Autoimmune NZB/NZW F1 mice utilize B cell receptor editing for generating high‐affinity anti‐dsDNA autoantibodies from low‐affinity precursors

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Abstract
We have previously constructed knock‐in (C57BL/6×BALB/c) F1 mice, each expressing an anti‐DNA heavy (H) chain (D42), combined with one of three different light (L) chains, namely Vκ1‐Jκ1, Vκ4‐Jκ4 or Vκ8‐Jκ5. All of these H/L chain combinations bind DNA with similar affinity and fine specificity. However, while mice carrying Vκ1‐Jκ1‐transgenic L chain were tolerized almost exclusively by L chain receptor editing, the mice expressing Vκ8‐Jκ5 L chains utilized clonal anergy as their principal mechanism of B cell tolerance. Vκ4‐Jκ4 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.