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

尽管对类风湿性关节炎（RA）病因学的研究大多集中在滑膜组织，但严重RA患者受累关节的滑膜组织增生相当轻微。我们发现，在严重类风湿关节炎患者患侧关节骨髓中，细胞表面抗原异常的髓样细胞来源于髂骨髓中细胞表面抗原明显正常的瓦细胞。在轻度RA患者的髂骨髓中，还观察到淋巴样细胞的增加和活化以及IL-1和IL-8水平的升高。此外，在从严重RA患者获得的髂骨骨髓细胞的培养中，检测到破骨细胞生成的增强，这表明破骨细胞是严重RA患者全身性骨质疏松的原因之一。 关于我们 在正常培养条件下，我们从严重RA患者的骨髓和滑膜中建立了基质“护士细胞”系。RA的护士细胞具有“假帝国”的特征，其下有类淋巴细胞，并在免疫反应中起重要作用，支持淋巴细胞的分化、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并观察到表现出假帝国时，它们不仅产生促炎细胞因子如IL-1 β和TNF-α，而且产生与RA中关节破坏直接相关的基质金属蛋白酶和组织蛋白酶。这些异常细胞的凋亡下调可能与我们在类风湿关节炎滑液中观察到的可溶性Fas配体的增加有关。因此，RA养育细胞作为细胞网络的中心，形成并维持了RA的发病机制，它们本身可能与关节的破坏有关。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