Unique Surface Structures on Synovial Cells

描述（由申请方提供）：类风湿性关节炎（RA） 伴随着炎症和关节结构的最终破坏 T淋巴细胞和巨噬细胞广泛浸润滑膜， 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，没有确凿的证据表明T细胞定向自身免疫， 因为RA。我们已经采取了几种方法来更好地了解途径， T细胞活化和T细胞在RA中的作用，包括产生 针对新的T细胞表面抗原的单克隆抗体和表面抗原的配体， 对T细胞活化重要的结构，包括SF上表达的配体。 此外，我们已经有证据表明，T细胞，即使是静息T细胞， 以双向方式与SF交互。因此，SF可以作为有效的 辅助细胞的T细胞活化，而静息T细胞可以刺激一个 SF中的促炎基因表达模式，即使在缺乏 激活T细胞的刺激物。我们把这种未激活的T细胞的能力称为 淋巴细胞刺激静息T细胞的SF效应子功能。“我们现在 提出RA中SF的攻击行为的重要组成部分 由T细胞和RA SF之间的直接相互作用引起。我们还假设 这种不寻常的致病细胞程序的分子基础 分化起源于T细胞之间形成的独特的免疫突触， 淋巴细胞和SF。目前的建议将进一步分析分子 T细胞和SF之间的相互作用及其功能后果 相互作用，使用形态学和免疫学方法。新型配体 SF表达的CD 6的分子特征和功能 研究了将产生新的抗体来分析T细胞/SF微阵列 SF基因表达和定量相互作用的分析，针对两者 已知的和新的细胞表面分子和分泌的CD 26相关细胞 相互作用分子吸引素SF的激活将使用 测量相关RNA种类和蛋白质产物，如破骨细胞 分化因子、细胞因子和组织破坏性蛋白酶。的 拟议的研究代表了一种新的方法来了解RA。

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.