title: A forward genetic screen reveals roles for Nfkbid, Zeb1, and Ruvbl2 in humoral immunity.
abstract: Using chemical germ-line mutagenesis, we screened mice for defects in the humoral immune response to a type II T-independent immunogen and an experimental alphavirus vector. A total of 26 mutations that impair humoral immunity were recovered, and 19 of these mutations have been positionally cloned. Among the phenovariants were bumble, cellophane, and Worker ascribed to mutations in Nfkbid, Zeb1, and Ruvbl2, respectively. We show that IκBNS, the nuclear IκB-like protein encoded by Nfkbid, is required for the development of marginal zone and peritoneal B-1 B cells and additionally required for extrafollicular antibody responses to T-independent and -dependent immunogens. Zeb1 is also required for marginal zone and peritoneal B-1 B-cell development as well as T-cell development, germinal center formation, and memory B-cell responses. Finally, Ruvbl2 is required for T-cell development and maximal T-dependent antibody responses. Collectively, the mutations that we identified give us insight into the points at which disruption of an antibody response can occur. All of the mutations identified to date directly affect lymphocyte development or function; none have an exclusive effect on cells of the innate immune system.
authors: Department of Genetics, The Scripps Research Institute, La Jolla, CA 92037, USA.
authors: Carrie N
authors: CN
authors: Arnold
authors: Elaine
authors: E
authors: Pirie
authors: Pia
authors: P
authors: Dosenovic
authors: Gerald M
authors: GM
authors: McInerney
authors: Yu
authors: Y
authors: Xia
authors: Nathaniel
authors: N
authors: Wang
authors: Xiaohong
authors: X
authors: Li
authors: Owen M
authors: OM
authors: Siggs
authors: Gunilla B
authors: GB
authors: Karlsson Hedestam
authors: Bruce
authors: B
authors: Beutler
mesh_terms: D000074183:ATPases Associated with Diverse Cellular Activities; D000818:Animals; D016175:B-Lymphocyte Subsets / Q000276:immunology*; D002478:Cells, Cultured; D004265:DNA Helicases / Q000235:genetics / Q000276:immunology*; D018398:Homeodomain Proteins / Q000235:genetics / Q000276:immunology*; D056724:Immunity, Humoral / Q000502:physiology*; D007113:Immunity, Innate / Q000502:physiology; D047908:Intracellular Signaling Peptides and Proteins; D051741:Kruppel-Like Transcription Factors / Q000235:genetics / Q000276:immunology*; D051379:Mice; D018345:Mice, Knockout; D009154:Mutation; D011506:Proteins / Q000235:genetics / Q000276:immunology*; D013601:T-Lymphocytes / Q000276:immunology; D000071799:Zinc Finger E-box-Binding Homeobox 1
chemical_list: D000074183:ATPases Associated with Diverse Cellular Activities; D004265:DNA Helicases; D018398:Homeodomain Proteins; D047908:Intracellular Signaling Peptides and Proteins; D051741:Kruppel-Like Transcription Factors; D011506:Proteins; D000071799:Zinc Finger E-box-Binding Homeobox 1; C454819:Nfkbid protein, mouse; C519422:ZEB1 protein, mouse; C518330:RUVBL2 protein, mouse