Antibodies to components of the cell nucleus have been viewed as specific serological markers of systemic lupus erythematosus (SLE). To determine whether these autoantibodies exhibit common regulation of their expression, antibody levels have been quantitatively assessed in serial samples from patients producing at least 2 different antibody specificities. In a comparison of the peak antibody levels as a measure of immune responsiveness, the magnitude of the antiDNA response varied independently of either the antiSm or the antiRNP responses. Serial analysis with selected patients demonstrated that antiDNA levels fluctuated according to a pattern related to disease activity. In the same patients, however, antiSm and antiRNP antibodies showed little variation in level, with no consistent relationship to disease activity. Furthermore, following therapy, antiDNA levels fell while neither antiSm nor antiRNP levels showed significant alteration. These results suggest that in SLE, autoantibodies may arise from distinct immunoregulatory disturbances, each characterized by a unique relationship to disease activity and response to therapy.