T cells and chemokines in rheumatoid arthritis

Abstract

In this thesis, we investigated if circulating proportions of specific CD4+ T cell subsets and blood chemokine levels were associated with disease activity and/or could predict remission in patients with early rheumatoid arthritis (eRA). We also compared the effect of different biological treatments on both T cell subset proportions and chemokine levels. Finally, we examined which T helper cell subsets are most abundant in the synovial fluid of inflamed joints, and which T cell associated cytokines induced the secretion of proinflammatory cytokines and chemokines by fibroblast-like synoviocytes (FLS). To enable these studies, we analysed blood samples and assessed disease activity in patients with untreated eRA who participated in the NORDSTAR randomised treatment trial. Synovial biopsies and paired blood and synovial fluid were sampled from patients with established RA. FLS were propagated from synovial biopsies. The proportions of T cell subsets were analysed by flow cytometry and cytokine and chemokine levels were measured by bead-based immunoassays and ELISA. In untreated eRA, circulating proportions of Th2, Th17 and CTLA-4+ conventional CD4+ T cells associated positively with disease activity in male, but not female patients. In patients treated with CTLA-4Ig, but not anti-TNF or anti-IL6R, baseline proportions of PD-1+TFh and CTLA-4+ conventional CD4+ T cells predicted remission at week 24. Only treatment with CTLA-4Ig reduced the proportions of PD-1+TFh. Plasma chemokine levels decreased in all treatment groups except in patients given anti-IL6R. Baseline chemokine levels did not predict remission in eRA. TPh, Th1 and CXCR3+Th2 were the most abundant CD4+ T cell subsets in RA synovial fluid, and the majority of B cell supporting TPh and PD-1highTFh cells expressed a Th1 or CXCR3+Th2 phenotype. IL-4, IL-13 and IL-17 induced FLS to secrete CXCL8, CCL2 and CXCL1, while IFNγ induced CXCL10. In conclusion, we show that baseline proportions of circulating T cell subsets may be used as biomarkers of remission for CTLA-4Ig treatment in eRA. Our findings also indicate that both classical and non-classical CXCR3+ T cell subsets mediate joint inflammation in RA and their associated cytokines induce secretion of proinflammatory chemokines by FLS.