systems immunology.
Publisher: Elsevier BV
Date: 05-2015
DOI: 10.1016/J.JACI.2014.12.1933
Abstract: The diagnosis of food allergy (FA) can be challenging because approximately half of food-sensitized patients are asymptomatic. Current diagnostic tests are excellent makers of sensitization but poor predictors of clinical reactivity. Thus oral food challenges (OFCs) are required to determine a patient's risk of reactivity. We sought to discover genomic biomarkers of clinical FA with utility for predicting food challenge outcomes. Genome-wide DNA methylation (DNAm) profiling was performed on blood mononuclear cells from volunteers who had undergone objective OFCs, concurrent skin prick tests, and specific IgE tests. Fifty-eight food-sensitized patients (aged 11-15 months) were assessed, half of whom were clinically reactive. Thirteen nonallergic control subjects were also assessed. Reproducibility was assessed in an additional 48 s les by using methylation data from an independent population of patients with clinical FA. Using a supervised learning approach, we discovered a DNAm signature of 96 CpG sites that predict clinical outcomes. Diagnostic scores were derived from these 96 methylation sites, and cutoffs were determined in a sensitivity analysis. Methylation biomarkers outperformed allergen-specific IgE and skin prick tests for predicting OFC outcomes. FA status was correctly predicted in the replication cohort with an accuracy of 79.2%. DNAm biomarkers with clinical utility for predicting food challenge outcomes are readily detectable in blood. The development of this technology in detailed follow-up studies will yield highly innovative diagnostic assays.
Publisher: Informa UK Limited
Date: 24-04-2014
DOI: 10.4161/EPI.28945
Publisher: Wiley
Date: 21-05-2017
DOI: 10.1111/CEA.12942
Abstract: Food allergies pose a considerable world-wide public health burden with incidence as high as one in ten in 12-month-old infants. Few food allergy genetic risk variants have yet been identified. The Th2 immune gene IL13 is a highly plausible genetic candidate as it is central to the initiation of IgE class switching in B cells. Here, we sought to investigate whether genetic polymorphisms at IL13 are associated with the development of challenge-proven IgE-mediated food allergy. We genotyped nine IL13 "tag" single nucleotide polymorphisms (tag SNPs) in 367 challenge-proven food allergic cases, 199 food-sensitized tolerant cases and 156 non-food allergic controls from the HealthNuts study. 12-month-old infants were phenotyped using open oral food challenges. SNPs were tested using Cochran-Mantel-Haenszel test adjusted for ancestry strata. A replication study was conducted in an independent, co-located s le of four paediatric cohorts consisting of 203 food allergic cases and 330 non-food allergic controls. Replication s le phenotypes were defined by clinical history of reactivity, 95% PPV or challenge, and IL13 genotyping was performed. IL13 rs1295686 was associated with challenge-proven food allergy in the discovery s le (P=.003 OR=1.75 CI=1.20-2.53). This association was also detected in the replication s le (P=.03, OR=1.37, CI=1.03-1.82) and further supported by a meta-analysis (P=.0006, OR=1.50). However, we cannot rule out an association with food sensitization. Carriage of the rs1295686 variant A allele was also associated with elevated total plasma IgE. We show for the first time, in two independent cohorts, that IL13 polymorphism rs1295686 (in complete linkage disequilibrium with functional variant rs20541) is associated with challenge-proven food allergy.
Publisher: Elsevier BV
Date: 07-2022
DOI: 10.1016/J.JACI.2021.11.028
Abstract: Recent evidence suggests that parental exposures before conception can increase the risk of asthma in offspring. We investigated the association between parents' preconception body mass index (BMI) trajectories from childhood to adolescence and subsequent risk of asthma in their offspring. Using group-based trajectory modeling from the Tasmanian Longitudinal Health Study, we identified BMI trajectories for index participants (parents) when aged 4 years to 15 years. Multinomial regression models adjusted for potential confounders were utilized to estimate the association between these early-life parents' BMI trajectories and asthma phenotypes in their subsequent offspring. The main analysis included 1822 parents and 4208 offspring. Four BMI trajectories from age 4 years to 15 years were identified as the best-fitting model: low (8.8%), normal (44.1%), above normal (40.2%), and high (7.0%). Associations were observed between father's high BMI trajectory and risk of asthma in offspring before the age of 10 years (relative risk ratio [RRR] =1.70 [95% CI = 0.98-2.93]) and also asthma ever (RRR = 1.72 [95% CI = 1.00-2.97]), especially allergic asthma ever (RRR = 2.05 [95% CI = 1.12-3.72]). These associations were not mediated by offspring birth weight. No associations were observed for maternal BMI trajectories and offspring asthma phenotypes. This cohort study over 6 decades of life and across 2 generations suggests that the high BMI trajectory in fathers, well before conception, increased the risk of asthma in their offspring.
