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.

FIG 1

IFNγ production is decreased in PBMC from ADEH+ as compared to ADEH− and NA human subjects. Panel A) shows IFNγ SFC after mock (left panel) or HSV stimulation (right panel) ex vivo. Panel B) shows IFNγ protein measurements in culture supernatants of HSV stimulated PBMC. PBMC from each subject group were stimulated for six days with mock or HSV antigens, then culture supernatants removed and analyzed for IFNγ secretion by ELISA. Datapoints represent the difference between IFNγ secretion in HSV vs mock stimulated PBMCs for each subject; P-values reflect adjusted (ANCOVA derived) comparisons. Horizontal lines represent median values.

FIG 2

Disseminated viral skin infection in IFNγ receptor KO mice after inoculation with vaccinia virus (VV). Clinical appearance of satellite lesions are shown after epicutaneous inoculation of C57 Bl/6 control mice (Panel A) and IFNRγ−/− mice (Panel B) with VV. Panel C demonstrates that the mean number of satellite lesions was significantly greater in IFNRγ−/− mice than control mice. Panel D shows data points of relative vaccinia gene expression (measured by real time PCR) was significantly greater at all timepoints in IFNRγ−/− mice than control mice.

FIG 3

Summary of genetic associations for six IFNGR1 SNPs. Panel A) the −log₁₀-transformed P-values for IFNGR1 SNPs and ADEH+ and ADEH−. The dashed gray line represents a P value of 0.05. The thick line represents a 2-SNP haplotype. Panel B) Gene structure and pattern of LD (D') in European American healthy controls, with red to green reflecting higher to lower D' values. Seven exons (color in blue) in IFNGR1 were presented (upper panel).*Functional SNPs.

FIG 4

Association of IFNG and IFNGR1SNPs with IFNγ production as determined by the log₁₀-transformed mean SFC/10⁶ cells. IFNG SNPs rs2069727 CC genotype and rs2430561 AA were significantly associated with reduced IFNγ production (P = 0.01[CC vs CT+TT] and P = 0.003 [AA vs AT+TT], respectively, Panel A and Panel B). IFNGR1SNP rs7749390 GG genotype was significantly associated with increased IFNγ production (P = 0.03 [GG vs GA+AA]), Panel C). ns: not significant.

FIG 5

Overview of Impaired Interferon Response Leading to Atopic Dermatitis Complicated by Eczema Herpeticum