Abstract
BackgroundB cells exert their pathogenic action in rheumatoid arthritis (RA) locally in the synovium. This study was undertaken to elucidate the chemokines responsible for the recruitment of B cells in the inflamed synovium, taking into account that the rich chemokine milieu present in the synovial tissue can fine-tune modulate discrete chemokine receptors.MethodsExpression levels of chemokine receptors from the CC and CXC family, as well as CD27, were assessed by flow cytometry in CD20+ mononuclear cells isolated from the peripheral blood (PB) and synovial fluid (SF) of RA and psoriatic arthritis patients. Transwell experiments were used to study migration of B cells in response to a chemokine or in the presence of multiple chemokines.ResultsB cells from the SF of arthritis patients showed a significant increase in the surface expression of CCR1, CCR2, CCR4, CCR5 and CXCR4 with respect to PB. Conversely, SF B cells expressed consistently lower amounts of CXCR5, CXCR7 and CCR6, independent of CD27 expression. Analysis of permeabilized B cells suggested internalization of CXCR5 and CCR6 in SF B cells. In Transwell experiments, CCL20 and CXCL13, ligands of CCR6 and CXCR5, respectively, caused a significantly higher migration of B cells from PB than of those from SF of RA patients. Together, these two chemokines synergistically increased B-cell migration from PB, but not from SF.ConclusionsThese results suggest that CXCL13 and CCL20 might play major roles in RA pathogenesis by acting singly on their selective receptors and synergistically in the accumulation of B cells within the inflamed synovium.
Highlights
B cells exert their pathogenic action in rheumatoid arthritis (RA) locally in the synovium
To investigate the role of this system in the migration of B cells to the inflamed synovial tissue, we first studied by flow cytometry the surface expression of a number of chemokine receptors from the CC and CXC family on CD20+ mononuclear cells isolated simultaneously from peripheral blood (PB) and synovial fluid (SF) of patients with active RA and psoriatic arthritis (PsA)
When the surface expression level data expressed as relative mean fluorescence intensity (rMFI) were plotted, either by disease diagnosis (Fig. 1a) or grouped (Fig. 1b), significant increments of CCR1, CCR2, CCR4, CCR5 and CXCR4 were observed on CD20+ cells from SF with respect to PB
Summary
B cells exert their pathogenic action in rheumatoid arthritis (RA) locally in the synovium. Rheumatoid arthritis (RA) and psoriatic arthritis (PsA) are systemic autoimmune diseases characterized by the chronic inflammation of joints which leads to the destruction of cartilage and bone [1]. Both T cells and B cells are present in the inflammatory infiltrate of synovial membranes in both diseases [1,2,3]. Most leukocytes express more than one chemokine receptor of varying promiscuity and are, in addition, potentially capable of responding synergistically to concomitant migration signals [14] Upon binding to their ligands, chemokine receptors are rapidly internalized following either a degradative or recycling pathway. This mechanism, known as desensitization [15], limits the magnitude and duration of signaling, protecting cells from chemokine overstimulation [16]
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