Publisher: American Thoracic Society
Date: 23-08-2023
Publisher: Elsevier BV
Date: 10-2011
Publisher: Wiley
Date: 02-06-2014
DOI: 10.1096/FJ.13-249029
Publisher: Wiley
Date: 23-11-2015
DOI: 10.1111/PAI.12498
Abstract: Regulatory T cells (Tregs) are critical for development of oral tolerance, and studies suggest that dysfunction of Tregs may lead to food allergy. However, to date, no study has investigated Treg responses following in vivo exposure to peanut or egg allergens in humans. To examine changes in peripheral blood CD4(+) CD25(+) Foxp3(+) Treg populations (total, activated and naive) in food-allergic, food-sensitized but tolerant, and healthy (non-sensitized non-allergic) patients over time following in vivo allergen exposure. A subset of infants from the HealthNuts study with egg or peanut allergy (n = 37), egg or peanut sensitization (n = 35), or who were non-sensitized non-allergic (n = 15) were studied. All subjects underwent oral food challenge (OFC) to egg or peanut. PBMCs were obtained within 1 h of OFC (in vivo allergen exposure), and Treg populations enumerated ex vivo on day 0, and after 2 and 6 days rest in vitro. Non-allergic infants showed stable total Treg frequencies over time food-sensitized infants had a transient fall in Treg percentage with recovery to baseline by day 6 (6.87% day 0, 5.27% day 2, 6.5% day 6) and food-allergic infants showed persistent reduction in Treg (6.85% day 0, 5.4% day 2, 6.2% day 6) following in vivo allergen exposure. Furthermore, food-allergic infants had a significantly lower ratio of activated Treg:activated T cells (10.5 ± 0.77) at day 0 compared to food-sensitized (14.6 ± 1.24) and non-allergic subjects (16.2 ± 1.23). Our data suggest that the state of allergen sensitization is associated with depletion of Treg following allergen exposure. Impaired capacity to regenerate the Treg pool following allergen exposure may be an important factor that determines clinical allergy vs. sensitization without allergic reaction.
Publisher: Wiley
Date: 06-07-2020
DOI: 10.1111/ALL.14333
Publisher: Springer Science and Business Media LLC
Date: 2013
Publisher: Springer Science and Business Media LLC
Date: 12-04-2012
DOI: 10.1038/GENE.2012.7
Abstract: The aim of this study was to investigate the dynamics and relationship between DNA methylation and gene expression during early T-cell development. Mononuclear cells were collected at birth and at 12 months from 60 infants and were either activated with anti-CD3 for 24 h or cultured in media alone, and the CD4+ T-cell subset purified. DNA and RNA were co-harvested and DNA methylation was measured in 450 000 CpG sites in parallel with expression measurements taken from 25 000 genes. In unstimulated cells, we found that a subset of 1188 differentially methylated loci were associated with a change in expression in 599 genes (adjusted P value 0.1). These genes were enriched in reprogramming regions of the genome known to control pluripotency. In contrast, over 630 genes were induced following low-level T-cell activation, but this was not associated with any significant change in DNA methylation. We conclude that DNA methylation is dynamic during early T-cell development, and has a role in the consolidation of T-cell-specific gene expression. During the early phase of clonal expansion, DNA methylation is stable and therefore appears to be of limited importance in short-term T-cell responsiveness.
Publisher: Wiley
Date: 02-04-2019
DOI: 10.1111/ALL.13767
Abstract: The genetic determinants of food allergy have not been systematically reviewed. We therefore systematically reviewed the literature on the genetic basis of food allergy, identifying areas for further investigation. We searched three electronic databases (MEDLINE, EMBASE and PubMed) on 9 January 2018. Two authors screened retrieved articles for review according to inclusion criteria and extracted relevant information on study characteristics and measures of association. Eligible studies included those that reported an unaffected nonatopic control group, had genetic information and were carried out in children. Of the 2088 studies retrieved, 32 met our inclusion criteria. Five were genome-wide association studies, and the remaining were candidate gene studies. Twenty-two of the studies were carried out in a predominantly Caucasian population with the remaining 10 from Asian-specific populations or unspecified ethnicity. We found FLG, HLA, IL10, IL13, as well as some evidence for other variants (SPINK5, SERPINB and C11orf30) that are associated with food allergy. Little genetic research has been carried out in food allergy, with FLG, HLA and IL13 being the most reproducible genes for an association with food allergy. Despite promising results, existing genetic studies on food allergy are inundated with issues such as inadequate s le size and absence of multiple testing correction. Few included replication analyses or population stratification measures. Studies addressing these limitations along with functional studies are therefore needed to unravel the mechanisms of action of the identified genes.
Publisher: Springer Science and Business Media LLC
Date: 17-08-2018
DOI: 10.1038/S41467-018-05608-4
Abstract: Food allergy poses a significant clinical and public health burden affecting 2–10% of infants. Using integrated DNA methylation and transcriptomic profiling, we found that polyclonal activation of naive CD4+ T cells through the T cell receptor results in poorer lymphoproliferative responses in children with immunoglobulin E (IgE)-mediated food allergy. Reduced expression of cell cycle-related targets of the E2F and MYC transcription factor networks, and remodeling of DNA methylation at metabolic ( RPTOR , PIK3D , MAPK1 , FOXO1 ) and inflammatory genes ( IL1R , IL18RAP , CD82 ) underpins this suboptimal response. Infants who fail to resolve food allergy in later childhood exhibit cumulative increases in epigenetic disruption at T cell activation genes and poorer lymphoproliferative responses compared to children who resolved food allergy. Our data indicate epigenetic dysregulation in the early stages of signal transduction through the T cell receptor complex, and likely reflects pathways modified by gene–environment interactions in food allergy.
