The signal transducer and activator of transcription 6 gene (STAT6) increases the propensity of patients with atopic dermatitis toward disseminated viral skin infections

Michael D. Howell, Peisong Gao, Byung Eui Kim, Leighann J. Lesley, Joanne E. Streib, Patricia A. Taylor, Daniel J. Zaccaro, Mark Boguniewicz, Lisa A. Beck, Jon Hanifin, Lynda C. Schneider, Tissa R. Hata, Richard L. Gallo, Mark H. Kaplan, Kathleen C. Barnes, Donald Y M Leung

Research output: Contribution to journalArticle

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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). Conclusion: 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.

Original languageEnglish (US)
Pages (from-to)1006-1014
Number of pages9
JournalJournal of Allergy and Clinical Immunology
Volume128
Issue number5
DOIs
StatePublished - Nov 2011

Fingerprint

Kaposi Varicelliform Eruption
STAT6 Transcription Factor
Vaccinia virus
Virus Diseases
Atopic Dermatitis
Skin
Genes
Single Nucleotide Polymorphism
Interleukin-13
Viral Genes
Genetic Association Studies
Virus Replication
Skin Diseases
Interleukin-4
Haplotypes
Transgenic Mice
Staining and Labeling
Biopsy
Gene Expression
Polymerase Chain Reaction

Keywords

  • Atopic dermatitis
  • eczema
  • infection
  • STAT6
  • virus

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

Cite this

The signal transducer and activator of transcription 6 gene (STAT6) increases the propensity of patients with atopic dermatitis toward disseminated viral skin infections. / Howell, Michael D.; Gao, Peisong; Kim, Byung Eui; Lesley, Leighann J.; Streib, Joanne E.; Taylor, Patricia A.; Zaccaro, Daniel J.; Boguniewicz, Mark; Beck, Lisa A.; Hanifin, Jon; Schneider, Lynda C.; Hata, Tissa R.; Gallo, Richard L.; Kaplan, Mark H.; Barnes, Kathleen C.; Leung, Donald Y M.

In: Journal of Allergy and Clinical Immunology, Vol. 128, No. 5, 11.2011, p. 1006-1014.

Research output: Contribution to journalArticle

Howell, MD, Gao, P, Kim, BE, Lesley, LJ, Streib, JE, Taylor, PA, Zaccaro, DJ, Boguniewicz, M, Beck, LA, Hanifin, J, Schneider, LC, Hata, TR, Gallo, RL, Kaplan, MH, Barnes, KC & Leung, DYM 2011, 'The signal transducer and activator of transcription 6 gene (STAT6) increases the propensity of patients with atopic dermatitis toward disseminated viral skin infections', Journal of Allergy and Clinical Immunology, vol. 128, no. 5, pp. 1006-1014. https://doi.org/10.1016/j.jaci.2011.06.003
Howell, Michael D. ; Gao, Peisong ; Kim, Byung Eui ; Lesley, Leighann J. ; Streib, Joanne E. ; Taylor, Patricia A. ; Zaccaro, Daniel J. ; Boguniewicz, Mark ; Beck, Lisa A. ; Hanifin, Jon ; Schneider, Lynda C. ; Hata, Tissa R. ; Gallo, Richard L. ; Kaplan, Mark H. ; Barnes, Kathleen C. ; Leung, Donald Y M. / The signal transducer and activator of transcription 6 gene (STAT6) increases the propensity of patients with atopic dermatitis toward disseminated viral skin infections. In: Journal of Allergy and Clinical Immunology. 2011 ; Vol. 128, No. 5. pp. 1006-1014.
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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). Conclusion: 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.",
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AU - Gao, Peisong

AU - Kim, Byung Eui

AU - Lesley, Leighann J.

AU - Streib, Joanne E.

AU - Taylor, Patricia A.

AU - Zaccaro, Daniel J.

AU - Boguniewicz, Mark

AU - Beck, Lisa A.

AU - Hanifin, Jon

AU - Schneider, Lynda C.

AU - Hata, Tissa R.

AU - Gallo, Richard L.

AU - Kaplan, Mark H.

AU - Barnes, Kathleen C.

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