The rearranged V-H domain of a physiologically selected anti-single-stranded DNA antibody as a precursor for formation of IgM and IgG antibodies to diverse antigens

It has been proposed that autoreactivity of modest affinity contributes to positive selection of a preimmunization B cell repertoire, whereas high-aff inity autoreactivity leads to negative selection. This hypothesis predicts that a B cell producing a physiologically selected unmutated ssDNA-binding Ab should be a precursor of cells that respond to diverse exogenous Ags. To test this prediction, we prepared transgenic mice bearing the rearranged V -H domain of an IgM Ab from a nonautoimmune mouse immunized with a DNA-prot ein complex, poly(dC)-methylated BSA. The Ab, dC1, binds both poly(dC) and ssDNA. It is encoded by V-H and V-L gene segments with no mutations, sugges ting that the producing cell may have been selected before and activated du ring immunization. The dC1V(H) transgene was targeted to the IgH locus. In heterozygous mice, on a nonautoimmune C57BL/6 background, the transgene all otype was expressed on B cell surfaces and in serum Ig, but about one-third of B cells expressed the endogenous allele instead. Total serum Ig concent rations were normal and included both transgene- and endogenous gene-coded IgM and IgG. The transgene V-H D(H)J(H) was expressed in splenic IgM cDNA w ith few or no mutations, and in IgG cDNA with multiple mutations. The trans gene allotype was also expressed in Abs formed on immunization with thyrogl obulin, pneumococcal polysaccharide, and ssDNA-methylated BSA. Consistent w ith the hypothesis, cells with a rearranged autoreactive V-H domain selecte d for reactivity with a form of ssDNA did serve as precursors for cells pro ducing IgM and IgG Abs to diverse Ags.