Rap1 signal controls B cell receptor repertoire and generation of self-reactive B1a cells.
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.
Ishida
Daisuke
D
Department of Immunology and Cell Biology, Graduate School of Biostudies, Kyoto University, Kyoto 606-8501, Japan.
Su
Li
L
Tamura
Akitoshi
A
Katayama
Yoshinori
Y
Kawai
Yohei
Y
Wang
Shu-Fang
SF
Taniwaki
Masafumi
M
Hamazaki
Yoko
Y
Hattori
Masakazu
M
Minato
Nagahiro
N
D000818:Animals; D000974:Antibodies, Antinuclear / Q000276:immunology; D000916:Antibody Diversity / Q000276:immunology*; D015551:Autoimmunity; D001402:B-Lymphocytes / Q000276:immunology*; D050882:CREB-Binding Protein / Q000276:immunology / Q000378:metabolism; D004797:Enzyme-Linked Immunosorbent Assay; D020690:GTPase-Activating Proteins / Q000276:immunology / Q000378:metabolism*; D015322:Gene Rearrangement, B-Lymphocyte / Q000276:immunology; D007108:Immune Tolerance; D015151:Immunoblotting; D015448:Leukemia, B-Cell / Q000235:genetics*; D008181:Lupus Nephritis / Q000235:genetics; D051379:Mice; D008822:Mice, Transgenic; D009687:Nuclear Proteins / Q000276:immunology / Q000378:metabolism*; D010766:Phosphorylation; D011947:Receptors, Antigen, B-Cell / Q000235:genetics* / Q000276:immunology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015534:Trans-Activators / Q000276:immunology / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases / Q000276:immunology / Q000378:metabolism
D000974:Antibodies, Antinuclear; D020690:GTPase-Activating Proteins; D009687:Nuclear Proteins; C490424:Pou2af1 protein, mouse; D011947:Receptors, Antigen, B-Cell; C091108:Sipa1 protein, mouse; D015534:Trans-Activators; D050882:CREB-Binding Protein; C494364:Crebbp protein, mouse; D048051:p38 Mitogen-Activated Protein Kinases