-This proposal is based on the principal investigator's recent observations demonstrating that (1) superficial cartilage chondrocytes are the cells that secrete most nitric oxide (NO) when appropriately stimulated by interleukins or bacterial lipopolysaccharide; (2) oxidative modification of proteins, i.e., covalent cross-linking and nitrosylation of tyrosine residues, may be mediated by the decay product of NO, i.e., nitrite (NO2), reacting with H2O2 and myeloperoxidase (MPO) to form peroxinitrite (ONOO), the radical responsible for the chemical modification of proteins; (3) there is abundant evidence that polymorphonuclear neutrophil (PMN) products, including MPO, are found at the cartilage-pannus junction in rheumatoid arthritis (RA). Taken together, these findings suggest that in inflammatory arthritis, high concentrations of oxygen radicals, PMN products, and NO may interact at the articular cartilage surface The proposed work is aimed at resolving the following questions (hypotheses): (1) Are the principal investigator's in vitro findings relevant to human disease? The principal investigator's preliminary work confirms the presence of nitrotyrosine in IgG purified from synovial fluids of RA patients. (2) Are the NO2-modified IgG and immune complexes (IC) more or less proinflammatory, in vivo and in vitro, than similar native molecules and IgG exposed to reactive oxygen species (ROS)? (3) Is there an immune response to nitrosylated proteins in RA, i.e., circulating and synovial fluid antibodies and sensitized lymphocytes directed against modified proteins? The data to be obtained, it is hoped, would add a novel and original pathogenic mechanism involved in the maintenance of chronic inflammation in RA.
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