Background/Purpose: Improved understanding of the immune events discriminating between seropositive arthralgia and clinical synovitis is of key importance in rheumatology research. Ample evidence suggests a role for Th17 cells in rheumatoid arthritis (RA). We hypothesized that CD4+CD161+ T-cells representing Th17 lineage cells may be modulated prior to or after development of clinical synovitis. Therefore, in a cross-sectional study, we investigated the occurrence of CD4+CD161+ T-cells in seropositive arthralgia patients who are at risk for developing RA and in newly diagnosed RA patients. In a prospective study, we evaluated the effect of methotrexate treatment on circulating CD4+CD161+ T-cells. Next, we assessed if these cells can be detected at the level of the RA joints.

Methods: Whole blood from healthy controls (n=20), ACPA and/or RF seropositive arthralgia patients (n=26) and newly diagnosed, DMARD-free RA patients (n=35), was analyzed by flow-cytometry using anti-CD4, -CD8, -CD45RO, -CCR7, -CD161 fluorochrome-conjugated antibodies. Next, CD4+CD161+ T-cells were prospectively assessed in 26 and 12 RA patients at 3 and 6 months after MTX treatment, respectively. Paired samples (peripheral blood and synovial fluid, n=11) and enzyme-digested synovial tissue cells (n=4) from late-stage RA patients were analyzed for the same markers. T-cell cytokine production potency (IL-17, IFNγ and TNFα) was assessed in peripheral blood mononuclear cells and in synovial fluid mononuclear cells.

Results: Precursor Th17 lineage cells were found to be increased in seropositive arthralgia patients. In contrast, circulating CD161+CD4+ T-cells were decreased in newly diagnosed RA patients. The decrease in CD4+CD161+ T-cells correlated inversely with C-reactive protein (r = -0,43 and p = 0.02) and with the swollen joint count 66 (r = -0,41 and p = 0.03).  Methotrexate treatment led to normalization of CD4+CD161+ T-cells and reduced disease activity. CD4+CD161+ T cells were readily detected in synovial tissue from both early and late stage rheumatoid arthritis. In addition, synovial fluid was found to be enriched for CD4+CD161+ T-cells compared to blood. Late stage synovial fluid CD4+CD161+ T-cells showed skewing towards the Th1 phenotype as evidenced by increased IFN-γ expression.

Conclusion: The changes in peripheral numbers of CD4+CD161+ T-cells in seropositive arthralgia and early RA and the enrichment of these cells at the level of the joint predict a role for CD4+CD161+ T-cells in the early immune events leading to clinical synovitis. Our findings may add to the development of RA prediction models and provide opportunities for early intervention.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/circulating-cd4cd161-t-lymphocytes-are-increased-in-seropositive-arthralgia-patients-but-decreased-in-patients-with-newly-diagnosed-rheumatoid-arthritis/