Atopic dermatitis complicated by recurrent eczema herpeticum is characterized by multiple, concurrent epidermal inflammatory endotypes
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PROVIDER: PRJNA1090124 | ENA |
REPOSITORIES: ENA
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Project description:A subgroup of atopic dermatitis (AD) patients suffers from recurrent, disseminated herpes simplex virus (HSV) skin infections, eczema herpeticum (EH). To determine transcriptional mechanisms of the skin and immune system pathobiology that underlies ADEH disease development, we performed RNA-sequencing analysis of non-lesional skin (epidermis, dermis) from AD patients with (ADEH+, n=15) and without (ADEH-, n=13) history of EH, and healthy controls (HC, n=15). We also performed RNA-sequencing on participants’ plasmacytoid dendritic cells (pDCs) infected in vitro with HSV-1. ADEH+ patients exhibited dysregulated gene expression, limited in dermis (differentially expressed genes [DEGs]=14) and more widespread in epidermis (DEGs=129). ADEH+-upregulated epidermal DEGs were enriched in type 2 cytokine (T2) (IL4R, CCL22, CRLF2, IL7R), interferon (CXCL10, ICAM1, IFI44, IRF7), and IL-36γ (IL36G) inflammatory gene pathways. All ADEH+ participants exhibited T2 and interferon endotypes and 87% were IL36G-high. In contrast, these endotypes were more variably expressed among ADEH- participants. ADEH+ skin also dysregulated epidermal differentiation complex (EDC) gene expression within LCE, S100, and SPRR families, which are involved in skin barrier function and antimicrobial activities. pDC transcriptional responses to HSV-1 infection were unaltered by ADEH status. Pathobiology underlying ADEH+ risk is associated with a unique, multi-faceted epidermal inflammation that accompanies dysregulation of EDC genes. These findings will help direct future studies that define how these inflammatory patterns may drive risk of eczema herpeticum in AD.
2024-03-26 | GSE262071 | GEO
Project description:Background: A subset of patients with atopic dermatitis (AD) is prone to disseminated herpes simplex virus (HSV) infection, i.e. eczema herpeticum (ADEH+). Biomarkers that identify ADEH+ are lacking. Objective: To search for novel ADEH+ gene signatures in peripheral blood mononuclear cells (PBMCs). Methods: A RNA-sequencing (RNA-seq) approach was applied to evaluate global transcriptional changes using PBMCs from ADEH+ and AD without a history of EH (ADEH-). Candidate genes were confirmed by qPCR or ELISA. Results: ADEH+ PBMCs had distinct changes to the transcriptome when compared to ADEH- PBMCs following HSV-1 stimulation: 792 genes were differentially expressed at a false discovery rate (FDR) < 0.05 (ANOVA), and 15 type I and type III interferon (IFN) genes were among the top 20 most down-regulated genes in ADEH+. We further validated that IFN-α and IL-29 mRNA and protein levels were significantly decreased in HSV-1 stimulated PBMCs from ADEH+ compared to ADEH- and normal. Ingenuity pathway analysis (IPA) demonstrated that the up-stream regulators of type I and type III IFNs, IRF3 and IRF7 was significantly inhibited in ADEH+ based on the down-regulation of their target genes. Furthermore, we found that gene expression of IRF3 and IRF7 were significantly decreased in HSV-1 stimulated PBMC from ADEH+ subjects. Conclusions: PBMCs from ADEH+ have a distinct immune response following HSV-1 exposure compared to ADEH- . Inhibition of the IRF3 and IRF7 innate immune pathways in ADEH+ may be the important mechanisms for increased susceptibility to disseminated viral infection.
