MRL/1 mice have an unusal stem cell defect that can manifest itself, depending on conditions, in either a lymphoproliferative lupus-like syndrome or in a runting graft-versus-host syndrome. Autoimmunity is associated with production of many auto- antibody specificities including exceptionally high titers of anti- IgG antibody, referred to as rheumatoid factors (RF). The proposed study addressed 4 main questions pertaining to the MRL/1 model: 1) What factors are necessary are sufficent for the massive T cell lymphoproliferation characteristic of MRL/1 mice and how does this autoimmune environment affect the differentiation of normal stem cells; 2) What are the target and effector cells involved in the MRL/1 runting syndrome; 3) What elicits RF production in MRL/1 mice and how do RF regulate other B cells and influence disease progression; and 4) What is the role of somatic muation in the generation of autoantibodies? To approach these issues, """"""""autoimmune x normal"""""""" chimeric mice will be produced in which a mixture of phenotypically distinct normal and autoimmune stem cells mature together in various kinds of autoimmune environments. B cell activity will be monitored by measuring serum Ig and autoantibody titers. T cell functional activity will be measured in limiting dilution cultures. The RF studies will involve the production and analysis of monoclonal RF derived from MRL/1 and MRL/1 backcross mice. Somatic mutation will be assessed by determining the rate and direction of diversification of a particular germline gene following antigen stimulation in an autoimmune environment. Overall these studies should contribute to our basic understanding of immunoregulatory pathways. The results of this proposal should eventually have clinical application with regard to the control of autoimmune disorders such as systemic lupus erythematosus and rheumatoid arthritis as well as certain forms of graft-versus-host disease.
