Chemokine receptor expression and functional effects of chemokines on B cells: implication in the pathogenesis of rheumatoid arthritis

• Published in: Arthritis research & therapy Vol. 11; no. 5; p. R149
• Main Authors: Nanki, Toshihiro, Takada, Kazuki, Komano, Yukiko, Morio, Tomohiro, Kanegane, Hirokazu, Nakajima, Atsuo, Lipsky, Peter E, Miyasaka, Nobuyuki
• Format: Journal Article
• Language: English
• Published: London BioMed Central 01.01.2009; BioMed Central Ltd; National Library of Medicine - MEDLINE Abstracts
• Subjects: Antigens, CD - biosynthesis; Arthritis, Rheumatoid - immunology; Arthritis, Rheumatoid - metabolism; B cells; B-Cell Activation Factor Receptor - biosynthesis; B-Lymphocytes - immunology; B-Lymphocytes - metabolism; Cell Proliferation; Chemokine receptors; Chemokines; Chemotaxis, Leukocyte - immunology; Development and progression; Enzyme-Linked Immunosorbent Assay; Flow Cytometry; Genetic aspects; Health aspects; Humans; Inducible T-Cell Co-Stimulator Ligand; Lymphocyte Activation - immunology; Medicine; Medicine & Public Health; Orthopedics; Receptors, Chemokine - biosynthesis; Receptors, Chemokine - immunology; Research Article; Rheumatoid arthritis; Rheumatology; Transmembrane Activator and CAML Interactor Protein - biosynthesis; Tumor Necrosis Factor-alpha - biosynthesis; Japan; Rheumatoid Arthritis; Peripheral Blood CD27; Tumor Necrosis Factor Production; Synovial Tissue; Rheumatoid Arthritis Synovium
• ISSN: 1478-6354; 1478-6362; 1478-6354; 1478-6362
• DOI: 10.1186/ar2823

Introduction Accumulation of B cells in the rheumatoid arthritis (RA) synovium has been reported, and it has been thought that these cells might contribute to the pathogenesis of RA by antigen presentation, autoantibody production, and/or inflammatory cytokine production. Chemokines could enhance the accumulation of B cells in the synovium. The aims of this study were to determine chemokine receptor expression by B cells both in the peripheral blood of normal donors and subjects with RA, and at the inflammatory site in RA, and the effects of chemokines on B cell activation. Methods Cell surface molecule expression was analyzed by flow cytometry. Cellular migration was assessed using chemotaxis chambers. Cellular proliferation was examined by 3 H-thymidine incorporation. Tumor necrosis factor (TNF) production was assayed by enzyme-linked immunosorbent assay. Results Significant numbers of peripheral blood B cells of healthy donors and subjects with RA expressed CC chemokine receptor (CCR)5 and CXCR3, and most B cells expressed CCR6, CCR7, CXCR4 and CXCR5. CCR5 expression was more frequent on CD27 + than CD27 - peripheral blood B cells of healthy donors and RA. Synovial B cells more frequently expressed CCR5, but less often expressed CCR6, CCR7 and CXCR5 compared to peripheral blood in RA. Further functional analyses were performed on peripheral blood B cells from healthy donors. Migration of peripheral blood B cells, especially CD27 + B cells, was enhanced by CC chemokine ligand (CCL)20, CCL19, CCL21 and CXCL12. All four chemokines alone induced B cell proliferation; with CCL21 being the most effective. CCL21 also enhanced the proliferation of anti-immunoglobulin (Ig)M-stimulated B cells and blockade of CCR7 inhibited this effect. CCL20, CCL21 and CXCL12 enhanced TNF production by anti-IgM mAb-stimulated B cells. Finally, stimulation with CXCL12, but not CCL20, CCL19 and CCL21, enhanced inducible costimulator-ligand (ICOSL) expression by peripheral blood B cells of healthy donors and RA, but did not increase B cell-activating factor receptor or transmembrane activator and CAML-interactor. Conclusions The data suggest that CCR5, CCR6, CCR7, CXCR3, CXCR4 and CXCR5 may be important for the B cell migration into the synovium of RA patients, and also their local proliferation, cytokine production and ICOSL expression in the synovium.