The Experts below are selected from a list of 279 Experts worldwide ranked by ideXlab platform
Donald Y M Leung - One of the best experts on this subject based on the ideXlab platform.
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ankyrin repeat domain 1 regulates innate immune responses against herpes simplex virus 1 a potential role in Eczema Herpeticum
The Journal of Allergy and Clinical Immunology, 2018Co-Authors: Xiaozhao Li, Joanne E Streib, Brittany N Richers, Patricia A Taylor, Jack W Hu, Donald Y M LeungAbstract:Background Atopic dermatitis (AD) is a common inflammatory skin disease. A subset of patients with AD are susceptible to disseminated herpes simplex virus (HSV) infection, a complication termed Eczema Herpeticum (ADEH+). The immune mechanisms causing ADEH+ remain elusive. Using RNA sequencing, we recently found that ankyrin repeat domain 1 (ANKRD1) was significantly induced in human PBMCs upon HSV-1 stimulation, and its induction in patients with ADEH+ was significantly reduced compared with that seen in AD patients without a history of Eczema Herpeticum (ADEH−). Objective We sought to validate ANKRD1 gene expression in nonatopic (NA) subjects, patients with ADEH−, and patients with ADEH+ and to delineate the biological function of ANKRD1 and the signaling pathway or pathways involved. Methods Purification of human PBMCs, monocytes, B cells, dendritic cells, T cells, and natural killer cells; RNA extraction and quantitative RT-PCR; small interfering RNA technique; co-immunoprecipitation; and Western blot assays were used. Results ANKRD1 expression was significantly reduced in PBMCs from patients with ADEH+ after HSV-1 stimulation compared with PBMCs from patients with ADEH−. We found that the induction of ANKRD1 by HSV-1 and multiple pattern recognition receptor agonists are mediated by inflammatory cytokines. Silencing ANKRD1 gene expression in antigen-presenting cells led to increased viral load and reduced IFNB1 and IL29 production. Using co-immunoprecipitation methods, we demonstrated that ANKRD1 formed protein complexes with interferon regulatory factor (IRF) 3 and IRF7, which are important transcription factors regulating signaling transduction of pattern recognition receptors. Overexpression of ANKRD1 enhanced the IRF3-mediated signaling pathways. Conclusion ANKRD1 is involved in IRF3-mediated antiviral innate immune signaling pathways. Its reduced expression in patients with ADEH+ might contribute to the pathogenesis of ADEH+.
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identification of novel gene signatures in patients with atopic dermatitis complicated by Eczema Herpeticum
The Journal of Allergy and Clinical Immunology, 2014Co-Authors: Michael G Edwards, Ryan Heiser, Joanne E Streib, Brittany N Richers, Clifton F Hall, Donald Y M LeungAbstract: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-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+. 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.
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identification of novel gene signatures in atopic dermatitis complicated by Eczema Herpeticum
The Journal of Allergy and Clinical Immunology, 2014Co-Authors: Michael G Edwards, Ryan Heiser, Joanne E Streib, Brittany N Richers, Donald Y M LeungAbstract: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.
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why is Eczema Herpeticum unexpectedly rare
Antiviral Research, 2013Co-Authors: Donald Y M LeungAbstract:Atopic dermatitis (AD) is the most common chronic inflammatory skin disease of humans, affecting approximately 17% of children. AD patients are especially susceptible to cutaneous bacterial and viral infections, and may develop severe or fatal herpes simplex virus (HSV) infection (Eczema Herpeticum, EH), requiring intensive antiviral therapy. However, even though a majority of adults show serologic evidence of previous HSV exposure, EH occurs in less than 3% of AD patients. The unexpected rarity of AD patients with EH (ADEH+) suggests that multiple host factors play a role in the clinical expression of this complex phenotype. Recent studies comparing ADEH+ versus ADEH− patients reveal that patients prone to ADEH+ have more severe AD skin disease, biomarkers associated with Th2 helper cell responses (reduced interferon levels, circulating eosinophil counts, increased serum IgE and allergen sensitization) and decreased epidermal expression of filaggrin and antimicrobial peptides. ADEH+ subjects are also more likely to have a history of food allergy or asthma, early onset of AD and a history of other cutaneous infections with Staphylococcus aureus or molluscum contagiosum.
