Human atopic dermatitis complicated by eczema herpeticum is associated with abnormalities in IFN-gamma response.

Authors: Leung, DY  Gao, PS  Grigoryev, DN  Rafaels, NM  Streib, JE  Howell, MD  Taylor, PA  Boguniewicz, M  Canniff, J  Armstrong, B  Zaccaro, DJ  Schneider, LC  Hata, TR  Hanifin, JM  Beck, LA  Weinberg, A  Barnes, KC 
Citation: Leung DY, etal., J Allergy Clin Immunol. 2011 Apr;127(4):965-73.e1-5.
Pubmed: (View Article at PubMed) PMID:21458658
DOI: Full-text: DOI:10.1016/j.jaci.2011.02.010

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-gamma and IFN-gamma receptor gene expression. IFN-gamma 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-gamma 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-gamma 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-gamma 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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CRRD Object Information
CRRD ID: 6480259
Created: 2012-03-20
Species: All species
Last Modified: 2012-03-20
Status: ACTIVE



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RGD is funded by grant HL64541 from the National Heart, Lung, and Blood Institute on behalf of the NIH.