title: Heterozygous Mutation in IκBNS Leads to Reduced Levels of Natural IgM Antibodies and Impaired Responses to T-Independent Type 2 Antigens.
abstract: Mice deficient in central components of classical NF-κB signaling have low levels of circulating natural IgM antibodies and fail to respond to immunization with T-independent type 2 (TI-2) antigens. A plausible explanation for these defects is the severely reduced numbers of B-1 and marginal zone B (MZB) cells in such mice. By using an ethyl-N-nitrosourea mutagenesis screen, we identified a role for the atypical IκB protein IκBNS in humoral immunity. IκBNS-deficient mice lack B-1 cells and have severely reduced numbers of MZB cells, and thus resemble several other strains with defects in classical NF-κB signaling. We analyzed mice heterozygous for the identified IκBNS mutation and demonstrate that these mice have an intermediary phenotype in terms of levels of circulating IgM antibodies and responses to TI-2 antigens. However, in contrast to mice that are homozygous for the IκBNS mutation, the heterozygous mice had normal frequencies of B-1 and MZB cells. These results suggest that there is a requirement for IκBNS expression from two functional alleles for maintaining normal levels of circulating natural IgM antibodies and responses to TI-2 antigens.
authors.affiliation: Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet , Stockholm , Sweden.
authors.forename: Gabriel K
authors.initials: GK
authors.lastname: Pedersen
authors.affiliation: Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet , Stockholm , Sweden.
authors.forename: Monika
authors.initials: M
authors.lastname: Ádori
authors.affiliation: Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet , Stockholm , Sweden.
authors.forename: Julian M
authors.initials: JM
authors.lastname: Stark
authors.affiliation: Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet , Stockholm , Sweden.
authors.forename: Sharesta
authors.initials: S
authors.lastname: Khoenkhoen
authors.affiliation: Department of Genetics, The Scripps Research Institute , La Jolla, CA , USA.
authors.forename: Carrie
authors.initials: C
authors.lastname: Arnold
authors.affiliation: Center for the Genetics of Host Defense, University of Texas Southwestern Medical Center , Dallas, TX , USA.
authors.forename: Bruce
authors.initials: B
authors.lastname: Beutler
authors.affiliation: Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet , Stockholm , Sweden.
authors.forename: Gunilla B
authors.initials: GB
authors.lastname: Karlsson Hedestam
keywords: B-1 cells; IκBNS; NF-κB; nfkbid; transitional B cells