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1.
Blood ; 121(20): 4101-9, 2013 May 16.
Artigo em Inglês | MEDLINE | ID: mdl-23558016

RESUMO

It is not known how naive B cells compute divergent chemoattractant signals of the T-cell area and B-cell follicles during in vivo migration. Here, we used two-photon microscopy of peripheral lymph nodes (PLNs) to analyze the prototype G-protein-coupled receptors (GPCRs) CXCR4, CXCR5, and CCR7 during B-cell migration, as well as the integrin LFA-1 for stromal guidance. CXCR4 and CCR7 did not influence parenchymal B-cell motility and distribution, despite their role during B-cell arrest in venules. In contrast, CXCR5 played a nonredundant role in B-cell motility in follicles and in the T-cell area. B-cell migration in the T-cell area followed a random guided walk model, arguing against directed migration in vivo. LFA-1, but not α4 integrins, contributed to B-cell motility in PLNs. However, stromal network guidance was LFA-1 independent, uncoupling integrin-dependent migration from stromal attachment. Finally, we observed that despite a 20-fold reduction of chemokine expression in virus-challenged PLNs, CXCR5 remained essential for B-cell screening of antigen-presenting cells. Our data provide an overview of the contribution of prototype GPCRs and integrins during naive B-cell migration and shed light on the local chemokine availability that these cells compute.


Assuntos
Linfócitos B/fisiologia , Comunicação Celular/fisiologia , Quimiocinas/fisiologia , Quimiotaxia de Leucócito/genética , Antígeno-1 Associado à Função Linfocitária/metabolismo , Receptores CCR7/fisiologia , Receptores CXCR4/fisiologia , Receptores CXCR5/fisiologia , Células Estromais/fisiologia , Animais , Células Apresentadoras de Antígenos/imunologia , Células Apresentadoras de Antígenos/fisiologia , Linfócitos B/efeitos dos fármacos , Linfócitos B/metabolismo , Comunicação Celular/efeitos dos fármacos , Quimiocinas/metabolismo , Quimiocinas/farmacologia , Quimiotaxia de Leucócito/efeitos dos fármacos , Feminino , Deleção de Genes , Antígeno-1 Associado à Função Linfocitária/fisiologia , Tecido Linfoide/citologia , Tecido Linfoide/imunologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Receptores CCR7/genética , Receptores CCR7/metabolismo , Receptores CXCR4/genética , Receptores CXCR4/metabolismo , Receptores CXCR5/genética , Receptores CXCR5/metabolismo , Células Estromais/metabolismo
2.
Blood ; 119(19): 4451-61, 2012 May 10.
Artigo em Inglês | MEDLINE | ID: mdl-22461490

RESUMO

To migrate efficiently through the interstitium, dendritic cells (DCs) constantly adapt their shape to the given structure of the extracellular matrix and follow the path of least resistance. It is known that this amoeboid migration of DCs requires Cdc42, yet the upstream regulators critical for localization and activation of Cdc42 remain to be determined. Mutations of DOCK8, a member of the atypical guanine nucleotide exchange factor family, causes combined immunodeficiency in humans. In the present study, we show that DOCK8 is a Cdc42-specific guanine nucleotide exchange factor that is critical for interstitial DC migration. By generating the knockout mice, we found that in the absence of DOCK8, DCs failed to accumulate in the lymph node parenchyma for T-cell priming. Although DOCK8-deficient DCs migrated normally on 2-dimensional surfaces, DOCK8 was required for DCs to crawl within 3-dimensional fibrillar networks and to transmigrate through the subcapsular sinus floor. This function of DOCK8 depended on the DHR-2 domain mediating Cdc42 activation. DOCK8 deficiency did not affect global Cdc42 activity. However, Cdc42 activation at the leading edge membrane was impaired in DOCK8-deficient DCs, resulting in a severe defect in amoeboid polarization and migration. Therefore, DOCK8 regulates interstitial DC migration by controlling Cdc42 activity spatially.


Assuntos
Imunidade Adaptativa/genética , Movimento Celular/genética , Células Dendríticas/fisiologia , Fatores de Troca do Nucleotídeo Guanina/fisiologia , Proteína cdc42 de Ligação ao GTP/metabolismo , Imunidade Adaptativa/imunologia , Animais , Técnicas de Cultura de Células , Movimento Celular/imunologia , Células Cultivadas , Células Dendríticas/metabolismo , Feminino , Fatores de Troca do Nucleotídeo Guanina/genética , Fatores de Troca do Nucleotídeo Guanina/metabolismo , Células HEK293 , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout
3.
Angew Chem Int Ed Engl ; 48(17): 3174-8, 2009.
Artigo em Inglês | MEDLINE | ID: mdl-19322854

RESUMO

Total synthesis through block glycosylation and selective chemical O-sulfation of tyrosine residues yielded the glycopeptide recognition domain A (X=SO(3) (-)) of the P-selectin glycoprotein ligand 1, in which the terminal sialic acid of the complex hexasaccharide side chain was replaced by (S)-cyclohexyl lactic acid. In binding assays the O-sulfated structure A showed high affinity towards P-selectin, the non-sulfated towards E-selectin.


Assuntos
Selectina E/química , Glicopeptídeos/química , Glicoproteínas de Membrana/química , Selectina-P/química , Animais , Glicopeptídeos/síntese química , Glicosilação , Humanos , Glicoproteínas de Membrana/síntese química , Camundongos , Estrutura Terciária de Proteína , Sulfatos/química
4.
PLoS One ; 4(8): e6641, 2009 Aug 14.
Artigo em Inglês | MEDLINE | ID: mdl-19680556

RESUMO

Individuals who live to 85 and beyond without developing major age-related diseases may achieve this, in part, by lacking disease susceptibility factors, or by possessing resistance factors that enhance their ability to avoid disease and prolong lifespan. Healthy aging is a complex phenotype likely to be affected by both genetic and environmental factors. We sequenced 24 candidate healthy aging genes in DNA samples from 47 healthy individuals aged eighty-five years or older (the 'oldest-old'), to characterize genetic variation that is present in this exceptional group. These healthy seniors were never diagnosed with cancer, cardiovascular disease, pulmonary disease, diabetes, or Alzheimer disease. We re-sequenced all exons, intron-exon boundaries and selected conserved non-coding sequences of candidate genes involved in aging-related processes, including dietary restriction (PPARG, PPARGC1A, SIRT1, SIRT3, UCP2, UCP3), metabolism (IGF1R, APOB, SCD), autophagy (BECN1, FRAP1), stem cell activation (NOTCH1, DLL1), tumor suppression (TP53, CDKN2A, ING1), DNA methylation (TRDMT1, DNMT3A, DNMT3B) Progeria syndromes (LMNA, ZMPSTE24, KL) and stress response (CRYAB, HSPB2). We detected 935 variants, including 848 single nucleotide polymorphisms (SNPs) and 87 insertion or deletions; 41% (385) were not recorded in dbSNP. This study is the first to present a comprehensive analysis of genetic variation in aging-related candidate genes in healthy oldest-old. These variants and especially our novel polymorphisms are valuable resources to test for genetic association in models of disease susceptibility or resistance. In addition, we propose an innovative tagSNP selection strategy that combines variants identified through gene re-sequencing- and HapMap-derived SNPs.


Assuntos
Envelhecimento/genética , Variação Genética , Idoso , Idoso de 80 Anos ou mais , Humanos , Polimorfismo de Nucleotídeo Único
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