Cell wall fragments isolated from group A streptococci (PG-APS) induce arthritis in rats, resembling the human disease in many features. The long term objective is to relate the rat model with the human disease in order to identify people who are susceptible to inflammatory arthritis and to devise preventative methods. Because phagocytic cells are involved in the pathogenesis of the experimental lesions, the specific aims of this proposal are to (1) investigate the mechanisms of phagocytosis of PG-APS by human phagocytes and to determine if PG-APS effects normal phagocytic function (i.e., subsequent chemotaxis and phagocytosis); (2) to relate phagocyte stimulation and induction of blood cell aggregation with structurally defined components of streptococcal cell walls; and (3) to compare the interactions of PG-APS and human phagocytes with those of rat phagocytes. One mechanism of phagocytosis of PG-APS by neutrophils involves the concentration of PG-APS to one pole of the cell as a cap by C3b receptors. Immunoelectron and immunofluorescence microscopy will be used to investigate the mechanism of capping and endocytosis. The cytoskeletal organization will be studied by high-voltage electron microscopy of whole cells, and implications for a defect in the cytoskeleton of phagocytes will be pursued. The mechanism of aggregation of phagocyte monolayers will be similarly studied. Oxygen reduction products and secretion of lysosomal enzymes to the extracellular space will relate PG-APS with the damage observed in arthritic lesions. The fate of whole streptococci and cell wall fragments will be examined by determining whether phagolysosome fusion takes place and by using immunoassay techniques to analyze the contents of the phagosomes. Controls include group D streptococci which are readily degraded by phagocytes. Processing of cell walls by human phagocytes will be compared to rat phagocytes and related to structurally defined cell wall fragments which have been shown to influence the course of the disease in the rat model.
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