Atopic dermatitis complicated by recurrent eczema herpeticum is characterized by multiple, concurrent epidermal inflammatory endotypes

Abstract

Background: A subgroup of atopic dermatitis (AD) patients suffer from recurrent, disseminated herpes simplex virus (HSV) skin infections, termed eczema herpeticum (EH), which can be life-threatening and contribute to AD morbidity. The pathobiology underlying ADEH is unknown.

Objective: To determine transcriptional mechanisms of skin and immune system pathobiology that underlie ADEH disease.

Methods: We performed whole transcriptome RNA-sequencing of non-lesional skin samples (epidermis, dermis) of AD patients with (ADEH ⁺ , n=15) and without (ADEH ^- , n=13) recurrent EH history, and healthy controls (HC, n=15). We also performed RNA-sequencing on plasmacytoid dendritic cells (pDCs) collected from these participants and infected in vitro with HSV-1. Differential expression, gene set enrichment, and endotyping analyses were performed.

Results: ADEH ⁺ disease was characterized by dysregulation in skin gene expression, which was limited in dermis (differentially expressed genes [DEGs]=14) and widespread in epidermis (DEGs=129). ADEH ⁺ -upregulated epidermal DEGs were enriched in type 2 cytokine (T2) ( IL4R, CCL22, CRLF2, IL7R ), interferon ( CXCL10, ICAM1, IFI44 , and IRF7) , and IL-36γ ( IL36G ) inflammatory pathway genes. At a person-level, all ADEH ⁺ participants exhibited T2 and interferon endotypes and 87% were IL36G-high. In contrast, these endotypes were more variably expressed among ADEH ^- participants. ADEH ⁺ patient skin also exhibited dysregulation in epidermal differentiation complex (EDC) genes within the LCE, S100 , and SPRR families, which are involved in skin barrier function, inflammation, and antimicrobial activities. pDC transcriptional responses to HSV-1 infection were not altered by ADEH status.

Conclusions: ADEH ⁺ pathobiology is characterized by a unique, multi-faceted epidermal inflammation that accompanies dysregulation in the expression of EDC genes.

Key messages: AD patients with a history of recurrent EH exhibit molecular skin pathobiology that is similar in form, but more severe in degree, than in AD patients without this complication. Non-lesional skin of ADEH ⁺ patients concurrently exhibits excessive type 2 cytokine, interferon, and IL-36γ-driven epidermal inflammation. Expression of these inflammatory skin endotypes among ADEH ⁺ patients is associated with dysregulation in expression of epidermal differentiation complex genes involved in barrier function, inflammation, and antimicrobial activity.

Capsule summary: AD patients with a history of recurrent disseminated HSV-1 skin infections form a unique molecular skin endotype group that concurrently exhibits type 2 cytokine, interferon, and IL-36γ-driven skin inflammation, accompanied by dysregulation in expression of epidermal differentiation complex genes involved in barrier function, inflammation, and antimicrobial activity.