Generation mechanism of RANKL + effector memory B cells: Relevance to the pathogenesis of rheumatoid arthritis

Yuri Ota, Hiroaki Niiro, Shun ichiro Ota, Naoko Ueki, Hirofumi Tsuzuki, Tsuyoshi Nakayama, Koji Mishima, Kazuhiko Higashioka, Siamak Jabbarzadeh-Tabrizi, Hiroki Mitoma, Mitsuteru Akahoshi, Yojiro Arinobu, Akiko Kukita, Hisakata Yamada, Hiroshi Tsukamoto, Koichi Akashi

研究成果: ジャーナルへの寄稿記事

10 引用 (Scopus)

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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 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. 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)-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. 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-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. 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.

元の言語英語
記事番号67
ジャーナルArthritis Research and Therapy
18
発行部数1
DOI
出版物ステータス出版済み - 3 16 2016

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B-Lymphocyte Subsets
Rheumatoid Arthritis
B-Lymphocytes
Interferons
Osteoprotegerin
Tumor Necrosis Factor-alpha
Synovial Fluid
Osteoclasts
Cytokines
Cytoplasmic and Nuclear Receptors
Cell- and Tissue-Based Therapy
Coculture Techniques
Osteogenesis
Real-Time Polymerase Chain Reaction
Flow Cytometry
Macrophages
Ligands
Phenotype
Bone and Bones
Messenger RNA

All Science Journal Classification (ASJC) codes

  • Rheumatology
  • Immunology and Allergy
  • Immunology

これを引用

Generation mechanism of RANKL + effector memory B cells : Relevance to the pathogenesis of rheumatoid arthritis. / 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.

:: Arthritis Research and Therapy, 巻 18, 番号 1, 67, 16.03.2016.

研究成果: ジャーナルへの寄稿記事

Ota, Y, Niiro, H, Ota, SI, Ueki, N, Tsuzuki, H, Nakayama, T, Mishima, K, Higashioka, K, Jabbarzadeh-Tabrizi, S, Mitoma, H, Akahoshi, M, Arinobu, Y, Kukita, A, Yamada, H, Tsukamoto, H & Akashi, K 2016, 'Generation mechanism of RANKL + effector memory B cells: Relevance to the pathogenesis of rheumatoid arthritis', Arthritis Research and Therapy, 巻. 18, 番号 1, 67. https://doi.org/10.1186/s13075-016-0957-6
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. / Generation mechanism of RANKL + effector memory B cells : Relevance to the pathogenesis of rheumatoid arthritis. :: Arthritis Research and Therapy. 2016 ; 巻 18, 番号 1.
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abstract = "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 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. 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)-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. 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-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. 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.",
author = "Yuri Ota and Hiroaki Niiro and Ota, {Shun ichiro} and Naoko Ueki and Hirofumi Tsuzuki and Tsuyoshi Nakayama and Koji Mishima and Kazuhiko Higashioka and Siamak Jabbarzadeh-Tabrizi and Hiroki Mitoma and Mitsuteru Akahoshi and Yojiro Arinobu and Akiko Kukita and Hisakata Yamada and Hiroshi Tsukamoto and Koichi Akashi",
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T1 - Generation mechanism of RANKL + effector memory B cells

T2 - Relevance to the pathogenesis of rheumatoid arthritis

AU - Ota, Yuri

AU - Niiro, Hiroaki

AU - Ota, Shun ichiro

AU - Ueki, Naoko

AU - Tsuzuki, Hirofumi

AU - Nakayama, Tsuyoshi

AU - Mishima, Koji

AU - Higashioka, Kazuhiko

AU - Jabbarzadeh-Tabrizi, Siamak

AU - Mitoma, Hiroki

AU - Akahoshi, Mitsuteru

AU - Arinobu, Yojiro

AU - Kukita, Akiko

AU - Yamada, Hisakata

AU - Tsukamoto, Hiroshi

AU - Akashi, Koichi

PY - 2016/3/16

Y1 - 2016/3/16

N2 - 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 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. 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)-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. 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-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. 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.

AB - 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 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. 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)-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. 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-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. 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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