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1.
Am J Respir Crit Care Med ; 202(12): 1678-1688, 2020 12 15.
Artigo em Inglês | MEDLINE | ID: mdl-32673495

RESUMO

Rationale: Workers' exposure to metalworking fluid (MWF) has been associated with respiratory disease.Objectives: As part of a public health investigation of a manufacturing facility, we performed a cross-sectional study using paired environmental and human sampling to evaluate the cross-pollination of microbes between the environment and the host and possible effects on lung pathology present among workers.Methods: Workplace environmental microbiota were evaluated in air and MWF samples. Human microbiota were evaluated in lung tissue samples from workers with respiratory symptoms found to have lymphocytic bronchiolitis and alveolar ductitis with B-cell follicles and emphysema, in lung tissue samples from control subjects, and in skin, nasal, and oral samples from 302 workers from different areas of the facility. In vitro effects of MWF exposure on murine B cells were assessed.Measurements and Main Results: An increased similarity of microbial composition was found between MWF samples and lung tissue samples of case workers compared with control subjects. Among workers in different locations within the facility, those that worked in the machine shop area had skin, nasal, and oral microbiota more closely related to the microbiota present in the MWF samples. Lung samples from four index cases and skin and nasal samples from workers in the machine shop area were enriched with Pseudomonas, the dominant taxa in MWF. Exposure to used MWF stimulated murine B-cell proliferation in vitro, a hallmark cell subtype found in the pathology of index cases.Conclusions: Evaluation of a manufacturing facility with a cluster of workers with respiratory disease supports cross-pollination of microbes from MWF to humans and suggests the potential for exposure to these microbes to be a health hazard.


Assuntos
Aerossóis/efeitos adversos , Poluentes Ocupacionais do Ar/efeitos adversos , Instalações Industriais e de Manufatura , Microbiota , Pseudomonas pseudoalcaligenes , Transtornos Respiratórios/fisiopatologia , Adulto , Microbiologia do Ar , Estudos Transversais , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Transtornos Respiratórios/etiologia , Estados Unidos
2.
J Immunol ; 201(5): 1442-1451, 2018 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-30012848

RESUMO

Phenotypic differences among substrains of laboratory mice due to spontaneous mutations or pre-existing genetic variation confound the interpretation of targeted mutagenesis experiments and contribute to challenges with reproducibility across institutions. Notably, C57BL/6 Hsd mice and gene-targeted mice that have been backcrossed to this substrain have been reported to harbor a duplication in exons 28 and 29 of Dock2 In this study, we demonstrate the presence of this Dock2 variant in the widely used Nod2-/- mice. Nucleotide-binding oligomerization domain-containing protein 2 (NOD2) is a cytosolic innate immune receptor associated with inflammatory bowel disease susceptibility. Consistent with a role of NOD2 in an immunological disorder, Nod2-/- mice bred at our institution displayed multiple B cell defects including deficiencies in recirculating B cells, marginal zone B cells, and B1a cells in vivo, as well as defects in class switch recombination in vitro. However, we found that these effects are due to the Dock2 variant and are independent of Nod2 deletion. Despite originating from the same gene-targeted founder mice, Nod2-/- mice from another source did not harbor the Dock2 variant or B cell defects. Finally, we show that Dock2-/- mice display the same B cell defects as mice harboring the Dock2 variant, confirming that the variant is a loss-of-function mutation and is sufficient to explain the alterations to the B cell compartment observed in Nod2-/- mice. Our findings highlight the effects of confounding mutations from widely used inbred strains on gene-targeted mice and reveal new functions of DOCK2 in B cells.


Assuntos
Linfócitos B/imunologia , Proteínas Ativadoras de GTPase , Doenças do Sistema Imunitário , Mutação , Proteína Adaptadora de Sinalização NOD2/deficiência , Animais , Linfócitos B/patologia , Proteínas Ativadoras de GTPase/genética , Proteínas Ativadoras de GTPase/imunologia , Fatores de Troca do Nucleotídeo Guanina , Doenças do Sistema Imunitário/genética , Doenças do Sistema Imunitário/imunologia , Doenças do Sistema Imunitário/patologia , Camundongos , Camundongos Knockout , Proteína Adaptadora de Sinalização NOD2/imunologia
3.
Proc Natl Acad Sci U S A ; 112(5): E458-66, 2015 Feb 03.
Artigo em Inglês | MEDLINE | ID: mdl-25609670

RESUMO

The genes encoding the variable (V) region of the B-cell antigen receptor (BCR) are assembled from V, D (diversity), and J (joining) elements through a RAG-mediated recombination process that relies on the recognition of recombination signal sequences (RSSs) flanking the individual elements. Secondary V(D)J rearrangement modifies the original Ig rearrangement if a nonproductive original joint is formed, as a response to inappropriate signaling from a self-reactive BCR, or as part of a stochastic mechanism to further diversify the Ig repertoire. VH replacement represents a RAG-mediated secondary rearrangement in which an upstream VH element recombines with a rearranged VHDHJH joint to generate a new BCR specificity. The rearrangement occurs between the cryptic RSS of the original VH element and the conventional RSS of the invading VH gene, leaving behind a footprint of up to five base pairs (bps) of the original VH gene that is often further obscured by exonuclease activity and N-nucleotide addition. We have previously demonstrated that VH replacement can efficiently rescue the development of B cells that have acquired two nonproductive heavy chain (IgH) rearrangements. Here we describe a novel knock-in mouse model in which the prerearranged IgH locus resembles an endogenously rearranged productive VHDHJH allele. Using this mouse model, we characterized the role of VH replacement in the diversification of the primary Ig repertoire through the modification of productive VHDHJH rearrangements. Our results indicate that VH replacement occurs before Ig light chain rearrangement and thus is not involved in the editing of self-reactive antibodies.


