This is an integrated program project to investigate the cellular and molecular mechanisms by which toxic, immunogenic, bacterial cell wall fragments produce chronic, erosive inflammatory arthritis. The focus will be on the experimental model of inflammatory arthritis induced in genetically susceptible rats by ststemic injection of peptidoglycanpolysaccharide polymers isolated from cell walls of Group A streptococci and other bacteria which colonize humans. The investigation will be extended to human disease by examination of tissue specimens. The major objectives of this program are: 1) To identify potential bacterial sources of arthropathic cell wall fragments in the microbial flora, and factors which regulate systemic dissemination of cell wall. 2) To characterize the degradation of bacterial cell in vivo to yield a spectrum of arthropathic cell wall fragments. Processing in rat tissues and rat and human phagocytic cells will be followed by quantitative immunoassay. 3) To analyze the transport of cell wall fragments to joint tissue and the factors of the host or bacteria which regulate distribution and retention. This will include studies on the role of complement and other plasma proteins on the interaction of cell walls with blood cells and vascular endothelium. 4) To investigate mechanisms of tissue injury, including: acute changes in vascular endothelium of articular and lymphoid tissues; the role of macrophages in the growth of pannus and the erosive process; the significance of oxygen metabolites and lysosomal enzymes released by activated neutrophils and macrophages; the relationship of macrophage activities in bone mineralization and demineralization to the metabolism of 25 OH vitamin D3; the factors responsible for the evolution of acute, reversible cell wall-induced arthritis into recurrent, proliferative, irreversible, chronic, erosive synovitis. 5) To assess the humoral and cellular immune responses against defined cell wall epitopes and the role of these immune responses in experimental arthritis, including the immunohistology of the evolving arthritis. 6) To investigate the role of bacterial cell wall fragments as etiological agents in inflammatory arthritis of humans by measurement of peptidoglycan in human joint specimens and by measurement of immune responses to peptidoglycan epitopes in patients. Detailed study of this animal model will provide insight into problems of the etiological factors, mechanisms of articular erosion and mechanisms of remission in inflammatory arthritis in humans. These studies may also provide a rationale for developing diagnostic and therapeutic methods in human disease.
