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A circulating reservoir of pathogenic-like CD4+ T cells shares a genetic and phenotypic signature with the inflamed synovial micro-environment
  1. Roberto Spreafico1,2,
  2. Maura Rossetti1,2,
  3. Jorg van Loosdregt1,
  4. Carol A Wallace3,
  5. Margherita Massa4,
  6. Silvia Magni-Manzoni5,
  7. Marco Gattorno6,
  8. Alberto Martini6,
  9. Daniel J Lovell7,8,
  10. Salvatore Albani1,2
  1. 1Translational Research Unit, Sanford-Burnham Medical Research Institute, San Diego, California, USA
  2. 2SingHealth Translational Immunology and Inflammation Centre, Singhealth and Duke-NUS Graduate Medical School, Singapore, Singapore
  3. 3Seattle Children's Hospital and Research Institute, Seattle, Washington, USA
  4. 4Lab Biotecnologie, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy
  5. 5Pediatric Rheumatology Unit, IRCCS Ospedale Pediatrico Bambino Gesù, Rome, Italy
  6. 6Second Pediatrics Division, University of Genoa and G Gaslini Institute, Genova, Italy
  7. 7Division of Rheumatology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA
  8. 8Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, Ohio, USA
  1. Correspondence to Dr Roberto Spreafico, SingHealth Translational Immunology and Inflammation Centre, The Academia, 20 College Road, Discovery Tower Level 8, Singapore 169856, Singapore; roberto.spreafico{at}gmail.com

Abstract

Objectives Systemic immunological processes are profoundly shaped by the micro-environments where antigen recognition occurs. Identifying molecular signatures distinctive of such processes is pivotal to understand pathogenic immune responses and manipulate them for therapeutic purposes. Unfortunately, direct investigation of peripheral tissues, enriched in pathogenic T cells, is often impossible or imposingly invasive in humans. Conversely, blood is easily accessible, but pathogenic signatures are diluted systemically as a result of the strict compartmentalisation of immune responses. In this work, we aimed at defining immune mediators shared between the bloodstream and the synovial micro-environment, and relevant for disease activity in autoimmune arthritis.

Methods CD4+ T cells from blood and synovium of patients with juvenile idiopathic arthritis (JIA) were immunophenotyped by flow cytometry. The TCR repertoire of a circulating subset showing similarity with the synovium was analysed through next-generation sequencing of TCR β-chain CDR3 to confirm enrichment in synovial clonotypes. Finally, clinical relevance was established by monitoring the size of this subset in the blood of patients with JIA and rheumatoid arthritis (RA).

Results We identified a small subset of circulating CD4+ T cells replicating the phenotypical signature of lymphocytes infiltrating the inflamed synovium. These circulating pathogenic-like lymphocytes (CPLs) were enriched in synovial clonotypes and they exhibited strong production of pro-inflammatory cytokines. Importantly, CPLs were expanded in patients with JIA, who did not respond to therapy, and also correlated with disease activity in patients with RA.

Conclusions CPLs provide an accessible reservoir of pathogenic cells recirculating into the bloodstream and correlating with disease activity, to be exploited for diagnostic and research purposes.

  • Autoimmunity
  • Juvenile Idiopathic Arthritis
  • Rheumatoid Arthritis
  • Synovial fluid
  • T Cells

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