Atopic dermatitis complicated by eczema herpeticum is associated with HLA B7 and reduced interferon-γ-producing CD8+ T cells.
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ABSTRACT: Background
The increased susceptibility of patients with atopic dermatitis (AD) to disseminated viral skin infections such as eczema herpeticum (ADEH+) is poorly understood.Objectives
The primary goal of the current study was to determine whether ADEH+ subjects have identifiable defects in cell-mediated immunity that reduce their ability to control viral infections.Materials and methods
In this study, we evaluated cytokine expression by various subsets of peripheral blood mononuclear cells from ADEH+ (n = 24) compared with AD without a history of viral infections (ADEH-) (n = 20) before and after treatment with herpes simplex virus (HSV).Results
We found that interferon (IFN)-γ expression after HSV treatment was lower in the CD8+ T cells and monocytes from patients with ADEH+ compared with patients who are ADEH- or nonatopic. Given the induction of CD8+ T cells as the result of antigen presentation by human leucocyte antigen (HLA) class I, consistent with the findings described above we also found that the HLA B7 allele was significantly associated with risk of the ADEH+ phenotype (odds ratio = 1·91, P = 0·02, 125 ADEH+ and 161 ADEH- subjects).Conclusions
These data suggest that defects in viral-induced IFN-γ from CD8+ T cells contribute to the ADEH+ phenotype.
SUBMITTER: Mathias RA
PROVIDER: S-EPMC8609667 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:BACKGROUND:A 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. OBJECTIVE:We sought to search for novel ADEH+ gene signatures in PBMCs. METHODS:An 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. RESULTS:PBMCs 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-? 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+. CONCLUSIONS:PBMCs 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
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: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: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:Interferon regulatory factor 2 (IRF2) is a member of a family of transcriptional factors involved in the modulation of IFN-induced immune responses to viral infection. To test whether genetic variants in IRF2 predict risk of atopic dermatitis (AD) and ADEH (atopic dermatitis complicated by eczema herpeticum), we genotyped 78 IRF2 tagging single-nucleotide polymorphisms (SNPs) in both European-American (n = 435) and African-American (n = 339) populations. Significant associations were observed between AD and two SNPs (rs793814, P = 0.007, odds ratio (OR) = 0.52; rs3756094, P = 0.037, OR = 0.66) among European Americans and one SNP (rs3775572, P = 0.016, OR = 0.46) among African Americans. Significant associations were also observed between ADEH and five SNPs (P = 0.049-0.022) among European Americans. The association with ADEH was further strengthened by haplotype analyses, wherein a five-SNP (CAGGA) haplotype showed the strongest association with ADEH (P = 0.0008). Eight IRF2 SNPs were significantly associated with IFN-? production after herpes simplex virus (HSV) stimulation (P = 0.048-0.0008), including an AD-associated SNP (rs13139310, P = 0.008). Our findings suggest that distinct markers in IRF2 may be associated with AD and ADEH, which may depend upon ethnic ancestry, and genetic variants in IRF2 may contribute to an abnormal immune response to HSV.
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Project description:BackgroundA subset of subjects with atopic dermatitis (AD) are susceptible to serious infections with herpes simplex virus, called eczema herpeticum, or vaccina virus, called eczema vaccinatum.ObjectiveThis National Institute of Allergy and Infectious Diseases-funded multicenter study was performed to establish a database of clinical information and biologic samples on subjects with AD with and without a history of eczema herpeticum (ADEH(+) and ADEH(-) subjects, respectively) and healthy control subjects. Careful phenotyping of AD subsets might suggest mechanisms responsible for disseminated viral infections and help identify at-risk individuals.MethodsWe analyzed the data from 901 subjects (ADEH(+) subjects, n = 134; ADEH(-) subjects, n = 419; healthy control subjects, n = 348) enrolled between May 11, 2006, and September 16, 2008, at 7 US medical centers.ResultsADEH(+) subjects had more severe disease based on scoring systems (Eczema Area and Severity Index and Rajka-Langeland score), body surface area affected, and biomarkers (circulating eosinophil counts and serum IgE, thymus and activation-regulated chemokine, and cutaneous T cell-attracting chemokine) than ADEH(-) subjects (P < .001). ADEH(+) subjects were also more likely to have a history of food allergy (69% vs 40%, P < .001) or asthma (64% vs 44%, P < .001) and were more commonly sensitized to many common allergens (P < .001). Cutaneous infections with Staphylococcus aureus or molluscum contagiosum virus were more common in ADEH(+) subjects (78% and 8%, respectively) than in ADEH(-) subjects (29% and 2%, respectively; P < .001).ConclusionSubjects with AD in whom eczema herpeticum develops have more severe T(H)2-polarized disease with greater allergen sensitization and more commonly have a history of food allergy, asthma, or both. They are also much more likely to experience cutaneous infections with S. aureus or molluscum contagiosum.
