Background and objectives Patients with rheumatoid arthritis (RA) positive for serum anti-citrullinated protein antibodies (ACPAs) have a worse disease course than ACPA- patients. Association of ACPA and HLA-DRB1 suggests the involvement of T cells in ACPA+ RA. Therefore we examined possible differences in memory CD4+ T (Th) cell distribution between ACPA+ and ACPA- patients and their functional relevance.
Materials and methods Th cell distribution profiles from ACPA+ and ACPA- patients with early RA were generated based on chemokine receptor, cytokine and transcription factor expression. On the basis of CXCR3 and CCR4 expression, four CCR6+ subpopulations were distinguished: Th17, Th17.1, CCR4/CXCR3 double positive (DP) and double negative (DN) cells. These Th cell populations were analysed for their pathological potential.
Results ACPA+ patients had higher proportions of peripheral CCR6+ Th cells, notably Th22, Th17.1 and DP cells. All CCR6+ subpopulations were also present in RA synovial fluid. These subpopulations shared Th17 characteristics including RORC and CD161 expression. However, expression of IL-17A, IL-17F, IFNg and the Th1-associated transcription factor TBX21 differed markedly between CCR6+ subpopulations. Nevertheless, all CCR6+ Th cell subpopulations showed higher pathological activity than naive and Th1 cells, as they were more effective in stimulating IL-1β, IL-6, IL-8, COX-2 and MMP-3 expression by synovial fibroblasts. Interestingly, CCR6+ Th populations are inverse correlated with disease duration in ACPA- patients but not in ACPA+ patients.
Conclusions ACPA+ and ACPA- patients can be distinguished by differences in pathogenic memory CCR6+ Th cell proportions, suggesting that these cells are involved in the worse disease course observed in ACPA+ RA.