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Pesquisa : G05.344.401.601 [Categoria DeCS]
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  1 / 541 MEDLINE  
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[PMID]:28760881
[Au] Autor:Iacoangeli A; Lui A; Haines A; Ohta Y; Flajnik M; Hsu E
[Ad] Endereço:Tisch Multiple Sclerosis Research Center of New York, New York, NY 10019.
[Ti] Título:Evidence for Ig Light Chain Isotype Exclusion in Shark B Lymphocytes Suggests Ordered Mechanisms.
[So] Source:J Immunol;199(5):1875-1885, 2017 Sep 01.
[Is] ISSN:1550-6606
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Unlike most vertebrates, the shark IgL gene organization precludes secondary rearrangements that delete self-reactive VJ rearranged genes. Nurse sharks express four L chain isotypes, κ, λ, σ, and σ-2, encoded by 35 functional minigenes or clusters. The sequence of gene activation/expression and receptor editing of these isotypes have not been studied. We therefore investigated the extent of isotypic exclusion in separated B cell subpopulations. Surface Ig (sIg)κ-expressing cells, isolated with mAb LK14 that recognizes Cκ, carry predominantly nonproductive rearrangements of other L chain isotypes. Conversely, after depletion with LK14, sIgM cells contained largely nonproductive κ and enrichment for in-frame VJ of the others. Because some isotypic inclusion was observed at the mRNA level, expression in the BCR was examined. Functional λ mRNA was obtained, as expected, from the LK14-depleted population, but was also in sIgκ splenocytes. Whereas λ somatic mutants from the depleted sample displayed evidence of positive selection, the λ genes in sIgκ cells accumulated bystander mutations indicating a failure to express their products at the cell surface in association with the BCR H chain. In conclusion, a shark B cell expresses one L chain isotype at the surface and other isotypes as nonproductive VJ, sterile transcripts, or in-frame VJ whose products may not associate with the H chain. Based on the mRNA content found in the B cell subpopulations, an order of L chain gene activation is suggested as: σ-2 followed by κ, then σ and λ.
[Mh] Termos MeSH primário: Subpopulações de Linfócitos B/fisiologia
Linfócitos B/fisiologia
Proteínas de Peixes/genética
Rearranjo Gênico de Cadeia Leve de Linfócito B
Isotipos de Imunoglobulinas/genética
Cadeias Leves de Imunoglobulina/genética
Receptores de Antígenos de Linfócitos B/genética
Tubarões/imunologia
[Mh] Termos MeSH secundário: Animais
Células Cultivadas
Feminino
Regulação da Expressão Gênica
Loci Gênicos
Estruturas Genéticas
Switching de Imunoglobulina
Masculino
RNA Mensageiro
Vertebrados
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Fish Proteins); 0 (Immunoglobulin Isotypes); 0 (Immunoglobulin Light Chains); 0 (RNA, Messenger); 0 (Receptors, Antigen, B-Cell)
[Em] Mês de entrada:1709
[Cu] Atualização por classe:170929
[Lr] Data última revisão:
170929
[Sb] Subgrupo de revista:AIM; IM
[Da] Data de entrada para processamento:170802
[St] Status:MEDLINE
[do] DOI:10.4049/jimmunol.1700762


  2 / 541 MEDLINE  
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[PMID]:28069803
[Au] Autor:Sinkora M; Sinkorova J; Stepanova K
[Ad] Endereço:Laboratory of Gnotobiology, Institute of Microbiology of the Czech Academy of Sciences, 54922 Novy Hradek, Czech Republic marek.sinkora@worldonline.cz.
[Ti] Título:Ig Light Chain Precedes Heavy Chain Gene Rearrangement during Development of B Cells in Swine.
[So] Source:J Immunol;198(4):1543-1552, 2017 Feb 15.
