Paediatrics (RCH) - Research Publications
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ItemImmuno-epigenomic analysis identifies attenuated interferon responses in naive CD4 T cells of adolescents with peanut and multifood allergy(WILEY, 2022-11)BACKGROUND: 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. METHODS: 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. RESULTS: 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 samples identified an attenuated interferon response in nCD4T cells from FA individuals following activation, with decreased expression of several interferon genes, including IFN-γ and a DMR at a key downstream gene, BST2. CONCLUSION: 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 sample size, and the consequent restraint on reporting adjusted p-value statistics as limitations of the study. Further study is required to validate these findings.
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ItemNo Preview AvailableEpigenomic variability is associated with age-specific naive CD4 T cell response to activation in infants and adolescents(WILEY, 2023-05)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 samples. 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.
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ItemEpigenetic programming underpins B-cell dysfunction in peanut and multi-food allergy(WILEY, 2021)OBJECTIVE: Rates of IgE-mediated food allergy (FA) have increased over the last few decades, and mounting evidence implicates disruption of epigenetic profiles in various immune cell types in FA development. Recent data implicate B-cell dysfunction in FA; however, few studies have examined epigenetic changes within these cells. METHODS: We assessed epigenetic and transcriptomic profiles in purified B cells from adolescents with FA, comparing single-food-allergic (peanut only), multi-food-allergic (peanut and ≥1 other food) and non-allergic (control) individuals. Adolescents represent a phenotype of persistent and severe FA indicative of a common immune deviation. RESULTS: We identified 144 differentially methylated probes (DMPs) and 116 differentially expressed genes (DEGs) that distinguish B cells of individuals with FA from controls, including differential methylation of the PM20D1 promoter previously associated with allergic disorders. Subgroup comparisons found 729 DMPs specific to either single-food- or multi-food-allergic individuals, suggesting epigenetic distinctions between allergy groups. This included two regions with increased methylation near three S100 genes in multi-food-allergic individuals. Ontology results of DEGs specific to multi-food-allergic individuals revealed enrichment of terms associated with myeloid cell activation. Motif enrichment analysis of promoters associated with DMPs and DEGs showed differential enrichment for motifs recognised by transcription factors regulating B- and T-cell development, B-cell lineage determination and TGF-β signalling pathway between the multi-food-allergic and single-food-allergic groups. CONCLUSION: Our data highlight epigenetic changes in B cells associated with peanut allergy, distinguishing features of the epigenome between single-food- and multi-food-allergic individuals and revealing differential developmental pathways potentially underpinning these distinct phenotypes.
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ItemHyper-Inflammatory Monocyte Activation Following Endotoxin Exposure in Food Allergic Infants(FRONTIERS MEDIA SA, 2020-09-24)Several recent studies have reported a key role for innate cell hyper-responsiveness in food allergy. This has predominantly been observed in early life, with evidence that innate immune function may return to baseline if food allergy resolves in later childhood. Hallmarks of hyper-responsiveness include increased circulating frequency of monocytes and altered innate cell cytokine responses to in vitro exposure with bacterial endotoxin. These features mirror the defining signatures of trained innate immunity, seen in other complex diseases. In this study, detailed immune cell and cytokine profiling was performed on peripheral blood mononuclear cells at baseline from 27 1 year old infants in the HealthNuts cohort (n = 16 egg allergic and n = 11 non-allergic healthy controls) and following monocyte stimulation. We show that egg allergic infants have increased frequency of circulating monocytes, reduced numbers of regulatory CD4 T cells and increased monocyte: CD4 T cell ratios relative to healthy controls. Monocytes from both egg allergic and non-allergic infants responded to endotoxin stimulation with rapid cytokine production and downregulation of the surface receptor CD16, however monocytes from egg allergic infants were hyper-responsive, producing significantly more inflammatory cytokines (TNFα, IL-6, IL-1β, IL-8) and innate cell recruiting factors (MIP-1α) than healthy controls. This work indicates that monocytes of food allergic infants are programmed to a hyper-inflammatory phenotype and that the development of food allergy may be associated with trained immunity in early life.
