title: Identification of novel gene signatures in patients with atopic dermatitis complicated by eczema herpeticum.
abstract: 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.
authors.affiliation: Department of Pediatrics, National Jewish Health, Denver, Colo.
authors.forename: Lianghua
authors.initials: L
authors.lastname: Bin
authors.affiliation: Division of Pulmonary Sciences and Critical Care Medicine, Department of Medicine, University of Colorado Denver, Aurora, Colo.
authors.forename: Michael G
authors.initials: MG
authors.lastname: Edwards
authors.affiliation: Department of Pediatrics, National Jewish Health, Denver, Colo.
authors.forename: Ryan
authors.initials: R
authors.lastname: Heiser
authors.affiliation: Department of Pediatrics, National Jewish Health, Denver, Colo.
authors.forename: Joanne E
authors.initials: JE
authors.lastname: Streib
authors.affiliation: Department of Pediatrics, National Jewish Health, Denver, Colo.
authors.forename: Brittany
authors.initials: B
authors.lastname: Richers
authors.affiliation: Department of Pediatrics, National Jewish Health, Denver, Colo.
authors.forename: Clifton F
authors.initials: CF
authors.lastname: Hall
authors.affiliation: Department of Pediatrics, National Jewish Health, Denver, Colo; Department of Pediatrics, University of Colorado School of Medicine, Aurora, Colo. Electronic address: leungd@njhealth.org.
authors.forename: Donald Y M
authors.initials: DY
authors.lastname: Leung
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000818:Animals; D002478:Cells, Cultured; D002648:Child; D003876:Dermatitis, Atopic / Q000150:complications / Q000235:genetics*; D015536:Down-Regulation; D005260:Female; D005819:Genetic Markers; D018259:Herpesvirus 1, Human / Q000276:immunology*; D006801:Humans; D007113:Immunity, Innate; D050838:Interferon Regulatory Factor-3 / Q000235:genetics*; D050839:Interferon Regulatory Factor-7 / Q000235:genetics*; D007370:Interferon Type I / Q000378:metabolism; D007372:Interferons; D007378:Interleukins / Q000235:genetics; D007617:Kaposi Varicelliform Eruption / Q000209:etiology / Q000235:genetics*; D007963:Leukocytes, Mononuclear / Q000276:immunology / Q000821:virology; D008297:Male; D008875:Middle Aged; D059467:Transcriptome; D055815:Young Adult; D000095022:Interferon Lambda
chemical_list: D005819:Genetic Markers; D050838:Interferon Regulatory Factor-3; D050839:Interferon Regulatory Factor-7; D007370:Interferon Type I; D007372:Interferons; D007378:Interleukins; C000624353:interferon-lambda, human; D000095022:Interferon Lambda; C494232:IRF3 protein, human; C494234:IRF7 protein, human
keywords: Atopic dermatitis; eczema herpeticum; herpes simplex virus; interferon regulatory factor 3; interferon regulatory factor 7; type I interferon; type III interferon