2015-08-18 | GSE60481 | GEO
Project description:Atopic dermatitis (AD) is a common skin disorder with elevated prevalence. Cataract induced by AD rarely occurs in adolescent and young adult patients, which is also called atopic cataract. Using whole exome sequencing, we aimed to explore genetic alterations among AD and atopic cataract.We recruited a 19 year-old Chinese male with AD accompanied with cataracts, his father with AD and his mother without AD or cataract. Through analysis of the exomic sequence of the 3 individuals from the same family, we identified that with respect to AD, there were 162 genes mutated in both this patient and his father but not in his mother. In addition, we found 10 genes mutated in this patient only without in his parents according to cataract.This research suggests that coinheritance of mutations in these genes may correlate with AD, and the pathogenesis of AD complicated with cataracts was related to genetic factors.
| S-EPMC5601745 | biostudies-literature
Project description:Background: DOCK8 deficiency is an autosomal recessive form of hyperimmunoglobulinemia E syndrome (HIES). Severe atopic dermatitis (AD) shares with DOCK8 deficiency some clinical symptoms, including eczema, eosinophilia, and increased serum IgE levels. The deficiency of DOCK8 protein is potentially a life-threatening autosomal recessive HIES and only curable with bone marrow transplantation. Despite identified metabolomics and cytokine biomarkers, novel proteomics biomarkers need to be identified, as the connecting networks are critical to our understanding of this disease. Hence we performed serum proteomics profiling using LC-MSE SynaptG2. Method: Label-free untargeted proteomics analysis was used to identify potentially reliable, sensitive, and specific protein biomarkers in serum collected from DOCK8 (n=10), AD (n=9) patients, which were compared to ctrls (n=5). Results: From a total of 275 quantifiable proteins, binary comparisons between AD vs. Ctrl, DOCK8 vs. Ctrl, and DOCK8 vs. AD revealed 109, 105 and 85 dysregulated proteins, respectively. 24 among 85 proteins were specific potential biomarkers among the DOCK8 and AD groups. The sensitivity and specificity of few proteins like Claspin, Immunoglobulin kappa and heavy, complement components as potential biomarkers to distinguish between DOCK8 and AD patients were evaluated using the receiver operating characteristic curve. DOCK8 deficiency and AD groups' profiling revealed a shared role of ERK1/2 among the commonly dysregulated proteins. Conclusion: In this study, we have identified potential proteomics biomarkers and profile to distinguish between DOCK8 and AD, with possible diagnostic and therapeutic applications to help create effective interventions for managing these diseases. Further studies to confirm these associations in prospective cohorts are warranted.
2022-05-17 | PXD029052 | Pride
Project description:The aim of this study was to find disease-associated genes in atopic eczema. Keywords: Skin biopsy, DNA microarray, atopic eczema
2006-10-13 | GSE6012 | GEO
Project description:This study used nasal transcriptomic profiling of the inferior turbinate in control and pediatric ARDS subjects to identify endotypes. This data set is for amplified specimens. The study identfied three pediatric ARDS endotypes.
2020-06-23 | GSE152979 | GEO
Project description:This study used nasal transcriptomic profiling of the inferior turbinate in control and pediatric ARDS subjects to identify endotypes. This data set is for non-amplified specimens. The study identfied three pediatric ARDS endotypes.
2020-06-23 | GSE152978 | GEO
Project description:Beyond classic "allergic"/atopic comorbidities, atopic dermatitis (AD) emerges as systemic disease with increased cardiovascular risk. To better define serum inflammatory and cardiovascular risk proteins, we used an OLINK high-throughput proteomic assay to analyze moderate-to-severe AD (n?=?59) compared to psoriasis (n?=?22) and healthy controls (n?=?18). Compared to controls, 10 proteins were increased in serum of both diseases, including Th1 (IFN-?, CXCL9, TNF-?) and Th17 (CCL20) markers. 48 proteins each were uniquely upregulated in AD and psoriasis. Consistent with skin expression, AD serum showed up-regulation of Th2 (IL-13, CCL17, eotaxin-1/CCL11, CCL13, CCL4, IL-10), Th1 (CXCL10, CXCL11) and Th1/Th17/Th22 (IL-12/IL-23p40) responses. Surprisingly, some markers of atherosclerosis (fractalkine/CX3CL1, CCL8, M-CSF, HGF), T-cell development/activation (CD40L, IL-7, CCL25, IL-2RB, IL-15RA, CD6) and angiogenesis (VEGF-A) were significantly increased only in AD. Multiple inflammatory pathways showed stronger enrichment in AD than psoriasis. Several atherosclerosis mediators in serum (e.g. E-selectin, PI3/elafin, CCL7, IL-16) correlated with SCORAD, but not BMI. Also, AD inflammatory mediators (e.g. MMP12, IL-12/IL-23p40, CXCL9, CCL22, PI3/Elafin) correlated between blood and lesional as well as non-lesional skin. Overall, the AD blood signature was largely different compared to psoriasis, with dysregulation of inflammatory and cardiovascular risk markers, strongly supporting its systemic nature beyond atopic/allergic association.