[Is] ISSN:1550-6606
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:The current mammalian paradigm states that 1) rearrangements in the IgH locus precede those in IgL loci, 2) IgLλ genes rearrange only when IgLκ genes are consumed, and 3) the surrogate L chain is necessary for selection of productive IgH gene rearrangements. We show in swine that IgL rearrangements precede IgH gene rearrangements, resulting in the expression of naked IgL on a surface of precursor B cells. Findings also suggest that there is no dependency on the surrogate L chain, and thus the authentic IgL proteins may be used for selection of the IgH repertoire. Although rearrangement starts with IgLκ genes, it is rapidly replaced by IgLλ rearrangement. Fast replacement is characterized by occurrence of IgLλ IgLκ dual-expressing precursors in which IgLκ expression is a remnant of a previous translation. Most IgLκ B cells are then generated later, indicating that there are two waves of IgLκ synthesis in different developmental stages with IgLλ gene rearrangements in between. In the absence of stromal cells, the stepwise order of rearrangements is blocked so that IgLλ gene rearrangements predominate in early B cell development. To our knowledge, this is the first evidence that some mammals can use an inverted order of Ig loci rearrangement. Moreover, a situation in which the generation of BCR-bearing IgLκ is delayed until after IgLλ becomes the dominant isotype may help explain the extreme deviations in the IgLκ/IgLλ ratios among mammals.
[Mh] Termos MeSH primário: Linfócitos B/imunologia
Rearranjo Gênico de Cadeia Leve de Linfócito B
Cadeias Leves de Imunoglobulina/genética
[Mh] Termos MeSH secundário: Animais
Linfócitos B/fisiologia
Rearranjo Gênico de Cadeia Pesada de Linfócito B
Genes de Imunoglobulinas
Cadeias Pesadas de Imunoglobulinas/genética
Cadeias Leves de Imunoglobulina/imunologia
Cadeias kappa de Imunoglobulina/genética
Receptores de Antígenos de Linfócitos B/genética
Receptores de Antígenos de Linfócitos B/imunologia
Suínos
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Immunoglobulin Heavy Chains); 0 (Immunoglobulin Light Chains); 0 (Immunoglobulin kappa-Chains); 0 (Receptors, Antigen, B-Cell)
[Em] Mês de entrada:1708
[Cu] Atualização por classe:170828
[Lr] Data última revisão:
170828
[Sb] Subgrupo de revista:AIM; IM
[Da] Data de entrada para processamento:170111
[St] Status:MEDLINE
[do] DOI:10.4049/jimmunol.1601035


  3 / 541 MEDLINE  
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[PMID]:26834154
[Au] Autor:Bednarski JJ; Pandey R; Schulte E; White LS; Chen BR; Sandoval GJ; Kohyama M; Haldar M; Nickless A; Trott A; Cheng G; Murphy KM; Bassing CH; Payton JE; Sleckman BP
[Ad] Endereço:Department of Pediatrics, Washington University School of Medicine, St. Louis, MO 63110.
[Ti] Título:RAG-mediated DNA double-strand breaks activate a cell type-specific checkpoint to inhibit pre-B cell receptor signals.
[So] Source:J Exp Med;213(2):209-23, 2016 Feb 08.
[Is] ISSN:1540-9538
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:DNA double-strand breaks (DSBs) activate a canonical DNA damage response, including highly conserved cell cycle checkpoint pathways that prevent cells with DSBs from progressing through the cell cycle. In developing B cells, pre-B cell receptor (pre-BCR) signals initiate immunoglobulin light (Igl) chain gene assembly, leading to RAG-mediated DNA DSBs. The pre-BCR also promotes cell cycle entry, which could cause aberrant DSB repair and genome instability in pre-B cells. Here, we show that RAG DSBs inhibit pre-BCR signals through the ATM- and NF-κB2-dependent induction of SPIC, a hematopoietic-specific transcriptional repressor. SPIC inhibits expression of the SYK tyrosine kinase and BLNK adaptor, resulting in suppression of pre-BCR signaling. This regulatory circuit prevents the pre-BCR from inducing additional Igl chain gene rearrangements and driving pre-B cells with RAG DSBs into cycle. We propose that pre-B cells toggle between pre-BCR signals and a RAG DSB-dependent checkpoint to maintain genome stability while iteratively assembling Igl chain genes.
