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. 2022 Oct;150(4):882-893.
doi: 10.1016/j.jaci.2022.04.027. Epub 2022 May 12.

Single-cell analysis implicates TH17-to-TH2 cell plasticity in the pathogenesis of palmoplantar pustulosis

Daniel McCluskey  1 , Natashia Benzian-Olsson  1 , Satveer K Mahil  2 , Niina Karoliina Hassi  1 , Christian T Wohnhaas  3 ; APRICOT and PLUM study team; A David Burden  4 , Christopher E M Griffiths  5 , John R Ingram  6 , Nick J Levell  7 , Richard Parslew  8 , Andrew E Pink  2 , Nick J Reynolds  9 , Richard B Warren  5 , Sudha Visvanathan  10 , Patrick Baum  3 , Jonathan N Barker  2 , Catherine H Smith  2 , Francesca Capon  11
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Free article

Single-cell analysis implicates TH17-to-TH2 cell plasticity in the pathogenesis of palmoplantar pustulosis

Daniel McCluskey et al. J Allergy Clin Immunol. 2022 Oct.
Free article

Abstract

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 TH2 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 TH17 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 TH17 (KLRB1/CD161) and TH2 (GATA3) markers, with pseudotime analysis suggesting that the population was the result of TH17 to TH2 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.

Keywords: PPP; Single-cell RNA sequencing; T-cell plasticity; palmoplantar pustulosis; scRNA-Seq.

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