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

McCluskey, Daniel, Benzian-Olsson, Natashia, Mahil, Satveer K., Hassi, Nina Karoliina, Wohnhaas, Christian T., Burden, A David, Griffiths, Christopher EM., Ingram, John R. ORCID: https://orcid.org/0000-0002-5257-1142, Levell, Nick J., Parslew, Richard, Pink, Andrew E., Reynolds, Nick J., Warren, Richard B., Visvanathan, Sudha, Baum, Patrick, Barker, Jonathan N., Smith, Catherine H., Capon, Francesca, Baudry, David, Cornelius, Victoria, Lachmann, Helen, McAteer, Helen, Meynell, Freya, Patel, Prakash, Pushparajah, Angela and Wilson, Rosemary 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. 10.1016/j.jaci.2022.04.027

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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:	Article
Date Type:	Publication
Status:	Published
Schools:	Medicine
Publisher:	Elsevier
ISSN:	0091-6749
Date of First Compliant Deposit:	21 May 2022
Date of Acceptance:	20 April 2022
Last Modified:	24 May 2023 13:39
URI:	https://orca.cardiff.ac.uk/id/eprint/149924

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