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

Abstract

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. © 2010 American Academy of Allergy, Asthma & Immunology.