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Circulating CD4+CD161+ T lymphocytes are increased in seropositive arthralgia patients but decreased in patients with newly diagnosed rheumatoid arthritis.

Chalan P, Kroesen BJ, van der Geest KS, Huitema MG, Abdulahad WH, Bijzet J, Brouwer E, Boots AM - PLoS ONE (2013)

Bottom Line: Precursor Th17 lineage cells bearing CD161 were found to be increased in seropositive arthralgia patients.The decrease in CD4+CD161+ T-cells correlated inversely with C-reactive protein and with the 66 swollen joint count.In addition, synovial fluid from late-stage disease was found to be enriched for CD4+CD161+ T-cells.

View Article: PubMed Central - PubMed

Affiliation: Department of Rheumatology and Clinical Immunology, University Medical Center Groningen, Groningen, The Netherlands ; Groningen research initiative on healthy ageing and immune longevity (GRAIL), Groningen, The Netherlands.

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.

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Circulating CD4+CD161+ T-cells normalize following MTX treatment.(A) DAS28 and (B) the absolute number of CD4+CD161+ T-cells from RA patients at baseline (newly diagnosed; n=30), after 3 months (n=22) and 6 months (n=7) of MTX treatment (GEE analysis); (C) Comparison of the absolute number of CD4+CD161+ T-cells between HC (n=20) and RA patients at baseline (n=30; Mann- Whitney test) or RA patients at baseline (n=30) and RA patients after 3 months (n=26) or 6 months (n=12) of MTX treatment (Wilcoxon matched pairs test). Horizontal line in the box represents the median value. Boxes represent interquartile ranges and whiskers represent the actual range. Statistical significance is indicated as * p ≤ 0.05, ** p ≤ 0.001.
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pone-0079370-g002: Circulating CD4+CD161+ T-cells normalize following MTX treatment.(A) DAS28 and (B) the absolute number of CD4+CD161+ T-cells from RA patients at baseline (newly diagnosed; n=30), after 3 months (n=22) and 6 months (n=7) of MTX treatment (GEE analysis); (C) Comparison of the absolute number of CD4+CD161+ T-cells between HC (n=20) and RA patients at baseline (n=30; Mann- Whitney test) or RA patients at baseline (n=30) and RA patients after 3 months (n=26) or 6 months (n=12) of MTX treatment (Wilcoxon matched pairs test). Horizontal line in the box represents the median value. Boxes represent interquartile ranges and whiskers represent the actual range. Statistical significance is indicated as * p ≤ 0.05, ** p ≤ 0.001.

Mentions: Newly diagnosed RA patients were assessed at baseline (before start of MTX treatment) and at 3 and 6 months after start of treatment for absolute numbers of circulating CD4+CD161+ T-cells and for clinical parameters of disease activity. MTX treatment significantly reduced CRP and Disease Activity Score (DAS)28, but not ESR, at 3 and 6 months when compared to baseline (Table 1). Importantly, the reduction in CRP and DAS28 was associated with an increase in the absolute number of circulating CD4+CD161+ T-cells (Figure 2A, B). Notably, the numbers of PB CD4+CD161+ T-cells increased to the level observed in healthy subjects at 3 and 6 months (Figure 2 C). The data merit further study into the utility of circulating CD4+CD161+ T-cells as a potential biomarker of synovitis in RA.


Circulating CD4+CD161+ T lymphocytes are increased in seropositive arthralgia patients but decreased in patients with newly diagnosed rheumatoid arthritis.

Chalan P, Kroesen BJ, van der Geest KS, Huitema MG, Abdulahad WH, Bijzet J, Brouwer E, Boots AM - PLoS ONE (2013)

Circulating CD4+CD161+ T-cells normalize following MTX treatment.(A) DAS28 and (B) the absolute number of CD4+CD161+ T-cells from RA patients at baseline (newly diagnosed; n=30), after 3 months (n=22) and 6 months (n=7) of MTX treatment (GEE analysis); (C) Comparison of the absolute number of CD4+CD161+ T-cells between HC (n=20) and RA patients at baseline (n=30; Mann- Whitney test) or RA patients at baseline (n=30) and RA patients after 3 months (n=26) or 6 months (n=12) of MTX treatment (Wilcoxon matched pairs test). Horizontal line in the box represents the median value. Boxes represent interquartile ranges and whiskers represent the actual range. Statistical significance is indicated as * p ≤ 0.05, ** p ≤ 0.001.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3815125&req=5

pone-0079370-g002: Circulating CD4+CD161+ T-cells normalize following MTX treatment.(A) DAS28 and (B) the absolute number of CD4+CD161+ T-cells from RA patients at baseline (newly diagnosed; n=30), after 3 months (n=22) and 6 months (n=7) of MTX treatment (GEE analysis); (C) Comparison of the absolute number of CD4+CD161+ T-cells between HC (n=20) and RA patients at baseline (n=30; Mann- Whitney test) or RA patients at baseline (n=30) and RA patients after 3 months (n=26) or 6 months (n=12) of MTX treatment (Wilcoxon matched pairs test). Horizontal line in the box represents the median value. Boxes represent interquartile ranges and whiskers represent the actual range. Statistical significance is indicated as * p ≤ 0.05, ** p ≤ 0.001.
Mentions: Newly diagnosed RA patients were assessed at baseline (before start of MTX treatment) and at 3 and 6 months after start of treatment for absolute numbers of circulating CD4+CD161+ T-cells and for clinical parameters of disease activity. MTX treatment significantly reduced CRP and Disease Activity Score (DAS)28, but not ESR, at 3 and 6 months when compared to baseline (Table 1). Importantly, the reduction in CRP and DAS28 was associated with an increase in the absolute number of circulating CD4+CD161+ T-cells (Figure 2A, B). Notably, the numbers of PB CD4+CD161+ T-cells increased to the level observed in healthy subjects at 3 and 6 months (Figure 2 C). The data merit further study into the utility of circulating CD4+CD161+ T-cells as a potential biomarker of synovitis in RA.

Bottom Line: Precursor Th17 lineage cells bearing CD161 were found to be increased in seropositive arthralgia patients.The decrease in CD4+CD161+ T-cells correlated inversely with C-reactive protein and with the 66 swollen joint count.In addition, synovial fluid from late-stage disease was found to be enriched for CD4+CD161+ T-cells.

View Article: PubMed Central - PubMed

Affiliation: Department of Rheumatology and Clinical Immunology, University Medical Center Groningen, Groningen, The Netherlands ; Groningen research initiative on healthy ageing and immune longevity (GRAIL), Groningen, The Netherlands.

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.

Show MeSH
Related in: MedlinePlus