Production of RANKL by Memory B Cells: A Link Between B Cells and Bone Erosion in Rheumatoid Arthritis.
Production of RANKL by Memory B Cells: A Link Between B Cells and Bone Erosion in Rheumatoid Arthritis.
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DOI：
10.1002/art.39489
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发表时间：
2016-04
期刊：
影响因子：
--
通讯作者：
Anolik JH
中科院分区：
文献类型：
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作者：
Meednu N;Zhang H;Owen T;Sun W;Wang V;Cistrone C;Rangel-Moreno J;Xing L;Anolik JH
风湿性关节炎（RA）是一种全身性自身免疫性疾病，常导致关节损伤. RA的骨损伤机制复杂，涉及滑膜细胞和Th17细胞对骨吸收破骨细胞（OC）的激活。本研究旨在研究B细胞是否通过产生RANKL（OC发育所必需的细胞因子）在破骨细胞生成中发挥直接作用。通过流式细胞术、实时聚合酶链反应、酶联免疫吸附试验和免疫组织化学分析，检测健康供体或抗环瓜氨酸肽阳性RA患者外周血和滑膜组织中总B细胞或分选的B细胞亚群的RANKL生成。为了确定对破骨细胞生成的直接影响，将B细胞与CD 14+单核细胞共培养，并通过抗酒石酸酸性磷酸酶染色计数OC。健康供体外周血B细胞能够在刺激后表达RANKL，其中转换记忆B细胞（CD 27 +IgD−）具有最高的RANKL产生倾向。值得注意的是，与健康对照相比，RA患者外周血中的转换记忆B细胞表达的RANKL显著更多。在RA滑液和组织中，记忆B细胞富集并自发表达RANKL，其中一些细胞邻近RANK+ OC前体可见。重要的是，B细胞以RANKL依赖性方式支持OC体外分化，RA B细胞培养物中的OC数量高于健康对照组。这些发现揭示了B细胞在骨稳态中的重要性，以及它们可能对RA关节破坏的贡献。
Rheumatoid arthritis (RA) is a systemic autoimmune disease that often leads to joint damage. The mechanisms of bone damage in RA are complex, involving activation of bone-resorbing osteoclasts (OCs) by synoviocytes and Th17 cells. This study was undertaken to investigate whether B cells play a direct role in osteoclastogenesis through the production of RANKL, the essential cytokine for OC development. RANKL production by total B cells or sorted B cell subpopulations in the peripheral blood and synovial tissue from healthy donors or anti–cyclic citrullinated peptide–positive patients with RA was examined by flow cytometry, real-time polymerase chain reaction, enzyme-linked immunosorbent assay, and immunohistochemical analysis. To define direct effects on osteoclastogenesis, B cells were cocultured with CD14+ monocytes, and OCs were enumerated by tartrate-resistant acid phosphatase staining. Healthy donor peripheral blood B cells were capable of expressing RANKL upon stimulation, with switched memory B cells (CD27+IgD−) having the highest propensity for RANKL production. Notably, switched memory B cells in the peripheral blood from RA patients expressed significantly more RANKL compared to healthy controls. In RA synovial fluid and tissue, memory B cells were enriched and spontaneously expressed RANKL, with some of these cells visualized adjacent to RANK+ OC precursors. Critically, B cells supported OC differentiation in vitro in a RANKL-dependent manner, and the number of OCs was higher in cultures with RA B cells than in those derived from healthy controls. These findings reveal the critical importance of B cells in bone homeostasis and their likely contribution to joint destruction in RA.