Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 6 de 6
Filtrar
Mais filtros

Base de dados
Tipo de documento
Assunto da revista
País de afiliação
Intervalo de ano de publicação
1.
Nat Immunol ; 11(4): 335-43, 2010 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-20190759

RESUMO

Here we describe a previously unknown form of inherited immunodeficiency revealed by an N-ethyl-N-nitrosourea-induced mutation called elektra. Mice homozygous for this mutation showed enhanced susceptibility to bacterial and viral infection and diminished numbers of T cells and inflammatory monocytes that failed to proliferate after infection and died via the intrinsic apoptotic pathway in response to diverse proliferative stimuli. They also had a greater proportion of T cells poised to replicate DNA, and their T cells expressed a subset of activation markers, suggestive of a semi-activated state. We positionally ascribe the elektra phenotype to a mutation in the gene encoding Schlafen-2 (Slfn2). Our findings identify a physiological role for Slfn2 in the defense against pathogens through the regulation of quiescence in T cells and monocytes.


Assuntos
Proteínas de Ciclo Celular/genética , Proteínas de Ciclo Celular/imunologia , Síndromes de Imunodeficiência/genética , Síndromes de Imunodeficiência/imunologia , Leucócitos Mononucleares/imunologia , Linfócitos T/imunologia , Animais , Apoptose/imunologia , Sequência de Bases , Separação Celular , Citometria de Fluxo , Ativação Linfocitária/imunologia , Camundongos , Camundongos Transgênicos , Mutação , Fenótipo , Transdução de Sinais/imunologia
2.
Proc Natl Acad Sci U S A ; 107(7): 3046-51, 2010 Feb 16.
Artigo em Inglês | MEDLINE | ID: mdl-20133626

RESUMO

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.


Assuntos
Síndromes de Imunodeficiência/genética , Peptídeos e Proteínas de Sinalização Intracelular/genética , Mutação/genética , Transdução de Sinais/genética , Animais , Western Blotting , Citocinas/metabolismo , Etilnitrosoureia , Citometria de Fluxo , Quinase I-kappa B/metabolismo , Peptídeos e Proteínas de Sinalização Intracelular/imunologia , Linfonodos/crescimento & desenvolvimento , Masculino , Camundongos , Camundongos Transgênicos , Mutagênese , Óxido Nítrico/metabolismo , Transdução de Sinais/imunologia , Linfócitos T Reguladores , Receptores Toll-Like/metabolismo
3.
J Immunol ; 184(7): 3743-54, 2010 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-20190135

RESUMO

Homeostatic control of the immune system involves mechanisms that ensure the self-tolerance, survival and quiescence of hematopoietic-derived cells. In this study, we demonstrate that the GTPase of immunity associated protein (Gimap)5 regulates these processes in lymphocytes and hematopoietic progenitor cells. As a consequence of a recessive N-ethyl-N-nitrosourea-induced germline mutation in the P-loop of Gimap5, lymphopenia, hepatic extramedullary hematopoiesis, weight loss, and intestinal inflammation occur in homozygous mutant mice. Irradiated fetal liver chimeric mice reconstituted with Gimap5-deficient cells lose weight and become lymphopenic, demonstrating a hematopoietic cell-intrinsic function for Gimap5. Although Gimap5-deficient CD4(+) T cells and B cells appear to undergo normal development, they fail to proliferate upon Ag-receptor stimulation although NF-kappaB, MAP kinase and Akt activation occur normally. In addition, in Gimap5-deficient mice, CD4(+) T cells adopt a CD44(high)CD62L(low)CD69(low) phenotype and show reduced IL-7ralpha expression, and T-dependent and T-independent B cell responses are abrogated. Thus, Gimap5-deficiency affects a noncanonical signaling pathway required for Ag-receptor-induced proliferation and lymphocyte quiescence. Antibiotic-treatment or the adoptive transfer of Rag-sufficient splenocytes ameliorates intestinal inflammation and weight loss, suggesting that immune responses triggered by microbial flora causes the morbidity in Gimap5-deficient mice. These data establish Gimap5 as a key regulator of hematopoietic integrity and lymphocyte homeostasis.


Assuntos
Linfócitos B/imunologia , Colite/imunologia , GTP Fosfo-Hidrolases/imunologia , Linfócitos T/imunologia , Síndrome de Emaciação/imunologia , Animais , Subpopulações de Linfócitos B/imunologia , Colite/genética , Feminino , GTP Fosfo-Hidrolases/genética , Proteínas de Ligação ao GTP , Hematopoese/genética , Hematopoese/imunologia , Células-Tronco Hematopoéticas/imunologia , Homeostase/genética , Homeostase/imunologia , Immunoblotting , Inflamação/genética , Inflamação/imunologia , Intestinos/imunologia , Intestinos/microbiologia , Intestinos/patologia , Hepatopatias/genética , Hepatopatias/imunologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Mutantes , Tolerância a Antígenos Próprios/imunologia , Transdução de Sinais/genética , Transdução de Sinais/imunologia , Subpopulações de Linfócitos T/imunologia , Síndrome de Emaciação/genética
4.
Proc Natl Acad Sci U S A ; 106(8): 2706-11, 2009 Feb 24.
Artigo em Inglês | MEDLINE | ID: mdl-19202056

