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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.

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Inverse correlation between proportions of CCR6+CD4+ T cell subpopulations and disease duration in ACPA− patients. Correlation of the percentage of CCR6+CD4+ cells (as percentage of total memory CD4+ T cells) with self-reported disease duration in ACPA+ and ACPA− patients with RA. Pearson correlation test was used to calculate the correlation coefficients (R2) and p-values.
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Fig4: Inverse correlation between proportions of CCR6+CD4+ T cell subpopulations and disease duration in ACPA− patients. Correlation of the percentage of CCR6+CD4+ cells (as percentage of total memory CD4+ T cells) with self-reported disease duration in ACPA+ and ACPA− patients with RA. Pearson correlation test was used to calculate the correlation coefficients (R2) and p-values.

Mentions: ACPA+ and ACPA− patients with RA have a similar clinical presentation in the very early phase of disease [40], but ACPA+ RA is associated with a more severe disease course and erosions [8–13, 41]. Therefore, we investigated whether the differing CCR6+ Th cell, CCR6− Th cell and Treg proportions between ACPA+ and ACPA− patients were associated with patient-reported disease duration. Disease duration was not associated with CCR6+ Th cell proportions in ACPA+ patients, whereas it was significantly inversely correlated with CCR6+ Th cell proportions in ACPA− patients (Fig. 4). Additionally, disease duration was significantly positively correlated with CCR6− Th cell proportions in ACPA−, but not in ACPA+ patients (Table 2). In contrast, neither in ACPA+ nor in ACPA− patients disease duration was associated with Treg proportion. Further analysis of the CCR6+ Th cell compartment in ACPA− patients showed that Th17 cells and CCR4/CXCR3 DP CCR6+ Th cells had a significant inverse correlation with the disease duration. Within the CCR6− Th cell subpopulations, no significant correlations were found (Table 2). In addition, we found a small but significant inverse correlation between the disease duration with the DAS in all patients together (R2 = −0.07, p < 0.05), but not in ACPA+ patients only (R2 = −0.13, p = 0.06) and ACPA− patients only (R2 = −0.04, p = 0.31).Fig. 4


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)

Inverse correlation between proportions of CCR6+CD4+ T cell subpopulations and disease duration in ACPA− patients. Correlation of the percentage of CCR6+CD4+ cells (as percentage of total memory CD4+ T cells) with self-reported disease duration in ACPA+ and ACPA− patients with RA. Pearson correlation test was used to calculate the correlation coefficients (R2) and p-values.
© Copyright Policy - OpenAccess
Related In: Results  -  Collection

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

Fig4: Inverse correlation between proportions of CCR6+CD4+ T cell subpopulations and disease duration in ACPA− patients. Correlation of the percentage of CCR6+CD4+ cells (as percentage of total memory CD4+ T cells) with self-reported disease duration in ACPA+ and ACPA− patients with RA. Pearson correlation test was used to calculate the correlation coefficients (R2) and p-values.
Mentions: ACPA+ and ACPA− patients with RA have a similar clinical presentation in the very early phase of disease [40], but ACPA+ RA is associated with a more severe disease course and erosions [8–13, 41]. Therefore, we investigated whether the differing CCR6+ Th cell, CCR6− Th cell and Treg proportions between ACPA+ and ACPA− patients were associated with patient-reported disease duration. Disease duration was not associated with CCR6+ Th cell proportions in ACPA+ patients, whereas it was significantly inversely correlated with CCR6+ Th cell proportions in ACPA− patients (Fig. 4). Additionally, disease duration was significantly positively correlated with CCR6− Th cell proportions in ACPA−, but not in ACPA+ patients (Table 2). In contrast, neither in ACPA+ nor in ACPA− patients disease duration was associated with Treg proportion. Further analysis of the CCR6+ Th cell compartment in ACPA− patients showed that Th17 cells and CCR4/CXCR3 DP CCR6+ Th cells had a significant inverse correlation with the disease duration. Within the CCR6− Th cell subpopulations, no significant correlations were found (Table 2). In addition, we found a small but significant inverse correlation between the disease duration with the DAS in all patients together (R2 = −0.07, p < 0.05), but not in ACPA+ patients only (R2 = −0.13, p = 0.06) and ACPA− patients only (R2 = −0.04, p = 0.31).Fig. 4

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