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genetic variants in interferon regulatory factor 2 irf2 are associated with atopic dermatitis and Eczema Herpeticum
Journal of Investigative Dermatology, 2012Co-Authors: Donald Y M Leung, Nicholas Rafaels, Lisa A Beck, Mark Boguniewicz, Tissa Hata, Lynda C Schneider, Jon M Hanifin, T Hand, Terri H Beaty, Adriana WeinbergAbstract: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-γ 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.
Andreas Wollenberg - One of the best experts on this subject based on the ideXlab platform.
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Recurrent Eczema Herpeticum ‐ A Retrospective European Multicenter Study Evaluating the Clinical Characteristics of Eczema Herpeticum Cases in Atopic Dermatitis Patients
Journal of The European Academy of Dermatology and Venereology, 2020Co-Authors: Marlene Seegraber, Natalija Novak, Margitta Worm, Thomas Werfel, Ake Svensson, Dagmar Simon, U Darsow, Matthias Augustin, Andreas WollenbergAbstract:Background Eczema Herpeticum (EH ) is a disseminated viral infection of Eczematous skin disease with the herpes simplex virus. Knowledge on clinical characteristics, risk factors and recurrent disease is limited. Our aim was to better define clinical characteristics and risk factors for EH and especially for recurrent EH . Methods A retrospective analysis of EH cases assessed the history, clinical signs, prior treatment and laboratory results using a predefined questionnaire. Results A total of 224 EH cases from eight European centres were included. Extrinsic AD was identified as risk factor for EH , and only one patient suffered from intrinsic AD . Early onset of AD was identified as risk factor for recurrent EH . Pretreatment with topical steroids, systemic steroids, topical calcineurin inhibitors or plain emollients reflected standard therapy. Many patients showed AD lesions without EH , but skin without AD lesions was never affected by herpetic lesions. Conclusion Patients with clinically active, extrinsic AD are at risk of EH . Recurrent EH is associated with confounders of severe atopic distortion and requires active AD lesions for clinical manifestation. Recurrent Eczema Herpeticum mainly affects patients with early onset of AD .
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recurrent Eczema Herpeticum a retrospective european multicenter study evaluating the clinical characteristics of Eczema Herpeticum cases in atopic dermatitis patients
Journal of The European Academy of Dermatology and Venereology, 2020Co-Authors: Marlene Seegraber, Natalija Novak, Margitta Worm, Thomas Werfel, Ake Svensson, Dagmar Simon, U Darsow, Matthias Augustin, Andreas WollenbergAbstract:Background Eczema Herpeticum (EH ) is a disseminated viral infection of Eczematous skin disease with the herpes simplex virus. Knowledge on clinical characteristics, risk factors and recurrent disease is limited. Our aim was to better define clinical characteristics and risk factors for EH and especially for recurrent EH . Methods A retrospective analysis of EH cases assessed the history, clinical signs, prior treatment and laboratory results using a predefined questionnaire. Results A total of 224 EH cases from eight European centres were included. Extrinsic AD was identified as risk factor for EH , and only one patient suffered from intrinsic AD . Early onset of AD was identified as risk factor for recurrent EH . Pretreatment with topical steroids, systemic steroids, topical calcineurin inhibitors or plain emollients reflected standard therapy. Many patients showed AD lesions without EH , but skin without AD lesions was never affected by herpetic lesions. Conclusion Patients with clinically active, extrinsic AD are at risk of EH . Recurrent EH is associated with confounders of severe atopic distortion and requires active AD lesions for clinical manifestation. Recurrent Eczema Herpeticum mainly affects patients with early onset of AD .
