期刊
JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY
卷 147, 期 5, 页码 1959-+出版社
MOSBY-ELSEVIER
DOI: 10.1016/j.jaci.2020.11.022
关键词
Atopic dermatitis; natural killer cells; skin transcriptome; RNA-Sequencing; gene expression
资金
- Sanofi-Aventis Deutschland GmbH
- BIOMAP (Biomarkers in Atopic Dermatitis and Psoriasis) - Innovative Medicines Initiative 2 Joint Undertaking [821511]
- European Union's Horizon 2020 research and innovation programme
- European Federation of Pharmaceutical Industries and Associations (EFPIA)
- DFG Cluster of Excellence Precision Medicine in Inflammation'' [EXC2167]
The skin of patients with AD shows dysregulation of NK cells, which is only partially reversed despite clinical improvement under systemic therapy. This may represent a yet underappreciated disease mechanism.
Background: Altered quantities, activity, and composition of natural killer (NK) cells in blood as well as expression changes of genes involved in NK-cell function in skin lesions of patients with atopic dermatitis (AD) were recently reported. Objectives: We sought to comprehensively analyze cutaneous NK-cell transcriptomic signatures in AD, and to examine changes under treatment. Methods: We analyzed NK-cell signatures in skin transcriptome data from 57 patients with moderate to severe AD and 31 healthy controls. In addition, changes after 12 weeks of systemic treatment (dupilumab n = 21, cyclosporine n = 8) were analyzed. Deconvolution of leucocyte fractions was conducted. Immunofluorescence staining of NK cells was performed on paraffin-embedded skin sections. Results: Immunofluorescence staining revealed a relatively high abundance of both NK cells and CD3(+)CD56(+) cells in lesional as compared with nonlesional and healthy skin. Lesional and to a lesser extent nonlesional skin showed a strong upregulation of NK-cell markers together with a dysbalanced expression of inhibitory and activating receptors, which was not reverted under treatment. Digital cytometry showed a decrease in activated and an increase in resting NK cells in both lesional and nonlesional skin, which was reverted by both treatment with dupilumab and cyclosporine. The NK-cell transcriptomic signature remained upregulated after treatment, but there was a shift on the qualitative level, indicating a compositional change in NK-cell subsets toward CD56(bright) NK cells. Conclusions: Lesional AD skin shows a NK-cell dysregulation, which despite clinical improvement under systemic therapy was only partially reverted, and which may represent a yet underappreciated disease mechanism.
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