Single-cell analysis implicates Th17 to Th2 cell plasticity in the pathogenesis of palmoplantar pustulosis

McCluskey, D. et al. (2022) Single-cell analysis implicates Th17 to Th2 cell plasticity in the pathogenesis of palmoplantar pustulosis. Journal of Allergy and Clinical Immunology, 150(4), pp. 882-893. (doi: 10.1016/j.jaci.2022.04.027) (PMID:35568077)

[img] Text
271931.pdf - Published Version
Available under License Creative Commons Attribution.

3MB

Abstract

Background: Palmoplantar pustulosis (PPP) is a severe inflammatory skin disorder, characterised by eruptions of painful, neutrophil-filled pustules on the palms and soles. While 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 methods to the analysis of skin biopsies and peripheral blood mononuclear cells. We validated our results by flow cytometry and immune fluorescence microscopy Results: Bulk RNA-sequencing of patient skin detected an unexpected signature of T-cell activation, with a significant overexpression of several Th2 genes typically upregulated in atopic dermatitis. To further explore these findings, we carried out single-cell RNA-sequencing in peripheral blood mononuclear cells of healthy and affected individuals. We found that the memory CD4+T-cells of PPP patients were skewed towards a Th17 phenotype, a phenomenon that was particularly significant among CLA+ skin-homing cells. We also identified a subset of memory CD4+ T-cells which expressed both Th17 (KLRB1/CD161) and Th2 (GATA3) markers, with pseudo-time analysis suggesting that the population was the result of Th17 to Th2 plasticity. Interestingly, the GATA3+/CD161+ cells were over-represented among the PBMCs of affected individuals, both in the scRNA-seq dataset and in independent flow-cytometry experiments. Dual positive cells were also detected in patient skin by means of immune fluorescence microscopy. Conclusions: These observations demonstrate that PPP is associated with complex T-cell activation patterns and may explain why biologics that target individual T-helper populations have shown limited therapeutic efficacy. Clinical implications: The simultaneous activation of Th17 and Th2 responses in PPP supports the therapeutic use of agents that inhibit multiple T-cell pathways.

Item Type:Articles
Keywords:PPP, palmoplantar pustulosis, T-cell plasticity, Single-cell RNA-sequencing, scRNA-seq
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Burden, Professor David
Authors: McCluskey, D., Benzian-Olsson, N., Mahil, S. K., Hassi, N. K., Wohnhaas, C. T., Burden, A. D., Griffiths, C. E., Ingram, J. R., Levell, N. J., Parslew, R., Pink, A. E., Reynolds, N. J., Warren, R. B., Visvanathan, S., Baum, P., Barker, J. N., Smith, C. H., and Capon, F.
College/School:College of Medical Veterinary and Life Sciences > School of Infection & Immunity
Journal Name:Journal of Allergy and Clinical Immunology
Publisher:Elsevier
ISSN:0091-6749
ISSN (Online):1097-6825
Published Online:12 May 2022
Copyright Holders:Copyright © 2022 The Authors
First Published:First published in Journal of Allergy and Clinical Immunology 150(4): 882-893
Publisher Policy:Reproduced under a Creative Commons License

University Staff: Request a correction | Enlighten Editors: Update this record