Reduced type I interferon response in plasmacytoid dendritic cells is associated with asthma in school-aged children
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE289352 | GEO | 2025/08/21
REPOSITORIES: GEO
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Project description:Background Impaired interferon response and allergic sensitisation may contribute to virus induced wheeze and asthma development in young children. Plasmacytoid dendritic cells (pDC) play a key role in antiviral immunity as critical producers of type I interferons (IFN-I). pDC also express the high affinity IgE receptor (FcRI) through which IFN-I production may be negatively regulated. If antiviral function of pDC is associated with recurrent episodes of wheeze in young children is not well understood. This study aimed to evaluate the phenotype and function of circulating pDC in children with a longitudinally defined wheezing phenotype. Methods We performed multiparameter flow cytometry on peripheral blood mononuclear cells from 38 children presenting to the emergency department with an acute episode of respiratory wheeze and 19 controls. RNA sequencing on isolated pDC from the same individuals was also performed. For each subject, their longitudinal exacerbation phenotype was determined using the Western Australia public hospital database. Results We observed a significant depletion of circulating pDC in young children with a persistent phenotype of wheeze. The same individuals also displayed upregulation of the IgE receptor (FcRI) on their pDC. Based on transcriptomic analysis, pDC from these individuals did not mount a robust systemic antiviral response as observed in children who displayed a non-recurrent wheezing phenotype. Conclusion Our data suggests that circulating pDC phenotype and function are altered in young children with a persistent longitudinal exacerbation phenotype. Expression of FcRI is increased and their function as major IFN producers is impaired during acute exacerbations of wheeze.
2023-12-17 | GSE243052 | GEO
Project description:Background: Epigenetic marks, like asthma, are heritable. They are influenced by the environment, direct the maturation of T cellslymphocytes, and have been shown to enhance the development of allergic airways disease in mice. Thus, we hypothesized that epigenetic marks are associated with allergic asthma in inner-city children. Methods: We compared methylation patterns and gene expression in inner-city children with persistent atopic asthma versus healthy controls, using DNA and RNA from peripheral blood mononuclear cells (PBMCs) from inner city children aged 6-12 years with persistent atopic asthma children and healthy controls. Results were externally validated with the GABRIELA study population. Results: Comparing asthmatics (N=97) to controls (N=97), we identified 81 regions that were differentially methylated. Several immune genes were hypomethylated in asthmatics, including IL-13, RUNX3, and a number of specific genes relevant to natural killer cells (KIR2DL4, KIR2DL3, KIR3DL1, and KLRD1) and T cells lymphocytes (TIGIT). 14 differentially methylated regions (DMRs) were associated with the serum IgE concentration of IgE, including RUNX3. These results were internally and externally validated with a global methylation assessment using a different methodology in our inner-city cohort and an independent European cohort (GABRIELA). Hypo- and hypermethylated genes tended to be associated with increased and decreased gene expression, respectively (P<0.6x10-11 for asthma and ; P<0.01 for IgE). To further explore the relationship between methylation and gene expression, we created a matrix of genomic changes in methylation versus transcriptional changes (methyl eQTL) for asthma, and identified cis- and trans-regulated genes whose expression was related to asthma asthma-associated methylation marks. peripheral blood mononuclear cells (PBMCs) from 97 atopic asthmatic and 97 nonatopic nonasthmatic children
2015-02-02 | E-GEOD-40732 | biostudies-arrayexpress
Project description:Background: Epigenetic marks, like asthma, are heritable. They are influenced by the environment, direct the maturation of T cellslymphocytes, and have been shown to enhance the development of allergic airways disease in mice. Thus, we hypothesized that epigenetic marks are associated with allergic asthma in inner-city children. Methods: We compared methylation patterns and gene expression in inner-city children with persistent atopic asthma versus healthy controls, using DNA and RNA from peripheral blood mononuclear cells (PBMCs) from inner city children aged 6-12 years with persistent atopic asthma children and healthy controls. Results were externally validated with the GABRIELA study population. Results: Comparing asthmatics (N=97) to controls (N=97), we identified 81 regions that were differentially methylated. Several immune genes were hypomethylated in asthmatics, including IL-13, RUNX3, and a number of specific genes relevant to natural killer cells (KIR2DL4, KIR2DL3, KIR3DL1, and KLRD1) and T cells lymphocytes (TIGIT). 14 differentially methylated regions (DMRs) were associated with the serum IgE concentration of IgE, including RUNX3. These results were internally and externally validated with a global methylation assessment using a different methodology in our inner-city cohort and an independent European cohort (GABRIELA). Hypo- and hypermethylated genes tended to be associated with increased and decreased gene expression, respectively (P<0.6x10-11 for asthma and ; P<0.01 for IgE). To further explore the relationship between methylation and gene expression, we created a matrix of genomic changes in methylation versus transcriptional changes (methyl eQTL) for asthma, and identified cis- and trans-regulated genes whose expression was related to asthma asthma-associated methylation marks. peripheral blood mononuclear cells (PBMCs) from 97 atopic asthmatic and 97 nonatopic nonasthmatic children