[Mh] Termos MeSH primário: Quebras de DNA de Cadeia Dupla
Proteínas de Homeodomínio/metabolismo
Receptores de Células Precursoras de Linfócitos B/metabolismo
Células Precursoras de Linfócitos B/imunologia
Células Precursoras de Linfócitos B/metabolismo
[Mh] Termos MeSH secundário: Proteínas Adaptadoras de Transdução de Sinal/metabolismo
Animais
Proteínas Mutadas de Ataxia Telangiectasia/deficiência
Proteínas Mutadas de Ataxia Telangiectasia/genética
Proteínas Mutadas de Ataxia Telangiectasia/metabolismo
Pontos de Checagem do Ciclo Celular/imunologia
Proliferação Celular
Proteínas de Ligação a DNA/deficiência
Proteínas de Ligação a DNA/genética
Proteínas de Ligação a DNA/metabolismo
Rearranjo Gênico de Cadeia Leve de Linfócito B
Proteínas de Homeodomínio/genética
Peptídeos e Proteínas de Sinalização Intracelular/metabolismo
Camundongos
Camundongos Knockout
Camundongos Transgênicos
Subunidade p52 de NF-kappa B/deficiência
Subunidade p52 de NF-kappa B/genética
Subunidade p52 de NF-kappa B/metabolismo
Células Precursoras de Linfócitos B/citologia
Proteínas Serina-Treonina Quinases/metabolismo
Proteínas Tirosina Quinases/metabolismo
Proteínas Proto-Oncogênicas/metabolismo
Transdução de Sinais/imunologia
Quinase Syk
Transativadores/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, N.I.H., EXTRAMURAL; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (Adaptor Proteins, Signal Transducing); 0 (B cell linker protein); 0 (DNA-Binding Proteins); 0 (Homeodomain Proteins); 0 (Intracellular Signaling Peptides and Proteins); 0 (NF-kappa B p52 Subunit); 0 (Nfkb2 protein, mouse); 0 (Pre-B Cell Receptors); 0 (Proto-Oncogene Proteins); 0 (Spic protein, mouse); 0 (Trans-Activators); 0 (proto-oncogene protein Spi-1); 128559-51-3 (RAG-1 protein); EC 2.7.10.1 (Protein-Tyrosine Kinases); EC 2.7.10.2 (Syk Kinase); EC 2.7.10.2 (Syk protein, mouse); EC 2.7.11.1 (Ataxia Telangiectasia Mutated Proteins); EC 2.7.11.1 (Atm protein, mouse); EC 2.7.11.1 (Protein-Serine-Threonine Kinases); EC 2.7.11.25 (NF-kappa B kinase)
[Em] Mês de entrada:1608
[Cu] Atualização por classe:170125
[Lr] Data última revisão:
170125
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:160203
[St] Status:MEDLINE
[do] DOI:10.1084/jem.20151048


  4 / 541 MEDLINE  
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[PMID]:26342033
[Au] Autor:Iacoangeli A; Lui A; Naik U; Ohta Y; Flajnik M; Hsu E
[Ad] Endereço:Department of Physiology and Pharmacology, State University of New York Health Science Center at Brooklyn, Brooklyn, NY 11203; and.
[Ti] Título:Biased Immunoglobulin Light Chain Gene Usage in the Shark.
[So] Source:J Immunol;195(8):3992-4000, 2015 Oct 15.
