GSE185856
Single-cell analysis implicates Th17 to Th2 cell plasticity in the pathogenesis of palmoplantar pustulosis [RNA-Seq]
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. To investigate the immune pathways that underlie disease pathogenesis, we first undertook bulk RNA-sequencing in patient skin. We detected a pervasive and unexpected signature of T-cell activation, with a significant enrichment of Th2 pathways and evidence for a modest upregulation of Th17 genes. 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.  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. Overall design: Bulk RNA-sequencing on 3 lesional and 8 non-lesional (3 matched) PPP and 7 healthy control skin biopsies