Publisher: Elsevier
Date: 2012
Publisher: Springer Science and Business Media LLC
Date: 31-08-2023
DOI: 10.1186/S13148-023-01540-7
Abstract: Experimental studies suggest that exposures may impact respiratory health across generations via epigenetic changes transmitted specifically through male germ cells. Studies in humans are, however, limited. We aim to identify epigenetic marks in offspring associated with father’s preconception smoking. We conducted epigenome-wide association studies (EWAS) in the RHINESSA cohort (7–50 years) on father’s any preconception smoking ( n = 875 offspring) and father’s pubertal onset smoking 15 years ( n = 304), using Infinium MethylationEPIC Beadchip arrays, adjusting for offspring age, own smoking and maternal smoking. EWAS of maternal and offspring personal smoking were performed for comparison. Father’s smoking-associated dmCpGs were checked in subpopulations of offspring who reported no personal smoking and no maternal smoking exposure. Father’s smoking commencing preconception was associated with methylation of blood DNA in offspring at two cytosine-phosphate-guanine sites (CpGs) (false discovery rate (FDR) 0.05) in PRR5 and CENPP . Father’s pubertal onset smoking was associated with 19 CpGs (FDR 0.05) mapped to 14 genes ( TLR9 , DNTT , FAM53B , NCAPG2 , PSTPIP2 , MBIP , C2orf39 , NTRK2 , DNAJC14 , CDO1 , PRAP1 , TPCN1 , IRS1 and CSF1R ). These differentially methylated sites were hypermethylated and associated with promoter regions capable of gene silencing. Some of these sites were associated with offspring outcomes in this cohort including ever-asthma (NTRK2), ever-wheezing (DNAJC14, TPCN1), weight (FAM53B, NTRK2) and BMI (FAM53B, NTRK2) ( p 0.05). Pathway analysis showed enrichment for gene ontology pathways including regulation of gene expression, inflammation and innate immune responses. Father’s smoking-associated sites did not overlap with dmCpGs identified in EWAS of personal and maternal smoking (FDR 0.05), and all sites remained significant ( p 0.05) in analyses of offspring with no personal smoking and no maternal smoking exposure. Father’s preconception smoking, particularly in puberty, is associated with offspring DNA methylation, providing evidence that epigenetic mechanisms may underlie epidemiological observations that pubertal paternal smoking increases risk of offspring asthma, low lung function and obesity.
Publisher: Elsevier BV
Date: 10-2014
DOI: 10.1016/J.JRI.2014.05.003
Abstract: Epigenetic mechanisms such as DNA methylation, histone modification, and micro RNA signaling regulate the activity of the genome. Virtually all aspects of immunity involve some level of epigenetic regulation, whether it be host defense or in mediating tolerance. These processes are critically important in mediating dynamic responses to the environment over the life course of the in idual, yet we are only just beginning to understand how dysregulation in these pathways may play a role in immune disease. Here, we give a brief chronological overview of epigenetic processes during immune development in health and disease.
Publisher: Public Library of Science (PLoS)
Date: 08-2022
DOI: 10.1371/JOURNAL.PBIO.3001728
Abstract: Children typically experience more mild symptoms of Coronavirus Disease 2019 (COVID-19) when compared to adults. There is a strong body of evidence that children are also less susceptible to Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) infection with the ancestral viral isolate. However, the emergence of SARS-CoV-2 variants of concern (VOCs) has been associated with an increased number of pediatric infections. Whether this is the result of widespread adult vaccination or fundamental changes in the biology of SARS-CoV-2 remain to be determined. Here, we use primary nasal epithelial cells (NECs) from children and adults, differentiated at an air–liquid interface to show that the ancestral SARS-CoV-2 replicates to significantly lower titers in the NECs of children compared to those of adults. This was associated with a heightened antiviral response to SARS-CoV-2 in the NECs of children. Importantly, the Delta variant also replicated to significantly lower titers in the NECs of children. This trend was markedly less pronounced in the case of Omicron. It is also striking to note that, at least in terms of viral RNA, Omicron replicated better in pediatric NECs compared to both Delta and the ancestral virus. Taken together, these data show that the nasal epithelium of children supports lower infection and replication of ancestral SARS-CoV-2, although this may be changing as the virus evolves.
