Identification of novel gene signatures in patients with atopic dermatitis complicated by eczema herpeticum

Abstract

Background A subset of patients with atopic dermatitis (AD) is prone to disseminated herpes simplex virus (HSV) infection, i.e. eczema herpeticum (ADEH+). Biomarkers that identify ADEH+ are lacking. Objective To search for novel ADEH+ gene signatures in peripheral blood mononuclear cells (PBMCs). Methods A RNA-sequencing (RNA-seq) approach was applied to evaluate global transcriptional changes using PBMCs from ADEH+ and AD without a history of EH (ADEH−). Candidate genes were confirmed by qPCR or ELISA. RESULTS ADEH+ PBMCs had distinct changes to the transcriptome when compared to ADEH− PBMCs following HSV-1 stimulation: 792 genes were differentially expressed at a false discovery rate (FDR) < 0.05 (ANOVA), and 15 type I and type III interferon (IFN) genes were among the top 20 most down-regulated genes in ADEH+. We further validated that IFN-α and IL-29 mRNA and protein levels were significantly decreased in HSV-1 stimulated PBMCs from ADEH+ compared to ADEH− and normal. Ingenuity pathway analysis (IPA) demonstrated that the up-stream regulators of type I and type III IFNs, IRF3 and IRF7, was significantly inhibited in ADEH+ based on the down-regulation of their target genes. Furthermore, we found that gene expression of IRF3 and IRF7 were significantly decreased in HSV-1 stimulated PBMC from ADEH+ subjects. CONCLUSIONS PBMCs from ADEH+ have a distinct immune response following HSV-1 exposure compared to ADEH−. Inhibition of the IRF3 and IRF7 innate immune pathways in ADEH+ may be important mechanism for increased susceptibility to disseminated viral infection.

Bacterial and Viral Infections in Atopic Dermatitis: a Comprehensive Review

“…Recent genetic data from ADRN indicate that defects in IFN type I, II, and III and their receptors may be involved in the pathogenesis of EH. Of note, IFN type I and III defects likely reside in the innate immune cells or antigenpresenting cells [66]. These studies may provide a rationale for the replacement of these cytokines to protect AD patients who are at a higher risk of developing EH.…”

“…However, the sample size for the African American patients was small in that study; a larger cohort will therefore be needed for replication of these results. More recent global transcriptomic analysis using the next-generation RNA sequencing (RNA-seq) technology showed that type I IFN-α4 and IFN-α5 gene transcripts were significantly downregulated in AD patients with a history of EH [66]. These findings were confirmed by quantitative PCR as well as at the protein level.…”

Advances in allergic skin disease, anaphylaxis, and hypersensitivity reactions to foods, drugs, and insects in 2014

“…During the past year, a series of publications have advanced our understanding of the role of abnormalities in innate and adaptive immune responses in patients with AD. [106][107][108][109][110][111] A polarized IL-13/IL-22 immune response is emerging as of critical importance in patients with AD. 112 This is supported by the observation that dupilumab, a humanized mAb that blocks the action of IL-4 and IL-13, can improve the skin severity of AD and the molecular signature of the inflammatory skin response in the majority of patients.…”

“…113 In the subset of patients with AD prone to eczema herpeticum, by using RNA sequencing, it has been found that these patients have a defective interferon response. 107 …”

Wyjaśnienie złożoności atopowego zapalenia skóry: Zmiana paradygmatu sposobów terapii

“…W celu określenia nowych podpisów genetycznych Bin i wsp. [122] zastosowali sekwencjonowanie RNA do oceny globalnych zmian transkrypcyjnych w PBMC u chorych z ADEH+ i z atopowym zapaleniem skóry bez wyprysku opryszczkowego w wywiadzie. Wykazali, że PBMC od chorych z ADEH+ stymulowane wirusem opryszczki zwykłej typu 1 wykazywały niedostateczną odpowiedź immunologiczną przeciwwirusową, obejmującą wrodzone szlaki immunologiczne związane z czynnikiem regulacyjnym interferonu 3 i 7.…”