Expression profiling of atopic dermatitis patients with a history of recurrent eczema herpeticum reveals dysregulation of type 2‐inflammation and barrier‐related pathways in uninvolved skin: 372

Abstract

Nathan T. Dyjack, BS, Elena Goleva, PhD, Cydney Rios, MS, Michael T. Montgomery, BS, Brittany N. Richers, BS, Kathryn A. Norquest, MS, Donald Y. M. Leung, MD, PhD, FAAAAI, and Max A. Seibold, PhD; National Jewish Health, Denver, CO. RATIONALE: A subgroup of atopic dermatitis patients exhibit increased susceptibility to episodes of eczema herpeticum (ADEH). We sought to characterize the molecular pathology of ADEH disease in non-lesional skin through whole transcriptome analysis. METHODS: Non-lesional skin biopsies were collected from non-atopic controls (NA, n513) and AD patients with (ADEH, n515) and without (ADEH, n513) a history of recurrent EH episodes. Biopsies were separated into dermal and epidermal layers followed by RNA extraction and whole transcriptome sequencing. Differential expression analyses were performed on the combined set of epidermal and dermal data. RESULTS: Differential expression of ADEH vs. NA subjects yielded 174 differentially expressed genes (DEGs). Amongst the DEGs upregulated in ADEH individuals were several biomarkers of type 2 inflammation (CCL17, CCL22, TSLP receptor sub-units IL7R and CRLF2), innate immunity (5 S100-type genes) and barrier function (3 LCE3 and 2 SPRR2). Principle component analysis (PCA) of these samples using the 174 DEGs yielded an inflammatory summary metric (PC2, 8% of variance explained) that was increased in ADEH compared to NA subjects, but highest in the ADEH group. This group trend in the ADEH summary metric was also observed in both the dermal and epidermal datasets when analyzed separately. We found 543 DEGs when comparing expression between ADEH vs (NA and ADEH) groups. Among these were novel upregulated genes such as gasdermin C (GSDMC) and TRIM15, and genes characteristic of increased interferon signaling. CONCLUSIONS: ADEH+ subjects represent a more severe AD endotypic group characterized by higher type 2 inflammation, interferon signaling, and barrier defects in uninvolved skin.