SDF1 IN MESENCHYMAL ALTERATIONS OF IMMUNE INJURY

这一建议解决了为什么细胞和分子生物学基础 类风湿性关节炎的滑膜细胞培养显示出独特的 表型特征为快速增殖，星状形态， 丰富的降解酶和组成的阐述， 各种促炎细胞因子和更普遍的潜力， 间充质和自身免疫反应之间的双向相互作用。 据推测，通过细胞间的相互作用， 细胞因子的组成性加工，这些独特的滑膜细胞 调节自身免疫反应的传入部分并将其定位于 接头。 该建议的一个基础是初步观察， 一个代表性的差异库，通过减去非 炎性骨关节炎滑膜细胞cDNA来自RA滑膜细胞cDNA， 得到44个在RA滑膜细胞中优先表达的候选基因。 这些基因中最突出的是SDF-1，它是CXC趋化因子的新成员 支持前B细胞分化的家族。 最初的重点 研究将描述这种趋化因子，以了解其作用 滑膜炎 这个基因和文库中的其他基因极大地扩展了 有可能定义这种独特的表型。 另一个初步的 发现IL-1和PMA主要诱导显著的星状突起， 从炎症关节培养的滑膜细胞的变化，表明 这些细胞来源于内膜滑膜衬里细胞系。 这 星状反应将被用作解开复杂的线索 特定基因表达的持续改变 炎症性滑膜炎 建议确定潜在作用 一个给定的过表达基因的细胞结构， 基因产物在不同疾病状态中的定位以及 过表达的基因在克隆实验中分离， 成纤维细胞样细胞分配到内膜滑膜细胞谱系， 内膜下层中存在调制的滑膜细胞。 最后，In Concert 与其他项目负责人，间充质细胞之间的相互作用， 小鼠自身免疫模型中的元件和局部免疫应答 将探讨以确定是否以及如何间充质 参与免疫环境的反应，印刻局部的 免疫应答，以增强B细胞的参与 并通过B细胞抗原呈递增强和扩大自身免疫 机制等

This proposal addresses the cell and molecular biologic basis of why cultured synovial cells from rheumatoid arthritis exhibit a distinctive phenotype characterized by rapid proliferation, stellate morphology, abundant degradative enzymes and the constitutive elaboration of a with variety of proinflammatory cytokines and the more general potential for bidirectional interaction between mesenchyme and the autoimmune response. It is hypothesized that, through cell-cell interactions and the constitutive elaboration of cytokines, these distinctive synoviocytes modulate the afferent portion of an autoimmune response and localize it to the joint. One basis of the proposal is the preliminary observation that a representational difference Library prepared by subtracting non- inflammatory osteoarthritis synoviocyte cDNA from RA synovlocyte cDNA, yielding 44 candidate genes preferentially expressed in RA synoviocytes. Prominent among these genes was SDF-1, a novel member of the CXC chemokine family that supports pre B-cell differentiation. The initial focus of investigation will be characterizing this chemokine to understand its role in synovitis. This and the other genes of the library greatly expand the potential to define this distinctive phenotype. Another preliminary finding is that IL-1 and PMA predominantly induce a striking stellate change in synoviocytes cultured from inflammatory joints, suggesting that the cells originate from the intimal synovial lining cell lineage. This stellate response will be used as a clue to unravel the complex relationships of the sustained alteration in expression of particular genes in inflammatory synovitis. It is proposed to identify the potential role of a given overexpressed gene both by examining the cytoarchitectural localization of the gene product in different disease states and by how the overexpressed genes segregate in cloning experiments designed to separate fibroblastoid cells allocated to the intimal synoviocyte lineage from modulated synoviocytes present in subintimal layers. Lastly, in concert with the other project leaders, the interaction between the mesenchymal elements and localized immune responses in murine models of autoimmunity will be explored with a view to determining whether and how the mesenchyme participates in the reaction of the immune milieu, imprinting the localized immune response in such a way as to enhance the participation of B-cells and reenforce and amplify autoimmunity through B-cell antigen presentation mechanisms.