P37 Drug reaction with eosinophilia and systemic symptoms eosinophil transcriptomes show distinct interleukin (IL)-5 and IL-3 regulation as compared with atopic dermatitis and asthma
Frederic Dezoteux, Kalum Clayton, Emily Ko, Ying Teo, Emma Corden, Rebecca Fulton, Arnaud Dendooven, Emeline Delaunay, Guillaume Lefèvre, Delphine Staumont-Sallé, Stéphane EsnaultAbstract
Introduction and aims
Eosinophils are hallmark cells of type 2 (TH2) immune responses, but their pathogenic role in skin disorders remains unclear. In atopic dermatitis (AD) and drug reaction with eosinophilia and systemic symptoms (DRESS), clinical data suggest contrasting involvement, possibly reflecting distinct endotypes. Conventional biomarkers, such as eosinophil counts, do not indicate whether these cells actively drive disease or act as bystanders. This study aimed to characterize transcriptomic programmes of circulating eosinophils in cutaneous TH2-mediated diseases to identify activation pathways and disease-specific signatures.
Methods
Fifteen adult individuals [DRESS, AD and healthy controls (HCs); n = 5 per group] were recruited. Pure populations of negatively isolated eosinophils were subjected to bulk RNA sequencing. Eosinophils stimulated with interleukin (IL)-3, IL-5 or granulocyte-macrophage colony-stimulating factor defined reference transcriptomic datasets for use in in silico deconvolution (CIBERSORT). Comparative analyses included public data from asthma and chronic obstructive pulmonary disease.
Results
HC, AD and DRESS eosinophils showed distinct transcriptomic clustering, but DRESS transcriptomes showed more heterogeneity with significantly greater Euclidian distances (P < 0.01). DRESS showed many more differentially expressed genes (DEGs) as compared with both HC and AD, and these were similar, indicating profound transcriptomic reprogramming in DRESS but AD eosinophils remain close to homeostatic states. Key upregulated DRESS DEGs included PRG2, MT1E/MT1F, GPR42 and FAM19A2. The DRESS transcriptome was shown to be significantly driven by IL-5 compared with AD (P = 0.008) and asthma (P = 0.016) and to a lesser extent IL-3 (vs. AD, P = 0.032; asthma, P = 0.01). The 351 genes underpinning deconvolution mirrored whole-transcriptome clustering. Pathway ontology analysis in DRESS showed enriched adhesion/activation pathways and downregulated migration/chemotaxis.
Conclusions
Eosinophils exhibit distinct transcriptomic programmes in cutaneous TH2 diseases, supporting these as eosinophil-driven vs. bystander conditions. DRESS represents a highly activated phenotype, contrasting with AD. These findings warrant deeper characterization of eosinophil subsets with tissue-resident spatial analysis to define their role in skin disease pathophysiology.