[Is] ISSN:1550-6606
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:This study of a large family of κ L chain clusters in nurse shark completes the characterization of its classical Ig gene content (two H chain isotypes, µ and ω, and four L chain isotypes, κ, λ, σ, and σ-2). The shark κ clusters are minigenes consisting of a simple VL-JL-CL array, where V to J recombination occurs over an ~500-bp interval, and functional clusters are widely separated by at least 100 kb. Six out of ~39 κ clusters are prerearranged in the germline (germline joined). Unlike the complex gene organization and multistep assembly process of Ig in mammals, each shark Ig rearrangement, somatic or in the germline, appears to be an independent event localized to the minigene. This study examined the expression of functional, nonproductive, and sterile transcripts of the κ clusters compared with the other three L chain isotypes. κ cluster usage was investigated in young sharks, and a skewed pattern of split gene expression was observed, one similar in functional and nonproductive rearrangements. These results show that the individual activation of the spatially distant κ clusters is nonrandom. Although both split and germline-joined κ genes are expressed, the latter are prominent in young animals and wane with age. We speculate that, in the shark, the differential activation of the multiple isotypes can be advantageously used in receptor editing.
[Mh] Termos MeSH primário: Proteínas de Peixes/imunologia
Rearranjo Gênico de Cadeia Leve de Linfócito B/fisiologia
Cadeias Leves de Imunoglobulina/imunologia
Tubarões/imunologia
Recombinação V(D)J/fisiologia
[Mh] Termos MeSH secundário: Animais
Proteínas de Peixes/genética
Cadeias Leves de Imunoglobulina/genética
Tubarões/genética
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, N.I.H., EXTRAMURAL
[Nm] Nome de substância:
0 (Fish Proteins); 0 (Immunoglobulin Light Chains)
[Em] Mês de entrada:1512
[Cu] Atualização por classe:170220
[Lr] Data última revisão:
170220
[Sb] Subgrupo de revista:AIM; IM
[Da] Data de entrada para processamento:150906
[St] Status:MEDLINE
[do] DOI:10.4049/jimmunol.1501426


  5 / 541 MEDLINE  
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[PMID]:26059604
[Au] Autor:Manoharan A; Du Roure C; Rolink AG; Matthias P
[Ad] Endereço:Friedrich Miescher Institute for Biomedical Research, Basel, Switzerland.
[Ti] Título:De novo DNA Methyltransferases Dnmt3a and Dnmt3b regulate the onset of Igκ light chain rearrangement during early B-cell development.
[So] Source:Eur J Immunol;45(8):2343-55, 2015 Aug.
[Is] ISSN:1521-4141
[Cp] País de publicação:Germany
[La] Idioma:eng
[Ab] Resumo:Immunoglobulin genes V(D)J rearrangement during early lymphopoiesis is a critical process involving sequential recombination of the heavy and light chain loci. A number of transcription factors act together with temporally activated recombinases and chromatin accessibility changes to regulate this complex process. Here, we deleted the de novo DNA methyltransferases Dnmt3a and Dnmt3b in early B cells of conditionally targeted mice, and monitored the process of V(D)J recombination. Dnmt3a and Dnmt3b deletion resulted in precocious recombination of the immunoglobulin κ light chain without impairing the differentiation of mature B cells or overall B-cell development. Ex vivo culture of IL-7 restricted early B-cell progenitors lacking Dnmt3a and Dnmt3b showed precocious Vκ-Jκ rearrangements that are limited to the proximal Vκ genes. Furthermore, B-cell progenitors deficient in Dnmt3a and Dnmt3b showed elevated levels of germline transcripts at the proximal Vκ genes, alterations in methylation patterns at Igκ enhancer sites and increased expression of the transcription factor E2A. Our data suggest that Dnmt3a and Dnmt3b are critical to regulate the onset of Igκ light chain rearrangement during early B-cell development.
