title: BH3-only protein Noxa regulates apoptosis in activated B cells and controls high-affinity antibody formation.
abstract: The efficiency of humoral immune responses depends on the selective outgrowth of B cells and plasma cells that produce high affinity antibodies. The factors responsible for affinity maturation of B cell clones in the germinal center (GC) have been well established but selection mechanisms that allow clones to enter the GC are largely unknown. Here we identify apoptosis, regulated by the proapoptotic BH3-only member Noxa (Pmaip1), as a critical factor for the selection of high-affinity clones during B cell expansion after antigen triggering. Noxa is induced in activated B cells, and its ablation provides a survival advantage both in vitro and in vivo. After immunization or influenza infection, Noxa(-/-) mice display enlarged GCs, in which B cells with reduced antigen affinity accumulate. As a consequence, Noxa(-/-) mice mount low affinity antibody responses compared with wild-type animals. Importantly, the low affinity responses correlate with increased immunoglobulin diversity, and cannot be corrected by booster immunization. Thus, normal elimination of low affinity cells favors outgrowth of the remaining high-affinity clones, and this is mandatory for the generation of proper antibody responses. Manipulation of this process may alter the breadth of antibody responses after immunization.
authors.affiliation: Department of Experimental Immunology, Academic Medical Center, Meibergdreef 9, Amsterdam, The Netherlands.
authors.forename: Felix M
authors.initials: FM
authors.lastname: Wensveen
authors.forename: Ingrid A M
authors.initials: IA
authors.lastname: Derks
authors.forename: Klaas P J M
authors.initials: KP
authors.lastname: van Gisbergen
authors.forename: Alex M
authors.initials: AM
authors.lastname: de Bruin
authors.forename: Joost C M
authors.initials: JC
authors.lastname: Meijers
authors.forename: HaciAli
authors.initials: H
authors.lastname: Yigittop
authors.forename: Martijn A
authors.initials: MA
authors.lastname: Nolte
authors.forename: Eric
authors.initials: E
authors.lastname: Eldering
authors.forename: René A W
authors.initials: RA
authors.lastname: van Lier
mesh_terms: D000818:Animals; D000915:Antibody Affinity / Q000276:immunology; D000917:Antibody Formation / Q000276:immunology*; D017209:Apoptosis / Q000235:genetics / Q000276:immunology*; D001402:B-Lymphocytes / Q000276:immunology* / Q000378:metabolism; D002470:Cell Survival / Q000235:genetics / Q000276:immunology; D002478:Cells, Cultured; D005260:Female; D005434:Flow Cytometry; D015870:Gene Expression; D018858:Germinal Center / Q000276:immunology / Q000378:metabolism; D006241:Haptens; D006433:Hemocyanins / Q000276:immunology; D007114:Immunization / Q000379:methods; D007074:Immunoglobulin G / Q000097:blood / Q000276:immunology; D008213:Lymphocyte Activation / Q000276:immunology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010950:Plasma Cells / Q000276:immunology / Q000378:metabolism; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000172:deficiency / Q000235:genetics / Q000276:immunology*; D011947:Receptors, Antigen, B-Cell / Q000276:immunology / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: D006241:Haptens; D007074:Immunoglobulin G; C408009:Pmaip1 protein, mouse; D019253:Proto-Oncogene Proteins c-bcl-2; D011947:Receptors, Antigen, B-Cell; C054401:trinitrophenyl keyhole limpet hemocyanin; D006433:Hemocyanins