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mannan binding lectin levels and activity are not altered in atopic dermatitis patients with a history of Eczema Herpeticum
Dermatology Research and Practice, 2011Co-Authors: Kemp W Bundy, Andreas Wollenberg, Lisa A Beck, Laura Y Mcgirt, Lora G Bankova, Anna De BenedettoAbstract:Background. Eczema Herpeticum (EH) is a potentially serious, systemic complication in subjects with atopic dermatitis (AD) caused by herpes simplex virus (HSV). The innate immune dysregulation that predisposes these subjects to cutaneous viral infections is not well understood. We tested the hypothesis that defects in mannan-binding lectin (MBL) may be associated with an increased risk of EH. Methods. We evaluated serum MBL levels and functional activity in 13 AD subjects with a history of EH (EH
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cathelicidin deficiency predisposes to Eczema Herpeticum
The Journal of Allergy and Clinical Immunology, 2006Co-Authors: Michael D Howell, Joanne E Streib, Andreas Wollenberg, Mark Boguniewicz, Richard L Gallo, Michael J Flaig, Cathy Wong, Tatjana Pavicic, Donald Y M LeungAbstract:Background The cathelicidin family of antimicrobial peptides is an integral component of the innate immune response that exhibits activity against bacterial, fungal, and viral pathogens. Eczema Herpeticum (ADEH) develops in a subset of patients with atopic dermatitis (AD) because of disseminated infection with herpes simplex virus (HSV). Objective This study investigated the potential role of cathelicidins in host susceptibility to HSV infection. Methods Glycoprotein D was measured by means of real-time RT-PCR as a marker of HSV replication in skin biopsy specimens and human keratinocyte cultures. Cathelicidin expression was evaluated in skin biopsy specimens from patients with AD (n = 10) without a history of HSV skin infection and from patients with ADEH (n = 10). Results The cathelicidin peptide LL-37 (human cathelicidin) exhibited activity against HSV in an antiviral assay, with significant killing (P Conclusion This study demonstrates that the cathelicidin peptide LL-37 possesses antiviral activity against HSV and demonstrates the importance of variable skin expression of cathelicidins in controlling susceptibility to ADEH. Additionally, serum IgE levels might be a surrogate marker for innate immune function and serve as a biomarker for which patients with AD are susceptible to ADEH. Clinical implications A deficiency of LL-37 might render patients with AD susceptible to ADEH. Therefore increasing production of skin LL-37 might prevent herpes infection in patients with AD.
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cathelicidin deficiency predisposes to Eczema Herpeticum
The Journal of Allergy and Clinical Immunology, 2006Co-Authors: Michael D Howell, Joanne E Streib, Andreas Wollenberg, Mark Boguniewicz, Richard L Gallo, Michael J Flaig, Cathy Wong, Tatjana Pavicic, Donald Y M LeungAbstract:Background The cathelicidin family of antimicrobial peptides is an integral component of the innate immune response that exhibits activity against bacterial, fungal, and viral pathogens. Eczema Herpeticum (ADEH) develops in a subset of patients with atopic dermatitis (AD) because of disseminated infection with herpes simplex virus (HSV). Objective This study investigated the potential role of cathelicidins in host susceptibility to HSV infection. Methods Glycoprotein D was measured by means of real-time RT-PCR as a marker of HSV replication in skin biopsy specimens and human keratinocyte cultures. Cathelicidin expression was evaluated in skin biopsy specimens from patients with AD (n = 10) without a history of HSV skin infection and from patients with ADEH (n = 10). Results The cathelicidin peptide LL-37 (human cathelicidin) exhibited activity against HSV in an antiviral assay, with significant killing ( P −/− ) mouse skin (2.6 ± 0.5 pg HSV/pg GAPDH, P P r 2 = 0.46, P Conclusion This study demonstrates that the cathelicidin peptide LL-37 possesses antiviral activity against HSV and demonstrates the importance of variable skin expression of cathelicidins in controlling susceptibility to ADEH. Additionally, serum IgE levels might be a surrogate marker for innate immune function and serve as a biomarker for which patients with AD are susceptible to ADEH. Clinical implications A deficiency of LL-37 might render patients with AD susceptible to ADEH. Therefore increasing production of skin LL-37 might prevent herpes infection in patients with AD.
Lisa A Beck - One of the best experts on this subject based on the ideXlab platform.
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targeted deep sequencing identifies rare loss of function variants in ifngr1 for risk of atopic dermatitis complicated by Eczema Herpeticum
The Journal of Allergy and Clinical Immunology, 2015Co-Authors: Nicholas Rafaels, Lynda C Schneider, Jon M Hanifin, R L Gallo, Amy S Paller, Terri H Beaty, Lili Huang, Joseph Potee, Ingo Ruczinski, Lisa A BeckAbstract:Background 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-γ (IFNG) and IFN-γ receptor 1 (IFNGR1) genes were associated with the ADEH+ phenotype. Objective We sought to interrogate the role of rare variants in interferon pathway genes for the risk of ADEH+. Methods 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. Results We identified 494 single nucleotide variants encompassing 105 kb of sequence, including 145 common, 349 (70.6%) rare (minor allele frequency 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). Conclusion 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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atopic dermatitis complicated by Eczema Herpeticum is associated with hla b7 and reduced interferon γ producing cd8 t cells
British Journal of Dermatology, 2013Co-Authors: Rasika A Mathias, Lisa A Beck, Mark Boguniewicz, Tissa Hata, Lynda C Schneider, Jon M Hanifin, Brian Armstrong, Adriana Weinberg, Daniel Zaccaro, Kathleen C BarnesAbstract:Summary 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.
