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Open Access Green as soon as Postprint is submitted to ZB.
292 Role of innate immunity in molecular differentiation and mechanistic validation of endotypes of Atopic Dermatitis.
J. Invest. Dermatol. 145, S318 - S318 (2025)
Phenotypic heterogeneity in atopic dermatitis (AD) remains poorly
defined. This study advances the identification and characterization of
AD endotypes using skin transcriptomes. We analyzed transcriptomic
profiles from 765 lesional (ADL), 535 non-lesional (ADNL) and 164
healthy control (HC) skin samples. Using machine learning, we identified
and replicated 2 distinct AD endotypes defined by 108 markers and
characterized by clinical, microbial, histological and cytometric
parameters. In vitro experiments were conducted in cell and tissue
culture to explore endotype-specific pathways. We demonstrate that the
endotype-distinguishing signature is temporally stable with only a small
subset of patients switching endotypes following AD treatment. ADL
endotype 2 (ADLE2) was characterized by increased severity,
Staphylococcus aureus (SA) load, M1 macrophage, granulocyte count and
elevated expression of innate immunity genes (e.g. IL6 and IL1B)
compared to ADLE1. In 2D keratinocyte cultures we observed synergistic
gene expression changes for endotype/AD markers (CXCL3, TNFAIP6, CCL2,
CCL26) by co-stimulation of Th2 cytokines (IL4, IL13) with IL-6/IL-1β.
In 3D organotypic skin cultures, IL-6/ IL-1β addition to the Th2
cytokine cocktail aggravated epidermal hallmarks of acute AD with
spongiosis, acanthosis, terminal differentiation defects and poor skin
barrier function. SA exposure of keratinocytes upregulated IL6/IL1B,
further amplified by adding Th2 cytokines. Expression of endotype/AD
markers normalized with addition of AD drugs. In conclusion, our study
reveals distinct AD endotypes defined by presence/absence of an
inflammatory component driven by innate immunity, highlighting potential
treatment options for a subgroup of patients.
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Publication type
Article: Journal article
Document type
Meeting abstract
ISSN (print) / ISBN
0022-202X
e-ISSN
1523-1747
Quellenangaben
Volume: 145,
Issue: 12,
Pages: S318 - S318
Publisher
Elsevier
Publishing Place
New York, NY
Reviewing status
Peer reviewed
Institute(s)
Institute for Allergy Research (IAF)