Anti–DNA B Cells in MRL/lpr Mice Show Altered Differentiation and Editing Pattern

We have studied the regulation of anti-DNA B cells in transgenic mice with a heavy chain transgene (3H9H/56R). This transgene codes for a heavy chain that forms anti-double-stranded DNA (dsDNA) antibody when paired with most members of the endogenous Vkappa repertoire, but certain L chains, referred to as Vkappa editors, do not sustain dsDNA binding in combination with 3H9H/56R. In the nonautoimmune 3H9H/56R BALB/c, most B cells generated do not bind DNA because the transgene itself is edited or is associated with a Vkappa editor. A minor population of B cells (30%) bind dsDNA and express the lambda1 light chain (known to sustain 3H9H/56R DNA binding). These 3H9/56R/lambda1 B cells coexpress a kappa editor, and we propose that the down-regulation of the anti-DNA BCR caused by the dual L chain expression may prevent activation of this kappa/lambda population. These kappa/lambda B cells are sequestered in the marginal zone. Here, we studied the influence of autoimmunity on expression and regulation of 3H9H/56R. In 3H9H/56R MRL/lpr mice, the expression of anti-dsDNA is vastly accelerated. Anti-dsDNA B cells use noneditor kappas but, in addition, most anti-dsDNA B cells have edited the heavy chain transgene. lambda1 B cells (without the coexpression of a kappa editor) are found and the kappa/lambda1 MZ population is absent. Our results suggest that improper editing and failure to sequester autoreactive B cells may contribute to the breakdown of tolerance in MRL/lpr mice.