2015-02-02 | E-GEOD-40576 | biostudies-arrayexpress
Project description:Background: Epigenetic marks, like asthma, are heritable. They are influenced by the environment, direct the maturation of T cellslymphocytes, and have been shown to enhance the development of allergic airways disease in mice. Thus, we hypothesized that epigenetic marks are associated with allergic asthma in inner-city children. Methods: We compared methylation patterns and gene expression in inner-city children with persistent atopic asthma versus healthy controls, using DNA and RNA from peripheral blood mononuclear cells (PBMCs) from inner city children aged 6-12 years with persistent atopic asthma children and healthy controls. Results were externally validated with the GABRIELA study population. Results: Comparing asthmatics (N=97) to controls (N=97), we identified 81 regions that were differentially methylated. Several immune genes were hypomethylated in asthmatics, including IL-13, RUNX3, and a number of specific genes relevant to natural killer cells (KIR2DL4, KIR2DL3, KIR3DL1, and KLRD1) and T cells lymphocytes (TIGIT). 14 differentially methylated regions (DMRs) were associated with the serum IgE concentration of IgE, including RUNX3. These results were internally and externally validated with a global methylation assessment using a different methodology in our inner-city cohort and an independent European cohort (GABRIELA). Hypo- and hypermethylated genes tended to be associated with increased and decreased gene expression, respectively (P<0.6x10-11 for asthma and ; P<0.01 for IgE). To further explore the relationship between methylation and gene expression, we created a matrix of genomic changes in methylation versus transcriptional changes (methyl eQTL) for asthma, and identified cis- and trans-regulated genes whose expression was related to asthma asthma-associated methylation marks.
2015-02-02 | GSE40576 | GEO
Project description:Background: Epigenetic marks, like asthma, are heritable. They are influenced by the environment, direct the maturation of T cellslymphocytes, and have been shown to enhance the development of allergic airways disease in mice. Thus, we hypothesized that epigenetic marks are associated with allergic asthma in inner-city children. Methods: We compared methylation patterns and gene expression in inner-city children with persistent atopic asthma versus healthy controls, using DNA and RNA from peripheral blood mononuclear cells (PBMCs) from inner city children aged 6-12 years with persistent atopic asthma children and healthy controls. Results were externally validated with the GABRIELA study population. Results: Comparing asthmatics (N=97) to controls (N=97), we identified 81 regions that were differentially methylated. Several immune genes were hypomethylated in asthmatics, including IL-13, RUNX3, and a number of specific genes relevant to natural killer cells (KIR2DL4, KIR2DL3, KIR3DL1, and KLRD1) and T cells lymphocytes (TIGIT). 14 differentially methylated regions (DMRs) were associated with the serum IgE concentration of IgE, including RUNX3. These results were internally and externally validated with a global methylation assessment using a different methodology in our inner-city cohort and an independent European cohort (GABRIELA). Hypo- and hypermethylated genes tended to be associated with increased and decreased gene expression, respectively (P<0.6x10-11 for asthma and ; P<0.01 for IgE). To further explore the relationship between methylation and gene expression, we created a matrix of genomic changes in methylation versus transcriptional changes (methyl eQTL) for asthma, and identified cis- and trans-regulated genes whose expression was related to asthma asthma-associated methylation marks.
2015-02-02 | GSE40732 | GEO
Project description:Background: Asthma is highly heterogeneous and severity evaluation is key to asthma management. DNA methylation (DNAm) contributes to asthma pathogenesis. This study aimed to identify nasal epithelial DNAm differences between severe and non-severe asthmatic children and evaluate the impact of environmental exposures. Methods: Thirty-three non-severe and 22 severe asthmatic African-American children were included in an epigenome-wide association study. Genome-wide nasal epithelial DNAm and gene expression were measured. CpG sites associated with asthma severity and environmental exposures and predictive of severe asthma were identified. DNAm was correlated with gene expression. Enrichment for transcription factor (TF) binding sites or histone modifications surrounding DNAm differences were determined. Results: We identified 816 differentially methylated CpG positions (DMPs) and 10 differentially methylated regions (DMRs) associated with asthma severity. Three DMPs exhibited discriminatory ability for severe asthma. Intriguingly, six DMPs were simultaneously associated with asthma, allergic asthma, total IgE, environmental IgE, and FeNO in an independent cohort of children. 27 DMPs were associated with traffic-related air pollution or secondhand smoke. DNAm at 22 DMPs were altered by diesel particles or allergen in human bronchial epithelial cells. DNAm levels at 39 DMPs were correlated with mRNA expression. Proximal to 816 DMPs, three histone marks and several TFs involved in asthma pathogenesis were enriched. Conclusions: Significant differences in nasal epithelial DNAm were observed between non-severe and severe asthma in African-American children, a subset of which may be useful to predict disease severity. These CpG sites are subject to the influences of environmental exposures and may regulate gene expression.
