Journal
ARTHRITIS & RHEUMATOLOGY
Volume 66, Issue 7, Pages 1955-1960Publisher
WILEY
DOI: 10.1002/art.38647
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Funding
- Nuffield Oliver Bird Programme
- Arthritis Research UK
- Great Ormond Street Hospital Children's Charity and Arthritis Research UK [20164]
- Wellcome Trust [097259]
- Great Ormond Street Hospital Childrens Charity [V1304] Funding Source: researchfish
- Versus Arthritis [19761] Funding Source: researchfish
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Objective. Granulocyte-macrophage colony stimulating factor (GM-CSF) is a potent inflammatory mediator that is responsible for recruitment and activation of innate immune cells. Recent data from murine studies have identified Th17 cells as a key source of GM-CSF and suggest that T cell-derived GM-CSF is instrumental in the induction of autoimmune disease. The present study was undertaken to analyze the expression of T cell-derived GM-CSF in the joints of patients with juvenile idiopathic arthritis (JIA) and to investigate the differentiation of Th17 cells and how this relates to GM-CSF+ T helper cells. Methods. Synovial fluid (SF) and peripheral blood (PB) samples from 24 patients with JIA were analyzed, by flow cytometry and reverse transcription-polymerase chain reaction, for expression of GM-CSF and the Th17 marker CD161. A cytokine capture assay was used to purify Th17 cells and test the plasticity of cytokine production in response to interleukin-12 (IL-12) and IL-23. Results. The frequency of GM-CSF-producing T helper cells was significantly enriched in SF mononuclear cells compared to PB mononuclear cells from the patients with JIA (24.1% of CD4+ T cells versus 2.9%) and closely correlated with the erythrocyte sedimentation rate (r(2) = 0.91, P < 0.001). Synovial GM-CSF+ T cells were predominantly CD161+ and coexpressed interferon-gamma (IFN gamma), but not IL-17. Culture of Th17 cells in the presence of IL-12 led to rapid up-regulation of GM-CSF and IFN gamma, recapitulating the phenotype of GM-CSF-expressing cells within the joint. Conclusion. Our results identify a novel outcome of Th17 plasticity in humans that may account for the enrichment of GM-CSF-expressing T cells in the joints of patients with JIA. The association of GM-CSF expression with systemic inflammation highlights the potential role of Th17-related cytokines in the pathology of JIA.
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