Abstract
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
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Antibodies, Antinuclear / immunology
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Antibody Diversity / immunology*
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Autoimmunity*
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B-Lymphocytes / immunology*
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CREB-Binding Protein / immunology
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CREB-Binding Protein / metabolism
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Enzyme-Linked Immunosorbent Assay
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GTPase-Activating Proteins / immunology
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GTPase-Activating Proteins / metabolism*
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Gene Rearrangement, B-Lymphocyte / immunology
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Immune Tolerance
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Immunoblotting
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Leukemia, B-Cell / genetics*
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Lupus Nephritis / genetics
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Mice
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Mice, Transgenic
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Nuclear Proteins / immunology
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Nuclear Proteins / metabolism*
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Phosphorylation
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Receptors, Antigen, B-Cell / genetics*
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Receptors, Antigen, B-Cell / immunology
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Reverse Transcriptase Polymerase Chain Reaction
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Trans-Activators / immunology
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Trans-Activators / metabolism
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p38 Mitogen-Activated Protein Kinases / immunology
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p38 Mitogen-Activated Protein Kinases / metabolism
Substances
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Antibodies, Antinuclear
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GTPase-Activating Proteins
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Nuclear Proteins
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Pou2af1 protein, mouse
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Receptors, Antigen, B-Cell
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Sipa1 protein, mouse
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Trans-Activators
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CREB-Binding Protein
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Crebbp protein, mouse
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p38 Mitogen-Activated Protein Kinases