Abstract
In non-autoimmune mice, the 3H9 transgenic Ig heavy chain can pair with endogenous Iglambda1 light chains to generate B cells with specificity for DNA. These autoreactive cells are actively regulated in vivo, as indicated by the exclusion of lambda1 cells from the splenic B cell follicle and the absence of auto-antibody production. To study the role of Fcgamma receptor IIb (FcgammaRIIb) in peripheral B cell tolerance, FcgammaRIIb(-/-) mice were crossed with C57BL/6 mice bearing a site-directed knock-in of the 3H9 transgene. 3H9FcgammaRIIb(-/-) mice become autoreactive, lose the follicular exclusion of anti-DNA B cells and instead have lambda1 B cells located within splenic germinal centers. They have increased frequencies of splenic auto-antibody-producing cells and elevated titers of IgG anti-DNA auto-antibody. The data implicate an FcgammaRIIb-dependent checkpoint that can exclude autoreactive B cells from splenic follicles. By restricting their participation in germinal center reactions, this putative checkpoint helps attenuate the production of potentially pathogenic auto-antibodies. The data further suggest that this FcgammaRIIb-dependent regulation is B cell autonomous.
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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Age Factors
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Animals
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Antibodies, Antinuclear / analysis
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Antibodies, Antinuclear / blood
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Antibodies, Antinuclear / genetics
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Antibodies, Antinuclear / immunology
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Antibodies, Antiphospholipid / analysis
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Antibodies, Antiphospholipid / genetics
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Antibodies, Antiphospholipid / immunology
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Autoimmunity / immunology*
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B-Lymphocytes / immunology*
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B-Lymphocytes / metabolism
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Bone Marrow Transplantation / immunology
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Female
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Germinal Center / cytology
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Germinal Center / immunology
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Homeodomain Proteins / analysis
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Homeodomain Proteins / genetics
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Immunoglobulin D / analysis
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Immunoglobulin M / analysis
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Immunoglobulin lambda-Chains / analysis
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Immunophenotyping
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Male
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Mice
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Mice, Inbred BALB C
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Mice, Knockout
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Mice, Transgenic
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Receptors, Complement 3d / analysis
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Receptors, IgE / analysis
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Receptors, IgG / genetics
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Receptors, IgG / immunology*
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Self Tolerance / immunology*
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Spleen / cytology
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Spleen / immunology
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Syndecan-1 / analysis
Substances
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3H9 protein, mouse
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Antibodies, Antinuclear
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Antibodies, Antiphospholipid
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Fcgr2b protein, mouse
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Homeodomain Proteins
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Immunoglobulin D
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Immunoglobulin M
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Immunoglobulin lambda-Chains
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Receptors, Complement 3d
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Receptors, IgE
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Receptors, IgG
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Sdc1 protein, mouse
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Syndecan-1
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RAG-1 protein