Somatically mutated IgG anti‐DNA antibody clonally related to germ‐line encoded IgM anti‐DNA antibody

Abstract

Among 15 anti‐DNA antibody‐producing hybridomas derived from a single NZB × NZW F₁ mouse, an IgM and an IgG were shown to use the same V_H gene of the Q52 family. Using a combination of two primers both consisting of a mixture of oligonucleotides (one complementary to the 5′ end of V_H segment and one to the 3′ end of V_H segment of Q52 family) we determined the sequences of several members of germ‐line V_H genes in the Q52 family derived from NZB and NZW strains. Comparison of the sequences with those of cloned V_H cDNA obtained from the hybridomas revealed that the V_H sequence of the IgM anti‐DNA antibody was identical to that of a cloned NZW germ‐line V_H gene, except for the priming sites. In contrast, the V_H sequence of the IgG counterpart contained somatically mutated nucleotides. Because the IgG anti‐DNA antibody showed a higher DNA binding activity than did the IgM antibody, we conclude that these changes in nucleotide sequences were induced and selected through an antigen‐driven mechanism as is the case in a normal immune response. It is tempting to speculate that the germ‐line encoded, low‐affinity IgM autoantibody undergoes somatic mutations and isotype switching, resulting in generation of pathogenic, high‐affinity autoantibodies in autoimmune diseases.