SDF1 IN MESENCHYMAL ALTERATIONS OF IMMUNE INJURY

这项建议涉及细胞和分子生物学基础 培养的类风湿性关节炎滑膜细胞表现出独特的 表型以快速增殖、星状形态、 丰富的降解酶及其构成要素的阐述 促炎症细胞因子的多样性和更普遍的潜在的 间充质与自身免疫反应的双向相互作用。 据推测，通过细胞间的相互作用和 细胞因子的结构性阐述，这些独特的滑膜细胞 调节自身免疫反应的传入部分，并将其定位为 那家大麻店。这项提议的一个基础是初步观察到 用减法构建的代表性差异库 炎症性骨关节炎滑膜细胞基因 有44个候选基因在RA滑膜细胞中优先表达。 这些基因中最突出的是SDF-1，它是CXC趋化因子的一个新成员 支持B细胞前分化的家族。最初的重点是 研究人员将对这种趋化因子进行表征，以了解其作用 在滑膜炎中。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。另一场预赛 研究发现，IL-1和PMA主要诱导一种显著的星状 炎性关节滑膜细胞培养的变化 这些细胞起源于内膜滑膜衬里细胞系。这 星状反应将被用作解开该综合体的线索 特定基因表达持续变化的关系 在炎性滑膜炎中。建议确定潜在的角色 通过检查细胞结构来确定给定的过表达基因 基因产物在不同疾病状态下的定位以及如何 在旨在分离的克隆实验中，过度表达的基因分离 成纤维细胞样细胞分配给内膜滑膜细胞谱系 调节的滑膜细胞存在于内膜下层。最后，协调一致 与其他项目负责人，间充质之间的相互作用 小鼠自身免疫模型中的成分和局部免疫反应 将进行探索，以期确定间充质是否以及如何 参与免疫环境的反应，印记局部的 增强B细胞参与的免疫反应 并通过B细胞抗原递呈来加强和放大自身免疫 机械装置。

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.