[Mh] Termos MeSH primário: Linfócitos B/imunologia
DNA (Citosina-5-)-Metiltransferases/imunologia
Rearranjo Gênico de Cadeia Leve de Linfócito B/imunologia
Cadeias kappa de Imunoglobulina/imunologia
Recombinação V(D)J/imunologia
[Mh] Termos MeSH secundário: Animais
Linfócitos B/citologia
Fatores de Transcrição Hélice-Alça-Hélice Básicos/genética
Fatores de Transcrição Hélice-Alça-Hélice Básicos/imunologia
DNA (Citosina-5-)-Metiltransferases/genética
Feminino
Regulação da Expressão Gênica/imunologia
Cadeias kappa de Imunoglobulina/genética
Camundongos
Camundongos Transgênicos
Células Precursoras de Linfócitos B/citologia
Células Precursoras de Linfócitos B/imunologia
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (Basic Helix-Loop-Helix Transcription Factors); 0 (Immunoglobulin kappa-Chains); 0 (Tcf3 protein, mouse); EC 2.1.1.37 (DNA (Cytosine-5-)-Methyltransferases); EC 2.1.1.37 (DNA methyltransferase 3A); EC 2.1.1.37 (DNA methyltransferase 3B)
[Em] Mês de entrada:1510
[Cu] Atualização por classe:171116
[Lr] Data última revisão:
171116
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:150611
[St] Status:MEDLINE
[do] DOI:10.1002/eji.201445035


  6 / 541 MEDLINE  
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[PMID]:26036683
[Au] Autor:Fraser LD; Zhao Y; Lutalo PM; D'Cruz DP; Cason J; Silva JS; Dunn-Walters DK; Nayar S; Cope AP; Spencer J
[Ad] Endereço:Programme in Infection and Immunobiology, King's College London, London, UK.
[Ti] Título:Immunoglobulin light chain allelic inclusion in systemic lupus erythematosus.
[So] Source:Eur J Immunol;45(8):2409-19, 2015 Aug.
[Is] ISSN:1521-4141
[Cp] País de publicação:Germany
[La] Idioma:eng
[Ab] Resumo:The principles of allelic exclusion state that each B cell expresses a single light and heavy chain pair. Here, we show that B cells with both kappa and lambda light chains (Igκ and Igλ) are enriched in some patients with the systemic autoimmune disease systemic lupus erythematosus (SLE), but not in the systemic autoimmune disease control granulomatosis with polyangiitis. Detection of dual Igκ and Igλ expression by flow cytometry could not be abolished by acid washing or by DNAse treatment to remove any bound polyclonal antibody or complexes, and was retained after two days in culture. Both surface and intracytoplasmic dual light chain expression was evident by flow cytometry and confocal microscopy. We observed reduced frequency of rearrangements of the kappa-deleting element (KDE) in SLE and an inverse correlation between the frequency of KDE rearrangement and the frequency of dual light chain expressing B cells. We propose that dual expression of Igκ and Igλ by a single B cell may occur in some patients with SLE when this may be a consequence of reduced activity of the KDE.
[Mh] Termos MeSH primário: Regulação da Expressão Gênica/imunologia
Rearranjo Gênico de Cadeia Leve de Linfócito B/imunologia
Cadeias kappa de Imunoglobulina
Cadeias lambda de Imunoglobulina
Lúpus Eritematoso Sistêmico
[Mh] Termos MeSH secundário: Adolescente
Adulto
Idoso
Feminino
Seres Humanos
Cadeias kappa de Imunoglobulina/genética
Cadeias kappa de Imunoglobulina/imunologia
Cadeias lambda de Imunoglobulina/genética
Cadeias lambda de Imunoglobulina/imunologia
Lúpus Eritematoso Sistêmico/genética
Lúpus Eritematoso Sistêmico/imunologia
Lúpus Eritematoso Sistêmico/patologia
Meia-Idade
[Pt] Tipo de publicação:CLINICAL TRIAL; JOURNAL ARTICLE; MULTICENTER STUDY; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (Immunoglobulin kappa-Chains); 0 (Immunoglobulin lambda-Chains)
[Em] Mês de entrada:1510
[Cu] Atualização por classe:170922
[Lr] Data última revisão:
170922
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:150604
[St] Status:MEDLINE
[do] DOI:10.1002/eji.201545599


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[PMID]:25700344
[Au] Autor:Hehle V; Fraser LD; Tahir R; Kipling D; Wu YC; Lutalo PM; Cason J; Choong L; D'Cruz DP; Cope AP; Dunn-Walters DK; Spencer J
[Ad] Endereço:Department of Immunobiology, King's College London, London, UK. Electronic address: verena.hehle@kcl.ac.uk.
