Molecular analysis of interaction between hematopoietic cells and nurse cells established from patients with rheumatoid arthritis

虽然类风湿关节炎(RA)的病因学研究大多集中在滑膜组织上，但其在重度RA患者受累关节中的增殖相当轻微。因此，我们认为该病的主要病变可能在滑膜以外的其他地方。在重症类风湿关节炎患者受累关节的骨髓中，细胞表面抗原异常的髓样细胞来源于髂骨骨髓中细胞表面抗原明显正常的细胞。IL-1β和GM-CSF促进分化，T细胞抑制分化，轻度RA患者髂骨骨髓中淋巴细胞增多和活化，IL-1和IL-8水平升高。此外，在重症RA患者的髂骨骨髓细胞培养中，发现破骨细胞的增强，这表明破骨细胞是重症RA全身骨质疏松的原因之一，因为这些异常细胞不能在…中维持在更多的正常培养条件下，我们从重症类风湿关节炎患者的骨髓和滑膜建立了基质“哺育细胞”系。类风湿关节炎(RA)中的哺乳细胞具有“假脓肿”的特点，在免疫反应中起重要作用，支持淋巴样细胞的分化、成熟和凋亡，其自身产生IL-6、IL-8、G-CSF、GM-CSF和透明质酸。此外，当与淋巴样细胞共培养时，观察到假性脓肿，它们不仅产生IL-1β和TNF-α等促炎细胞因子，而且还产生与RA关节破坏直接相关的基质金属蛋白酶和组织蛋白。这些异常细胞的凋亡下调可以通过类风湿滑液中可溶性Fas配体的增强来解释。结论：处于细胞网络中心的类风湿关节炎滋养细胞形成并维持了类风湿关节炎的发病机制，它们可能与关节破坏有关。较少

Although most of all investigations on etiology of rheumatoid arthritis (RA) have been focusing on synovial tissue, its proliferation in affected joints of patients with severe RA is rather mild. Thus we thought that the main lesion of the disease might be elsewhere than synovium.We found. In bone marrow of affected joints of severe RA patients, myeloid cells with abnormal cell surface antigens which originated from tile cells with apparently normal cell surface antigens in iliac bone marrow. The differentiation was accelerated by IL-1 beta and GM-CSF, and was obstructed by T cells.Also observed was, in iliac bone marrow in mild RA patients, increase arid activation of lymphoid cells with elevated levels of IL-1 and IL-8. Furthermore, in culture of iliac bone marrow cells obtained from severe RA patients, enhancement of osteoclastogenesis was detected, suggesting osteoclasts are one of tile causes of general osteoporosis in severe RA.Since these abnormal cells could not be maintained i … More n normal culture conditions, we established stromal 'nurse cell' lines from bone marrow and synovium of severe RA patients. Nurse cells are characterized by 'pseudoemperipolesis', holding lymnphoid cells underneath, as well as their important roles in immune reaction, supporting lymphoid cells in differentiation, maturation, and apoptosis.RA nurse cells produce IL-6, IL-8, G-CSF, GM-CSF and hyaluronan by themselves. Moreover, when co-cultured with lymphoid cells and observed manifesting pseudoemperipolesis, they produce not only proinflammatory cytokines such as IL-1 beta and TNF-alpha, but also matrix metalloproteinases and cathepsins which directly associate with joint destruction in RA. The down-regulation of apoptosis of these abnormal cells can be explained by enhancement of soluble Fas ligand which we observed in rheumatoid synovial fluidIt can he concluded that RA nurse cells, in the center of cellular network, form and maintain the pathogenesis of RA, and that they possibly associate with joint destruction by themselves. Less