Independently derived IgG anti-DNA autoantibodies from two lupus-prone mouse strains express a VH gene that is not present in most murine strains

The origin and structure of two clonally unrelated IgG anti-DNA autoantibodies from lupus-prone MRL/lpr mice were examined. One of these antibodies, H241, binds dsDNA and glomeruli and deposits in the kidneys of normal mice, whereas the other, H102, binds only ssDNA and does not deposit in kidneys. The VH genes of these two antibodies were almost identical to each other and were frequently expressed in anti-DNA antibodies derived from lupus-prone mice. Six other clonally unrelated anti-DNA antibodies from the literature or from data banks expressed nearly identical VH genes (≤4 nucleotide differences) and eight others had nearly identical protein sequences (≤3 amino acid differences). Analysis of the germ line with oligonucleotide probes from the CDR regions suggests that all 10 autoantibodies are derived from a single member of the J558 gene family, which is present only in mice with the j haplotype for the J558 gene family. The amount of somatic mutation in these VH genes appears to be low, suggesting that some V, N, and D gene combinations can generate high affinity IgC anti-DNA autoantibodies with little or no somatic mutation. Unusual reading frames, D-D fusions, and inversions were common in the IgC antibodies and may have been co-selected. Although the N and D regions of one IgM and all five IgG autoantibodies contained Arg residues, the presence of Arg residues was not correlated with binding to dsDNA or with pathogenicity. These results suggest that differences in the Ag-binding properties and the pathogenicity of these antibodies are determined by the CDR3 region and the L chain.