[Ti] Título:Immunoglobulin kappa variable region gene selection during early human B cell development in health and systemic lupus erythematosus.
[So] Source:Mol Immunol;65(2):215-23, 2015 Jun.
[Is] ISSN:1872-9142
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:The unique specificity of the B cell receptor is generated by an ordered sequence of gene rearrangement events. Once IGH genes have rearranged, rearrangement at the IGK locus is initiated followed by the IGL locus if functional IGK rearrangement is not achieved. Receptor specificity can subsequently be altered by secondary light chain editing based on the features of the heavy and light chain combination. The final profile of expressed genes is not random and biases in this profile are associated with several autoimmune diseases. However, how and when biases are created is not known. To increase our understanding of the processes of selection and editing of IGK rearrangements, we compared four groups of rearrangements of IGK acquired by next generation sequencing. First, expressed rearrangements of IGK from cDNA of IGK expressing B cells. Second, productive rearrangements of IGK from DNA of the same kappa expressing B cells. Third, non-productive rearrangements of IGK from DNA of IGK and IGL expressing B cells, and fourth productively rearranged IGK from DNA of IGL expressing B cells. The latter group would have been rejected during B cell development in favour of rearrangement at the IGL locus and are therefore selected against. We saw evidence that rearranged IGK segments can be selected at a checkpoint where the decision to rearrange the IGL locus is made. In addition, our data suggest that mechanisms regulating the expression or not of IGK rearrangements may also contribute to repertoire development and also that this latter component of the selection process is defective in SLE.
[Mh] Termos MeSH primário: Linfócitos B/imunologia
Rearranjo Gênico de Cadeia Leve de Linfócito B/imunologia
Loci Gênicos/imunologia
Região Variável de Imunoglobulina/imunologia
Cadeias kappa de Imunoglobulina/imunologia
Lúpus Eritematoso Sistêmico/imunologia
[Mh] Termos MeSH secundário: Adulto
Linfócitos B/patologia
DNA Complementar/genética
DNA Complementar/imunologia
Feminino
Regulação da Expressão Gênica/imunologia
Rearranjo Gênico de Cadeia Leve de Linfócito B/genética
Seres Humanos
Região Variável de Imunoglobulina/genética
Cadeias kappa de Imunoglobulina/genética
Lúpus Eritematoso Sistêmico/genética
Lúpus Eritematoso Sistêmico/patologia
Masculino
[Pt] Tipo de publicação:CLINICAL TRIAL; JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (DNA, Complementary); 0 (Immunoglobulin Variable Region); 0 (Immunoglobulin kappa-Chains)
[Em] Mês de entrada:1505
[Cu] Atualização por classe:170922
[Lr] Data última revisão:
170922
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:150221
[St] Status:MEDLINE


  8 / 541 MEDLINE  
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[PMID]:25564405
[Au] Autor:Iacovelli S; Hug E; Bennardo S; Duehren-von Minden M; Gobessi S; Rinaldi A; Suljagic M; Bilbao D; Bolasco G; Eckl-Dorna J; Niederberger V; Autore F; Sica S; Laurenti L; Wang H; Cornall RJ; Clarke SH; Croce CM; Bertoni F; Jumaa H; Efremov DG
[Ad] Endereço:Molecular Hematology, International Centre for Genetic Engineering and Biotechnology, Rome, Italy;
[Ti] Título:Two types of BCR interactions are positively selected during leukemia development in the Eµ-TCL1 transgenic mouse model of CLL.
[So] Source:Blood;125(10):1578-88, 2015 Mar 05.
