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

此前，我们已经证明了长期存活的浆细胞存在于骨髓中的环境缝隙中，并且在自身免疫性系统性红斑狼疮(SLE)中，这些细胞的数量严重增加。虽然浆细胞的存活在这些利基中得到支持，但利基和浆细胞之间的对话似乎是双向的。越来越多的证据表明，骨髓浆细胞与多种驻留细胞类型相互作用，包括成骨细胞和破骨细胞-骨代谢的细胞。骨髓浆细胞产生细胞因子CCL3(可能还有其他)，诱导破骨细胞激活。CCL3在多发性骨髓瘤骨疾病中介导骨破坏，当产生肿瘤的CCL3骨髓瘤浆细胞-类似于长寿命骨髓浆细胞的肿瘤对应物-大量积累时。由于不明原因，自身免疫性系统性红斑狼疮患者也观察到低骨密度。在这里，我们认为，通过CCL3和其他细胞因子的产生，长寿命浆细胞数量的增加也介导了这种自身免疫性疾病的骨代谢异常。我们计划在嵌合小鼠中测试这一假设(I)包含来自系统性红斑狼疮易患高反应背景的血浆细胞但野生型成骨细胞和破骨细胞的嵌合小鼠，(Ii)在野生型和B细胞缺陷μMT小鼠中通过蛋白酶体抑制特异性去除长寿命的血浆细胞，(Iii)在体外血浆细胞成骨细胞-破骨细胞联合培养中。

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.