Autor: |
Ota, Yuri, Niiro, Hiroaki, Ota, Shun-ichiro, Ueki, Naoko, Tsuzuki, Hirofumi, Nakayama, Tsuyoshi, Mishima, Koji, Higashioka, Kazuhiko, Jabbarzadeh-Tabrizi, Siamak, Mitoma, Hiroki, Akahoshi, Mitsuteru, Arinobu, Yojiro, Kukita, Akiko, Yamada, Hisakata, Tsukamoto, Hiroshi, Akashi, Koichi |
Zdroj: |
Arthritis Research & Therapy (formerly Arthritis Research); December 2016, Vol. 18 Issue: 1 p1-10, 10p |
Abstrakt: |
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 κB 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. 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)-α, 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. 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-γ (IFN-γ) but suppressed by interleukin-21. Strikingly, IFN-γ also enhanced TNF-α expression, while it strongly suppressed osteoprotegerin expression in B cells. IFN-γ 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-α facilitated osteoclast differentiation in vitro. 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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