2022-04-15 | GSE161485 | GEO
Project description:Obesity-associated asthma is recognized as a distinct entity with non-atopic T-helper 1 polarized systemic inflammation. DNA methylation is linked with T helper cell maturation and is associated with inflammatory patterns in asthma and obesity. However, it is unknown whether pathologic dysregulation of DNA methylation patterns occurs in obesity-associated asthma. Using HELP-tagging, we studied epigenome wide DNA methylation in peripheral blood mononuclear cells in 8 urban minority obese asthmatic pre-adolescent children and compared it to methylation in groups of 8 children with asthma alone, obesity alone and healthy controls. Ingenuity Pathway Analysis was used to identify biological pathways that were differentially targeted by methylation dysregulation. We found that obese asthmatics had distinct epigenome wide methylation patterns associated with decreased promoter methylation of a subset of genes, including RANTES, IL-12R and TBX21 and increased promoter methylation of CD23, a low affinity receptor for IgE and of TGFM-NM-2, inhibitor of Th cell activation. T cell signaling and macrophage activation were the two primary pathways that were selectively hypomethylated in obese asthmatics. These methylation patterns suggest that methylation is associated with non-atopic inflammation observed in obese asthmatic children compared to children with asthma alone and obesity alone. Our findings suggest a role of DNA methylation in the observed inflammatory patterns in pediatric obesity-associated asthma in minorities. 32 HpaII test
2014-04-14 | E-GEOD-43705 | biostudies-arrayexpress
Project description:<p>Plasmacytoid dendritic cells (pDC) are a subset of dendritic cells with unique immunophenotypic properties and functions. While their role in antiviral immunity through production of type I interferons is well-established, their contributions to anti-tumor immunity are less clear. While some evidence demonstrates that pDC in the tumor microenvironment (TME) may drive CD4+ T cell to become <a href="https://www.ncbi.nlm.nih.gov/gene/50943">Foxp3</a>+ T regulatory cells, little is understood about the relationship of pDC with cytotoxic CD8+ T cell, the key player in antitumor immune responses.</p> <p>In this study, we perform comprehensive immunophenotyping and functional analysis of pDC from the TME and draining lymph nodes of patients with head and neck squamous cell carcinoma (HNSCC) and identify a novel pDC subset characterized by expression of the TNF receptor superfamily member <a href="https://www.ncbi.nlm.nih.gov/gene/?term=7293">CD134 (OX40)</a>. We show that OX40 expression is expressed on intratumoral pDC in both humans and mice in a tumor-model specific fashion and that this subset of pDC enhances tumor associated-antigen (TAA)-specific CD8+ T cell responses. Through transcriptomic profiling of OX40-expressing pDC from the TME, we further characterize gene signatures unique to this pDC subset that support its role as an important immunostimulatory immune population in the TME.</p>
| phs001824 | dbGaP
Project description:Identifying children at risk of developing asthma is crucial in guiding targeted preventive therapies. In recent years, researchers have proposed several candidate biomarkers for predicting AM. One such biomarker is fatty-acid-binding protein 5 (FABP5), which correlates with interleukin-17A levels in both the skin and serum, suggesting its potential as a biomarker for AM. Specific IgE, skin prick tests, and cytokine ratios show promise in predicting asthma development.3 However, while these proposed biomarkers are the subject of research on the skin, no biomarkers are identified through blood proteomics. Although AD may initially result from skin barrier dysfunction, systemic sensitization and changes in systemic immune response may predominantly contribute to asthma after AD. Therefore, this study aims to identify blood biomarkers in early life to predict AM progression among infants initially diagnosed with AD. The study participants included 20 healthy controls, 15 with AD, 11 with asthma, and 21 with AM (children aged 7 years old). All participants were diagnosed with asthma, and a history of AD was confirmed by a physician. The protein expression profiles in plasma samples collected from 3-year-olds before the onset of AM were evaluated using sequential window acquisition of all theoretical mass spectra.
2025-05-06 | PXD050231 | Pride
Project description:Plasmacytoid dendritic cells (pDCs) chronically produce type I interferon (IFN-I) in multiple autoimmune diseases, such as systemic sclerosis (SSc) and systemic lupus erythematosus (SLE). Here, we report that the IRE1α-XBP1 branch of the unfolded protein response (UPR) inhibits the production of IFN-α by TLR7- or TLR9-activated pDCs. In SSc patients, pDCs demonstrated reduced expression of UPR marker genes, which inversely correlated with the levels of IFN-I-stimulated genes. CXCL4, a chemokine that is elevated in SSc patients, downregulated IRE1α-XBP1-controlled genes and promoted IFN-α production by pDCs. Mechanistically, IRE1α-XBP1 activation rewired glycolysis to serine biosynthesis by inducing phosphoglycerate dehydrogenase (PHGDH) expression. This process reduced pyruvate access to the tricarboxylic acid (TCA) cycle and blunted mitochondrial ATP generation and cAMP signaling, which are essential for pDC IFN-I responses. Notably, PHGDH expression was reduced in pDCs from patients with SSc and SLE, and pharmacological blockade of TCA cycle reactions inhibited IFN-I responses in pDCs from these patients. Hence, modulating the IRE1α-XBP1-PHGDH axis may represent a hitherto unexplored strategy for alleviating chronic pDC activation in autoimmune disorders.
2022-08-15 | GSE211230 | GEO