RESUMO

The classical recessive coat color mutation misty (m) arose spontaneously on the DBA/J background and causes generalized hypopigmentation and localized white-spotting in mice, with a lack of pigment on the belly, tail tip, and paws. Here we describe moonlight (mnlt), a second hypopigmentation and white-spotting mutation identified on the C57BL/6J background, which yields a phenotypic copy of m/m coat color traits. We demonstrate that the 2 mutations are allelic. m/m and mnlt/mnlt phenotypes both result from mutations that truncate the dedicator of cytokinesis 7 protein (DOCK7), a widely expressed Rho family guanine nucleotide exchange factor. Although Dock7 is transcribed at high levels in the developing brain and has been implicated in both axon development and myelination by in vitro studies, we find no requirement for DOCK7 in neurobehavioral function in vivo. However, DOCK7 has non-redundant role(s) related to the distribution and function of dermal and follicular melanocytes.


Assuntos
Fatores de Troca do Nucleotídeo Guanina/genética , Mutação , Fenômenos Fisiológicos do Sistema Nervoso , Transtornos da Pigmentação/genética , Animais , Sequência de Bases , Comportamento Animal , Feminino , Proteínas Ativadoras de GTPase , Masculino , Camundongos , Camundongos Endogâmicos C3H , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos DBA , Dados de Sequência Molecular
5.
J Immunol ; 183(12): 7975-83, 2009 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-19923465

RESUMO

Sluggish was identified in a population of third generation mice descended from N-ethyl-N-nitrosourea-mutagenized sires. Macrophages from homozygotes exhibited impaired TNF-alpha production in response to all TLR ligands tested and displayed impaired type I IFN production in response to TLR7 and TLR9 stimulations. The phenotype was confined to a critical region on mouse chromosome 18 and then ascribed to a T to A transversion in the acceptor splice site of intron 4 at position 13346 of the Map3k8 gene, resulting in defective splicing. The Map3k8(Sluggish) mutation does not result in susceptibility to viral infections, but Sluggish mice displayed high susceptibility to group B streptococcus infection, with impaired TNF-alpha and type I IFN production in infected macrophages. Our data demonstrate that the encoded protein kinase Tpl2 plays an essential role in cell signaling in the immune response to certain pathogens.


Assuntos
Etilnitrosoureia , Predisposição Genética para Doença , Interferon Tipo I/antagonistas & inibidores , MAP Quinase Quinase Quinases/genética , Mutagênese , Proteínas Proto-Oncogênicas/genética , Infecções Estreptocócicas/enzimologia , Infecções Estreptocócicas/imunologia , Streptococcus agalactiae/imunologia , Animais , Infecções por Herpesviridae/genética , Infecções por Herpesviridae/imunologia , Interferon Tipo I/biossíntese , Listeriose/genética , Listeriose/imunologia , MAP Quinase Quinase Quinases/fisiologia , Masculino , Camundongos , Camundongos Endogâmicos C3H , Camundongos Endogâmicos C57BL , Camundongos Knockout , Camundongos Transgênicos , Muromegalovirus/imunologia , Mutagênese/imunologia , Proteínas Proto-Oncogênicas/fisiologia , Splicing de RNA/genética , Transdução de Sinais/genética , Transdução de Sinais/imunologia , Infecções Estreptocócicas/genética
6.
Science ; 320(5879): 1088-92, 2008 May 23.
Artigo em Inglês | MEDLINE | ID: mdl-18451267

RESUMO

Hepcidin, a liver-derived protein that restricts enteric iron absorption, is the key regulator of body iron content. Several proteins induce expression of the hepcidin-encoding gene Hamp in response to infection or high levels of iron. However, mechanism(s) of Hamp suppression during iron depletion are poorly understood. We describe mask: a recessive, chemically induced mutant mouse phenotype, characterized by progressive loss of body (but not facial) hair and microcytic anemia. The mask phenotype results from reduced absorption of dietary iron caused by high levels of hepcidin and is due to a splicing defect in the transmembrane serine protease 6 gene Tmprss6. Overexpression of normal TMPRSS6 protein suppresses activation of the Hamp promoter, and the TMPRSS6 cytoplasmic domain mediates Hamp suppression via proximal promoter element(s). TMPRSS6 is an essential component of a pathway that detects iron deficiency and blocks Hamp transcription, permitting enhanced dietary iron absorption.


Assuntos
Peptídeos Catiônicos Antimicrobianos/genética , Deficiências de Ferro , Proteínas de Membrana/metabolismo , Serina Endopeptidases/metabolismo , Anemia Macrocítica/genética , Anemia Macrocítica/metabolismo , Animais , Peptídeos Catiônicos Antimicrobianos/metabolismo , Linhagem Celular Tumoral , Regulação da Expressão Gênica , Hepcidinas , Humanos , Ferro/sangue , Ferro/metabolismo , Proteínas de Membrana/química , Proteínas de Membrana/genética , Camundongos , Camundongos Mutantes , Camundongos Transgênicos , Modelos Biológicos , Mutação , Fenótipo , Regiões Promotoras Genéticas , Estrutura Terciária de Proteína , Serina Endopeptidases/química , Serina Endopeptidases/genética , Transdução de Sinais , Transfecção
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA