Systemic lupus erythematosus (SLE) is characterized by the production of autoantibodies with a broad range of antigenic specificities, including specificity for double-stranded DNA. Analysis of the idiotypic profile of anti-DNA antibodies both in humans and mice has demonstrated presence of cross-reactive idiotypes, suggesting that they arise from a restricted number of germline genes. Our laboratory has previously reported the generation of 3I, a monoclonal anti-idiotypic antibody which recognizes a cross-reactive idiotype on anti-DNA antibodies in a majority of unrelated humans with SLE. We have recently studied the expression of 3I in sera of three human kindreds with familial SLE. We found 6 of 8 SLE patients and 15 of 19 unaffected family members had elevated 3I reactivity. Eleven of these family members had no anti-DNA activity despite elevated 3I reactivity, suggesting that expression of this idiotype in certain individuals is part of the normal immune response. In another set of experiments using an in vitro culture system we examined somatic mutants of the S107 mouse myeloma cell line. This line makes an antibody which bears the T15 idiotype, a common idiotype on antibodies to the bacterial antigen phosphoryl choline (PC). U4, a mutant, makes an immunoglobulin which varies by one amino acid from the parent protein, retains the T15 idiotype, but loses reactivity with PC and acquires reactivity with DNA. We have found that some anti-DNA antibodies in mice with spontaneous lupus and in mice immunologically induced to make anti-DNA antibodies bear the T15 idiotype and may represent somatic mutants arising in vivo.