Single-cell analysis implicates TH17-to-TH2 cell plasticity in the pathogenesis of palmoplantar pustulosis - 04/10/22
APRICOT and PLUM study team∗
A. David Burden, MD d, Christopher E.M. Griffiths, MD e, John R. Ingram, MD f, Nick J. Levell, MD g, Richard Parslew, MD h, Andrew E. Pink, MD b, Nick J. Reynolds, MD i, Richard B. Warren, PhD e, Sudha Visvanathan, PhD j, Patrick Baum, PhD c, Jonathan N. Barker, MD b, Catherine H. Smith, MD b, Francesca Capon, PhD a, ⁎
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.
Le texte complet de cet article est disponible en PDF.Graphical abstract |
Key words : Single-cell RNA sequencing, scRNA-Seq, T-cell plasticity, palmoplantar pustulosis, PPP
Abbreviations used : CLA, FDR, HC, NL, PBMC, PPP, RNA-Seq, scRNA-Seq, UMAP
Plan
| The bulk and single-cell RNA sequencing data we report here have been uploaded to the publicly accessible Gene Expression Omnibus repository (www.ncbi.nlm.nih.gov/geo; series accession no. GSE185858). |
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| Support was received from the Department of Health via the NIHR BioResource Clinical Research Facility and comprehensive Biomedical Research Centre awards to Guy’s and St Thomas’ NHS Foundation Trust in partnership with King’s College London and King’s College Hospital NHS Foundation Trust (guysbrc-2012-1). Support was also received from the Newcastle NIHR Biomedical Research Centre. The APRICOT trial was funded by the Efficacy and Mechanism Evaluation (EME) Programme, a UK Medical Research Council (M.R.C.) and NIHR partnership (grant EME 13/50/17 to C.H.S., F.C., J.N.B., A.D.B., R.B.W., N.J.R., and C.E.M.G.). This work was also supported by the European Academy of Dermatology and Venereology (grant PPRC-2018-25 to F.C. and J.N.B.) and the Psoriasis Association (grant BSTOP50/5 to C.H.S.). D.Mc. is supported by the Medical Research Council (MRC; grant MR/R015643/1) and King’s College London as member of the MRC Doctoral Training Partnership in Biomedical Sciences. N.B.O. was funded by a NIHR predoctoral fellowship (grant NIHR300473). S.K.M. is funded by an MRC Clinical Academic Research Partnership award (MR/T02383X/1). C.E.M.G. is funded in part by the NIHR Manchester Biomedical Research Centre and is an NIHR emeritus senior investigator. N.J.R. is an NIHR senior investigator. He acknowledges support from the Newcastle MRC/EPSRC Molecular Pathology Node and the Newcastle NIHR Medtech and In Vitro Diagnostic Co-operative. R.B.W. is supported by the Manchester NIHR Biomedical Research Centre. The views expressed in this publication are those of the authors and not necessarily those of the MRC, NHS, NIHR, or the Department of Health. |
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| Disclosure of potential conflict of interest: F. Capon and J. N. Barker have received funding from Boehringer-Ingelheim. C. T. Wohnhaas, P. Baum and S. Visvanathan are Boehringer-Ingelheim employees. J. R. Ingram is editor in chief of the British Journal of Dermatology and receives an author honorarium from UpToDate. He is a consultant for UCB Pharma, Novartis, Boehringer Ingelheim, and ChemoCentryx and participated in advisory boards for Kymera Therapeutics and Viela Bio, all in the field of hidradenitis suppurativa. He is a co-copyright holder of the HiSQOL and Patient Global Assessment instruments for hidradenitis suppurativa. R. B. Warren has received research grant and/or consultancy fees from AbbVie, Almirall, Amgen, Arena, Astellas, Avillion, Biogen, Boehringer Ingelheim, Bristol Myers Squibb, Celgene, DiCE, GSK, Janssen, Lilly, Leo, Medac, Novartis, Pfizer, Sanofi, Sun Pharma, UCB, and UNION. The rest of the authors declare that they have no relevant conflicts of interest. |
Vol 150 - N° 4
P. 882-893 - octobre 2022 Retour au numéro
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