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Distinct stromal and immune cell interactions shape the pathogenesis of rheumatoid and psoriatic arthritis
  1. Achilleas Floudas1,2,
  2. Conor M Smith3,
  3. Orla Tynan1,2,
  4. Nuno Neto4,
  5. Vinod Krishna5,
  6. Sarah M Wade1,2,
  7. Megan Hanlon1,2,
  8. Clare Cunningham1,2,
  9. Viviana Marzaioli1,2,
  10. Mary Canavan1,2,
  11. Jean M Fletcher3,
  12. Ronan H Mullan6,
  13. Suzanne Cole5,
  14. Ling-Yang Hao5,
  15. Michael G Monaghan4,
  16. Sunil Nagpal5,
  17. Douglas J Veale2,
  18. Ursula Fearon1,2
  1. 1 Molecular Rheumatology, Clinical Medicine, Trinity Biomedical Science Institute, Dublin, Ireland
  2. 2 Eular Centre for Arthritis and Rheumatic Diseases, St Vincent's University Hospital, Univeristy College Dublin, Dublin, Ireland
  3. 3 Translational Immunology, Trinity Biomedical Sciences Institute, Trinity College Dublin, Dublin, Ireland
  4. 4 Department of Mechanical and Manufacturing Engineering, Trinity College Dublin, Dublin, Ireland
  5. 5 Immunology, Janssen Research & Development, Spring House, PA, USA
  6. 6 Department of Rheumatology, Tallaght University Hospital, Trinity College Dublin, Dublin, Ireland
  1. Correspondence to Professor Ursula Fearon, TCD, Dublin, Ireland; Fearonu{at}tcd.ie

Abstract

Objectives Immune and stromal cell communication is central in the pathogenesis of rheumatoid arthritis (RA) and psoriatic arthritis (PsA), however, the nature of these interactions in the synovial pathology of the two pathotypes can differ. Identifying immune-stromal cell crosstalk at the site of inflammation in RA and PsA is challenging. This study creates the first global transcriptomic analysis of the RA and PsA inflamed joint and investigates immune-stromal cell interactions in the pathogenesis of synovial inflammation.

Methods Single cell transcriptomic profiling of 178 000 synovial tissue cells from five patients with PsA and four patients with RA, importantly, without prior sorting of immune and stromal cells. This approach enabled the transcriptomic analysis of the intact synovial tissue and identification of immune and stromal cell interactions. State of the art data integration and annotation techniques identified and characterised 18 stromal and 14 immune cell clusters.

Results Global transcriptomic analysis of synovial cell subsets identifies actively proliferating synovial T cells and indicates that due to differential λ and κ immunoglobulin light chain usage, synovial plasma cells are potentially not derived from the local memory B cell pool. Importantly, we report distinct fibroblast and endothelial cell transcriptomes indicating abundant subpopulations in RA and PsA characterised by differential transcription factor usage. Using receptor–ligand interactions and downstream target characterisation, we identify RA-specific synovial T cell-derived transforming growth factor (TGF)-β and macrophage interleukin (IL)-1β synergy in driving the transcriptional profile of FAPα+THY1+ invasive synovial fibroblasts, expanded in RA compared with PsA. In vitro characterisation of patient with RA synovial fibroblasts showed metabolic switch to glycolysis, increased adhesion intercellular adhesion molecules 1 expression and IL-6 secretion in response to combined TGF-β and IL-1β treatment. Disrupting specific immune and stromal cell interactions offers novel opportunities for targeted therapeutic intervention in RA and PsA.

  • Autoimmunity
  • Arthritis, Rheumatoid
  • Arthritis, Psoriatic

Data availability statement

Data are available in a public, open access repository. Data are available upon reasonable request. All raw and processed files as well clinical information for each sample are deposited on national center for biotechnology information (NCBI), ascension number GSE200815 and are publically available without any restrictions of their subsequent use. Additionally, while detailed vignettes and base code is available on the bioinformatics platform GitHubgithub (as indicated in methods) for all packages used in the analysis, if specific parts of the code are needed, they will become available upon reasonable request.

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Data availability statement

Data are available in a public, open access repository. Data are available upon reasonable request. All raw and processed files as well clinical information for each sample are deposited on national center for biotechnology information (NCBI), ascension number GSE200815 and are publically available without any restrictions of their subsequent use. Additionally, while detailed vignettes and base code is available on the bioinformatics platform GitHubgithub (as indicated in methods) for all packages used in the analysis, if specific parts of the code are needed, they will become available upon reasonable request.

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Footnotes

  • DJV and UF are joint senior authors.

  • Handling editor Josef S Smolen

  • Twitter @Sarah_M_Wade, @mary_canavan, @drmgmonaghan

  • Contributors Guarantor, AF,UF, Conceptualisation, AF, UF, DJV; methodology, AF, CMS, OT; software, AF, CMS, VK; validation, AF, CMS, OT; formal analysis, AF, UF, DJV, SN, CMS, OT, NN; investigation, AF, UF, DJV; resources, UF, DJV; data curation, AF, UF, DJV, VK, MC, SN, OT, NN, MGM, VM, JMF, SC, MH, CC, SMW, L-YH; writing—original draft preparation, AF, CMS, UF, DJV; writing—review and editing, AF, CMS, OT, UF, DJV; visualisation, AF, UF, DJV, CMS, NN; supervision, UF, DJV; project administration, UF, DJV; funding acquisition, UF, DJV.

  • Funding This research was funded by Health Research Board of Ireland, grant number ILP-POR-2017–047; Centre for Arthritis and Rheumatic Diseases, CARD-2019–01; and Arthritis Ireland.

  • Competing interests None declared.

  • Patient and public involvement Patients and/or the public were not involved in the design, or conduct, or reporting, or dissemination plans of this research.

  • 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.