O09 Drug reaction with eosinophilia and systemic symptoms (DRESS) eosinophil transcriptomes show distinct interleukin-5 and interleukin-3 regulation compared with atopic dermatitis and asthma

Abstract

Drug reaction with eosinophilia and systemic symptoms (DRESS) is a severe cutaneous adverse reaction characterized by eosinophilia and multiorgan involvement. Despite prominence of eosino­phils, their pathogenic role in DRESS remains unclear, limiting therapeutic innovation. In contrast, atopic dermatitis (AD), another T helper (Th) 2-driven condition, shows modest eosinophil involvement, and biologics targeting interleukin (IL)-5/IL-5 receptor have largely failed. Understanding whether eosinophils act as drivers or bystanders in different Th2 diseases is critical for guiding biologic strategies. We aimed to transcriptomically phenotype circulating eosinophils in patients with DRESS, patients with AD and healthy controls (HC) to identify activation pathways and disease-specific signatures relevant for targeted therapy. Pure eosinophil populations from 15 adults (DRESS, AD and HC; n = 5 per group) were isolated and subjected to bulk RNA sequencing. CIBERSORT deconvolution was achieved using expression data from eosinophils stimulated with IL-3, IL-5, or granulocyte–macrophage colony-stimulating factor. Comparative analyses included public data for asthma and chronic obstructive pulmonary disease. DRESS eosinophils exhibited profound transcriptomic reprogramming compared with AD and HC, with greater heterogeneity visible from principal component analysis quantified by Euclidean distance analysis of global transcriptomes (P < 0.01). Within-condition heterogeneity was comparable with across-condition measurements only for DRESS, not AD or HC. Differentially expressed genes were more numerous in DRESS than in both AD and HC, whereas AD eosinophils remained close to baseline. Key upregulated genes in DRESS included PRG2, MT1E, MT1F, GPR42 and TAFA2, which are linked to activation and inflammatory adaptation. IL-5-driven CIBERSORT-imputed subpopulations characterized asthma eosinophils, where anti-IL5 treatments are successful, but dominated in DRESS compared with asthma (P = 0.02) and AD (P = 0.008). DRESS fractions from IL-3 stimulation contributed significantly but modestly. Pathway analysis revealed enrichment of adhesion/activation and downregulation of migration/chemotaxis in DRESS. In conclusion, DRESS shows strong IL-5-related eosinophil activation, supporting the rationale for IL-5/IL-5 receptor blockade. In contrast, AD eosinophils show minimal activation, possibly explaining the limited efficacy of anti-IL-5 therapies. These results highlight the need for precision approaches targeting eosinophil subsets.