Abstract
Background: Atopic dermatitis (AD) is an inflammatory disorder characterized by dominant type 2 inflammation leading to chronic pruritic skin lesions, allergic comorbidities, and Staphylococcus aureus skin colonization and infections. S aureus is thought to play a role in AD severity. Objectives: This study characterized the changes in the host-microbial interface in subjects with AD following type 2 blockade with dupilumab. Methods: Participants (n = 71) with moderate-severe AD were enrolled in a randomized (dupilumab vs placebo; 2:1), double-blind study at Atopic Dermatitis Research Network centers. Bioassays were performed at multiple time points: S aureus and virulence factor quantification, 16s ribosomal RNA microbiome, serum biomarkers, skin transcriptomic analyses, and peripheral blood T-cell phenotyping. Results: At baseline, 100% of participants were S aureus colonized on the skin surface. Dupilumab treatment resulted in significant reductions in S aureus after only 3 days (compared to placebo), which was 11 days before clinical improvement. Participants with the greatest S aureus reductions had the best clinical outcomes, and these reductions correlated with reductions in serum CCL17 and disease severity. Reductions (10-fold) in S aureus cytotoxins (day 7), perturbations in TH17-cell subsets (day 14), and increased expression of genes relevant for IL-17, neutrophil, and complement pathways (day 7) were also observed. Conclusions: Blockade of IL-4 and IL-13 signaling, very rapidly (day 3) reduces S aureus abundance in subjects with AD, and this reduction correlates with reductions in the type 2 biomarker, CCL17, and measures of AD severity (excluding itch). Immunoprofiling and/or transcriptomics suggest a role for TH17 cells, neutrophils, and complement activation as potential mechanisms to explain these findings.
Original language | English (US) |
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Pages (from-to) | 1179-1195 |
Number of pages | 17 |
Journal | Journal of Allergy and Clinical Immunology |
Volume | 152 |
Issue number | 5 |
DOIs | |
State | Published - Nov 2023 |
Keywords
- Atopic dermatitis
- IL-13
- IL-17
- IL-4
- Staphylococcus aureus
- barrier
- cytotoxins
- dupilumab
- microbiome
- type 2 immunity
ASJC Scopus subject areas
- Immunology and Allergy
- Immunology