Human anti-DNA idiotype (Id)-bearing cells in peripheral blood were sought using mouse monoclonal anti-Id antibodies to human monoclonal anti-DNA antibodies. Pretreatment with acid pH or pronase P or preincubation in human serum-free medium markedly decreased the number of anti-Id-reactive cells. Pronase P-treated cells were able to bind to anti-Id once more after incubation for 18 hr at 37 degrees C, indicating the resynthesis of internal idiotypic determinants on the cells. Antiidiotype-reactive cells retained the same idiotypes in their cytoplasma. The cells expressing anti-DNA idiotypes, termed 0-81 and NE-1, were detected in the circulation of most patients with active lupus nephritis but not in those of inactive systemic lupus erythematosus (SLE) and healthy subjects. The idiotype-positive cells occurred in up to 5-10% of B cells from some patients with SLE in the active stage but became undetectable in remission. A limited number of anti-DNA Id-positive cells responsible for anti-DNA production might be preferentially expanded during acute episodes of the disease in some patients with SLE.