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Project description:A subset of atopic dermatitis is associated with increased susceptibility to eczema herpeticum (ADEH+). We previously reported that common single nucleotide polymorphisms (SNPs) in the IFN-? (IFNG) and IFN-? receptor 1 (IFNGR1) genes were associated with the ADEH+ phenotype.We sought to interrogate the role of rare variants in interferon pathway genes for the risk of ADEH+.We performed targeted sequencing of interferon pathway genes (IFNG, IFNGR1, IFNAR1, and IL12RB1) in 228 European American patients with AD selected according to their eczema herpeticum status, and severity was measured by using the Eczema Area and Severity Index. Replication genotyping was performed in independent samples of 219 European American and 333 African American subjects. Functional investigation of loss-of-function variants was conducted by using site-directed mutagenesis.We identified 494 single nucleotide variants encompassing 105 kb of sequence, including 145 common, 349 (70.6%) rare (minor allele frequency <5%), and 86 (17.4%) novel variants, of which 2.8% were coding synonymous, 93.3% were noncoding (64.6% intronic), and 3.8% were missense. We identified 6 rare IFNGR1 missense variants, including 3 damaging variants (Val14Met [V14M], Val61Ile, and Tyr397Cys [Y397C]) conferring a higher risk for ADEH+ (P = .031). Variants V14M and Y397C were confirmed to be deleterious, leading to partial IFNGR1 deficiency. Seven common IFNGR1 SNPs, along with common protective haplotypes (2-7 SNPs), conferred a reduced risk of ADEH+ (P = .015-.002 and P = .0015-.0004, respectively), and both SNP and haplotype associations were replicated in an independent African American sample (P = .004-.0001 and P = .001-.0001, respectively).Our results provide evidence that both genetic variants in the gene encoding IFNGR1 are implicated in susceptibility to the ADEH+ phenotype.
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Project description:Acrodermatitis enteropathica (AcE) is a rare, autosomal recessive inherited disorder caused by mutation of the SLC39A4 gene coding for zinc transport protein (ZIP 4). The disease appears during childhood especially in breastfeeding or post-breastfeeding infant. Eczema herpeticum refers to a disseminated skin infection of herpes simplex virus that usually leads to vesicular eruptions commonly seen on a background of atopic dermatitis (AD). We describe an 11-year-old boy with periorificial erosions in periorbital, perinasal, perioral, perineal, and gluteal areas, accompanied with itchy vesicles, some covered with hemorrhagic crusts. A clinical diagnosis of AcE and eczema herpeticum with AD was supported by typical lesions and acute and chronic eczematous changes found mainly in the flexural aspects of extremities, which is diagnostic of AD. Laboratory findings showed anti HSV1 IgG (23.43) and high levels of IgE (478.9 IU/L). There was no multinucleated giant cell in the Tzanck test. Skin histology was compatible with AcE. Direct immunofluorescent examination showed no deposits of IgG, IgM, IgA, or complement. Complete resolution occurred within 2 weeks of acyclovir and oral zinc supplementation.
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Project description:Loss-of-function null mutations R501X and 2282del4 in the skin barrier gene, filaggrin (FLG), represent the most replicated genetic risk factors for atopic dermatitis (AD). Associations have not been reported in African ancestry populations. Atopic dermatitis eczema herpeticum (ADEH) is a rare but serious complication of AD resulting from disseminated cutaneous herpes simplex virus infections.We aimed to determine whether FLG polymorphisms contribute to ADEH susceptibility.Two common loss-of-function mutations plus 9 FLG single nucleotide polymorphisms were genotyped in 278 European American patients with AD, of whom 112 had ADEH, and 157 nonatopic controls. Replication was performed on 339 African American subjects.Significant associations were observed for both the R501X and 2282del4 mutations and AD among European American subjects (P = 1.46 x 10(-5), 3.87 x 10(-5), respectively), but the frequency of the R501X mutation was 3 times higher (25% vs 9%) for ADEH than for AD without eczema herpeticum (EH) (odds ratio [OR], 3.4; 1.7-6.8; P = .0002). Associations with ADEH were stronger with the combined null mutations (OR, 10.1; 4.7-22.1; P = 1.99 x 10(-11)). Associations with the R501X mutation were replicated in the African American population; the null mutation was absent among healthy African American subjects, but present among patients with AD (3.2%; P = .035) and common among patients with ADEH (9.4%; P = .0049). However, the 2282del4 mutation was absent among African American patients with ADEH and rare (<1%) among healthy individuals.The R501X mutation in the gene encoding filaggrin, one of the strongest genetic predictors of AD, confers an even greater risk for ADEH in both European and African ancestry populations, suggesting a role for defective skin barrier in this devastating condition.
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Project description:Factors favoring the emergence of eczema herpeticum (EH) in patients with atopic dermatitis (AD) remain elusive. The aim of this work was to identify changes in clinical and laboratory parameters in acute EH patients, before and after 6 weeks of treatment, as well as differences between AD patients with and without a history of EH.A total of 235 adult subjects were included and subdivided into six groups: (i) AD patients with acute EH, (ii) AD patients with history of EH, (iii) AD without EH but with recurrent herpes simplex virus (HSV) infections, (iv) AD without EH or recurrent HSV infections and healthy non-AD controls (v) with and (vi) without recurrent HSV infections. Clinical examination of AD, assessment of atopic status and severity were performed. Total IgE, allergen-specific IgE and differential blood count were analyzed. Clinical diagnosis of acute EH was confirmed by PCR.More male patients with AD were affected by EH than female patients. Acute episodes of EH are characterized by lower levels of lymphocytes and higher levels of monocytes. AD patients with history of EH display higher total IgE serum levels (ADEH(+) HSV(+) vs ADEH(-) HSV(+) , P < 0.001) and higher sensitization profiles and stronger severity of AD (EASI and SCORAD; ADEH(+) HSV(+) vs ADEH(-) HSV(+) , P < 0.001). Concomitant asthma and rhinitis were identified as correlates of EH.From these data, we conclude that AD patients with EH display a distinct clinical and biological phenotype.
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