Publisher: American Society for Clinical Investigation
Date: 06-09-2018
Publisher: Cold Spring Harbor Laboratory
Date: 23-09-2021
DOI: 10.1101/2021.09.20.461150
Abstract: Respiratory viral infections in early-life are linked to the development of chronic lung diseases that persist into adulthood. The aim of this study was to develop a mouse model of early-life respiratory viral infection that would lead to impaired lung function in adulthood. BALB/c pups were infected at seven days of life with one of the following respiratory viruses: influenza A/Mem/1/71 “M71”, influenza A/Puerto Rico/8/34 “PR8” or attenuated mengovirus “Mengo”. Lung function and airways responsiveness (AHR) to methacholine were assessed seven weeks later, using the forced oscillation technique, and data were compared between male and female mice. PR8 infection was associated with significantly increased responsiveness to methacholine (for airway resistance, tissue d ing, tissue elastance and hystersivity) for both sexes. M71 infection resulted in less severe responses especially in adult males. Early-life Mengo infection led to significantly higher responsiveness to MCh for males only (for airway resistance and tissue d ing), suggesting sex dependant effects in lung function parameters measured. In summary, we have established a murine model where respiratory viral infection on day seven of life leads to AHR in adulthood. Importantly, the model recapitulates key variations in susceptibility related to sex and nature of viral pathogen that have previously been observed in human epidemiological studies. Our findings reveal new insights into the early origins of AHR and provide a tractable model system for future studies to unlock the mechanisms that determine pathogenesis.
Publisher: Wiley
Date: 02-08-2013
DOI: 10.1111/PAI.12100
Abstract: Prevalence rates of food allergy have increased rapidly in recent decades. Of concern, rates of increase are greatest among children under 5 yrs of age and for those food allergies that persist into adulthood such as peanut or tree nut allergy and shellfish allergy. Given these trends, the overall prevalence of food allergy will compound over time as the number of children affected by food allergy soars and a greater proportion of food-allergic children are left with persistent disease into adulthood. It is therefore vital to identify novel curative treatment approaches for food allergy. Acquisition of oral tolerance to the erse array of ingested food antigens and intestinal microbiota is an active immunologic process that is successfully established in the majority of in iduals. In subjects who develop food allergy, there is a failure or loss of oral tolerance acquisition to a limited number of food allergens. Oral immunotherapy (OIT) offers a promising approach to induce specific oral tolerance to selected food allergens and represents a potential strategy for long-term curative treatment of food allergy. This review will summarize the current understanding of oral tolerance and clinical trials of OIT for the treatment of food allergy.
Publisher: Springer International Publishing
Date: 2019
Publisher: Elsevier BV
Date: 10-2016
DOI: 10.1016/J.COI.2016.05.005
Abstract: The rise in IgE-mediated food allergy in recent times is the likely result of gene-environment interactions mediated via epigenetic pathways. As epigenetic modifications, including DNA methylation, are at the interface between the environment and the genome, they may be ideal biomarkers of modifiable disease pathways. High-throughput methylation profiling of immune cell subtypes or whole blood from patients allows the identification of disease specific epigenetic variants. If faithfully tracking with disease parameters, these 'signatures' may have clinical applications as biomarkers of disease or therapeutic response. Development of such tools will depend on a number of factors, including determining the most appropriate experimental approach, analysis methodology, patient groups, and informative target cells/tissues. Here we discuss these potential applications and their implications for food allergy practise.
Publisher: Elsevier BV
Date: 03-2011
Abstract: Uterine life is arguably the most critical time in developmental programming, when environmental exposures may have the greatest potential to influence evolving fetal structure and function. There has been substantial progress in understanding the epigenetic mechanisms through which environmental exposures can permanently alter the expression of fetal genes and contribute to the increasing propensity for many complex diseases. These concepts of "developmental origins" of disease are being applied across virtually all fields of medicine, and emerging epigenetic paradigms are the likely mechanism behind the environment-driven epidemic of asthma and allergic disease. Here, we examine the epigenetic regulation of immune development and the early immune profiles that contribute to allergic risk. In particular we review new evidence that key environmental exposures, such as microbial exposure, dietary changes, tobacco smoke, and pollutants, can induce epigenetic changes in gene expression and alter disease risk. Although most of these factors have already been clearly implicated in epidemiologic studies of asthma and allergic disease, new studies investigating the mechanisms of these effects may provide new avenues for using these pathways for disease prevention.
Publisher: Cold Spring Harbor Laboratory
Date: 03-05-2023
DOI: 10.1101/2023.04.29.23289314
Abstract: Recurrent wheezing disorders including asthma are complex and heterogeneous diseases that affect up to 30% of all children, contributing to a major burden on children, their families, and global healthcare systems. It is now recognized that a dysfunctional airway epithelium plays a central role in the pathogenesis of recurrent wheeze, although the underlying mechanisms are still not fully understood. This prospective birth cohort aims to bridge this knowledge gap by investigating the influence of intrinsic epithelial dysfunction on the risk for developing respiratory disorders and the modulation of this risk by maternal morbidities, in utero exposures, and respiratory exposures in the first year of life. The Airway Epithelium Respiratory Illnesses and Allergy (AERIAL) study is nested within the ORIGINS Project and will monitor 400 infants from birth to five years. The primary outcome of the AERIAL study will be the identification of epithelial endotypes and exposure variables that influence the development of recurrent wheezing, asthma, and allergic sensitisation. Nasal respiratory epithelium at birth to six weeks, one, three, and five years will be analysed by bulk RNA-seq and DNA methylation sequencing. Maternal morbidities and in utero exposures will be identified on maternal history and their effects measured through transcriptomic and epigenetic analyses of the amnion and newborn epithelium. Exposures within the first year of life will be identified based on infant medical history as well as on background and symptomatic nasal s ling for viral PCR and microbiome analysis. Daily temperatures and symptoms recorded in a study-specific Smartphone App will be used to identify symptomatic respiratory illnesses. Ethical approval has been obtained from Ramsey Health Care HREC WA-SA (#1908). Results will be disseminated through open-access peer-reviewed manuscripts, conference presentations, and through different media channels to consumers, ORIGINS families, and the wider community.
