title: CCR6(+) Th cell populations distinguish ACPA positive from ACPA negative rheumatoid arthritis.
abstract: BACKGROUND
  Patients with rheumatoid arthritis (RA) can be separated into two major subpopulations based on the absence or presence of serum anti-citrullinated protein antibodies (ACPAs). The more severe disease course in ACPA(+) RA and differences in treatment outcome between these subpopulations suggest that ACPA(+) and ACPA(-) RA are different disease subsets. The identification of T-helper (Th) cells specifically recognizing citrullinated peptides, combined with the strong association between HLA-DRB1 and ACPA positivity, point toward a pathogenic role of Th cells in ACPA(+) RA. In this context we recently identified a potential pathogenic role for CCR6(+) Th cells in RA. Therefore, we examined whether Th cell population distributions differ by ACPA status.
  
  
  METHODS
  We performed a nested matched case-control study including 27 ACPA(+) and 27 ACPA(-) treatment-naive early RA patients matched for disease activity score in 44 joints, presence of rheumatoid factor, sex, age, duration of complaints and presence of erosions. CD4(+)CD45RO(+) (memory) Th cell distribution profiles from these patients were generated based on differential chemokine receptor expression and related with disease duration.
  
  
  RESULTS
  ACPA status was not related to differences in total CD4(+) T cell or memory Th cell proportions. However, ACPA(+) patients had significantly higher proportions of Th cells expressing the chemokine receptors CCR6 and CXCR3. Similar proportions of CCR4(+) and CCR10(+) Th cells were found. Within the CCR6(+) cell population, four Th subpopulations were distinguished based on differential chemokine receptor expression: Th17 (CCR4(+)CCR10(-)), Th17.1 (CXCR3(+)), Th22 (CCR4(+)CCR10(+)) and CCR4/CXCR3 double-positive (DP) cells. In particular, higher proportions of Th22 (p = 0.02), Th17.1 (p = 0.03) and CCR4/CXCR3 DP (p = 0.01) cells were present in ACPA(+) patients. In contrast, ACPA status was not associated with differences in Th1 (CCR6(-)CXCR3(+); p = 0.90), Th2 (CCR6(-)CCR4(+); p = 0.27) and T-regulatory (CD25(hi)FOXP3(+); p = 0.06) cell proportions. Interestingly, CCR6(+) Th cells were inversely correlated with disease duration in ACPA(-) patients (R(2) = -0.35; p < 0.01) but not in ACPA(+) (R(2) < 0.01; p = 0.94) patients.
  
  
  CONCLUSIONS
  These findings demonstrate that increased peripheral blood CCR6(+) Th cells proportions distinguish ACPA(+) RA from ACPA(-) RA. This suggests that CCR6(+) Th cells are involved in the differences in disease severity and treatment outcome between ACPA(+) and ACPA(-) RA.
authors.affiliation: Departments of Rheumatology and Immunology, Erasmus MC, University Medical Center, Rotterdam, P.O. Box 2040, 3000, CA, Rotterdam, The Netherlands. s.paulissen@erasmusmc.nl.
authors.forename: Sandra M J
authors.initials: SM
authors.lastname: Paulissen
authors.affiliation: Departments of Rheumatology and Immunology, Erasmus MC, University Medical Center, Rotterdam, P.O. Box 2040, 3000, CA, Rotterdam, The Netherlands. j.vanhamburg@erasmusmc.nl.
authors.forename: Jan Piet
authors.initials: JP
authors.lastname: van Hamburg
authors.affiliation: Departments of Rheumatology and Immunology, Erasmus MC, University Medical Center, Rotterdam, P.O. Box 2040, 3000, CA, Rotterdam, The Netherlands. n.davelaar@erasmusmc.nl.
authors.forename: Nadine
authors.initials: N
authors.lastname: Davelaar
authors.affiliation: Department of Pulmonary Medicine, Erasmus MC, University Medical Center, Rotterdam, The Netherlands. h.vroman@erasmusmc.nl.
authors.forename: Heleen
authors.initials: H
authors.lastname: Vroman
authors.affiliation: Department of Rheumatology, Erasmus MC, University Medical Center, Rotterdam, The Netherlands. j.hazes@erasmusmc.nl.
authors.forename: Johanna M W
authors.initials: JM
authors.lastname: Hazes
authors.affiliation: Department of Rheumatology, Erasmus MC, University Medical Center, Rotterdam, The Netherlands. p.h.p.dejong@erasmusmc.nl.
authors.forename: Pascal H P
authors.initials: PH
authors.lastname: de Jong
authors.affiliation: Departments of Rheumatology and Immunology, Erasmus MC, University Medical Center, Rotterdam, P.O. Box 2040, 3000, CA, Rotterdam, The Netherlands. e.lubberts@erasmusmc.nl.
authors.forename: Erik
authors.initials: E
authors.lastname: Lubberts
mesh_terms: D001172:Arthritis, Rheumatoid / Q000097:blood / Q000276:immunology*; D001323:Autoantibodies / Q000097:blood / Q000276:immunology*; D001324:Autoantigens / Q000276:immunology; D016022:Case-Control Studies; D002469:Cell Separation; D005260:Female; D005434:Flow Cytometry; D006801:Humans; D008297:Male; D008875:Middle Aged; D060888:Real-Time Polymerase Chain Reaction; D054399:Receptors, CCR6 / Q000276:immunology; D016176:T-Lymphocyte Subsets / Q000276:immunology*; D006377:T-Lymphocytes, Helper-Inducer / Q000276:immunology*
chemical_list: D001323:Autoantibodies; D001324:Autoantigens; C106311:CCR6 protein, human; D054399:Receptors, CCR6