title: DBC1 is a suppressor of B cell activation by negatively regulating alternative NF-κB transcriptional activity.
abstract: CD40 and BAFFR signaling play important roles in B cell proliferation and Ig production. In this study, we found that B cells from mice with deletion of Dbc1 gene (Dbc1(-/-)) show elevated proliferation, and IgG1 and IgA production upon in vitro CD40 and BAFF, but not BCR and LPS stimulation, indicating that DBC1 inhibits CD40/BAFF-mediated B cell activation in a cell-intrinsic manner. Microarray analysis and chromatin immunoprecipitation experiments reveal that DBC1 inhibits B cell function by selectively suppressing the transcriptional activity of alternative NF-κB members RelB and p52 upon CD40 stimulation. As a result, when immunized with nitrophenylated-keyhole limpet hemocyanin, Dbc1(-/-) mice produce significantly increased levels of germinal center B cells, plasma cells, and Ag-specific Ig. Finally, loss of DBC1 in mice leads to higher susceptibility to experimental autoimmune myasthenia gravis. Our study identifies DBC1 as a novel regulator of B cell activation by suppressing the alternative NF-κB pathway.
authors.affiliation: Department of Pathology, Northwestern University Feinberg School of Medicine, Chicago, IL 60611;
authors.forename: Sinyi
authors.initials: S
authors.lastname: Kong
authors.affiliation: Department of Microbiology and Immunology, University of Illinois College of Medicine, Chicago, Chicago, IL 60612;
authors.forename: Muthusamy
authors.initials: M
authors.lastname: Thiruppathi
authors.affiliation: Department of Pathology, Northwestern University Feinberg School of Medicine, Chicago, IL 60611;
authors.forename: Quan
authors.initials: Q
authors.lastname: Qiu
authors.affiliation: Department of Pathology, Northwestern University Feinberg School of Medicine, Chicago, IL 60611;
authors.forename: Zhenghong
authors.initials: Z
authors.lastname: Lin
authors.affiliation: Department of Pathology, Northwestern University Feinberg School of Medicine, Chicago, IL 60611; Department of Psychiatry and Behavioral Sciences, Northwestern University Feinberg School of Medicine, Chicago, IL 60611; and.
authors.forename: Hongxin
authors.initials: H
authors.lastname: Dong
authors.affiliation: Laboratory of Signal Transduction, Department of Anesthesiology and Robert and Arlene Kogod Center on Aging, Mayo Clinic College of Medicine, Rochester, MN 55905.
authors.forename: Eduardo N
authors.initials: EN
authors.lastname: Chini
authors.affiliation: Department of Microbiology and Immunology, University of Illinois College of Medicine, Chicago, Chicago, IL 60612;
authors.forename: Bellur S
authors.initials: BS
authors.lastname: Prabhakar
authors.affiliation: Department of Pathology, Northwestern University Feinberg School of Medicine, Chicago, IL 60611; fangd@northwestern.edu.
authors.forename: Deyu
authors.initials: D
authors.lastname: Fang
mesh_terms: D000818:Animals; D000917:Antibody Formation / Q000235:genetics; D053264:B-Cell Activating Factor / Q000378:metabolism; D001402:B-Lymphocytes / Q000276:immunology*; D019013:CD40 Antigens / Q000378:metabolism; D018797:Cell Cycle Proteins; D002454:Cell Differentiation / Q000235:genetics; D057809:HEK293 Cells; D006801:Humans; D007108:Immune Tolerance; D008213:Lymphocyte Activation / Q000235:genetics; D051379:Mice; D008815:Mice, Inbred Strains; D018345:Mice, Knockout; D046228:Microarray Analysis; D020720:Myasthenia Gravis, Autoimmune, Experimental / Q000235:genetics / Q000276:immunology*; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism*; D041681:NIH 3T3 Cells; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism*; D010950:Plasma Cells / Q000276:immunology*; D015533:Transcriptional Activation / Q000235:genetics
chemical_list: D053264:B-Cell Activating Factor; C491992:BRINP1 protein, mouse; D019013:CD40 Antigens; D018797:Cell Cycle Proteins; D016328:NF-kappa B; D009419:Nerve Tissue Proteins; C505720:Tnfsf13b protein, mouse