: 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.
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