Publisher: Springer Science and Business Media LLC
Date: 15-07-2013
Abstract: The endothelial compartment, comprising arterial, venous and lymphatic cell types, is established prenatally in association with rapid phenotypic and functional changes. The molecular mechanisms underpinning this process in utero have yet to be fully elucidated. The aim of this study was to investigate the potential for DNA methylation to act as a driver of the specific gene expression profiles of arterial and venous endothelial cells. Placenta-derived venous and arterial endothelial cells were collected at birth prior to culturing. DNA methylation was measured at ,000 CpG sites in parallel with expression measurements taken from 25,000 annotated genes. A consistent set of genomic loci was found to show coordinate differential methylation between the arterial and venous cell types. This included many loci previously not investigated in relation to endothelial function. An inverse relationship was observed between gene expression and promoter methylation levels for a limited subset of genes implicated in endothelial function, including NOS3 , encoding endothelial Nitric Oxide Synthase. Endothelial cells derived from the placental vasculature at birth contain widespread methylation of key regulatory genes. These are candidates involved in the specification of different endothelial cell types and represent potential target genes for environmentally mediated epigenetic disruption in utero in association with cardiovascular disease risk later in life.
Publisher: Wiley
Date: 22-03-2012
DOI: 10.1111/J.1399-3038.2012.01287.X
Abstract: Neonatal Innate immunity is distinct compared with later ages with some inflammatory cytokines produced in excess of adult levels in response to microbial products such as lipopolysaccharide (LPS). The molecular mechanisms underpinning this specific pattern of neonatal immunity are unknown. In this study, we compared gene expression and cytokine production from LPS stimulated mononuclear cell cultures from 60 in iduals at birth and at 12-months. Neonatal mononuclear cell responses were characterized by high levels of IL-1β, IL-10, and IFNγ compared with mononuclear cell responses at 12 months. Microarray analysis of gene expression revealed widespread differences between the neonatal versus infant LPS response. We found expression of a subset of interleukin-1 receptor/Toll-like receptor (IL-1R/TLR) signaling genes was highly expressed in the neonatal period and rapidly down regulated by 12 months. The data suggest that IL-1R1 expression in the neonatal period provides an additional level of Myd88-dependent signaling during this period of heighted susceptibility to infection.
Publisher: Public Library of Science (PLoS)
Date: 25-01-2012
Publisher: MDPI AG
Date: 21-03-2019
Abstract: Modernization has now been linked to poor developmental experience, the onset of immune dysregulation and rising rates of chronic diseases in many parts of the world. Research across the epidemiological, clinical, and basic science domains supports the concept that poor developmental experience, particularly during prenatal life, can increase the risk of chronic disease, with enduring effects on long-term health. Single ‘omics’ approaches are ill-suited to dealing with the level of complexity that underpins immune dysregulation in early life. A more comprehensive systems-level view is afforded by combining multiple ‘omics’ datasets in order to delineate correlations across multiple resolutions of the genome, and of the genomes of the microorganisms that inhabit us. In this concept paper, we discuss multiomic approaches to studying immune dysregulation and highlight some of the challenges and opportunities afforded by this new domain of medical science.
Publisher: Wiley
Date: 11-2007
DOI: 10.1111/J.1365-2222.2007.02856.X
Abstract: Variations in early intestinal colonization patterns have been implicated in the predispostion to allergic disease through effects on mucosal and systemic immune function. Colonization patterns and mucosal IgA production at 6 months of age were examined in relation to early exposures, systemic immune development and early allergic outcomes. This was performed in a cohort (n=189) who had received either Lactobacillus acidophilus or a placebo since birth. Children who developed sensitization to one or more allergens by 12 months of age had significantly higher total (but not secretory) IgA levels at 6 months (P=0.024), but this was independent of probiotic treatment. There were no relationships between colonization patterns and IgA (total or secretory IgA) levels or allergic outcomes (sensitization, atopic dermatitis or food allergies). Breastfeeding, and the use of yoghurt or probiotic supplements were independently associated with significantly higher proportions of 'favourable' lactobacilli and bifidobacteria species. Caesarean delivery and the use of antibiotics during the first 6 months were not associated with significant variations in colonization. Higher proportions of 'favourable' bacteria (notably bifidobacteria) were associated with reduced production of most cytokine response to allergens, but increased expression of regulatory cell markers (P=0.009) and transforming growth factor-beta (P=0.016). 'Favourable' colonization, particularly with bifidobacteria, was associated with effects on cellular immune function, but this was not associated with mucosal immunity (secretory IgA) or reduced risk of allergic disease.
