Single-cell analysis implicates T H 17-to-T H 2 cell plasticity in the pathogenesis of palmoplantar pustulosis.

Autor: McCluskey D; Department of Medical and Molecular Genetics, Faculty of Life Sciences and Medicine, King's College London, London, United Kingdom., Benzian-Olsson N; Department of Medical and Molecular Genetics, Faculty of Life Sciences and Medicine, King's College London, London, United Kingdom., Mahil SK; St John's Institute of Dermatology, Faculty of Life Sciences and Medicine, King's College London, London, United Kingdom., Hassi NK; Department of Medical and Molecular Genetics, Faculty of Life Sciences and Medicine, King's College London, London, United Kingdom., Wohnhaas CT; Boehringer Ingelheim Pharma GmbH & Co KG, Biberach, Germany., Burden AD; Institute of Infection Immunity and Inflammation, University of Glasgow, Glasgow, United Kingdom., Griffiths CEM; Dermatology Centre, Salford Royal National Health Service (NHS) Foundation Trust, National Institute for Health Research (NIHR) Manchester Biomedical Research Centre, University of Manchester, Manchester, United Kingdom., Ingram JR; Department of Dermatology, Division of Infection & Immunity, Cardiff University, Cardiff, United Kingdom., Levell NJ; Norwich Medical School, University of East Anglia, Norwich, United Kingdom., Parslew R; Department of Dermatology, Royal Liverpool Hospitals, Liverpool, United Kingdom., Pink AE; St John's Institute of Dermatology, Faculty of Life Sciences and Medicine, King's College London, London, United Kingdom., Reynolds NJ; Translational and Clinical Research Institute, Newcastle University and Department of Dermatology and NIHR Newcastle Biomedical Research Centre, Newcastle Hospitals NHS Foundation Trust, Newcastle upon Tyne, United Kingdom., Warren RB; Dermatology Centre, Salford Royal National Health Service (NHS) Foundation Trust, National Institute for Health Research (NIHR) Manchester Biomedical Research Centre, University of Manchester, Manchester, United Kingdom., Visvanathan S; Boehringer Ingelheim Pharmaceuticals, Ridgefield, Conn., Baum P; Boehringer Ingelheim Pharma GmbH & Co KG, Biberach, Germany., Barker JN; St John's Institute of Dermatology, Faculty of Life Sciences and Medicine, King's College London, London, United Kingdom., Smith CH; St John's Institute of Dermatology, Faculty of Life Sciences and Medicine, King's College London, London, United Kingdom., Capon F; Department of Medical and Molecular Genetics, Faculty of Life Sciences and Medicine, King's College London, London, United Kingdom. Electronic address: francesca.capon@kcl.ac.uk.
Jazyk: angličtina
Zdroj: The Journal of allergy and clinical immunology [J Allergy Clin Immunol] 2022 Oct; Vol. 150 (4), pp. 882-893. Date of Electronic Publication: 2022 May 12.
DOI: 10.1016/j.jaci.2022.04.027
Abstrakt: Background: Palmoplantar pustulosis (PPP) is a severe inflammatory skin disorder characterized by eruptions of painful, neutrophil-filled pustules on the palms and soles. Although PPP has a profound effect on quality of life, it remains poorly understood and notoriously difficult to treat.
Objective: We sought to investigate the immune pathways that underlie the pathogenesis of PPP.
Methods: We applied bulk and single-cell RNA sequencing (RNA-Seq) methods to the analysis of skin biopsy samples and peripheral blood mononuclear cells. We validated our results by flow cytometry and immune fluorescence microscopy RESULTS: Bulk RNA-Seq of patient skin detected an unexpected signature of T-cell activation, with a significant overexpression of several T H 2 genes typically upregulated in atopic dermatitis. To further explore these findings, we carried out single-cell RNA-Seq in peripheral blood mononuclear cells of healthy and affected individuals. Memory CD4 + T cells of PPP patients were skewed toward a T H 17 phenotype, a phenomenon that was particularly significant among cutaneous lymphocyte-associated antigen-positive skin-homing cells. We also identified a subset of memory CD4 + T cells that expressed both T H 17 (KLRB1/CD161) and T H 2 (GATA3) markers, with pseudotime analysis suggesting that the population was the result of T H 17 to T H 2 plasticity. Interestingly, the GATA3 + /CD161 + cells were overrepresented among the peripheral blood mononuclear cells of affected individuals, both in the single-cell RNA-Seq data set and in independent flow cytometry experiments. Dual-positive cells were also detected in patient skin by immune fluorescence microscopy.
Conclusions: PPP is associated with complex T-cell activation patterns and may explain why biologic drugs that target individual T helper cell populations have shown limited therapeutic efficacy.
(Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)
Databáze: MEDLINE
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