The purpose of the proposed study is to delineate the basic immunological defects responsible for B cell hyperactivity in MRL/1 autoimmune mice. Three specific issues will be addressed: (1) In order to identify the intrinsic immune defect(s) resulting in excessive B cell activity, """"""""autoimmune x normal"""""""" chmieric mice will be produced in which T cells and B cells derived from a mixture of normal and auto-immune stem cells mature together in an autoimmune environment. The strains selected for the study differ with respect to their Thy-1 and Igh allotype markers such that it will be possible to monitor the extent and source (normal or autoimmune parent) of B cell antibody production as well as T cell lymphokine production; (2) To clarify the relationship between non-self antigen induced responses and autoantibody production, autoimmune mice capable of making a hapten specific cross-reactive idiotype (CRI) will be immunized with hapten-protein conjugates and screened periodically for expression of the CRI-associated VHDHJH in the polyclonally activated B cell pool; (3) To examine the role of autologous antigen in inducing an autoimmune response, backcross mice derived from mating autoimmune with normal mice will be produced and allotype specificity of rheumatoid factors derived from the Igh homozygous mice will be compared to the allotype specificity of rheumatoid factors derived from the Igh heterozygous mice. The autoimmune Igh heterozygous mice will also be used to look for possible linkage between anti-IgG binding specificities and the igh haplotype of the autoimmune parent. 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 as well as certain forms of graft-versus-host disease.
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