Publisher: Cold Spring Harbor Laboratory
Date: 30-07-2020
DOI: 10.1101/2020.07.30.228106
Abstract: T-cell activation induces context-specific gene expression programs that promote energy generation and biosynthesis, progression through the cell cycle and ultimately cell differentiation. The aim of this study was to apply the omni ATAC-seq method to characterize the landscape of chromatin changes induced by T-cell activation in mature naïve CD4+ T-cells. Using a well-established ex vivo protocol of canonical T-cell receptor signaling, we generated genome-wide chromatin maps of naïve T-cells from pediatric donors in quiescent or recently activated states. We identified thousands of in idual chromatin accessibility peaks that are associated with T-cell activation. The majority of these were localized to intronic and intergenic enhancer regions, marked by active histone modifications whilst quiescence was maintained by repressive histone marks. Regions of activation-associated gains in chromatin accessibility were enriched for well-known pioneer transcription factor motifs, and super-enhancer regions associated with distinct gene regulatory networks. These cis -regulatory elements together brought about distinct transcriptional signatures in activated cells including TNFa-NFkB signaling, hormone-responsive genes, inflammatory response genes and IL2-STAT5 signaling. Our data provides novel insights into the chromatin dynamics and motif usage of T-cell receptor signaling events in early life. The characterized pathways demonstrate the utility of chromatin profiling techniques applied to bio-banked s les for characterizing gene regulatory elements.
Publisher: Springer Science and Business Media LLC
Date: 08-07-2021
DOI: 10.1038/S41598-021-93509-W
Abstract: T-cell activation induces context-specific gene expression programs that promote energy generation and biosynthesis, progression through the cell cycle and ultimately cell differentiation. The aim of this study was to apply the omni ATAC-seq method to characterize the landscape of chromatin changes induced by T-cell activation in mature naïve CD4+ T-cells. Using a well-established ex vivo protocol of canonical T-cell receptor signaling, we generated genome-wide chromatin maps of naïve T-cells from pediatric donors in quiescent or recently activated states. We identified thousands of in idual chromatin accessibility peaks that are associated with T-cell activation, the majority of which were annotated intronic and intergenic enhancer regions. A core set of 3268 gene promoters underwent chromatin remodeling and concomitant changes in gene expression in response to activation, and were enriched in multiple pathways controlling cell cycle regulation, metabolism, inflammatory response genes and cell survival. Leukemia inhibitory factor (LIF) was among those factors that gained the highest accessibility and expression, in addition to IL2-STAT5 dependent chromatin remodeling in the T-cell activation response. Using publicly available data we found the chromatin response was far more dynamic at 24-h compared with 72-h post-activation. In total 546 associations were reproduced at both time-points with similar strength of evidence and directionality of effect. At the pathways level, the IL2-STAT5, KRAS signalling and UV response pathways were replicable at both time-points, although differentially modulated from 24 to 72 h post-activation.
Publisher: Wiley
Date: 03-2023
DOI: 10.1111/IMCB.12628
Abstract: Childhood is a critical period of immune development. During this time, naïve CD4 (nCD4) T cells undergo programmed cell differentiation, mediated by epigenetic changes, in response to external stimuli leading to a baseline homeostatic state that may determine lifelong disease risk. However, the ontogeny of epigenetic signatures associated with CD4 T cell activation during key developmental periods are yet to be described. We investigated genome‐wide DNA methylation (DNAm) changes associated with nCD4 T activation following 72 h culture in media+anti‐CD3/CD28 beads in healthy infants (aged 12 months, n = 18) and adolescents (aged 10–15 years, n = 15). We integrated these data with transcriptomic and cytokine profiling from the same s les. nCD4 T cells from both age groups show similar extensive epigenetic reprogramming following activation, with the majority of genes involved in the T cell receptor signaling pathway associated with differential methylation. Additionally, we identified differentially methylated probes showing age‐specific responses, that is, responses in only infants or adolescents, including within a cluster of T cell receptor (TCR) genes. These encoded several TCR alpha joining (TRAJ), and TCR alpha variable (TRAV) genes. Cytokine data analysis following stimulation revealed enhanced release of IFN‐γ, IL‐2 and IL‐10, in nCD4 T cells from adolescents compared with infants. Overlapping differential methylation and cytokine responses identified four probes potentially underpinning these age‐specific responses. We show that DNAm in nCD4T cells in response to activation is dynamic in infancy and adolescence, with additional evidence for age‐specific effects potentially driving variation in cytokine responses between these ages.
