Somatic mutation in autoantibody-associated VH genes of circulating IgM+IgD+ B cells.

Naive B cells expressing IgM and IgD on their surface have no or little somatic mutations in V genes. We have demonstrated that the human IgM+IgD+B cell clone (0-81), which expresses nephritogenic idiotypes, produces IgM anti-DNA antibodies which show monospecificity to DNA. Using a DNA probe which specifically links to the VH gene of antibody 0-81, we identified the counterpart germ-line V gene of 0-81, V3-7, which appears to be used by pathogenic autoantibodies in humans. Clone 0-81, which may belong to naive B cells in terms of cell phenotype, uses a somatically mutated V3-7 gene. We further studied DNA sequences of V3-7 genes in circulating IgM+IgD+B cells from normal subjects and patients with systemic lupus erythematosus (SLE). The results revealed that rearranged V3-7 genes in IgM+IgD+B cells from patients with SLE contained somatically mutated sequences at significantly increased frequencies. These data indicate an abnormal maturation of B cells in autoimmune states that may be associated with an escape of self-reactive B cells from the elimination process in the germinal center.