Human lymphoma mutations reveal CARD11 as the switch between self-antigen-induced B cell death or proliferation and autoantibody production

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 rewir...

Full description

Saved in:
Bibliographic Details
Published in:The Journal of experimental medicine 2012-10, Vol.209 (11), p.1907-1917
Main Authors: Jeelall, Yogesh S, Wang, James Q, Law, Hsei-Di, Domaschenz, Heather, Fung, Herman K H, Kallies, Axel, Nutt, Stephen L, Goodnow, Christopher C, Horikawa, Keisuke
Format: Article
Language:English
Subjects:
Adoptive Transfer
Animals
Autoantibodies - immunology
Autoantibodies - metabolism
Autoantigens - immunology
Autoantigens - metabolism
B-Lymphocytes - immunology
B-Lymphocytes - metabolism
B-Lymphocytes - transplantation
Blotting, Western
Brief Definitive Report
CARD Signaling Adaptor Proteins - genetics
CARD Signaling Adaptor Proteins - immunology
CARD Signaling Adaptor Proteins - metabolism
Cell Death - immunology
Cell Differentiation - immunology
Cell Proliferation
Female
Flow Cytometry
Guanylate Cyclase - genetics
Guanylate Cyclase - immunology
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
Citations: Items that this one cites
Items that cite this one
Online Access:Get full text
Tags: Add Tag
No Tags, Be the first to tag this record!
Description
Summary: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.
ISSN:0022-1007
1540-9538
DOI:10.1084/jem.20112744