Atopic dermatitis displays stable and dynamic skin transcriptome signatures

Lena Möbus; Elke Rodriguez; Inken Harder; Dora Stölzl; Nicole Boraczynski; Sascha Gerdes; Andreas Kleinheinz; Susanne Abraham; Annice Heratizadeh; Christiane Handrick; Eva Haufe; Thomas Werfel; Jochen Schmitt; Stephan Weidinger; TREATgermany study group

doi:10.1016/j.jaci.2020.06.012

Atopic dermatitis displays stable and dynamic skin transcriptome signatures

J Allergy Clin Immunol. 2021 Jan;147(1):213-223. doi: 10.1016/j.jaci.2020.06.012. Epub 2020 Jun 29.

Affiliations

¹ Department of Dermatology and Allergy, University Hospital Schleswig-Holstein, Campus Kiel, Kiel, Germany.
² Department of Dermatology, Elbe Medical Centre, Buxtehude, Germany.
³ University Allergy Centre, Carl Gustav Carus University Medical Centre, TU Dresden, Dresden, Germany.
⁴ Division of Immunodermatology and Allergy Research, Department of Dermatology, Allergy, and Venereology, Hannover Medical School, Hannover, Germany.
⁵ Practice for Dermatology and Venereology, Christiane Handrick, MD, Berlin, Germany.
⁶ Center for Evidence-Based Health Care, Medical Faculty Carl Gustav Carus, TU Dresden, Dresden, Germany.
⁷ Department of Dermatology and Allergy, University Hospital Schleswig-Holstein, Campus Kiel, Kiel, Germany. Electronic address: sweidinger@dermatology.uni-kiel.de.

PMID: 32615169
DOI: 10.1016/j.jaci.2020.06.012

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, T_H17 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 T_H17 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 T_H17 and natural killer cell signaling.

Keywords: Atopic dermatitis; RNA-sequencing; cyclosporine; dupilumab; gene expression; residual signatures; transcriptome; type 2 inflammation.

Publication types

Multicenter Study
Research Support, Non-U.S. Gov't

MeSH terms

Adult
Cytokines* / genetics
Cytokines* / immunology
Dermatitis, Atopic* / genetics
Dermatitis, Atopic* / immunology
Dermatitis, Atopic* / pathology
Female
Humans
Keratinocytes* / immunology
Keratinocytes* / pathology
Male
Middle Aged
Skin* / immunology
Skin* / pathology
Th17 Cells* / immunology
Th17 Cells* / pathology
Transcriptome / immunology*

Substances

Cytokines