The STAT6 Gene Increases Propensity of Atopic Dermatitis Patients Toward Disseminated Viral Skin Infections

Background— Atopic dermatitis is a chronic inflammatory skin disease associated with increased susceptibility to recurrent skin infections. Objective— To determine why a subset of atopic dermatitis patients have an increased risk of developing disseminated viral skin infections. Methods— Human subjects with atopic dermatitis with a history of eczema herpeticum and various control groups were enrolled. Vaccinia virus expression was measured by PCR and immunofluorescent staining in skin biopsies from each study group after incubation with vaccinia virus. Transgenic mice with a constitutively active STAT6 gene were characterized for response to vaccinia virus skin inoculation. Genotyping for ten STAT6 single nucleotide polymorphisms (SNP) was performed in a European American sample (n=444). Results— Vaccinia virus gene and protein expression were significantly increased in the skin of eczema herpeticum subjects, as compared to other subject groups, following incubation with vaccinia virus in vitro . Antibody neutralization of IL-4 and IL-13 resulted in lower vaccinia virus replication in subjects with a history of eczema herpeticum. Mice that expressed a constitutively active STAT6 , compared to wild type mice, had increased mortality and satellite lesion formation following vaccinia virus skin inoculation. Significant associations were observed between STAT6 SNPs and eczema herpeticum (rs3024975, rs841718, rs167769, and rs703817) and IFN γ production. The strongest association was observed for a 2-SNP (CT) haplotype (ADEH+ vs ADEH − , 24.9% vs 9.2% P = 5.17×10 − 6 ). Conclusion— The STAT6 gene increases viral replication in the skin of atopic dermatitis patients with a history of eczema herpeticum. Further genetic association studies and functional investigations are warranted. in a multicenter case-control study. Although the mechanisms remain unclear, our findings suggest that STAT6 SNPs may be involved in the regulation of IFN γ production and also serve as important genetic markers in determining those AD patients with greater susceptibility to develop disseminated VV infection following smallpox vaccination. This is the first study to implicate STAT6 as a potential candidate gene for ADEH. However, replication in an independent population with sufficient sample size, evidence of association between STAT6 SNPs and skin IL-4 and IL-13 expression, and evidence of functional relevance to disease, are clearly needed in the future studies. Additionally, given that FLG in our previous studies have been shown to have a significant impact on ADEH, further analysis on an interaction between FLG and STAT6 is essential. Taken together, our data suggest that the STAT6 gene increases viral replication in the skin of atopic dermatitis patients with a history of eczema herpeticum. Further genetic association studies and functional investigations are warranted.