The purpose of the proposed study is to delineate the basic immunological mechanisms responsible for B cell hyperactivity in the autoimmune MRL/1pr mouse model. The major goals of this proposal will be to examine the direct effect of the 1pr mutation on specific B cell lineages, to assess the relative roles of polyclonal activation and antigen specific activation in driving autoantibody production, and to determine the pathogenic and immunoregulatory effects of rheumatoid factors on the 1pr disease process. The specific approaches that will be used to address these issues will include: the production of chimeric mice expressing the 1pr mutation in which the development and functional activity of B cells derived from a mixture of normal and autoimmune stem cells will be monitored; the molecular analysis of B cells committed to the production of a crossreactive idiotype following immunization with specific hapten in the context of an autoimmune 1pr environment; the characterization of the in vivo and in vitro proliferative capacity of B cell clones associated with monoclonal gammapathies in 1pr mice; the assessment of the ability of passively transferred monoclonal rheumatoid factors to cause nephritis in mice with preformed IgG2a antibody in normal and autoimmune mice injected at a young age. Overall these studies should contribute to our basic understanding of the mechanisms regulating B cell activation and antibody production. The results of this proposal should eventually have clinical application with regard to the control of the basic immunoregulatory defects involved in autoimmune disorders such as systemic lupus erythematosus and rheumatoid arthritis.