Abstract
Self-tolerance and immunity are actively acquired in parallel through a poorly understood ability of antigen receptors to switch between signaling death or proliferation of antigen-binding lymphocytes in different contexts. It is not known whether this tolerance-immunity switch requires global rewiring of the signaling apparatus or if it can arise from a single molecular change. By introducing individual CARD11 mutations found in human lymphomas into antigen-activated mature B lymphocytes in mice, we find here that lymphoma-derived CARD11 mutations switch the effect of self-antigen from inducing B cell death into T cell-independent proliferation, Blimp1-mediated plasmablast differentiation, and autoantibody secretion. Our findings demonstrate that regulation of CARD11 signaling is a critical switch governing the decision between death and proliferation in antigen-stimulated mature B cells and that mutations in this switch represent a powerful initiator for aberrant B cell responses in vivo.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Adoptive Transfer
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Animals
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Autoantibodies / immunology*
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Autoantibodies / metabolism
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Autoantigens / immunology*
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Autoantigens / metabolism
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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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Blotting, Western
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CARD Signaling Adaptor Proteins / genetics
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CARD Signaling Adaptor Proteins / immunology*
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CARD Signaling Adaptor Proteins / metabolism
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Cell Death / immunology
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Cell Differentiation / immunology
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Cell Proliferation*
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Female
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Flow Cytometry
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Guanylate Cyclase / genetics
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Guanylate Cyclase / immunology*
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Guanylate Cyclase / metabolism
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Homeodomain Proteins / genetics
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Homeodomain Proteins / immunology
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Homeodomain Proteins / metabolism
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Humans
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Immunoglobulin G / immunology
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Immunoglobulin G / metabolism
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Lymphoma / genetics
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Male
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Mice
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Mice, Inbred C57BL
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Mice, Knockout
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Mice, Transgenic
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Mutation
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Plasma Cells / immunology
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Plasma Cells / metabolism
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Positive Regulatory Domain I-Binding Factor 1
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Transcription Factors / genetics
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Transcription Factors / immunology
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Transcription Factors / metabolism
Substances
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Autoantibodies
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Autoantigens
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CARD Signaling Adaptor Proteins
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Homeodomain Proteins
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Immunoglobulin G
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Prdm1 protein, mouse
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Transcription Factors
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RAG-1 protein
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Positive Regulatory Domain I-Binding Factor 1
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CARD11 protein, human
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Guanylate Cyclase