The fate of anti-DNA antibodies in non-autoimmune and MRL-lpr/lpr mice

Serum anti-DNA Abs are diagnostic for the autoimmune disease SLE and have been implicated in renal pathology. We have investigated the regulation of anti-DNA B cells in a non-autoimmune (BALB/c) background by using Ig transgenes (Tgs) encoding a variety of anti-DNA Abs. We show that anti-DNA Abs are not expressed in the serum of Tg BALB/c mice due to active regulation of anti-DNA B cells. Furthermore, the regulation of different anti-DNA specificities involves different manifestations. Anti-ssDNA VH3H9/Vk8 Tg B cells are present in the periphery but are phenotypically distinct from normal resting B cells and functionally compromised in vitro. Despite being anergic, however, VH3H9/Vk8 Tg B cells have a normal in vivo turnover rate. VH3H9/Vl2 Tg anti-dsDNA B cells, in contrast, are severely compromised functionally and have an increased in vivo turnover rate. Previously we have observed that MRL-lpr/lpr mice are defective in regulating anti-DNA B cells. We have now crossed the VH3H9 and VH3H9/Vk8 Tgs onto the MRL-lpr/lpr genetic background to examine the impact of their expression or absence on serum Ig titers and specificity and on renal pathology. We find that, in contrast to anti-dsDNA B cells, anti-ssDNA B cells in VH3H9/Vk8 Tg MRL-lpr/lpr mice behave similarly to those in BALB/c mice, suggesting that regulation of this anti-ssDNA specificity is intact in MRL-lpr/lpr mice. While the fate of VH3H9/Vk8 Tg B cells is clear, the effects of the Tgs on serum Ig are more complex, indicating that the behavior of B cells at the population level does not correlate with expressed serum Ig. Lastly, we observe a dramatic reduction in renal pathology in VH3H9/Vk8 Tg MRL-lpr/lpr mice, and a variable effect in VH3H9 Tg animals. We thus conclude that, while B cells or Ig are necessary for renal disease, the presence of B cells per se is not sufficient, and that appropriate specificity or functional competence may play the decisive role