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Single-cell transcriptome analysis identifies skin-specific T-cell responses in systemic sclerosis
  1. Alyxzandria M Gaydosik1,
  2. Tracy Tabib1,
  3. Robyn Domsic1,
  4. Dinesh Khanna2,
  5. Robert Lafyatis1,
  6. Patrizia Fuschiotti1
  1. 1Division of Rheumatology and Clinical Immunology, Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
  2. 2Division of Rheumatology, University of Michigan Medical School, Ann Arbor, Michigan, USA
  1. Correspondence to Dr Patrizia Fuschiotti, Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA; paf23{at}pitt.edu

Abstract

Objectives Although T cells have been implicated in the pathogenesis of systemic sclerosis (SSc), a comprehensive study of T-cell-mediated immune responses in the affected skin of patients with progressive SSc is lacking. Droplet-based single-cell transcriptome analysis of SSc skin biopsies opens avenues for dissecting patient-specific T-cell heterogeneity, providing a basis for identifying novel gene expression related to functional pathways associated with severity of SSc skin disease.

Methods Single-cell RNA sequencing was performed by droplet-based sequencing (10x Genomics), focusing on 3729 CD3+ lymphocytes (867 cells from normal and 2862 cells from SSc skin samples) from skin biopsies of 27 patients with active SSc and 10 healthy donors. Confocal immunofluorescence microscopy of progressive SSc skin samples validated transcriptional results and visualised spatial localisations of T-cell subsets.

Results We identified several subsets of recirculating and tissue-resident T cells in healthy and SSc skin that were associated with distinct signalling pathways. While most clusters shared a common gene expression signature between patients and controls, we identified a unique cluster of recirculating CXCL13+ T cells in SSc skin which expressed a T helper follicular-like gene expression signature and that appears to be poised to promote B-cell responses within the inflamed skin of patients.

Conclusions Current available therapies to reverse or even slow progression of SSc lead to broad killing of immune cells and consequent toxicities, including death. Identifying the precise immune mechanism(s) driving SSc pathogenesis could lead to innovative therapies that selectively target the aberrant immune response, resulting in better efficacy and less toxicity.

  • systemic sclerosis
  • T-lymphocyte subsets
  • autoimmune diseases

Data availability statement

Data are available in a public, open access repository. All scRNA-seq data have been deposited in the Gene Expression Omnibus: GSE138669.

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Data availability statement

Data are available in a public, open access repository. All scRNA-seq data have been deposited in the Gene Expression Omnibus: GSE138669.

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Footnotes

  • Handling editor Josef S Smolen

  • Contributors AMG and TT performed experiments and data analysis; RD, DK and RL acquired samples and collected clinical descriptions; RL contributed to project development and to manuscript preparation; PF developed the project, performed experiments, analysed data and prepared the manuscript.

  • Funding This work was supported by the National Institutes of Health grant P50-AR060780 (principal investigator: RL) and by the Pittsburgh Autoimmunity Center of Excellence in Rheumatology (PACER) to PF.

  • Competing interests None declared.

  • Provenance and peer review Not commissioned; externally peer reviewed.

  • Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.

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