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

Autor: McCluskey, Daniel, Benzian-Olsson, Natashia, Mahil, Satveer K., Hassi, Nina Karoliina, Wohnhaas, Christian T., Burden, A David, Griffiths, Christopher EM., Ingram, John R., 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, Wilson, Rosemary
Jazyk: angličtina
Rok vydání: 2022
Předmět:
Zdroj: 2022, ' Single-cell analysis implicates Th17 to Th2 cell plasticity in the pathogenesis of palmoplantar pustulosis ', Journal of Allergy and Clinical Immunology, vol. 150, no. 4, pp. 882-893 . https://doi.org/10.1016/j.jaci.2022.04.027
ISSN: 0091-6749
DOI: 10.1016/j.jaci.2022.04.027
Popis: Background\ud\udPalmoplantar 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.\udObjective\ud\udWe sought to investigate the immune pathways that underlie the pathogenesis of PPP.\udMethods\ud\udWe 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\udResults\ud\udBulk 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.\udConclusions\ud\udThese 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.\udClinical implications\ud\udThe simultaneous activation of Th17 and Th2 responses in PPP supports the therapeutic use of agents that inhibit multiple T-cell pathways.
Databáze: OpenAIRE
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