Rap1 Signal Controls B Cell Receptor Repertoire and Generation of Self-Reactive B1a Cells

SummaryWe previously reported that the mice deficient for SPA-1, a Rap1 GTPase-activating protein, developed hematopoietic stem cell disorders. Here, we demonstrate that SPA-1−/− mice show an age-dependent increase in B220high B1a cells producing anti-dsDNA antibody and lupus-like nephritis. SPA-1−/− peritoneal B1 cells revealed the altered Vκ gene repertoire, including skewed Vκ4 usage and the significant Igκ/Igλ isotype inclusion indicative of extensive receptor editing. Rap1GTP induced OcaB gene activation via p38MAPK-dependent Creb phosphorylation, and consistently, SPA-1−/− immature BM B cells showing high Rap1GTP exhibited the augmented expression of OcaB and Vκ4 genes. SPA-1−/− BM cells could transfer the autoimmunity in association with the generation of peritoneal B220high B1a cells in Rag-2−/− recipients. Finally, a portion of SPA-1−/− mice developed B1 cell leukemia with hemolytic autoantibody. Present results suggest that the regulated Rap1 signal in the immature B cells plays a role in modifying the B cell receptor repertoire and in maintaining the self-tolerance.