Publisher: Elsevier BV
Date: 03-2018
DOI: 10.1016/J.JACI.2017.09.015
Abstract: Peanut allergy (PA) is a complex disease with both environmental and genetic risk factors. Previously, PA loci were identified in filaggrin (FLG) and HLA in candidate gene studies, and loci in HLA were identified in a genome-wide association study and meta-analysis. We sought to investigate genetic susceptibility to PA. Eight hundred fifty cases and 926 hyper-control subjects and more than 7.8 million genotyped and imputed single nucleotide polymorphisms (SNPs) were analyzed in a genome-wide association study to identify susceptibility variants for PA in the Canadian population. A meta-analysis of 2 phenotypes (PA and food allergy) was conducted by using 7 studies from the Canadian, American (n = 2), Australian, German, and Dutch (n = 2) populations. An SNP near integrin α6 (ITGA6) reached genome-wide significance with PA (P = 1.80 × 10 This study identifies multiple novel loci as risk factors for PA and food allergy and establishes C11orf30 as a risk locus for both PA and food allergy. Multiple genes (C11orf30/EMSY, SKAP1, and CTNNA3) identified by this study are involved in epigenetic regulation of gene expression.
Publisher: Informa UK Limited
Date: 02-12-2014
Publisher: Wiley
Date: 24-10-2020
DOI: 10.1111/PAI.13128
Abstract: High folate status in pregnancy has been implicated in the increased prevalence of allergic disease, but there are no published data relating directly measured folate status in pregnancy to challenge-proven food allergy among offspring. The study aim was to examine the association between red blood cell (RBC) folate status in trimester three of pregnancy and allergic disease among offspring. Red blood cell folate levels were measured at 28-32 weeks' gestation in a prospective birth cohort (n = 1074). Food allergy outcomes were assessed in 1-year-old infants by skin prick testing and subsequent food challenge. Eczema was assessed by questionnaire and clinical review. High trimester three RBC folate was defined as greater than (>) 1360 nmol/L. Binomial regression was used to examine associations between trimester three RBC folate and allergic outcomes, adjusting for potential confounders. Red blood cell folate levels were measured in 88% (894/1064) of pregnant women. The mean concentration was 1695.6 nmol/L (standard deviation 415.4) with 82% (731/894) >1360 nmol/L. There was no evidence of either linear or non-linear relationships between trimester three RBC folate and allergic outcomes, nor evidence of associations between high RBC folate and food allergy (adjusted risk ratio (aRR) 2.89, 95% CI 0.90-9.35), food sensitization (aRR 1.72, 95% CI 0.85-3.49), or eczema (aRR 0.97, 95% CI 0.67-1.38). The majority of pregnant women in this study had high RBC folate levels. There was no evidence of associations between trimester three RBC folate and food allergy, food sensitization, or eczema among the offspring, although larger studies are required.
Publisher: Elsevier BV
Date: 02-2019
DOI: 10.1016/J.JAIP.2018.07.042
Abstract: We previously reported that infants with Asian-born parents are 3 times more likely to have IgE-mediated food allergy than those with Australian-born parents. It is unknown whether this translates to the increased risk of other allergic diseases later in childhood and whether ancestry interacts with other risk factors for allergic disease development. To compare prevalence and risk factors for allergic rhinitis, asthma, and aeroallergen sensitization at age 6 between children with East Asian-born and Caucasian-born parents. A total of 5276 1-year-old infants were recruited into a population-based longitudinal study of allergy. A total of 4455 children participated in age 6 follow-up (84.4%), including 3015 with Caucasian-born parents and 415 with East Asian-born parents. Children underwent skin prick tests to aeroallergens and questionnaires captured data on asthma, eczema, and allergic rhinitis. Compared with children with Caucasian-born parents, children of East Asian-born parents had more allergic rhinitis (19.9% [95% confidence interval (CI) 14.9-26] vs 9.3% [95% CI 8-10.8], P < .001) and aeroallergen sensitization (64.3% [95% CI 57.5-70.5] vs 34.4% [95% CI 32.2-36.7], P < .001) at age 6. Asthma was similar in both groups (9.1% [95% CI 6.2-13.2] vs 11.7% [95% CI 10.4-13.1]), P = .21. Children with IgE-mediated food allergy and eczema in infancy were 3 times more likely to have asthma and 2 times more likely to have allergic rhinitis at age 6, irrespective of ancestry. Children of East Asian ancestry born in Australia have a higher burden of most allergic diseases in the first 6 years of life, whereas asthma may follow a different pattern. IgE-mediated food allergy and eczema at age 1 increase the risk of asthma and allergic rhinitis irrespective of ancestry.