[Is] ISSN:1528-0020
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Chronic lymphocytic leukemia (CLL) is a common B-cell malignancy characterized by a highly variable course and outcome. The disease is believed to be driven by B-cell receptor (BCR) signals generated by external antigens and/or cell-autonomous BCR interactions, but direct in vivo evidence for this is still lacking. To further define the role of the BCR pathway in the development and progression of CLL, we evaluated the capacity of different types of antigen/BCR interactions to induce leukemia in the Eµ-TCL1 transgenic mouse model. We show that cell autonomous signaling capacity is a uniform characteristic of the leukemia-derived BCRs and represents a prerequisite for CLL development. Low-affinity BCR interactions with autoantigens generated during apoptosis are also positively selected, suggesting that they contribute to the pathogenesis of the disease. In contrast, high-affinity BCR interactions are not selected, regardless of antigen form or presentation. We also show that the capacity of the leukemic cells to respond to cognate antigen correlates inversely with time to leukemia development, suggesting that signals induced by external antigen increase the aggressiveness of the disease. Collectively, these findings provide in vivo evidence that the BCR pathway drives the development and can influence the clinical course of CLL.
[Mh] Termos MeSH primário: Leucemia Linfocítica Crônica de Células B/etiologia
Leucemia Linfocítica Crônica de Células B/imunologia
Receptores de Antígenos de Linfócitos B/metabolismo
[Mh] Termos MeSH secundário: Sequência de Aminoácidos
Animais
Apresentação do Antígeno
Autoantígenos/genética
Progressão da Doença
Rearranjo Gênico de Cadeia Pesada de Linfócito B
Rearranjo Gênico de Cadeia Leve de Linfócito B
Seres Humanos
Leucemia Experimental/etiologia
Leucemia Experimental/genética
Leucemia Experimental/imunologia
Leucemia Linfocítica Crônica de Células B/genética
Camundongos
Camundongos Endogâmicos C57BL
Camundongos Transgênicos
Dados de Sequência Molecular
Muramidase/genética
Muramidase/imunologia
Proteínas Proto-Oncogênicas/genética
Receptores de Antígenos de Linfócitos B/genética
Transdução de Sinais/imunologia
Proteínas Centrais de snRNP/genética
Proteínas Centrais de snRNP/imunologia
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (Autoantigens); 0 (Proto-Oncogene Proteins); 0 (Receptors, Antigen, B-Cell); 0 (TCL1A protein, human); 0 (snRNP Core Proteins); EC 3.2.1.17 (Muramidase)
[Em] Mês de entrada:1504
[Cu] Atualização por classe:170922
[Lr] Data última revisão:
170922
[Sb] Subgrupo de revista:AIM; IM
[Da] Data de entrada para processamento:150108
[St] Status:MEDLINE
[do] DOI:10.1182/blood-2014-07-587790


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[PMID]:25359572
[Au] Autor:Fitzsimmons SP; Aydanian AG; Clark KJ; Shapiro MA
[Ti] Título:Multiple factors influence the contribution of individual immunoglobulin light chain genes to the naïve antibody repertoire.
[So] Source:BMC Immunol;15:51, 2014 Oct 30.
[Is] ISSN:1471-2172
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:BACKGROUND: The naïve antibody repertoire is initially dependent upon the number of germline V(D)J genes and the ability of recombined heavy and light chains to pair. Individual VH and VL genes are not equally represented in naïve mature B cells, suggesting that positive and negative selection also shape the antibody repertoire. Among the three member murine Vκ10 L chain family, the Vκ10C gene is under-represented in the antibody repertoire. Although it is structurally functional and accessible to both transcriptional and recombination machinery, the Vκ10C promoter is inefficient in pre-B cell lines and productive Vκ10C rearrangements are lost as development progresses from pre-B cells through mature B cells. This study examined VH/Vκ10 pairing, promoter mutations, Vκ10 transcript levels and receptor editing as possible factors that are responsible for loss of productive Vκ10C rearrangements in developing B cells. RESULTS: We demonstrate that the loss of Vκ10C expression is not due to an inability to pair with H chains, but is likely due to a combination of other factors. Levels of mRNA are low in sorted pre-B cells and undetectable in B cells. Mutation of a single base in the three prime region of the Vκ10C promoter increases Vκ10C promoter function in pre-B cell lines. Pre-B and B cells harbor disproportionate levels of receptor-edited productive Vκ10C rearrangements. CONCLUSIONS: Our findings suggest that the weak Vκ10C promoter initially limits the amount of available Vκ10C L chain for pairing with H chains, resulting in sub-threshold levels of cell surface B cell receptors, insufficient tonic signaling and subsequent receptor editing to limit the numbers of Vκ10C-expressing B cells emigrating from the bone marrow to the periphery.