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genetic variants in interferon regulatory factor 2 irf2 are associated with atopic dermatitis and Eczema Herpeticum
Journal of Investigative Dermatology, 2012Co-Authors: Donald Y M Leung, Nicholas Rafaels, Lisa A Beck, Mark Boguniewicz, Tissa Hata, Lynda C Schneider, Jon M Hanifin, T Hand, Terri H Beaty, Adriana WeinbergAbstract: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-γ 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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mannan binding lectin levels and activity are not altered in atopic dermatitis patients with a history of Eczema Herpeticum
Dermatology Research and Practice, 2011Co-Authors: Kemp W Bundy, Andreas Wollenberg, Lisa A Beck, Laura Y Mcgirt, Lora G Bankova, Anna De BenedettoAbstract:Background. Eczema Herpeticum (EH) is a potentially serious, systemic complication in subjects with atopic dermatitis (AD) caused by herpes simplex virus (HSV). The innate immune dysregulation that predisposes these subjects to cutaneous viral infections is not well understood. We tested the hypothesis that defects in mannan-binding lectin (MBL) may be associated with an increased risk of EH. Methods. We evaluated serum MBL levels and functional activity in 13 AD subjects with a history of EH (EH
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filaggrin mutations that confer risk of atopic dermatitis confer greater risk for Eczema Herpeticum
The Journal of Allergy and Clinical Immunology, 2009Co-Authors: Nicholas Rafaels, Mark Boguniewicz, Tissa Hata, Lynda C Schneider, Jon M Hanifin, Richard L Gallo, T Hand, Tanda Murray, Terri H Beaty, Lisa A BeckAbstract:Background 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. Objective We aimed to determine whether FLG polymorphisms contribute to ADEH susceptibility. Methods 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. Results Significant associations were observed for both the R501X and 2282del4 mutations and AD among European American subjects ( P = 1.46 × 10 −5 , 3.87 × 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 × 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 ( Conclusion 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.
Natalija Novak - One of the best experts on this subject based on the ideXlab platform.
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Recurrent Eczema Herpeticum ‐ A Retrospective European Multicenter Study Evaluating the Clinical Characteristics of Eczema Herpeticum Cases in Atopic Dermatitis Patients
Journal of The European Academy of Dermatology and Venereology, 2020Co-Authors: Marlene Seegraber, Natalija Novak, Margitta Worm, Thomas Werfel, Ake Svensson, Dagmar Simon, U Darsow, Matthias Augustin, Andreas WollenbergAbstract:Background Eczema Herpeticum (EH ) is a disseminated viral infection of Eczematous skin disease with the herpes simplex virus. Knowledge on clinical characteristics, risk factors and recurrent disease is limited. Our aim was to better define clinical characteristics and risk factors for EH and especially for recurrent EH . Methods A retrospective analysis of EH cases assessed the history, clinical signs, prior treatment and laboratory results using a predefined questionnaire. Results A total of 224 EH cases from eight European centres were included. Extrinsic AD was identified as risk factor for EH , and only one patient suffered from intrinsic AD . Early onset of AD was identified as risk factor for recurrent EH . Pretreatment with topical steroids, systemic steroids, topical calcineurin inhibitors or plain emollients reflected standard therapy. Many patients showed AD lesions without EH , but skin without AD lesions was never affected by herpetic lesions. Conclusion Patients with clinically active, extrinsic AD are at risk of EH . Recurrent EH is associated with confounders of severe atopic distortion and requires active AD lesions for clinical manifestation. Recurrent Eczema Herpeticum mainly affects patients with early onset of AD .