Publisher: Wiley
Date: 04-04-2017
DOI: 10.1111/ALL.13143
Abstract: A defective skin barrier is hypothesized to be an important route of sensitization to dietary antigens and may lead to food allergy in some children. Missense mutations in the serine peptidase inhibitor Kazal type 5 (SPINK5) skin barrier gene have previously been associated with allergic conditions. To determine whether genetic variants in and around SPINK5 are associated with IgE-mediated food allergy. We genotyped 71 "tag" single nucleotide polymorphisms (tag-SNPs) within a region spanning ~263 kb including SPINK5 (~61 kb) in n=722 (n=367 food-allergic, n=199 food-sensitized-tolerant and n=156 non-food-allergic controls) 12-month-old infants (discovery s le) phenotyped for food allergy with the gold standard oral food challenge. Transepidermal water loss (TEWL) measures were collected at 12 months from a subset (n=150) of these in iduals. SNPs were tested for association with food allergy using the Cochran-Mantel-Haenszel test adjusting for ancestry strata. Association analyses were replicated in an independent s le group derived from four paediatric cohorts, total n=533 (n=203 food-allergic, n=330 non-food-allergic), mean age 2.5 years, with food allergy defined by either clinical history of reactivity, 95% positive predictive value (PPV) or challenge, corrected for ancestry by principal components. SPINK5 variant rs9325071 (A⟶G) was associated with challenge-proven food allergy in the discovery s le (P=.001, OR=2.95, CI=1.49-5.83). This association was further supported by replication (P=.007, OR=1.58, CI=1.13-2.20) and by meta-analysis (P=.0004, OR=1.65). Variant rs9325071 is associated with decreased SPINK5 gene expression in the skin in publicly available genotype-tissue expression data, and we generated preliminary evidence for association of this SNP with elevated TEWL also. We report, for the first time, association between SPINK5 variant rs9325071 and challenge-proven IgE-mediated food allergy.
Publisher: American Academy of Pediatrics (AAP)
Date: 10-2012
Abstract: Relative deficiency of dietary omega 3 polyunsaturated fatty acids (n-3 PUFA) has been implicated in the rising allergy prevalence in Westernized countries. Fish oil supplementation may provide an intervention strategy for primary allergy prevention. The objective of this study was to assess the effect of fish oil n-3 PUFA supplementation from birth to 6 months of age on infant allergic disease. In a double-blind randomized controlled trial, 420 infants at high atopic risk received a daily supplement of fish oil containing 280 mg docosahexaenoic acid and 110 mg eicosapentaenoic acid or a control (olive oil), from birth to age 6 months. PUFA levels were measured in 6-month-old infants’ erythrocytes and plasma and their mothers’ breast milk. Eczema, food allergy, asthma and sensitization were assessed in 323 infants for whom clinical follow-up was completed at 12 months of age. At 6 months of age, infant docosahexaenoic acid and eicosapentaenoic acid levels were significantly higher (both P & .05) and erythrocyte arachidonic acid levels were lower (P = .003) in the fish oil group. Although n-3 PUFA levels at 6 months were associated with lower risk of eczema (P = .033) and recurrent wheeze (P = .027), the association with eczema was not significant after multiple comparisons and there was no effect of the intervention per se on the primary study outcomes. Specifically, between-group comparisons revealed no differences in the occurrence of allergic outcomes including sensitization, eczema, asthma, or food allergy. Postnatal fish oil supplementation improved infant n-3 status but did not prevent childhood allergic disease.
Publisher: European Respiratory Society (ERS)
Date: 14-09-2022
Publisher: Springer Science and Business Media LLC
Date: 2013
DOI: 10.1186/GM500
Publisher: MDPI AG
Date: 20-01-2019
Abstract: This concept paper discusses the potential impact of chlorinated public drinking water on the assembly of the intestinal microbiome in infancy. The addition of chlorine or hypochlorite to metropolitan drinking water is routinely used worldwide as a sanitizer because of its potent anti-microbial properties. It is one of the most effective means of delivering safe drinkable water because it produces a residual disinfectant that persists within the distribution system. Levels of chlorine used to treat metropolitan water are considered safe for the in idual, based on toxicity studies. However, to our knowledge there have been no studies examining whether levels of persistent chlorine exposure from tap water are also safe for the ecosystem of microorganisms that colonize the gastrointestinal tract. Given the importance of the microbiome in health, persistent exposure to low levels of chlorine may be a hitherto unrecognized risk factor for gut dysbiosis, which has now been linked to virtually every chronic non-communicable disease of the modern era. Although effects may be subtle, young children and infants are more susceptible to ecological disturbance, given that the microbiome is highly influenced by environmental factors during this period. Here I outline considerations for the safety of water disinfectants not just in terms of toxicity to the host, but also for the ecosystem of microorganisms that inhabit us. Research in this is likely to bear fruitful information that could either bring attention to this issue, potentially driving new innovations in public water management or could help confirm the safety profile of chlorine levels in public drinking water.
Publisher: Wiley
Date: 17-01-2019
DOI: 10.1111/ALL.13707
Start Date: 2019
End Date: 2020
Funder: National Health and Medical Research Council
View Funded ActivityStart Date: 2018
End Date: 2022
Funder: National Health and Medical Research Council
View Funded ActivityStart Date: 2011
End Date: 2015
Funder: National Health and Medical Research Council
View Funded ActivityStart Date: 2015
End Date: 2016
Funder: National Health and Medical Research Council
View Funded ActivityStart Date: 2020
End Date: 2022
Funder: Department of Health, Government of Western Australia
View Funded ActivityStart Date: 2017
End Date: 2020
Funder: National Health and Medical Research Council
View Funded Activity