Atopic dermatitis displays stable and dynamic skin transcriptome signatures - 09/01/21
and the
TREATgermany study group
Abstract |
Background |
Skin transcriptome studies in atopic dermatitis (AD) showed broad dysregulation as well as “improvement” under therapy. These observations were mainly made in trials and based on microarray data.
Objectives |
Our aim was to explore the skin transcriptome and the impact of systemic treatment in patients of the TREATgermany registry.
Methods |
Biopsy specimens from 59 patients with moderate-to-severe AD before and 30 patients 12 weeks after start of systemic treatment (dupilumab [n = 22] or cyclosporine [n = 8]) and from 31 healthy controls were subjected to mRNA sequencing. Differential expression, pathway enrichment, correlation, and coexpression network analysis were conducted.
Results |
Both lesional and nonlesional skin showed a stable “core” signature characterized by disturbed epidermal differentiation and activation of IL-31/IL-1 signaling. A second dynamic signature showed progressive enrichment for type 2 inflammation, TH17 signaling, and natural killer cell function. Markers correlated with disease activity have functions in epidermal barrier properties and immune modulation. IL4RA was among the top 3 central dysregulated genes. Cyclosporine led to a more pronounced global transcriptome reversion and normalized TH17 cell/IL23 signaling, whereas dupilumab led to a stronger increase in level of epidermal differentiation markers. Both treatments strongly decreased levels of type 2 markers, but overall the residual profile was still profoundly different from that of healthy skin. Lower levels of IL4RA and IL13 and high IL36A expression were related to a stronger clinical response to dupilumab.
Conclusion |
The AD core signature is characterized by dysregulation of genes related to keratinocyte differentiation and itch signaling. A dynamic signature reflects progressive immune responses dominated by type 2 cytokines with an additional role of TH17 and natural killer cell signaling.
Il testo completo di questo articolo è disponibile in PDF.Key words : Atopic dermatitis, transcriptome, RNA-sequencing, gene expression, dupilumab, cyclosporine, type 2 inflammation, residual signatures
Abbreviations used : AL, AN, NN, DEG, EASI, FDR, LFC, NK, oSCORAD, POEM, RNA-Seq
Mappa
| TREATgermany is financially supported by Sanofi-Aventis Deutschland GmbH. This work also received support through BIOMAP (Biomarkers in Atopic Dermatitis and Psoriasis), a project funded by the Innovative Medicines Initiative 2 Joint Undertaking under grant agreement no. 821511. The joint undertaking receives support from the European Union's Horizon 2020 research and innovation programme and the European Federation of Pharmaceutical Industries and Associations (EFPIA). Infrastructure support was provided through the German Research Council (DFG) cluster of excellence Precision Medicine in Inflammation (grant EXC2167). |
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| Disclosure of potential conflict of interest: S. Abraham received lecture and/or consultancy fees from Novartis, LEO Pharma, Lilly, Sanofi, Beiersdorf, and AbbVie. E. Haufe is an employee at the Centre for Evidence-Based Health Care at TU Dresden, which received institutional support for self-designed scientific studies from ALK, Novartis, Pfizer, and Sanofi. A. Heratizadeh received lecture and/or consultancy fees from LEO Pharma, Novartis, Pierre Fabre, Sanofi, Beiersdorf, Hans Karrer, Nutricia, and Meda. S. Gerdes has been an advisor and/or received speakers’ honoraria and/or received grants and/or participated in clinical trials of the following companies: Abbott/AbbVie, Affibody AB, Akari Therapeutics Plc, Almirall-Hermal, Amgen, Anaptys Bio, Baxalta, Bayer Health Care, Biogen Idec, Bioskin, Boehringer-Ingelheim, Celgene, Centocor, Dermira, Eli Lilly, Foamix, Forward Pharma, Galderma, Hexal AG, Incyte Inc, Isotechnika, Janssen-Cilag, Johnson & Johnson, Kymab, Leo Pharma, Medac, Merck Serono, Mitsubishi Tanabe, MSD, Novartis, Pfizer, Polichem SA, Regeneron Pharmaceutical, Sandoz Biopharmaceuticals, Sanofi-Aventis, Schering-Plough, Sienna Biopharmaceuticals, Takeda, Teva, UCB Pharma, VBL Therapeutics, and Wyeth Pharma. T. Werfel is coprincipal investigator of the German Atopic Eczema Registry TREATgermany; has received institutional research grants from LEO Pharma and Novartis; performed consultancies for AbbVie, Janssen, Galderma, LEO, Sanofi-Genzyme, and Novartis; has also lectured at educational events sponsored by AbbVie, Janssen, Celgene, Galderma, LEO Pharma, Sanofi, and Novartis; and is involved in performing clinical trials for various pharmaceutical enterprises that manufacture drugs used for the treatment of and atopic dermatitis. S. Weidinger is coprincipal investigator of the German Atopic Eczema Registry TREATgermany; has received institutional research grants from Sanofi Deutschland GmbH, Leo Pharma, and La Roche Posay; has performed consultancies for Sanofi-Genzyme, Regeneron, LEO Pharma, AbbVie, Pfizer, Eli Lilly, Kymab, and Novartis; has also lectured at educational events sponsored by Sanofi-Genzyme, Regeneron, LEO Pharma, AbbVie, Novartis, and Galderma; and is involved in performing clinical trials with many pharmaceutical enterprises that manufacture drugs used for the treatment of psoriasis and atopic eczema. The rest of the authors declare that they have no relevant conflicts of interest. |
Vol 147 - N° 1
P. 213-223 - Gennaio 2021 Ritorno al numero
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