Circulating CD4+CD161+ T Lymphocytes Are Increased in Seropositive Arthralgia Patients but Decreased in Patients with Newly Diagnosed Rheumatoid Arthritis

Abstract

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. We hypothesized that CD4+CD161+ 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 rheumatoid arthritis and in newly diagnosed rheumatoid arthritis 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. Precursor Th17 lineage cells bearing CD161 were found to be increased in seropositive arthralgia patients. In contrast, circulating CD4+CD161+T-cells were decreased in newly diagnosed rheumatoid arthritis patients. The decrease in CD4+CD161+ T-cells correlated inversely with C-reactive protein and with the 66 swollen joint count. Methotrexate treatment led to normalization of CD4+CD161+ T-cells and reduced disease activity. CD4+CD161+ T cells were readily detected in synovial tissues from both early and late-stage rheumatoid arthritis. In addition, synovial fluid from late-stage disease was found to be enriched for CD4+CD161+ T-cells. Notably, synovial fluid accumulated CD4+CD161+T-cells showed skewing towards the Th1 phenotype as evidenced by increased interferon-γ expression. The changes in peripheral numbers of CD4+CD161+ T-cells in seropositive arthralgia and early rheumatoid arthritis 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.

Regulatory CD4+ T-Cell Subsets and Anti-Citrullinated Protein Antibody Repertoire: Potential Biomarkers for Arthritis Development in Seropositive Arthralgia Patients?

“…Rather, the Fr III subset tended to decrease in RA patients compared to SAP. The latter is in line with previous work from our group indicating that peripheral CD4+CD161+ T cells (Th17 lineage cells) are increased in SAP, but decreased in RA patients at disease onset with an enrichment of these cells in the joints [ 28 ]. The tendency that peripheral Fr III numbers are lower at inclusion in switched SAP compared to non-switched SAP might indicate that Th17-cells migrate to inflammatory sites in the joints, although an earlier immunohistochemical study could not detect an increase of T-cells in synovial biopsies from SAP who later developed RA compared to HC [ 29 ].…”

The Plasticity of Th17 Cells in the Pathogenesis of Rheumatoid Arthritis

“…The ratio of IFNγ+Th17 cells in memory T cells was inversely correlated to the titers of anti-CCP antibodies. It has been reported that cell populations in synovial tissues may shift inversely to those in peripheral blood in RA [ 13 ]. Thus, we speculated that IFNγ+Th17 cells are infiltrated in synovial tissue with inflammation in RA patients with high titers of ACPA with decreased peripheral ratio of IFNγ+Th17.…”

“…In addition, the levels of IL-17 in individuals before RA onset is significantly higher than that in patients after RA onset [ 12 ]. In 2013, Chalan et al reported that the number of circulating CD4+CD161+T lymphocytes are elevated in seropositive arthralgia before the onset of RA but decreased in patients with newly diagnosed RA [ 13 ]. In contrast, a regulatory variant in CC chemokine receptor 6 (CCR6, a specific marker for Th17 cells [ 14 , 15 ]) is related to RA susceptibility [ 16 ].…”

Percentages of CD4+CD161+ and CD4−CD8−CD161+ T Cells in the Synovial Fluid Are Correlated with Disease Activity in Rheumatoid Arthritis

“…Moreover, Maggi et al provided evidence that CD161 is a marker of all human IL-17-producing T cell subsets, including CD3+CD4+CD8−, CD3+CD4−CD8+, and CD3+CD4−CD8− cells [ 14 ]. It has been reported that circulating CD4+CD161+ T cells are increased in seropositive arthralgia patients but decreased in newly diagnosed RA patients [ 15 ]. Furthermore, this study showed that CD4+CD161+ T cells were enriched in synovial fluid (SF), while CD8+CD161+ T cells were not accumulated in SF of RA patients [ 15 ].…”

“…It has been reported that circulating CD4+CD161+ T cells are increased in seropositive arthralgia patients but decreased in newly diagnosed RA patients [ 15 ]. Furthermore, this study showed that CD4+CD161+ T cells were enriched in synovial fluid (SF), while CD8+CD161+ T cells were not accumulated in SF of RA patients [ 15 ]. In fact, we have previously demonstrated that RA patients seemed to have higher percentages of circulating CD161+ cells in CD4+ T cells than healthy controls, but the difference did not reach statistical significance [ 16 ].…”