The Rearranged VH Domain of a Physiologically Selected Anti-Single-Stranded DNA Antibody as a Precursor for Formation of IgM and IgG Antibodies to Diverse Antigens

Abstract

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 VH 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 VH and VL gene segments with no mutations, suggesting that the producing cell may have been selected before and activated during immunization. The dC1VH 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 VH DHJH 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 VH domain selected for reactivity with a form of ssDNA did serve as precursors for cells producing IgM and IgG Abs to diverse Ags.

Naturally occurring B-cell autoreactivity: A critical overview

“…Thus, these recent results support the hypothesis already advanced that since each NAb exhibits a distinct polyreactivity profile that is unique, it might recognize closely related three-dimensional structures [33]. Furthermore, the observation that the amino acid residues within the sites of the paratope of the polyreactive antibody can undergo somatic mutations which are involved in the affinity maturation of the antibody are in accordance with the hypothesis previously raised, that is, some polyreactive NAbs producing cells may be precursors of monoreactive antibody producing cells [20,31,45]. …”

Gammaherpesvirus-infected germinal center cells express a distinct immunoglobulin repertoire

“…In particular, a cationic binding pocket formed by CDR2 has a role (Maranhao et al, 2013). Several autoantibodies where 10-1 participates in binding have also been described (Brigido & Stollar, 1991;Brigido et al, 1993;Li et al, 2001). In humans, EBV has been found in self-reactive cells (Tracy et al, 2012).…”

Production of IgG autoantibody requires expression of activation‐induced deaminase in early‐developing B cells in a mouse model of SLE

“…All experiments with mice were performed in accordance with the regulations and with the approval of Tufts/NEMC IACUC protocol B2012‐50. The creation of 564Igi mice was previously described . Aicda −/− and Aicda tg mice were obtained from Dr. T. Honjo (Kyoto University).…”