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

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 1. 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. 2. Non-lesional skin of ADEH+ patients concurrently exhibits excessive type 2 cytokine, interferon, and IL-36γ-driven epidermal inflammation. 3. 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. ### Competing Interest Statement The authors have declared no competing interest. * AD : atopic dermatitis ADEH+/- : atopic dermatitis with/without recurrent complication of eczema herpeticum DE : differential expression DEG : differentially expressed gene EASI : Eczema Area and Severity Index EDC : epidermal differentiation complex EH : eczema herpeticum FDR : false discovery rate FLG : filaggrin GSEA : gene set enrichment analysis HC : healthy control HSV : Herpes Simplex Virus LFC : log2 fold change MDS : multi-dimensional scaling NHEK : Normal human embryonic keratinocyte pDC : plasmacytoid dendritic cell pfu : plaque forming unit PBMC : peripheral blood mononuclear cell SCORAD : Scoring Atopic Dermatitis T2 : type 2 cytokine TMAP : torrent mapping alignment program VST : variance stabilized transformation WGCNA : weighted gene co-expression network analysis WTS : whole transcriptome sequencing