This study analyzed the distribution of an idiotype, B3-Id, in patients with active SLE, classified according to organ involvement, normal controls, and other autoimmune rheumatic diseases. A polyclonal anti-idiotype was raised by immunizing a rabbit with a monoclonal IgG anti-double-stranded (ds) DNA antibody, B3, generated from a patient with SLE who had active arthritis. The idiotype is present on the X chain and is at or near the binding site for double-stranded DNA. The X chain, which was characterized by nucleotide sequencing, was 90% homologous to the VX2.1 germline, which is known to be involved in coding for nephritogenic anti-DNA antibodies carrying the 8.12 idiotype. There were four changes to positively charged amino acids, known to be involved in DNA binding, in the complementarity determining regions of B3 X chain compared with a non-DNA binding, 8.12 positive antibody, PVll. Only one change to a positively charged amino acid occurs in the heavy chain of B3, which is 93.5% homologous to VH-26.The B3-Id was present on IgG antibodies in the serum of 20% of patients with SLE but was not found in the normal controls. Within the SLE group, there is a statistically significant association of B3-Id on IgG in the arthritis group (42%) compared to the other manifestations (9%) (P < 0.001). In four B3-Id-positive SLE patients tested serially, the level of B3-Id reflected the arthritis disease activity more closely than the overall disease activity (P < 0.05). The B3-Id was also present on IgM antibodies in one third of patients with rheumatoid arthritis.This idiotype is the first to be derived from a human monoclonal anti-DNA antibody of the IgG class, the isotype associated with active disease. Sequence analysis shows that positively charged amino acids on the X chain may contribute to DNA binding. (J. Clin. Invest. 1994. 93:1787-1797