title: Human lymphoma mutations reveal CARD11 as the switch between self-antigen-induced B cell death or proliferation and autoantibody production.
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.
authors.affiliation: Department of Immunology and Genetics, John Curtin School of Medical Research, The Australian National University, Canberra, Australian Capital Territory 2601, Australia.
authors.forename: Yogesh S
authors.initials: YS
authors.lastname: Jeelall
authors.forename: James Q
authors.initials: JQ
authors.lastname: Wang
authors.forename: Hsei-Di
authors.initials: HD
authors.lastname: Law
authors.forename: Heather
authors.initials: H
authors.lastname: Domaschenz
authors.forename: Herman K H
authors.initials: HK
authors.lastname: Fung
authors.forename: Axel
authors.initials: A
authors.lastname: Kallies
authors.forename: Stephen L
authors.initials: SL
authors.lastname: Nutt
authors.forename: Christopher C
authors.initials: CC
authors.lastname: Goodnow
authors.forename: Keisuke
authors.initials: K
authors.lastname: Horikawa
mesh_terms: D019264:Adoptive Transfer; D000818:Animals; D001323:Autoantibodies / Q000276:immunology* / Q000378:metabolism; D001324:Autoantigens / Q000276:immunology* / Q000378:metabolism; D001402:B-Lymphocytes / Q000276:immunology* / Q000378:metabolism / Q000637:transplantation; D015153:Blotting, Western; D053468:CARD Signaling Adaptor Proteins / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D016923:Cell Death / Q000276:immunology; D002454:Cell Differentiation / Q000276:immunology; D049109:Cell Proliferation; D005260:Female; D005434:Flow Cytometry; D006162:Guanylate Cyclase / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D018398:Homeodomain Proteins / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D006801:Humans; D007074:Immunoglobulin G / Q000276:immunology / Q000378:metabolism; D008223:Lymphoma / Q000235:genetics; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D009154:Mutation; D010950:Plasma Cells / Q000276:immunology / Q000378:metabolism; D000074462:Positive Regulatory Domain I-Binding Factor 1; D014157:Transcription Factors / Q000235:genetics / Q000276:immunology / Q000378:metabolism
chemical_list: D001323:Autoantibodies; D001324:Autoantigens; D053468:CARD Signaling Adaptor Proteins; D018398:Homeodomain Proteins; D007074:Immunoglobulin G; C513258:Prdm1 protein, mouse; D014157:Transcription Factors; C064658:RAG-1 protein; D000074462:Positive Regulatory Domain I-Binding Factor 1; C426242:CARD11 protein, human; D006162:Guanylate Cyclase