Bone marrow plasma cells in autoimmune lupus modulating the function of bone metabolizing cells - osteoblasts and osteoclasts

自身免疫性狼疮中的骨髓浆细胞调节骨代谢细胞（成骨细胞和破骨细胞）的功能

• 批准号: 168777232
• 负责人: Professor Dr. Rudolf Manz
• 金额: --
• 依托单位: Institut für Systemische Entzündungsforschung (ISEF)
• 依托单位国家: 德国
• 项目类别: Priority Programmes
• 财政年份: 2010
• 资助国家: 德国
• 起止时间: 2009-12-31 至 2013-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/168777232?language=en
• 关键词: Bone; marrow; plasma; cells; autoimmune

Previously, we have shown that long-lived plasma cells home into environmental niches in the bone marrow and that the number of these cells is severely increased in autoimmune systemic lupus erythematosus (SLE). While plasma cell survival is supported within these niches, the dialog between niche and plasma cell seems to be bi-directional. There is increasing evidence that bone marrow plasma cells interact with multiple resident cell types, including osteoblasts and osteoclasts - cells of the bone metabolism. Bone marrow plasma cells produce the cytokine CCL3 (and possibly others) which induces osteoclast activation. CCL3 mediates bone destruction in multiple myeloma bone disease when neoplastic CCL3 producing myeloma plasma cells – resembling the neoplastic counterpart of long-lived bone marrow plasma cells - accumulate in high numbers. For unknown reasons, low bone mineral density is also observed in autoimmune SLE. Here, we propose that via the production of CCL3 and other cytokines, increased numbers of long-lived plasma cells also mediate abnormalities in bone metabolism in this autoimmune disease. We plan to test this hypothesis (I) in chimeric mice containing plasma cells derived from SLE-prone hyperreactive NZM2410 background but wild type osteoblasts and osteoclasts, (II) after specific depletion of long-lived plasma cells via proteasome inhibition in wild type and B cell deficient μMT mice, (III) in plasma cell osteoblast-osteoclast co-cultures in vitro.

以前，我们已经表明，长寿命的浆细胞回家到骨髓中的环境龛，这些细胞的数量是严重增加的自身免疫性系统性红斑狼疮（SLE）。虽然浆细胞的生存是支持这些小生境，小生境和浆细胞之间的对话似乎是双向的。越来越多的证据表明，骨髓浆细胞与多种常驻细胞类型相互作用，包括成骨细胞和破骨细胞-骨代谢细胞。骨髓浆细胞产生诱导破骨细胞活化的细胞因子CCL 3（可能还有其他细胞因子）。当产生肿瘤性CCL 3的骨髓瘤浆细胞-类似于长寿命骨髓浆细胞的肿瘤性对应物-大量积累时，CCL 3介导多发性骨髓瘤骨疾病中的骨破坏。由于未知的原因，在自身免疫性SLE中也观察到低骨矿物质密度。在这里，我们提出，通过CCL 3和其他细胞因子的产生，长寿的浆细胞数量的增加也介导这种自身免疫性疾病中骨代谢的异常。我们计划（I）在含有来源于SLE易感高反应性NZM 2410背景但野生型成骨细胞和破骨细胞的浆细胞的嵌合小鼠中，（II）在野生型和B细胞缺陷型μMT小鼠中通过蛋白酶体抑制特异性消耗长寿浆细胞后，（III）在体外浆细胞成骨细胞-破骨细胞共培养物中检验这一假设。