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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 Antigens¹

Jing Li^*, Luis Fernandez, Kevin C. O’Connor^2,*, Thereza Imanishi-Kari and B. David Stollar^3,*

^* Department of Biochemistry and Division of Immunology, Tufts University School of Medicine and Sackler School of Graduate Biomedical Sciences, Boston, MA 02111

It has been proposed that autoreactivity of modest affinity contributes to positive selection of a preimmunization B cell repertoire, whereas high-affinity 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-protein 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, suggesting that the producing cell may have been selected before and activated during immunization. The dC1V_H transgene was targeted to the IgH locus. In heterozygous mice, on a nonautoimmune C57BL/6 background, the transgene allotype 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 concentrations were normal and included both transgene- and endogenous gene-coded IgM and IgG. The transgene V_H D_HJ_H was expressed in splenic IgM cDNA with few or no mutations, and in IgG cDNA with multiple mutations. The transgene allotype was also expressed in Abs formed on immunization with thyroglobulin, pneumococcal polysaccharide, and ssDNA-methylated BSA. Consistent with the hypothesis, cells with a rearranged autoreactive V_H domain selected for reactivity with a form of ssDNA did serve as precursors for cells producing IgM and IgG Abs to diverse Ags.

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