The theme of this grant is modulation of pathogenic and therapeutic mechanisms in rheumatoid arthritis (RA). Projects 1, 2, and 3 will focus on T cell-macrophage and T cell-synovial cell interactions and cytokine-synovial cell interactions in the generation of synovial lesions of RA. Using new monoclonal antibodies, new assay systems for the study of molecules involved in T cell interaction with RA synovial microenvironment cells, and measurements of cytokine (e.g. IL-1 and TNF) effect on synovial microenvironment cells and cytokine messenger RNA production using Northern blot and in situ hybridization analysis, the specific mechanisms and molecules in T cell-synovial microenvironment cell interactions and their sequelae will be studied. In addition cellular and molecular events associated with synovial lining cell activation to proliferation on inflammatory cytokine release with be studied. Project 4 will investigate B cell auto-antibody production in Sjogren's Syndrome and RA using cloned Ro and La recombinant autoantigens. Project 5 explores the pathogenesis of the MRL mouse model of arthritis using many of the same techniques and concepts discussed in projects 1, 2, and 3. Project 6 uses proven and innovative modalities of pain modification to alter RA patients' response to chronic pain -- thereby modifying a pathogenic mechanism (chronic pain) that is a major cause of morbidity in RA. Taken together, the work proposed in this SCOR grant represents a multidisciplinary effort to use innovative and novel approaches to modify joint inflammation, bone loss, and chronic pain in RA. By understanding basic mechanisms of pathogenesis of RA at the molecular, cellular, metabolic, and neuropsychiatric levels, hopefully novel therapies capable of modifying, and ultimately abrogating, the pathogenic mechanisms that lead to morbidity and mortality in RA can be developed.