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recurrent Eczema Herpeticum a retrospective european multicenter study evaluating the clinical characteristics of Eczema Herpeticum cases in atopic dermatitis patients
Journal of The European Academy of Dermatology and Venereology, 2020Co-Authors: Marlene Seegraber, Natalija Novak, Margitta Worm, Thomas Werfel, Ake Svensson, Dagmar Simon, U Darsow, Matthias Augustin, Andreas WollenbergAbstract:Background Eczema Herpeticum (EH ) is a disseminated viral infection of Eczematous skin disease with the herpes simplex virus. Knowledge on clinical characteristics, risk factors and recurrent disease is limited. Our aim was to better define clinical characteristics and risk factors for EH and especially for recurrent EH . Methods A retrospective analysis of EH cases assessed the history, clinical signs, prior treatment and laboratory results using a predefined questionnaire. Results A total of 224 EH cases from eight European centres were included. Extrinsic AD was identified as risk factor for EH , and only one patient suffered from intrinsic AD . Early onset of AD was identified as risk factor for recurrent EH . Pretreatment with topical steroids, systemic steroids, topical calcineurin inhibitors or plain emollients reflected standard therapy. Many patients showed AD lesions without EH , but skin without AD lesions was never affected by herpetic lesions. Conclusion Patients with clinically active, extrinsic AD are at risk of EH . Recurrent EH is associated with confounders of severe atopic distortion and requires active AD lesions for clinical manifestation. Recurrent Eczema Herpeticum mainly affects patients with early onset of AD .
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atopic dermo respiratory syndrome is a correlate of Eczema Herpeticum
Allergy, 2011Co-Authors: Torsten Hinz, Natalija Novak, D Zaccaro, M Byron, K Brendes, T. Krieg, Thomas BieberAbstract:To cite this article: Hinz T, Zaccaro D, Byron M, Brendes K, Krieg T, Novak N, Bieber T. Atopic dermo-respiratory syndrome is a correlate of Eczema Herpeticum. Allergy 2011; 66: 925–933. Abstract Background: 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. Methods: 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. Results: 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. Conclusion: From these data, we conclude that AD patients with EH display a distinct clinical and biological phenotype.
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Atopic dermo-respiratory syndrome is a correlate of Eczema Herpeticum.
Allergy, 2011Co-Authors: Torsten Hinz, Natalija Novak, D Zaccaro, M Byron, K Brendes, T. Krieg, Thomas BieberAbstract:To cite this article: Hinz T, Zaccaro D, Byron M, Brendes K, Krieg T, Novak N, Bieber T. Atopic dermo-respiratory syndrome is a correlate of Eczema Herpeticum. Allergy 2011; 66: 925–933. Abstract Background: 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. Methods: 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. Results: 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
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molecular pathogenesis and clinical implications of Eczema Herpeticum
Expert Reviews in Molecular Medicine, 2008Co-Authors: Caroline Bussmann, Wenming Peng, Thomas Bieber, Natalija NovakAbstract:A subgroup of patients with atopic dermatitis develops one or more episodes of a severe viral skin infection caused by herpes simplex virus superimposed on Eczematous skin lesions. This condition is named atopic dermatitis complicated by Eczema Herpeticum. Characteristic features of patients developing Eczema Herpeticum include an early age of onset of atopic dermatitis with a persistent and severe course into adulthood, predilection for Eczematous skin lesions in the head and neck area, elevated total serum IgE levels and increased allergen sensitisation. Deficiencies at the level of both the innate and the adaptive immune system, which have been identified in atopic dermatitis, are much more pronounced in this subgroup. Predisposing cellular factors include a reduced number of plasmacytoid dendritic cells in the epidermis and a modified capacity of these cells to produce type I interferons after allergen challenge. In addition, lower levels of antimicrobial peptides in the skin of atopic dermatitis patients, resulting in part from a Th2-prone micromilieu, contribute to the lack of an effective defence against viral attack. In this review, we summarise the current knowledge of the molecular pathogenesis of Eczema Herpeticum.
Nicholas Rafaels - One of the best experts on this subject based on the ideXlab platform.
