SLAP deficiency decreases dsDNA autoantibody production

• Increased BCR signaling due to SLAP deficiency decreases autoantibody production.
• SLAP-deficient mice injected with a dsDNA mimetope do not produce autoantibodies.
• SLAP deficiency decreased autoantibodies in 56R anti-dsDNA Ig heavy chain tg-mice.
• Reduced dsDNA-reactive autoantibody production is due to biased light chain usage.
• Manipulating BCR signaling could be a strategy for treating autoimmune disease.

Src-like adaptor protein (SLAP) adapts c-Cbl, an E3 ubiquitin ligase, to activated components of the BCR signaling complex regulating BCR levels and signaling in developing B cells. Based on this function, we asked whether SLAP deficiency could decrease the threshold for tolerance and eliminate development of autoreactive B cells in two models of autoantibody production. First, we sensitized mice with a dsDNA mimetope that causes an anti-dsDNA response. Despite equivalent production of anti-peptide antibodies compared to BALB/c controls, SLAP−/− mice did not produce anti-dsDNA. Second, we used the 56R tolerance model. SLAP−/− 56R mice had decreased levels of dsDNA-reactive antibodies compared to 56R mice due to skewed light chain usage. Thus, SLAP is a critical regulator of B-cell development and function and its deficiency leads to decreased autoreactive B cells that are otherwise maintained by inefficient receptor editing or failed negative selection.