Abstract
T-helper cells producing interleukin (IL)-17A and IL-17F cytokines (Th17 cells) are considered the source of autoimmunity in rheumatoid arthritis (RA). In this study, we characterized specific pathogenic features of Th17 cells in RA. By using nano-string technology, we analyzed transcription of 419 genes in the peripheral blood CCR6(+)CXCR3(-) CD4(+) cells of 14 RA patients and 6 healthy controls and identified 109 genes discriminating Th17 cells of RA patients from the controls. Th17 cells of RA patients had an aggressive pathogenic profile and in addition to signature cytokines IL-17, IL-23 and IL-21, and transcriptional regulators RAR-related orphan receptor gamma of T cells (RORγt) and Janus kinase 2 (JAK2), they produced high levels of IL-23R, C-C chemokine ligand type 20 (CCL20), granulocyte-monocyte colony-stimulating factor (GM-CSF ) and transcription factor Tbet required for synovial homing. We showed that Th17 cells are enriched with Helios-producing Foxp3- and IL2RA-deficient cells, indicating altered regulatory profile. The follicular T-helper (Tfh) cells presented a functional profile of adaptor molecules, transcriptional regulator Bcl-6 and B-cell activating cytokines IL-21, IL-31 and leukemia inhibitory factor (LIF ). We observed that anti-tumor necrosis factor (TNF) treatment had a limited effect on the transcription signature of Th17 cells. Patients in remission retained the machinery of receptors (IL-23R and IL-1R1), proinflammatory cytokines (IL-17F, IL-23, IL-21 and TNF ) and adaptor molecules (C-X-C chemokine receptor 5 [CXCR5] and cytotoxic T-lymphocyte-associated protein 4 [CTLA-4]), essential for efficient transdifferentiation and accumulation of Th17 cells. This study convincingly shows that the peripheral blood CCR6(+)CXCR3(-) CD4(+) cells of RA patients harbor pathogenic subsets of Th17 and Tfh cells, which may transdifferentiate from Tregs and contribute to perpetuation of the disease.
Highlights
T-helper cells characterized by high production of the cytokines interleukin (IL)17A and IL-17F, are associated with the induction of autoimmunity and have important roles in the pathogenesis of rheumatoid arthritis (RA) [1]
The produced IL17 amplifies the inflammation induced by other cytokines, tumor necrosis factor (TNF) and IL-1 [2,3], and induces extensive inflammatory cell migration and massive cartilage and bone
We performed transcriptional and functional analysis of circulating chemokine receptor type 6 (CCR6)+CXCR3– CD4+ cells in RA patients on anti-TNF treatment and in healthy controls. We show that these cells displayed an evident pathogenic transcriptional profile characterized by high IL-23R, C chemokine ligand type 20 (CCL20), granulocyte-monocyte colony-stimulating factor (GM-CSF) and the combined upregulation of master transcription factors RORγt and Tbet
Summary
T-helper cells characterized by high production of the cytokines interleukin (IL)17A and IL-17F, are associated with the induction of autoimmunity and have important roles in the pathogenesis of rheumatoid arthritis (RA) [1]. The produced IL17 amplifies the inflammation induced by other cytokines, tumor necrosis factor (TNF) and IL-1 [2,3], and induces extensive inflammatory cell migration and massive cartilage and bone degradation [4]. The prevalence of IL-17 producing CD4 T-cells is increased in the circulation of RA patients [5] and correlates to the number of swollen joints and to systemic inflammation [6]. A reduction of circulating Th17 cells has been a suggested prerequisite of clinically efficient treatment in RA [7,8,9]. Clinical trials with monoclonal antibodies against IL-17 and IL-17 receptor report a favorable therapeutic effect in patients with severe arthritis [11,12,13]
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