title: A circulating reservoir of pathogenic-like CD4+ T cells shares a genetic and phenotypic signature with the inflamed synovial micro-environment.
abstract: OBJECTIVE
  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.
authors.affiliation: Translational Research Unit, Sanford-Burnham Medical Research Institute, San Diego, California, USA SingHealth Translational Immunology and Inflammation Centre, Singhealth and Duke-NUS Graduate Medical School, Singapore, Singapore.
authors.forename: Roberto
authors.initials: R
authors.lastname: Spreafico
authors.affiliation: Translational Research Unit, Sanford-Burnham Medical Research Institute, San Diego, California, USA SingHealth Translational Immunology and Inflammation Centre, Singhealth and Duke-NUS Graduate Medical School, Singapore, Singapore.
authors.forename: Maura
authors.identifier: http://orcid.org/0000-0003-3347-6200
authors.initials: M
authors.lastname: Rossetti
authors.affiliation: Translational Research Unit, Sanford-Burnham Medical Research Institute, San Diego, California, USA.
authors.forename: Jorg
authors.initials: J
authors.lastname: van Loosdregt
authors.affiliation: Seattle Children's Hospital and Research Institute, Seattle, Washington, USA.
authors.forename: Carol A
authors.initials: CA
authors.lastname: Wallace
authors.affiliation: Lab Biotecnologie, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy.
authors.forename: Margherita
authors.initials: M
authors.lastname: Massa
authors.affiliation: Pediatric Rheumatology Unit, IRCCS Ospedale Pediatrico Bambino Gesù, Rome, Italy.
authors.forename: Silvia
authors.initials: S
authors.lastname: Magni-Manzoni
authors.affiliation: Second Pediatrics Division, University of Genoa and G Gaslini Institute, Genova, Italy.
authors.forename: Marco
authors.initials: M
authors.lastname: Gattorno
authors.affiliation: Second Pediatrics Division, University of Genoa and G Gaslini Institute, Genova, Italy.
authors.forename: Alberto
authors.initials: A
authors.lastname: Martini
authors.affiliation: Division of Rheumatology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, Ohio, USA.
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Lovell
authors.affiliation: Translational Research Unit, Sanford-Burnham Medical Research Institute, San Diego, California, USA SingHealth Translational Immunology and Inflammation Centre, Singhealth and Duke-NUS Graduate Medical School, Singapore, Singapore.
authors.forename: Salvatore
authors.initials: S
authors.lastname: Albani
mesh_terms: D001171:Arthritis, Juvenile / Q000097:blood / Q000276:immunology* / Q000473:pathology; D001172:Arthritis, Rheumatoid / Q000097:blood / Q000276:immunology; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D005434:Flow Cytometry; D019674:Genes, T-Cell Receptor beta / Q000276:immunology*; D006801:Humans; D016130:Immunophenotyping; D013583:Synovial Membrane / Q000276:immunology* / Q000473:pathology
keywords: Autoimmunity; Juvenile Idiopathic Arthritis; Rheumatoid Arthritis; Synovial fluid; T Cells