title: Inflamed target tissue provides a specific niche for highly expanded T-cell clones in early human autoimmune disease.
abstract: OBJECTIVE
  To profile quantitatively the T-cell repertoire in multiple joints and peripheral blood of patients with recent onset (early) or established rheumatoid arthritis (RA) using a novel next-generation sequencing protocol to identify potential autoreactive clones.
  
  
  METHODS
  Synovium of patients with recent onset (early) RA (<6 months) (n=6) or established RA (>18 months) (n=6) was screened for T-cell clones by sequencing over 10 000 T-cell receptors (TCR) per sample. T cells from paired blood samples were analysed for comparison. From two patients synovial T cells were obtained from multiple inflamed joints. The degree of expansion of each individual clone was based on its unique CDR3 sequence frequency within a sample. Clones with a frequency of over 0.5% were considered to be highly expanded clones (HEC).
  
  
  RESULTS
  In early RA synovium, the T-cell repertoire was dominated by 35 HEC (median, range 2-70) accounting for 56% of the TCR sequenced. The clonal dominance in the synovium was patient specific and significantly greater than in established RA (median of 11 HEC (range 5-24) in established RA synovium accounting for 9.8% of T cells; p<0.01). 34% (range 28-40%) of the most expanded T-cell clones were shared between different joints in the same patients, compared with only 4% (range 0-8%) between synovium and blood (p=0.01).
  
  
  CONCLUSIONS
  In RA, a systemic autoimmune disease, the inflamed synovium forms a niche for specific expanded T-cell clones, especially in early disease. This suggests that, at least in RA, autoreactive T cells should be addressed specifically in the inflamed tissue, preferably in the early phase of the disease.
authors.affiliation: Department of Clinical Immunology and Rheumatology, Academic Medical Center/ University of Amsterdam, Amsterdam, The Netherlands.
authors.forename: P L
authors.initials: PL
authors.lastname: Klarenbeek
authors.forename: M J H
authors.initials: MJ
authors.lastname: de Hair
authors.forename: M E
authors.initials: ME
authors.lastname: Doorenspleet
authors.forename: B D C
authors.initials: BD
authors.lastname: van Schaik
authors.forename: R E E
authors.initials: RE
authors.lastname: Esveldt
authors.forename: M G H
authors.initials: MG
authors.lastname: van de Sande
authors.forename: T
authors.initials: T
authors.lastname: Cantaert
authors.forename: D M
authors.initials: DM
authors.lastname: Gerlag
authors.forename: D
authors.initials: D
authors.lastname: Baeten
authors.forename: A H C
authors.initials: AH
authors.lastname: van Kampen
authors.forename: F
authors.initials: F
authors.lastname: Baas
authors.forename: P P
authors.initials: PP
authors.lastname: Tak
authors.forename: N
authors.initials: N
authors.lastname: de Vries
mesh_terms: D001172:Arthritis, Rheumatoid / Q000276:immunology* / Q000473:pathology*; D015551:Autoimmunity / Q000276:immunology*; D001706:Biopsy; D060833:Cellular Microenvironment / Q000276:immunology; D002999:Clone Cells / Q000166:cytology / Q000276:immunology; D018450:Disease Progression; D006801:Humans; D013583:Synovial Membrane / Q000276:immunology / Q000473:pathology; D013601:T-Lymphocytes / Q000166:cytology* / Q000276:immunology*