Human atopic dermatitis complicated by eczema herpeticum is associated with abnormalities in IFN-γ response - 11/08/11
, Pei-Song Gao, MD, PhD c, Dmitry N. Grigoryev, MD, PhD c, Nicholas M. Rafaels, MS c, Joanne E. Streib, BA a, Michael D. Howell, PhD a, Patricia A. Taylor, NP a, Mark Boguniewicz, MD a, b, Jennifer Canniff, BS b, Brian Armstrong, MPH d, Daniel J. Zaccaro, MS d, Lynda C. Schneider, MD e, Tissa R. Hata, MD f, Jon M. Hanifin, MD g, Lisa A. Beck, MD h, Adriana Weinberg, MD, PhD b, Kathleen C. Barnes, PhD c
Reprint requests: Donald Y. M. Leung, MD, PhD, National Jewish Health, 1400 Jackson St, Room K926i, Denver, CO 80206.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.
Le texte complet de cet article est disponible en PDF.Key words : Atopic dermatitis, infection, eczema herpeticum, IFNG, IFNGR1
Abbreviations used : AD, ADEH–, ADEH+, ADVN, EH, EV, HSV, IFN-γ R-/-, LD, MAF, SFC, SNP, VV
Plan
| Supported by the Clinical Translational Scientific Award from the National Center for Research Resources, UL1 RR02580, and the Atopic Dermatitis Vaccinia Network, National Institutes of Health/National Institute of Allergy and Infectious Diseases contracts N01 AI40029, N01 AI40030, and N01 AI40033. D.Y.M.L. was supported in part by NIAMS grant AR41256 and the Edelstein Family Foundation. K.C.B. was supported in part by the Mary Beryl Patch Turnbull Scholar Program. |
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| Disclosure of potential conflict of interest: M. Boguniewicz receives research support from the National Institutes of Health (NIH). L. C. Schneider receives research support from Astellas and Novartis. L. A. Beck has consultant arrangements with Regeneron and receives research support from the NIH/National Institute of Allergy and Infectious Diseases, the National Eczema Association, and Centocor, Inc. K. C. Barnes receives research support from the NIH and Sanofi-Aventis. The rest of the authors declare that they have no relevant conflicts of interest. |
Vol 127 - N° 4
P. 965 - avril 2011 Retour au numéro
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