Autoimmune NZB/NZW F1 mice utilize B cell receptor editing for generating high-affinity anti-dsDNA autoantibodies...

We have previously constructed knock-in (C57BL/6xBALB/c) F1 mice, each expressing an anti-DNA heavy (H) chain (D42), combined with one of three different light (L) chains, namely Vkappa1-Jkappa1, Vkappa4-Jkappa4 or Vkappa8-Jkappa5. All of these H/L chain combinations bind DNA with similar affinity and fine specificity. However, while mice carrying Vkappa1-Jkappa1-transgenic L chain were tolerized almost exclusively by L chain receptor editing, the mice expressing Vkappa8-Jkappa5 L chains utilized clonal anergy as their principal mechanism of B cell tolerance. Vkappa4-Jkappa4 targeted mice exhibited an intermediate phenotype. In the present study, these three H/L chain combinations were backcrossed onto the autoimmune NZB/NZW F1 mice. We find that the mechanism of clonal anergy is abrogated in these mice, but that receptor editing is maintained. Moreover, diseased NZB/NZW mice utilize L chain secondary rearrangements for the generation of high-affinity, anti-dsDNA-producing B cells from low-affinity precursors. The edited B cell clones are not deleted or anergized in the autoimmune animal; rather they are selected for activation, class-switching and affinity maturation by somatic mutation. These results suggest that B cell receptor editing plays an important role not only in tolerance induction, but also in generating high-affinity autoreactive B cells in autoimmune diseases.