SOMATIC DIVERSIFICATION IN THE HEAVY-CHAIN VARIABLE REGION GENES EXPRESSED BY HUMAN AUTOANTIBODIES BEARING A LUPUS-ASSOCIATED NEPHRITOGENIC- ANTI-DNA IDIOTYPE

Monoclonal anti-DNA antibodies bearing a lupus nephritis-associated id iotype were derived from five patients with systemic lupus erythematos us (SLE). Genes encoding their heavy (H)-chain variable (V-H) regions were cloned and sequenced. When compared with their closest V-H germ-l ine gene relatives, these sequences exhibit a number of silent (S) and replacement (R) substitutions. The ratios of R/S mutations were much higher in the complementarity-determining regions (CDRs) of the antibo dies than in the framework regions. Molecular amplification of genomic V-H genes and Southern hybridization with somatic CDR2-specific oligo nucleotide probes showed that the configuration of the V-H genes corre spending to V-H sequences in the nephritogenic antibodies is not prese nt in the patient's own germ-line DNA, implying that the B-cell clones underwent somatic mutation in vivo. These findings, together with the characteristics of the diversity and junctional gene elements utilize d to form the antibody, indicate that these autoantibodies have been d riven through somatic selection processes reminiscent of those that go vern antibody responses triggered by exogenous stimuli.