Atopic Dermatitis Is an IL-13–Dominant Disease with Greater Molecular Heterogeneity Compared to Psoriasis

Abstract

Atopic dermatitis (AD) affects up to 20% of children and adults worldwide. To gain a deeper understanding of the pathophysiology of AD, we conducted a large-scale transcriptomic study of AD with deeply sequenced RNA-sequencing samples using long (126-bp) paired-end reads. In addition to the comparisons against previous transcriptomic studies, we conducted in-depth analysis to obtain a high-resolution view of the global architecture of the AD transcriptome and contrasted it with that of psoriasis from the same cohort. By using 147 RNA samples in total, we found striking correlation between dysregulated genes in lesional psoriasis and lesional AD skin with 81% of AD dysregulated genes being shared with psoriasis. However, we described disease-specific molecular and cellular features, with AD skin showing dominance of IL-13 pathways, but with near undetectable IL-4 expression. We also demonstrated greater disease heterogeneity and larger proportion of dysregulated long noncoding RNAs in AD, and illustrated the translational impact, including skin-type classification and drug-target prediction. This study is by far the largest study comparing the AD and psoriasis transcriptomes using RNA sequencing and demonstrating the shared inflammatory components, as well as specific discordant cytokine signatures of these two skin diseases.

Review—Current Concepts in Inflammatory Skin Diseases Evolved by Transcriptome Analysis: In-Depth Analysis of Atopic Dermatitis and Psoriasis

“…On the other hand, using a small gene set consisting of IL17A, IL13, and IL36G, their classifier identified the diseases almost perfectly. This supports the presence of distinct features [187]. This finding is consistent with investigations by Kamsteeg and colleagues.…”

Shaping the diversity of Th2 cell responses in epithelial tissues and its potential for allergy treatment

“…It showed good efficacy in randomized, placebo controlled phase 3 clinical trials (SOLO 1, SOLO 2) . Also single cytokine blockade of IL‐13 resulted in improvement of atopic dermatitis . Surprisingly, IL‐13 blockade did not prove to be effective for the treatment of asthma in two large randomized, double‐blind, placebo‐controlled, phase 3 clinical trials (STRATOS 1, STRATOS 2) despite its anticipated effects on reducing eosinophilic inflammation, IgE production, macrophage and DC activation as well as airway smooth muscle remodeling.…”

The IL‐13–OVOL1–FLG axis in atopic dermatitis

“…22 Notably, more recent, large-scale transcriptomic analysis revealed the specific and dominant role of IL-13 in the lesional skin of AD, because IL-4 expression was almost undetectable. 23 Consistent with this notion, the anti-IL-13 antibody tralokinumab successfully improved AD. 24 In this review, we focus on IL-13 as the major driving force of AD development.…”