DELETION AND EDITING OF B-CELLS THAT EXPRESS ANTIBODIES TO DNA

We previously demonstrated that in m ice transgenic for genes coding f or an anti-ssDNA autoantibody B cells were functionally inactivated bu t not physically deleted. We have now extended this model by introduci ng an arginine into the CDR2 of the heavy chain transgene. This change alters the specificity of the Ab from anti-ssDNA to anti-dsDNA and in creases the affinity for ssDNA. Mice carrying this transgene displayed a significant reduction of peripheral B cells and anti-dsDNA B cells were not recovered from the spleens. The remaining B cells escape dele tion by revising their Ag receptors in several ways: 1) elimination of the transgenic heavy chain gene via intrachromosomal recombination, f ollowed by rearrangement and expression of endogenous V-H genes; 2) on going rearrangement of endogenous kappa light chain genes to generate a non-dsDNA-binding Ab; and 3) expression of a rare V lambda gene, V l ambda x, to generate a non-DNA-binding Ab.