Abstract
Survival of mature B cells is regulated by B cell receptor and BAFFR-dependent signals. We show that B cells from mice lacking the G(alphaq) subunit of trimeric G proteins (Gnaq(-/-) mice) have an intrinsic survival advantage over normal B cells, even in the absence of BAFF. Gnaq(-/-) B cells develop normally in the bone marrow but inappropriately survive peripheral tolerance checkpoints, leading to the accumulation of transitional, marginal zone, and follicular B cells, many of which are autoreactive. Gnaq(-/-) chimeric mice rapidly develop arthritis as well as other manifestations of systemic autoimmune disease. Importantly, we demonstrate that the development of the autoreactive B cell compartment is the result of an intrinsic defect in Gnaq(-/-) B cells, resulting in the aberrant activation of the prosurvival factor Akt. Together, these data show for the first time that signaling through trimeric G proteins is critically important for maintaining control of peripheral B cell tolerance induction and repressing autoimmunity.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Anemia / blood
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Anemia / immunology
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Animals
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Antibodies, Anti-Idiotypic / immunology
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Antibodies, Antinuclear / blood
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Antibodies, Antinuclear / immunology
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Antibodies, Monoclonal / immunology
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Antibodies, Monoclonal / pharmacology
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Antigen-Antibody Complex / metabolism
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Arthritis / immunology
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Arthritis / pathology
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Autoantigens / immunology
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Autoimmune Diseases / genetics
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Autoimmune Diseases / immunology
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Autoimmune Diseases / mortality
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Autoimmune Diseases / pathology
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Autoimmunity / genetics
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Autoimmunity / immunology*
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B-Cell Activating Factor / immunology
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B-Cell Activating Factor / pharmacology
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B-Lymphocyte Subsets / cytology
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B-Lymphocytes / cytology*
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B-Lymphocytes / drug effects
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B-Lymphocytes / immunology*
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B-Lymphocytes / metabolism
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B-Lymphocytes / transplantation
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Cell Differentiation / genetics
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Cell Differentiation / immunology*
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Cell Movement / genetics
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Cell Movement / immunology
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Cell Survival / genetics
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Cell Survival / immunology
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GTP-Binding Protein alpha Subunits, Gq-G11 / genetics*
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Heterotrimeric GTP-Binding Proteins / physiology*
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Homeostasis / immunology
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Immune Tolerance*
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Kidney / metabolism
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Kidney / pathology
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Lymphocyte Activation / genetics
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Lymphocyte Activation / immunology
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Mice
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Mice, Inbred C57BL
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Mice, Knockout
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Proto-Oncogene Proteins c-akt / metabolism
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Radiation Chimera / immunology
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Receptors, Antigen, B-Cell / immunology
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Spleen / cytology
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Spleen / drug effects
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T-Lymphocytes / cytology
Substances
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Antibodies, Anti-Idiotypic
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Antibodies, Antinuclear
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Antibodies, Monoclonal
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Antigen-Antibody Complex
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Autoantigens
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B-Cell Activating Factor
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Receptors, Antigen, B-Cell
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Tnfsf13b protein, mouse
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anti-IgM
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Proto-Oncogene Proteins c-akt
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GTP-Binding Protein alpha Subunits, Gq-G11
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Heterotrimeric GTP-Binding Proteins