[Mh] Termos MeSH primário: Anticorpos/genética
Genes de Cadeia Leve de Imunoglobulina
[Mh] Termos MeSH secundário: Animais
Sequência de Bases
Feminino
Rearranjo Gênico de Cadeia Leve de Linfócito B
Cadeias Pesadas de Imunoglobulinas/genética
Masculino
Camundongos Endogâmicos BALB C
Dados de Sequência Molecular
Células Precursoras de Linfócitos B/metabolismo
Regiões Promotoras Genéticas/genética
Receptores de Antígenos de Linfócitos B/metabolismo
Recombinação Genética/genética
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, U.S. GOV'T, P.H.S.
[Nm] Nome de substância:
0 (Antibodies); 0 (Immunoglobulin Heavy Chains); 0 (Receptors, Antigen, B-Cell)
[Em] Mês de entrada:1505
[Cu] Atualização por classe:151029
[Lr] Data última revisão:
151029
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:141101
[St] Status:MEDLINE
[do] DOI:10.1186/s12865-014-0051-2


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[PMID]:25299065
[Au] Autor:Abbas F; Yazbek SN; Shammaa D; Hoteit R; Fermanian P; Mahfouz R
[Ad] Endereço:1 Department of Pathology and Laboratory Medicine, American University of Beirut Medical Center , Beirut, Lebanon .
[Ti] Título:Invivoscribe BIOMED-2 primer mixes in B-cell immunoglobulin gene rearrangement studies: experience of a molecular diagnostics laboratory in a major tertiary care center.
[So] Source:Genet Test Mol Biomarkers;18(12):787-90, 2014 Dec.
[Is] ISSN:1945-0257
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:AIMS: To determine the frequency of positive reactions obtained using the Invivoscribe BIOMED-2 kit for B-cell gene rearrangement studies in leukemias and lymphomas. MATERIALS AND METHODS: We reviewed the gel patterns for 192 samples tested, using the above-mentioned kit and matched the positive signal with the corresponding mix available in the assay kit. RESULTS: 92.2% had immunoglobulin heavy-chain clonality, of which 74% were detected by the IgH VH-FR1+JH primer set, 75.5% by IgH VH-FR2+JH primer set, 65.1% by IgH VH-FR3+JH primer set, 26% by IgH DH+JH primer set, and 2.1% by IgH DH7+JH primer set. In addition, 55.7% had clonality in the kappa light chain, where 33.3% were positive by the IgK Vκ +Jκ primer set and 39.6% by IgK Vκ and INTR+Kde primer sets. Clonality in the lambda light chain of immunoglobulins was detected in 17.7% of specimens tested using the IgL Vλ +Jλ primer set. CONCLUSION: All primer mixes provided by the assay were positive. Thus, the Invivoscribe BIOMED-2 B-cell gene rearrangement kit is very reliable in adequately covering all targets represented by the master mixes. This assay is an integral part of the differential diagnosis of clonal populations of cells. Our report is the first in the literature that describes the full range of coverage of the BIOMED-2 primer mixes provided in this assay.
[Mh] Termos MeSH primário: Primers do DNA/química
Rearranjo Gênico de Cadeia Pesada de Linfócito B
Rearranjo Gênico de Cadeia Leve de Linfócito B
Leucemia de Células B/genética
Linfoma de Células B/genética
Reação em Cadeia da Polimerase/métodos
[Mh] Termos MeSH secundário: Primers do DNA/genética
Feminino
Seres Humanos
Masculino
Patologia Molecular/métodos
Centros de Atenção Terciária
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (DNA Primers)
[Em] Mês de entrada:1508
[Cu] Atualização por classe:160511
[Lr] Data última revisão:
160511
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:141010
[St] Status:MEDLINE
[do] DOI:10.1089/gtmb.2014.0174



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