The goal of this project is to further understand the genetic basis of the autoimmune disease, systemic lupus erythematosus. The experiments proposed are designed to test whether the multiple genetic loci that are involved in the inheritance of autoimmune disease function exclusively in a regulatory fashion or whether some of these loci encode structural genes. The particular hypothesis being tested is whether germline genes which code for the variable regions of autoantibodies might be one of the structural genes which must be inherited for autoimmune disease to occur. It is possible to test this hypothesis because of the existence of autoantibody producing hybridomas made from the spleens of unimmunized MRL/1pr mice. These mice produce the autoantibodies characteristic of SLE and die of a severe autoimmune disease resembling SLE at a young age. One of the hybridomas that produces an anti-ssDNA autoantibody defines a high frequency idiotype family that is present in the sera of all MRL/1pr mice and also among a group of anti-DNA autoantibodies synthesized by other hybridoma cell lines. The cloned VH gene which is expressed by the prototype member of this idiotype family is being used to test (1) whether the autoantibody is encoded by a germline gene and (2) whether this high frequency idiotype family is encoded by the same germline gene or by a group of closely or distantly related germline genes. If the idiotype family is encoded by single germline gene, then it will be determined (3) whether this germline gene is present in normal and in strains of mice that develop other autoimmune diseases. These experiments will assess the relative contributions of structural gene information and immunoregulatory defects in the genesis of autoimmunity. In addition, the elucidation of the structural gene(s) coding for these autoantibodies will provide a foundation for future study of the immunoregulatory defects that must be a part of any model seeking to elucidate the cause(s) of autoimmunity.
