Recent advances in the understanding of the ontogeny of the normal B cell response and of the molecular mechanisms that are used to generate a diverse B cell repertoire have resulted in new approaches to the study of autoimmune diseases. B cell lines with autoantibody specificity can easily be generated from normal individuals. These low affinity and generally polyspecific "natural autoantibodies" have features of a B cell response prior to antigenic stimulation and are encoded by germline or relatively unmutated genes. Pathogenic autoantibodies from autoimmune individuals on the other hand, appear to be higher affinity antibodies that have features of an antigen selected response. The relationship between these two different classes of autoantibodies remains to be determined. Our studies of anti-DNA antibodies in human SLE have revealed that anti-DNA antibodies from unrelated patients share dominant cross-reactive idiotypes. Analysis of monoclonal anti-DNA antibodies bearing two SLE related idiotypes, 3I and F4, have indicated to us that DNA binding activity is acquired by somatic mutation, suggesting that these autoantibodies are not germline encoded but require antigenic stimulation and T cell help. Molecular analysis of genes encoding 3I reactive light chains from a panel of EBV transformed B cell lines have revealed that 3I reactive light chains are nearly all encoded by a member of the VK 1 gene family. Thus for this idiotypic system, there is restricted gene usage to encode anti-DNA antibodies. Further molecular analysis may reveal the structural features that determine idiotype reactivity and autoreactivity and may help determine what features of these genes could account for their preferential expression in SLE patients and their family members.(ABSTRACT TRUNCATED AT 250 WORDS)