Unique Surface Structures on Synovial Cells

描述(由申请人提供)：类风湿性关节炎(RA) 伴随着炎症和关节结构的最终破坏 通过T淋巴细胞和巨噬细胞对滑膜的广泛渗透，以及 滑膜成纤维细胞(SF)增生。T淋巴细胞的作用仍然存在 有争议的，没有确凿的证据证明T细胞导向的自身免疫是 类风湿性关节炎的原因。我们采取了几种方法来更好地了解 T细胞活化和T细胞在RA中的作用，包括产生 抗新型T细胞表面抗原的单抗和表面配体 对T细胞活化很重要的结构，包括表达在SF上的配体。 此外，我们还发现证据表明，T细胞，甚至静止的T细胞，都可以 与顺丰双向互动。因此，SF可以发挥强大的作用 辅助细胞用于T细胞的激活，而静止的T细胞可以刺激 SF中致炎基因表达的模式，即使在缺乏 激活T细胞的刺激。我们将这种未激活的T细胞的能力称为 淋巴细胞刺激SF的“效应器”功能的静息T细胞。我们现在 提出类风湿关节炎患者攻击性行为的一个重要组成部分 起源于T细胞和RA SF之间的直接相互作用。我们还假设 这种不寻常和致病的细胞程序的分子基础 分化源于T细胞之间形成的一种独特的免疫突触 淋巴细胞和SF。目前的提议将进一步分析分子 T细胞与SF的相互作用及其功能后果 相互作用，使用形态和免疫学方法。一种新型配体 由SF表达的CD6的分子特征和功能 学习。将产生新的抗体来分析T细胞/SF微阵列 分析SF基因的表达，并针对两者进行定量相互作用 已知和新的细胞表面分子以及分泌的CD26相关细胞 相互作用分子吸引力。将使用以下方法研究SF的激活 相关RNA种类和蛋白质产品的测量，如破骨细胞 分化因子、细胞因子和组织破坏性蛋白酶。这个 拟议的研究为理解RA提供了一种新的途径。

DESCRIPTION (provided by the applicant): In rheumatoid arthritis (RA) inflammation and ultimate destruction of articular structures are accompanied by extensive infiltration of synovium by T lymphocytes and macrophages, and hyperplasia of synovial fibroblasts (SF). The role of T lymphocytes remains controversial, with no conclusive proof for T cell directed autoimmunity as the cause of RA. We have taken several approaches to better understand pathways of T cell activation and of the role of T cells in RA, including generation of monoclonal antibodies to novel T cell surface antigens, and ligands of surface structures important for T cell activation, including ligands expressed on SF. In addition we have developed evidence that T cells, even resting T cells, can interact with SF in a bi-directional manner. Thus SF can function as potent accessory cells for T cell activation, while resting T cells can stimulate a proinflammatory pattern of gene expression in SF, even in the absence of stimuli that activate the T cell. We have termed this ability of unactivated T lymphocytes to stimulate the SF "effector function of resting T cells." We now propose that a significant component of the aggressive behavior of SF in RA arises from direct interactions between T cells and RA SF. We also hypothesize that the molecular basis for this unusual and pathogenic program of cell differentiation arises from a unique immunologic synapse formed between the T lymphocyte and the SF. The current proposal would further analyze the molecular interactions between T cells and SF and the functional consequences of these interactions, using both morphologic and immunologic approaches. A novel ligand of CD6 expressed by SF will be molecularly characterized and functionally studied. New antibodies will be generated to analyze the T cell/SF microarray analysis of SF gene expression, and quantitative interaction, directed at both known and novel cell surface molecules and at the secreted CD26-related cell interaction molecule attractin. Activation of SF will be studied using measurement of relevant RNA species and protein products, such as osteoclast differentiation factor, cytokines, and tissue destructive proteases. The proposed studies represent a fresh approach to understanding RA.