Background/Purpose: Presence of serum anti-citrullinated protein antibodies (ACPAs) in patients with rheumatoid arthritis (RA) predicts worse disease course and a more erosive disease. In the pathogenesis of RA, inflammatory T cells play a central role. In this context, we recently found increased proportions of pathogenic peripheral CCR6+ memory T helper cells in patients with early RA compared to healthy individuals. However, it is unclear how T cell proportions are distributed between ACPA+ and ACPA- patients. Therefore alterations in peripheral T cell populations and their pathogenic potential were examined in ACPA+ and ACPA- patient groups.

Methods: A nested matched case control study was performed including n=27 ACPA+ and n=27 ACPA- patients with early RA. T cell profiles (Treg, Th1, Th2, Th17, Th22 and various less well classified populations) from these ACPA+ and ACPA- patients were generated based on chemokine receptor, cytokine and transcription factor expression. Differentially present T cell populations were isolated from peripheral blood and analyzed for their pathologic potential in a co-culture system with RA derived synovial fibroblasts (RASF).

Results: In comparison to ACPA- patients, ACPA+ patients have higher proportions of regulatory T cells (Treg) and CD4+ memory CCR6+ T cells. Since the CCR6+ T cell population is still a heterogeneous population, four CCR6+ T cell subpopulations were distinguished by differential expression of CXCR3 and CCR4. All four CCR6+ subpopulations shared Th17 cell characteristics such as Rorγt and CCL20 expression, but IL-17A, IL-17F, IL-22 and IFN-γ expression differed greatly between these subpopulations. However, even the population with lowest expression of these cytokines showed high pathological potential as shown by stimulating IL-1β, IL-6, IL-8, COX-2 and MMP-3 expression upon co-culture with RASF. Indeed, despite dissimilar Th17 and Th1 characteristics between the CCR6+ subpopulations, all four showed highly increased pathological potential in co-culture compared to naive and T-helper-1 cells.

Conclusion: ACPA+ and ACPA- patients can be distinguished by the distribution of Treg and CCR6+ T helper cell subpopulations. These CCR6+ subpopulations exhibit dissimilar T-helper-17 and T-helper-1 characteristics, but all possess high pathological potential, including the population that has low IL-17A/F and IL-22 expression. These findings indicate a prominent role of CCR6+ T helper cells in the pathogenesis of ACPA+ patients with early RA and may contribute to the worse disease outcome in ACPA+ patients.