| S-EPMC5562859 | biostudies-other
Project description:BackgroundThe basis for increased susceptibility of patients with atopic dermatitis (AD) to develop disseminated viral skin infections such as eczema herpeticum (AD with a history of eczema herpeticum, ADEH(+)) is poorly understood.ObjectiveWe sought to determine whether subjects with AD prone to disseminated viral skin infections have defects in their IFN responses.MethodsGeneChip profiling was used to identify differences in gene expression of PBMCs from patients with ADEH(+) compared with patients with AD without a history of eczema herpeticum (ADEH(-)) and nonatopic controls. Key differences in protein expression were verified by enzyme-linked immunosorbent spot assay and/or ELISA. Clinical relevance was further demonstrated by a mouse model of disseminated viral skin infection and genetic association analysis for genetic variants in IFNG and IFNGR1 and ADEH among 435 cases and controls.ResultsWe demonstrate by global gene expression analysis selective transcriptomic changes within the IFN superfamily of PBMCs from subjects with ADEH(+) reflecting low IFN-? and IFN-? receptor gene expression. IFN-? protein production was also significantly lower in patients with ADEH(+) (n = 24) compared with patients with ADEH(-) (n = 20) and nonatopic controls (n = 20). IFN-? receptor knockout mice developed disseminated viral skin infection after epicutaneous challenge with vaccinia virus. Genetic variants in IFNG and IFNGR1 single nucleotide polymorphisms (SNPs) were significantly associated with ADEH (112 cases, 166 controls) and IFN-? production: a 2-SNP (A-G) IFNGR1 haplotype (rs10457655 and rs7749390) showed the strongest association with a reduced risk of ADEH+ (13.2% ADEH(+) vs 25.5% ADEH(-); P = .00057).ConclusionPatients with ADEH(+) have reduced IFN-? production, and IFNG and IFNGR1 SNPs are significantly associated with ADEH(+) and may contribute to an impaired immune response to herpes simplex virus.
| S-EPMC3074534 | biostudies-literature
Project description:BackgroundA subset of patients with atopic dermatitis (AD) is prone to disseminated herpes simplex virus (HSV) infection (ie, atopic dermatitis with a history of eczema herpeticum [ADEH+]). Biomarkers that identify ADEH+ are lacking.ObjectiveWe sought to search for novel ADEH+ gene signatures in PBMCs.MethodsAn RNA-sequencing approach was applied to evaluate global transcriptional changes by using PBMCs from patients with ADEH+ and patients with atopic dermatitis without a history of eczema herpeticum (ADEH-). Candidate genes were confirmed by means of quantitative PCR or ELISA.ResultsPBMCs from patients with ADEH+ had distinct changes to the transcriptome when compared with those from patients with ADEH- after HSV-1 stimulation: 792 genes were differentially expressed at a false discovery rate of less than 0.05 (ANOVA), and 15 type I and type III interferon genes were among the top 20 most downregulated genes in patients with ADEH+. We further validated that IFN-α and IL-29 mRNA and protein levels were significantly decreased in HSV-1-stimulated PBMCs from patients with ADEH+ compared with those from patients with ADEH- and healthy subjects. Ingenuity Pathway Analysis demonstrated that the upstream regulators of type I and type III interferons, interferon regulatory factor (IRF) 3 and IRF7, were significantly inhibited in patients with ADEH+ based on the downregulation of their target genes. Furthermore, we found that gene expression of IRF3 and IRF7 was significantly decreased in HSV-1-stimulated PBMCs from patients with ADEH+.ConclusionsPBMCs from patients with ADEH+ have a distinct immune response after HSV-1 exposure compared with those from patients with ADEH-. Inhibition of the IRF3 and IRF7 innate immune pathways in patients with ADEH+ might be an important mechanism for increased susceptibility to disseminated viral infection.
| S-EPMC4186924 | biostudies-literature