Somatic diversification and affinity maturation of IgM and IgG anti‐DNA antibodies in murine lupus

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Abstract
Molecular events occurring during the process of generation of pathogenic immunoglobulin (Ig)G anti‐DNA antibodies in systemic lupus erythematosus (SLE) were studied using a newly established method. We analyzed the Ig variable (V) region gene sequence and DNA‐binding activity of IgM and IgG anti‐DNA monoclonal antibodies (mAb) from individual SLE‐prone (NZB × NZW) F1 mice. The first event appeared to be clonal selection and expansion of IgM anti‐DNA clones, in which several clones had intraclonal V gene mutations. Although the number of mutations was small, the mutated IgM clones were associated with an increase in DNA‐binding activity. The somatic mutations located in complementarity‐determining regions (CDR) and in framework regions (FR) of V genes were apparently related to changes in DNA‐binding activity. IgG anti‐DNA clones that progressively increased in number with aging had numerous somatic mutations in the V region genes and there was a pair of clones which showed an intraclonal accumulation of mutations, in association with increase in the DNA‐binding activity. All these findings show that somatic mutations associated with affinity maturation of the V region begin immediately before isotype‐switching from IgM to IgG of the clones that have been selected and expanded, in an antigen‐driven manner and/or by other forces. We propose that further accumulations of intraclonal somatic hypermutation, in association with selection and expansion of high affinity IgG clones, may lead to formation of highly pathogenic anti‐DNA antibodies.