Cartilage specific type II collagen (CII) plus complete Freund's adjuvant (CFA) induces arthritis in mice that has many of the clinical and pathological features of rheumatoid arthritis and other chronic arthropathies in man. Since its pathogenesis is poorly understood we postulate the following: (i) susceptibility to CII arthritis is genetically controlled by cells of the mononuclear phagocytic system (macro-phages), (ii) CFA plays a key role by causing immunoregulatory dysfunction via macrophage activation and (iii) the development of CII arthritis in a susceptible host is dependent on antibody binding to cartilage antigens, thus setting up a continuous inflammatory reaction. To test these hypotheses, peritoneal macrophages from congenic mice bearing H-2q and H-2r haplotypes, respectively, will be incubated with collagens of different types and species. Macrophage activation, with and without the addition of CFA and other adjuvant-like substances such as muramyl dipeptide (MDP), will be measured by cytotoxicity assays; phagocytic indices; prostaglandin, leukotriene and cyclic AMP production and neutral protease activities. Differences in the processing of CII antigens will be determined by comparing profiles resulting from incubation of radio-labelled chick and bovine CII with peritoneal exudates of H-2q and H-2r mice. The molecular specificity of CII antibodies to native CII, collagen chains or fragments thereof will be determined by immunoassay and direct adsorption onto cartilage slices. Monoclonal antibodies and the fluorescence activated cell sorter will help to enumerate and compare T cells, B cells and macrophages in the spleens of mice immunized with CII plus adjuvant; cellular immune function will be assayed in vitro following incubation of normal lymphocytes with CII stimulated macrophages. Finally genetic analysis of CII arthritis will be performd using offspring from arthritis susceptible versus arthritis resistant mice.