Uptake of nucleic acid-containing antigens by antigen receptors (BCRs) on B cells leading to endosomal TLR activation is thought to be critical for antinuclear autoantibody (ANA) production in lupus. However, it has been difficult to study this in peripheral B cells that acquire ANA specificity because current ANA BCR models are subjected to central tolerance mechanisms. To overcome this, we generated a FLEx-autoantibody (autoAb) transgenic model in which VH specificity can be changed from a non-self-reactive anti-nitrophenyl (NP) to anti-chromatin (3H9-56R) reactivity following Cre recombinase expression induced by tamoxifen (all B cells) or the activation induced cytidine deaminase promoter (during class-switch recombination/somatic hypermutation). In nonautoimmune C57BL/6 mice, B cells that acquire self-reactivity to chromatin were completely deleted after several days at all stages of development, although numbers of plasma cells were too low to analyze. Faslpr mutation enabled the development of only low levels of anti-id positive (56R+) plasma cells but did not rescue B cells at any other stages of development after tamoxifen. The provision of excess T cell help, through induction of chronic graft-versus-host disease in B6-Faslpr mice resulted in a marked increase in 56R+ plasma cells. These findings suggest that ANA-specificity and engagement of endogenous TLR is not sufficient to rescue autoreactive B cells even in mice with Fas deficiency.
- Copyright © 2013 by The American Association of Immunologists, Inc.