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ItemA Potential Role for Epigenetically Mediated Trained Immunity in Food Allergy(CELL PRESS, 2020-06-26)The prevalence of IgE-mediated food allergy is increasing at a rapid pace in many countries. The association of high food allergy rates with Westernized lifestyles suggests the role of gene-environment interactions, potentially underpinned by epigenetic variation, in mediating this process. Recent studies have implicated innate immune system dysfunction in the development and persistence of food allergy. These responses are characterized by increased circulating frequency of innate immune cells and heightened inflammatory responses to bacterial stimulation in food allergic patients. These signatures mirror those described in trained immunity, whereby innate immune cells retain a "memory" of earlier microbial encounters, thus influencing subsequent immune responses. Here, we propose that a robust multi-omics approach that integrates immunological, transcriptomic, and epigenomic datasets, combined with well-phenotyped and longitudinal food allergy cohorts, can inform the potential role of trained immunity in food allergy.
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ItemMass cytometry reveals cellular fingerprint associated with IgE plus peanut tolerance and allergy in early life(NATURE PUBLISHING GROUP, 2020-02-27)IgE-mediated peanut allergic is common, often serious, and usually lifelong. Not all individuals who produce peanut-specific IgE will react upon consumption of peanut and can eat the food without adverse reactions, known as sensitized tolerance. Here, we employ high-dimensional mass cytometry to define the circulating immune cell signatures associated with sensitized tolerance and clinical allergy to peanut in the first year of life. Key features of clinical peanut allergic are increased frequency of activated B cells (CD19hiHLADRhi), overproduction of TNFα and increased frequency of peanut-specific memory CD4 T cells. Infants with sensitized tolerance display reduced frequency but hyper-responsive naive CD4 T cells and an increased frequency of plasmacytoid dendritic cells. This work demonstrates the utility and power of high-dimensional mass cytometry analysis to interrogate the cellular interactions that are associated with allergic sensitization and clinical food allergy in the first year of life.
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ItemAltered immune cell profiles and impaired CD4 T-cell activation in single and multi-food allergic adolescents(WILEY, 2021-05)BACKGROUND: Approximately 5% of adolescents have a food allergy, with peanut and tree nut allergies the most common. Having two or more food allergies in adolescence also doubles the risk of any adverse food reaction, and is associated with increased dietary and social burden. Investigations of immune function in persistently food allergic children are rare. OBJECTIVE: In the present study, we aimed to investigate the immune mechanisms that underlie food allergy in adolescence. METHODS: We used high-dimensional flow cytometry, unsupervised computational analysis and functional studies to comprehensively phenotype a range of non-antigen-specific immune parameters in a group of well-characterized adolescents with clinically defined single peanut allergy, multi-food allergy and aged-matched non-food allergic controls. RESULTS: We show that food allergic adolescents have higher circulating proportions of dendritic cells (p = .0084, FDR-adjusted p = .087, median in no FA: 0.63% live cells, in FA: 0.93%), and higher frequency of activated, memory-like Tregs relative to non-food allergic adolescents (p = .011, FDR-adjusted p = .087, median in no FA: 0.49% live cells, in FA: 0.65%). Cytokine profiling revealed that CD3/CD28 stimulated naïve CD4 T cells from food allergic adolescents produced less IL-6 (p = .0020, FDR-adjusted p = .018, median log2 fold change [stimulated/unstimulated] in no FA: 3.03, in FA: 1.92) and TNFα (p = .0044, FDR-adjusted p = .020, median in no FA: 9.16, in FA: 8.64) and may secrete less IFNγ (p = .035, FDR-adjusted p = .11, median in no FA: 6.29, in FA: 5.67) than naïve CD4 T cells from non-food allergic controls. No differences between clinical groups were observed for LPS-stimulated monocyte secretion of cytokines. CONCLUSIONS: These results have important implications for understanding the evolution of the immune response in food allergy throughout childhood, revealing that dendritic cell and T-cell signatures previously identified in early life may persist through to adolescence.