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replicated methylation changes associated with Eczema Herpeticum and allergic response
Clinical Epigenetics, 2019Co-Authors: Meher Preethi Boorgula, Nicholas Rafaels, Michelle Daya, Monica Campbell, Sameer Chavan, Aniket Shetty, Chris Cheadle, Sangjucta Barkataki, Margaret A Taub, Gloria DavidAbstract:Although epigenetic mechanisms are important risk factors for allergic disease, few studies have evaluated DNA methylation differences associated with atopic dermatitis (AD), and none has focused on AD with Eczema Herpeticum (ADEH+). We will determine how methylation varies in AD individuals with/without EH and associated traits. We modeled differences in genome-wide DNA methylation in whole blood cells from 90 ADEH+, 83 ADEH−, and 84 non-atopic, healthy control subjects, replicating in 36 ADEH+, 53 ADEH−, and 55 non-atopic healthy control subjects. We adjusted for cell-type composition in our models and used genome-wide and candidate-gene approaches. We replicated one CpG which was significantly differentially methylated by severity, with suggestive replication at four others showing differential methylation by phenotype or severity. Not adjusting for eosinophil content, we identified 490 significantly differentially methylated CpGs (ADEH+ vs healthy controls, genome-wide). Many of these associated with severity measures, especially eosinophil count (431/490 sites). We identified a CpG in IL4 associated with serum tIgE levels, supporting a role for Th2 immune mediating mechanisms in AD. Changes in eosinophil level, a measure of disease severity, are associated with methylation changes, providing a potential mechanism for phenotypic changes in immune response-related traits.
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targeted deep sequencing identifies rare loss of function variants in ifngr1 for risk of atopic dermatitis complicated by Eczema Herpeticum
The Journal of Allergy and Clinical Immunology, 2015Co-Authors: Nicholas Rafaels, Lynda C Schneider, Jon M Hanifin, R L Gallo, Amy S Paller, Terri H Beaty, Lili Huang, Joseph Potee, Ingo Ruczinski, Lisa A BeckAbstract:Background 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-γ (IFNG) and IFN-γ receptor 1 (IFNGR1) genes were associated with the ADEH+ phenotype. Objective We sought to interrogate the role of rare variants in interferon pathway genes for the risk of ADEH+. Methods 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. Results We identified 494 single nucleotide variants encompassing 105 kb of sequence, including 145 common, 349 (70.6%) rare (minor allele frequency 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). Conclusion 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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genetic variants in interferon regulatory factor 2 irf2 are associated with atopic dermatitis and Eczema Herpeticum
Journal of Investigative Dermatology, 2012Co-Authors: Donald Y M Leung, Nicholas Rafaels, Lisa A Beck, Mark Boguniewicz, Tissa Hata, Lynda C Schneider, Jon M Hanifin, T Hand, Terri H Beaty, Adriana WeinbergAbstract: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-γ 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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human atopic dermatitis complicated by Eczema Herpeticum is associated with abnormalities in ifn γ response
The Journal of Allergy and Clinical Immunology, 2011Co-Authors: Donald Y M Leung, Nicholas Rafaels, Joanne E Streib, Mark Boguniewicz, Dmitry N Grigoryev, Michael D Howell, Patricia A Taylor, Jennifer Canniff, Brian Armstrong, Daniel ZaccaroAbstract:Background The 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. Objective We sought to determine whether subjects with AD prone to disseminated viral skin infections have defects in their IFN responses. Methods GeneChip 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. Results We demonstrate by global gene expression analysis selective transcriptomic changes within the IFN superfamily of PBMCs from subjects with ADEH(+) reflecting low IFN-γ and IFN-γ receptor gene expression. IFN-γ 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-γ 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-γ 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). Conclusion Patients with ADEH(+) have reduced IFN-γ production, and IFNG and IFNGR1 SNPs are significantly associated with ADEH(+) and may contribute to an impaired immune response to herpes simplex virus.
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filaggrin mutations that confer risk of atopic dermatitis confer greater risk for Eczema Herpeticum
The Journal of Allergy and Clinical Immunology, 2009Co-Authors: Nicholas Rafaels, Mark Boguniewicz, Tissa Hata, Lynda C Schneider, Jon M Hanifin, Richard L Gallo, T Hand, Tanda Murray, Terri H Beaty, Lisa A BeckAbstract:Background 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. Objective We aimed to determine whether FLG polymorphisms contribute to ADEH susceptibility. Methods 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. Results Significant associations were observed for both the R501X and 2282del4 mutations and AD among European American subjects ( P = 1.46 × 10 −5 , 3.87 × 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 × 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 ( Conclusion 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.
