Rap1 signal controls B cell receptor repertoire and generation of self-reactive B1a cells

Immunity. 2006 Apr;24(4):417-27. doi: 10.1016/j.immuni.2006.02.007.


We 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 B220(high) B1a cells producing anti-dsDNA antibody and lupus-like nephritis. SPA-1(-/-) peritoneal B1 cells revealed the altered Vkappa gene repertoire, including skewed Vkappa4 usage and the significant Igkappa/Iglambda 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 Vkappa4 genes. SPA-1(-/-) BM cells could transfer the autoimmunity in association with the generation of peritoneal B220(high) 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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antibodies, Antinuclear / immunology
  • Antibody Diversity / immunology*
  • Autoimmunity*
  • B-Lymphocytes / immunology*
  • CREB-Binding Protein / immunology
  • CREB-Binding Protein / metabolism
  • Enzyme-Linked Immunosorbent Assay
  • GTPase-Activating Proteins / immunology
  • GTPase-Activating Proteins / metabolism*
  • Gene Rearrangement, B-Lymphocyte / immunology
  • Immune Tolerance
  • Immunoblotting
  • Leukemia, B-Cell / genetics*
  • Lupus Nephritis / genetics
  • Mice
  • Mice, Transgenic
  • Nuclear Proteins / immunology
  • Nuclear Proteins / metabolism*
  • Phosphorylation
  • Receptors, Antigen, B-Cell / genetics*
  • Receptors, Antigen, B-Cell / immunology
  • Reverse Transcriptase Polymerase Chain Reaction
  • Trans-Activators / immunology
  • Trans-Activators / metabolism
  • p38 Mitogen-Activated Protein Kinases / immunology
  • p38 Mitogen-Activated Protein Kinases / metabolism


  • Antibodies, Antinuclear
  • GTPase-Activating Proteins
  • Nuclear Proteins
  • Pou2af1 protein, mouse
  • Receptors, Antigen, B-Cell
  • Sipa1 protein, mouse
  • Trans-Activators
  • CREB-Binding Protein
  • Crebbp protein, mouse
  • p38 Mitogen-Activated Protein Kinases