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Katharina Brandl,
Wataru Tomisato,
Xiaohong Li,
Christina Neppl, Elaine Pirie,
Werner Falk,
Yu Xia,
Eva Marie Y Moresco,
Roberto Baccala,
Argyrios N Theofilopoulos,
Bernd Schnabl,
Bruce Beutler
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ABSTRACT: Using an environmentally sensitized genetic screen we identified mutations that cause inflammatory colitis in mice. The X-linked Klein-Zschocher (KLZ) mutation created a null allele of Yipf6, a member of a gene family believed to regulate vesicular transport in yeast, but without known functions in mammals. Yipf6 is a five transmembrane-spanning protein associated with Golgi compartments. Klein-Zschocher mutants were extremely sensitive to colitis induced by dextran sodium sulfate (DSS) and developed spontaneous ileitis and colitis after 16 mo of age in specific pathogen-free housing conditions. Electron microscopy, gene expression, and immunocytochemistry analyses provided evidence that impaired intestinal homeostasis stemmed from defective formation and secretion of large secretory granules from Paneth and goblet cells. These studies support a tissue- and organ-specific function for Yipf6 in the maintenance of intestinal homeostasis and implicate the orthologous human gene as a disease susceptibility locus.
Proceedings of the National Academy of Sciences 07/2012; 109(31):12650-5. · 9.68 Impact Factor
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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.
Proceedings of the National Academy of Sciences 07/2012; 109(31):12286-93. · 9.68 Impact Factor
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ABSTRACT: B lymphopoiesis begins in the fetal liver, switching after birth to the bone marrow, where it persists for life. The unique developmental outcomes of each phase are well documented, yet their molecular requirements are not. Here we describe two allelic X-linked mutations in mice that caused cell-intrinsic arrest of adult B lymphopoiesis. Mutant fetal liver progenitors generated B cells in situ but not in irradiated adult bone marrow, which emphasizes a necessity for the affected pathway only in the context of adult bone marrow. The causative mutations were ascribed to Atp11c, which encodes a P4-type ATPase with no previously described function. Our data establish an essential, cell-autonomous and context-sensitive function for ATP11C, a putative aminophospholipid flippase, in B cell development.
Nature Immunology 03/2011; 12(5):434-40. · 26.01 Impact Factor
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Owen M Siggs,
Michael Berger,
Philippe Krebs,
Carrie N Arnold,
Celine Eidenschenk,
Christoph Huber, Elaine Pirie,
Nora G Smart,
Kevin Khovananth,
Yu Xia,
Gerald McInerney,
Gunilla B Karlsson Hedestam,
David Nemazee,
Bruce Beutler
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ABSTRACT: Null alleles of the gene encoding NEMO (NF-kappaB essential modulator) are lethal in hemizygous mice and men, whereas hypomorphic alleles typically cause a syndrome of immune deficiency and ectodermal dysplasia. Here we describe an allele of Ikbkg in mice that impaired Toll-like receptor signaling, lymph node formation, development of memory and regulatory T cells, and Ig production, but did not cause ectodermal dysplasia. Degradation of IkappaB alpha, which is considered a primary requirement for NEMO-mediated immune signaling, occurred normally in response to Toll-like receptor stimulation, yet ERK phosphorylation and NF-kappaB p65 nuclear translocation were severely impaired. This selective loss of function highlights the immunological importance of NEMO-regulated pathways beyond IkappaB alpha degradation, and offers a biochemical explanation for rare immune deficiencies in man.
Proceedings of the National Academy of Sciences 02/2010; 107(7):3046-51. · 9.68 Impact Factor
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Owen M. Siggs,
Michael Berger,
Philippe Krebs,
Carrie N. Arnold,
Celine Eidenschenk,
Christoph Huber, Elaine Pirie,
Nora G. Smart,
Kevin Khovananth,
Yu Xia,
Gerald McInerney,
Gunilla B. Karlsson Hedestam,
David Nemazee,
Bruce Beutler
[show abstract]
[hide abstract]
ABSTRACT: Null alleles of the gene encoding NEMO (NF-κB essential modulator) are lethal in hemizygous mice and men, whereas hypomorphic
alleles typically cause a syndrome of immune deficiency and ectodermal dysplasia. Here we describe an allele of Ikbkg in mice that impaired Toll-like receptor signaling, lymph node formation, development of memory and regulatory T cells, and
Ig production, but did not cause ectodermal dysplasia. Degradation of IκBα, which is considered a primary requirement for
NEMO-mediated immune signaling, occurred normally in response to Toll-like receptor stimulation, yet ERK phosphorylation and
NF-κB p65 nuclear translocation were severely impaired. This selective loss of function highlights the immunological importance
of NEMO-regulated pathways beyond IκBα degradation, and offers a biochemical explanation for rare immune deficiencies in man.
Proceedings of the National Academy of Sciences 02/2010; 107(7):3046-3051. · 9.68 Impact Factor
