Limits...
CCR6(+) Th cell populations distinguish ACPA positive from ACPA negative rheumatoid arthritis.

Paulissen SM, van Hamburg JP, Davelaar N, Vroman H, Hazes JM, de Jong PH, Lubberts E - Arthritis Res. Ther. (2015)

Bottom Line: Similar proportions of CCR4(+) and CCR10(+) Th cells were found.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.This suggests that CCR6(+) Th cells are involved in the differences in disease severity and treatment outcome between ACPA(+) and ACPA(-) RA.

View Article: PubMed Central - PubMed

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.

ABSTRACT

Introduction: 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.

Show MeSH

Related in: MedlinePlus

Differences in CCR6−CD4+ T cell subpopulations and Tregs between ACPA+ patients and matched ACPA− patients. a Gating strategy for the identification of peripheral blood Th1, Th2 and CCR4/CXCR3 DP cell subpopulations. CCR6− cells were gated on CD4+CD45RO+CD25− T cells. b Gating strategy to identify Treg (CD25hiFOXP3+) cells within the memory CD4+ T cell population. Cells were gated on the total lymphocyte population. c Proportions of the indicated CD4+ T cell subpopulations within the total memory CD4+ T cell population of 27 ACPA+ and 27 ACPA− patients with RA. For statistical analysis Wilcoxon matched-pairs signed-ranks test was performed (* = p < 0.05).
© Copyright Policy - OpenAccess
Related In: Results  -  Collection

License 1 - License 2
getmorefigures.php?uid=PMC4663738&req=5

Fig3: Differences in CCR6−CD4+ T cell subpopulations and Tregs between ACPA+ patients and matched ACPA− patients. a Gating strategy for the identification of peripheral blood Th1, Th2 and CCR4/CXCR3 DP cell subpopulations. CCR6− cells were gated on CD4+CD45RO+CD25− T cells. b Gating strategy to identify Treg (CD25hiFOXP3+) cells within the memory CD4+ T cell population. Cells were gated on the total lymphocyte population. c Proportions of the indicated CD4+ T cell subpopulations within the total memory CD4+ T cell population of 27 ACPA+ and 27 ACPA− patients with RA. For statistical analysis Wilcoxon matched-pairs signed-ranks test was performed (* = p < 0.05).

Mentions: Similar as described above, CCR6− Th cells were gated within the CD4+CD45RO+CD25− T cell population. Cells with a Th1 and Th2 profile were gated as CXCR3+CCR4− and CXCR3−CCR4+ respectively [32]. CCR4/CXCR3 DP cells were identified in the CCR6− Th cell fraction (Fig. 3a). The combination of FOXP3 and high CD25 expression by memory CD4+ T cells was used to identify T regulatory (Treg) cells (Fig. 3b). Proportions of Th1 and Th2 cells did not differ between the groups. In contrast, the CCR4/CXCR3 DP CCR6- Th cell subpopulation was higher in ACPA+ patients than in ACPA− patients (Fig. 3c). Moreover, we found a trend for larger Treg proportions in ACPA+ patients than in ACPA− patients (p = 0.06).Fig. 3


CCR6(+) Th cell populations distinguish ACPA positive from ACPA negative rheumatoid arthritis.

Paulissen SM, van Hamburg JP, Davelaar N, Vroman H, Hazes JM, de Jong PH, Lubberts E - Arthritis Res. Ther. (2015)

Differences in CCR6−CD4+ T cell subpopulations and Tregs between ACPA+ patients and matched ACPA− patients. a Gating strategy for the identification of peripheral blood Th1, Th2 and CCR4/CXCR3 DP cell subpopulations. CCR6− cells were gated on CD4+CD45RO+CD25− T cells. b Gating strategy to identify Treg (CD25hiFOXP3+) cells within the memory CD4+ T cell population. Cells were gated on the total lymphocyte population. c Proportions of the indicated CD4+ T cell subpopulations within the total memory CD4+ T cell population of 27 ACPA+ and 27 ACPA− patients with RA. For statistical analysis Wilcoxon matched-pairs signed-ranks test was performed (* = p < 0.05).
© Copyright Policy - OpenAccess
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC4663738&req=5

Fig3: Differences in CCR6−CD4+ T cell subpopulations and Tregs between ACPA+ patients and matched ACPA− patients. a Gating strategy for the identification of peripheral blood Th1, Th2 and CCR4/CXCR3 DP cell subpopulations. CCR6− cells were gated on CD4+CD45RO+CD25− T cells. b Gating strategy to identify Treg (CD25hiFOXP3+) cells within the memory CD4+ T cell population. Cells were gated on the total lymphocyte population. c Proportions of the indicated CD4+ T cell subpopulations within the total memory CD4+ T cell population of 27 ACPA+ and 27 ACPA− patients with RA. For statistical analysis Wilcoxon matched-pairs signed-ranks test was performed (* = p < 0.05).
Mentions: Similar as described above, CCR6− Th cells were gated within the CD4+CD45RO+CD25− T cell population. Cells with a Th1 and Th2 profile were gated as CXCR3+CCR4− and CXCR3−CCR4+ respectively [32]. CCR4/CXCR3 DP cells were identified in the CCR6− Th cell fraction (Fig. 3a). The combination of FOXP3 and high CD25 expression by memory CD4+ T cells was used to identify T regulatory (Treg) cells (Fig. 3b). Proportions of Th1 and Th2 cells did not differ between the groups. In contrast, the CCR4/CXCR3 DP CCR6- Th cell subpopulation was higher in ACPA+ patients than in ACPA− patients (Fig. 3c). Moreover, we found a trend for larger Treg proportions in ACPA+ patients than in ACPA− patients (p = 0.06).Fig. 3

Bottom Line: Similar proportions of CCR4(+) and CCR10(+) Th cells were found.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.This suggests that CCR6(+) Th cells are involved in the differences in disease severity and treatment outcome between ACPA(+) and ACPA(-) RA.

View Article: PubMed Central - PubMed

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.

ABSTRACT

Introduction: 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.

Show MeSH
Related in: MedlinePlus