Journal
ARTHRITIS RESEARCH & THERAPY
Volume 18, Issue -, Pages -Publisher
BMC
DOI: 10.1186/s13075-016-0957-6
Keywords
B cells; RANKL; Rheumatoid arthritis
Categories
Funding
- Ministry of Education, Culture, Sports, Science, and Technology in Japan
- Grants-in-Aid for Scientific Research [15K09528] Funding Source: KAKEN
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Background: The efficacy of B cell-depleting therapies for rheumatoid arthritis underscores antibody-independent functions of effector B cells such as cognate T-B interactions and production of pro-inflammatory cytokines. Receptor activator of nuclear factor kappa B ligand (RANKL) is a key cytokine involved in bone destruction and is highly expressed in synovial fluid B cells in patients with rheumatoid arthritis. In this study we sought to clarify the generation mechanism of RANKL(+) effector B cells and their impacts on osteoclast differentiation. Methods: Peripheral blood and synovial fluid B cells from healthy controls and patients with rheumatoid arthritis were isolated using cell sorter. mRNA expression of RANKL, osteoprotegerin, tumor necrosis factor (TNF)-alpha, and Blimp-1 was analyzed by quantitative real-time polymerase chain reaction. Levels of RANKL, CD80, CD86, and CXCR3 were analyzed using flow cytometry. Functional analysis of osteoclastogenesis was carried out in the co-culture system using macrophage RAW264 reporter cells. Results: RANKL expression was accentuated in CD80(+)CD86(+) B cells, a highly activated B-cell subset more abundantly observed in patients with rheumatoid arthritis. Upon activation via B-cell receptor and CD40, switched-memory B cells predominantly expressed RANKL, which was further augmented by interferon-gamma (IFN-gamma) but suppressed by interleukin-21. Strikingly, IFN-gamma also enhanced TNF-alpha expression, while it strongly suppressed osteoprotegerin expression in B cells. IFN-gamma increased the generation of CXCR3(+)RANKL(+) effector B cells, mimicking the synovial B cell phenotype in patients with rheumatoid arthritis. Finally, RANKL(+) effector B cells in concert with TNF-alpha facilitated osteoclast differentiation in vitro. Conclusions: Our current findings have shed light on the generation mechanism of pathogenic RANKL(+) effector B cells that would be an ideal therapeutic target for rheumatoid arthritis in the future.
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