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A forward genetic screen reveals roles for Nfkbid, Zeb1, and Ruvbl2 in humoral immunity.

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.

Pubmed ID: 22761313


  • Arnold CN
  • Pirie E
  • Dosenovic P
  • McInerney GM
  • Xia Y
  • Wang N
  • Li X
  • Siggs OM
  • Karlsson Hedestam GB
  • Beutler B


Proceedings of the National Academy of Sciences of the United States of America

Publication Data

July 31, 2012

Associated Grants

  • Agency: NIGMS NIH HHS, Id: R37 GM067759

Mesh Terms

  • Animals
  • B-Lymphocyte Subsets
  • Cells, Cultured
  • DNA Helicases
  • Homeodomain Proteins
  • Immunity, Humoral
  • Immunity, Innate
  • Kruppel-Like Transcription Factors
  • Mice
  • Mice, Knockout
  • Mutation
  • Proteins
  • T-Lymphocytes