title: CD4⁺CD25⁺/highCD127low/⁻ regulatory T cells are enriched in rheumatoid arthritis and osteoarthritis joints--analysis of frequency and phenotype in synovial membrane, synovial fluid and peripheral blood.
abstract: BACKGROUND
  CD4⁺CD25⁺/highCD127low/⁻ regulatory T cells (Tregs) play a crucial role in maintaining peripheral tolerance. Data about the frequency of Tregs in rheumatoid arthritis (RA) are contradictory and based on the analysis of peripheral blood (PB) and synovial fluid (SF). Because Tregs exert their anti-inflammatory activity in a contact-dependent manner, the analysis of synovial membrane (SM) is crucial. Published reports regarding this matter are lacking, so we investigated the distribution and phenotype of Tregs in concurrent samples of SM, SF and PB of RA patients in comparison to those of osteoarthritis (OA) patients.
  
  
  METHODS
  Treg frequency in a total of 40 patients (18 RA and 22 OA) matched for age and sex was assessed by flow cytometry. Functional status was assessed by analysis of cell surface markers representative of activation, memory and regulation.
  
  
  RESULTS
  CD4⁺ T cells infiltrate the SM to higher frequencies in RA joints than in OA joints (P = 0.0336). In both groups, Tregs accumulate more within the SF and SM than concurrently in PB (P < 0.0001). Relative Treg frequencies were comparable in all compartments of RA and OA, but Treg concentration was significantly higher in the SM of RA patients (P = 0.025). Both PB and SM Tregs displayed a memory phenotype (CD45RO⁺RA⁻), but significantly differed in activation status (CD69 and CD62L) and markers associated with Treg function (CD152, CD154, CD274, CD279 and GITR) with only minor differences between RA and OA.
  
  
  CONCLUSIONS
  Treg enrichment into the joint compartment is not specific to inflammatory arthritis, as we found that it was similarly enriched in OA. RA pathophysiology might not be due to a Treg deficiency, because Treg concentration in SM was significantly higher in RA. Synovial Tregs represent a distinct phenotype and are activated effector memory cells (CD62L⁻CD69⁺), whereas peripheral Tregs are resting central memory cells (CD62L⁺CD69⁻).
authors.forename: Babak
authors.initials: B
authors.lastname: Moradi
authors.forename: Philipp
authors.initials: P
authors.lastname: Schnatzer
authors.forename: Sébastien
authors.initials: S
authors.lastname: Hagmann
authors.forename: Nils
authors.initials: N
authors.lastname: Rosshirt
authors.forename: Tobias
authors.initials: T
authors.lastname: Gotterbarm
authors.forename: Jan Philippe
authors.initials: JP
authors.lastname: Kretzer
authors.forename: Marc
authors.initials: M
authors.lastname: Thomsen
authors.forename: Hanns-Martin
authors.initials: HM
authors.lastname: Lorenz
authors.forename: Felix
authors.initials: F
authors.lastname: Zeifang
authors.forename: Theresa
authors.initials: T
authors.lastname: Tretter
mesh_terms: D000368:Aged; D001172:Arthritis, Rheumatoid / Q000097:blood / Q000276:immunology*; D005260:Female; D005434:Flow Cytometry; D006801:Humans; D007719:Knee Joint / Q000276:immunology*; D008297:Male; D008875:Middle Aged; D010003:Osteoarthritis / Q000097:blood / Q000276:immunology*; D010641:Phenotype; D013582:Synovial Fluid / Q000276:immunology; D013583:Synovial Membrane / Q000276:immunology; D050378:T-Lymphocytes, Regulatory / Q000276:immunology*
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