title: The signal transducer and activator of transcription 6 gene (STAT6) increases the propensity of patients with atopic dermatitis toward disseminated viral skin infections.
abstract: BACKGROUND
  Atopic dermatitis (AD) is a chronic inflammatory skin disease associated with increased susceptibility to recurrent skin infections.
  
  
  OBJECTIVE
  We sought to determine why a subset of patients with AD have an increased risk of disseminated viral skin infections.
  
  
  METHODS
  Human subjects with AD with a history of eczema herpeticum (EH) and various control groups were enrolled. Vaccinia virus (VV) expression was measured by means of PCR and immunofluorescent staining in skin biopsy specimens from each study group after incubation with VV. Transgenic mice with a constitutively active signal transducer and activator of transcription 6 gene (STAT6) were characterized for response to VV skin inoculation. Genotyping for 10 STAT6 single nucleotide polymorphisms (SNPs) was performed in a white patient sample (n = 444).
  
  
  RESULTS
  VV gene and protein expression were significantly increased in the skin of patients with EH compared with other subject groups after incubation with VV in vitro. Antibody neutralization of IL-4 and IL-13 resulted in lower VV replication in patients with a history of EH. Mice that expressed a constitutively active STAT6 gene compared with wild-type mice had increased mortality and satellite lesion formation after VV skin inoculation. Significant associations were observed between STAT6 SNPs and EH (rs3024975, rs841718, rs167769, and rs703817) and IFN-γ production. The strongest association was observed for a 2-SNP haplotype (patients with AD with a history of EH vs patients with AD without a history of EH, 24.9% vs 9.2%; P = 5.17 × 10(-6)).
  
  
  CONCLUSIONS
  The STAT6 gene increases viral replication in the skin of patients with AD with a history of EH. Further genetic association studies and functional investigations are warranted.
authors.affiliation: Department of Pediatrics, National Jewish Health, Denver, Colo 80206, USA.
authors.forename: Michael D
authors.initials: MD
authors.lastname: Howell
authors.forename: Peisong
authors.initials: P
authors.lastname: Gao
authors.forename: Byung Eui
authors.initials: BE
authors.lastname: Kim
authors.forename: Leighann J
authors.initials: LJ
authors.lastname: Lesley
authors.forename: Joanne E
authors.initials: JE
authors.lastname: Streib
authors.forename: Patricia A
authors.initials: PA
authors.lastname: Taylor
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Zaccaro
authors.forename: Mark
authors.initials: M
authors.lastname: Boguniewicz
authors.forename: Lisa A
authors.initials: LA
authors.lastname: Beck
authors.forename: Jon M
authors.initials: JM
authors.lastname: Hanifin
authors.forename: Lynda C
authors.initials: LC
authors.lastname: Schneider
authors.forename: Tissa R
authors.initials: TR
authors.lastname: Hata
authors.forename: Richard L
authors.initials: RL
authors.lastname: Gallo
authors.forename: Mark H
authors.initials: MH
authors.lastname: Kaplan
authors.forename: Kathleen C
authors.initials: KC
authors.lastname: Barnes
authors.forename: Donald Y M
authors.initials: DY
authors.lastname: Leung
mesh_terms: D000328:Adult; D000818:Animals; D003876:Dermatitis, Atopic / Q000150:complications* / Q000235:genetics* / Q000821:virology; D005455:Fluorescent Antibody Technique; D020022:Genetic Predisposition to Disease / Q000235:genetics; D006801:Humans; D007617:Kaposi Varicelliform Eruption / Q000150:complications* / Q000235:genetics* / Q000821:virology; D051379:Mice; D008822:Mice, Transgenic; D020641:Polymorphism, Single Nucleotide; D050800:STAT6 Transcription Factor / Q000235:genetics*; D017193:Skin Diseases, Viral / Q000150:complications* / Q000235:genetics; D012900:Smallpox Vaccine / Q000009:adverse effects; D014615:Vaccinia / Q000150:complications / Q000235:genetics; D014616:Vaccinia virus
chemical_list: D050800:STAT6 Transcription Factor; C494101:STAT6 protein, human; D012900:Smallpox Vaccine