1. Human lymphoma mutations reveal CARD11 as the switch between self-antigen-induced B cell death or proliferation and autoantibody production.
- Author
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Jeelall YS, Wang JQ, Law HD, Domaschenz H, Fung HK, Kallies A, Nutt SL, Goodnow CC, and Horikawa K
- Subjects
- Adoptive Transfer, Animals, Autoantibodies metabolism, Autoantigens metabolism, B-Lymphocytes metabolism, B-Lymphocytes transplantation, Blotting, Western, CARD Signaling Adaptor Proteins genetics, CARD Signaling Adaptor Proteins metabolism, Cell Death immunology, Cell Differentiation immunology, Female, Flow Cytometry, Guanylate Cyclase genetics, Guanylate Cyclase metabolism, Homeodomain Proteins genetics, Homeodomain Proteins immunology, Homeodomain Proteins metabolism, Humans, Immunoglobulin G immunology, Immunoglobulin G metabolism, Lymphoma genetics, Male, Mice, Mice, Inbred C57BL, Mice, Knockout, Mice, Transgenic, Mutation, Plasma Cells immunology, Plasma Cells metabolism, Positive Regulatory Domain I-Binding Factor 1, Transcription Factors genetics, Transcription Factors immunology, Transcription Factors metabolism, Autoantibodies immunology, Autoantigens immunology, B-Lymphocytes immunology, CARD Signaling Adaptor Proteins immunology, Cell Proliferation, Guanylate Cyclase immunology
- 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.
- Published
- 2012
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