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

• Published in: Immunity (Cambridge, Mass.) Mass.), 2006-04, Vol.24 (4), p.417-427
• Main Authors: Ishida, Daisuke, Su, Li, Tamura, Akitoshi, Katayama, Yoshinori, Kawai, Yohei, Wang, Shu-Fang, Taniwaki, Masafumi, Hamazaki, Yoko, Hattori, Masakazu, Minato, Nagahiro
• Format: Article
• Language: English
• Subjects: Age; Animals; Antibodies, Antinuclear - immunology; Antibody Diversity - immunology; Autoimmunity; B-Lymphocytes - immunology; Binding sites; CELLIMMUNO; Cloning; CREB-Binding Protein - immunology; CREB-Binding Protein - metabolism; Enzyme-Linked Immunosorbent Assay; Gene Rearrangement, B-Lymphocyte - immunology; GTPase-Activating Proteins - immunology; GTPase-Activating Proteins - metabolism; HUMDISEASE; Immune Tolerance; Immunoblotting; Kinases; Leukemia, B-Cell - genetics; Lupus; Lupus Nephritis - genetics; Lymphocytes; Mice; Mice, Transgenic; MOLIMMUNO; Nuclear Proteins - immunology; Nuclear Proteins - metabolism; p38 Mitogen-Activated Protein Kinases - immunology; p38 Mitogen-Activated Protein Kinases - metabolism; Phosphorylation; Proteins; Receptors, Antigen, B-Cell - genetics; Receptors, Antigen, B-Cell - immunology; Reverse Transcriptase Polymerase Chain Reaction; T cell receptors; Trans-Activators - immunology; Trans-Activators - metabolism
• ISSN: 1074-7613; 1097-4180
• 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 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 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.