Assuntos
Região Variável de Imunoglobulina/genética , Animais , Linfócitos B/imunologia , Compartimento Celular , Camundongos , Camundongos Transgênicos , Processos Estocásticos
4.
Proc Natl Acad Sci U S A ; 111(25): E2622-9, 2014 Jun 24.
Artigo em Inglês | MEDLINE | ID: mdl-24927543

RESUMO

Antibody repertoires are known to be shaped by selection for antigen binding. Unexpectedly, we now show that selection also acts on a non-antigen-binding antibody region: the heavy-chain variable (VH)-encoded "elbow" between variable and constant domains. By sequencing 2.8 million recombined heavy-chain genes from immature and mature B-cell subsets in mice, we demonstrate a striking gradient in VH gene use as pre-B cells mature into follicular and then into marginal zone B cells. Cells whose antibodies use VH genes that encode a more flexible elbow are more likely to mature. This effect is distinct from, and exceeds in magnitude, previously described maturation-associated changes in heavy-chain complementarity determining region 3, a key antigen-binding region, which arise from junctional diversity rather than differential VH gene use. Thus, deep sequencing reveals a previously unidentified mode of B-cell selection.


Assuntos
Linfócitos B/imunologia , Regiões Determinantes de Complementaridade/imunologia , Cadeias Pesadas de Imunoglobulinas/imunologia , Animais , Regiões Determinantes de Complementaridade/genética , Feminino , Sequenciamento de Nucleotídeos em Larga Escala , Cadeias Pesadas de Imunoglobulinas/genética , Camundongos
5.
J Immunol ; 191(6): 3100-11, 2013 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-23966625

RESUMO

Th17 cells are a proinflammatory subset of effector T cells that have been implicated in the pathogenesis of asthma. Their production of the cytokine IL-17 is known to induce local recruitment of neutrophils, but the direct impact of IL-17 on the lung epithelium is poorly understood. In this study, we describe a novel mouse model of spontaneous IL-17-driven lung inflammation that exhibits many similarities to asthma in humans. We have found that STAT3 hyperactivity in T lymphocytes causes an expansion of Th17 cells, which home preferentially to the lungs. IL-17 secretion then leads to neutrophil infiltration and lung epithelial changes, in turn leading to a chronic inflammatory state with increased mucus production and decreased lung function. We used this model to investigate the effects of IL-17 activity on airway epithelium and identified CXCL5 and MIP-2 as important factors in neutrophil recruitment. The neutralization of IL-17 greatly reduces pulmonary neutrophilia, underscoring a key role for IL-17 in promoting chronic airway inflammation. These findings emphasize the role of IL-17 in mediating neutrophil-driven pulmonary inflammation and highlight a new mouse model that may be used for the development of novel therapies targeting Th17 cells in asthma and other chronic pulmonary diseases.


Assuntos
Asma/imunologia , Doenças do Sistema Imunitário/imunologia , Interleucina-17/imunologia , Transtornos Leucocíticos/imunologia , Neutrófilos/imunologia , Mucosa Respiratória/imunologia , Animais , Asma/metabolismo , Separação Celular , Modelos Animais de Doenças , Ensaio de Imunoadsorção Enzimática , Citometria de Fluxo , Interleucina-17/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Pneumonia/imunologia , Pneumonia/metabolismo , Reação em Cadeia da Polimerase em Tempo Real , Mucosa Respiratória/metabolismo , Células Th17/imunologia , Células Th17/metabolismo , Transfecção
6.
Arthritis Rheum ; 65(6): 1510-21, 2013 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-23508476

RESUMO

OBJECTIVE: Recent genome-wide association studies have revealed numerous genetic associations between specific single-nucleotide polymorphisms (SNPs) and immune-mediated inflammatory diseases. The current challenge is to identify associations of the genetic variants with effector mechanisms implicated in pathogenesis. This study was undertaken to investigate the link between genetic variation at loci associated with spondyloarthritis (SpA) and the effector function of CD4+ T lymphocyte subsets involved in chronic inflammatory disease. METHODS: Expression of Th17 and Th1 cytokines and transcription factors was measured in CD4+ T cells isolated from patients with SpA. Correlation analyses were performed to assess potential associations of these expression levels with the patient's genotype at loci genetically linked to SpA. RESULTS: The effector functions of Th17 and Th1 cells in patients with SpA were found to be under combinatorial control by multiple SNPs at genes associated with the interleukin-23 (IL-23)/Th17 pathway. Patients with SpA carrying risk-associated alleles of genes in the IL-23/Th17 pathway expressed the highest levels of genes involved in the differentiation and function of Th17 and Th1 cells, whereas the presence of protective alleles was associated with low-level expression of these genes. In contrast, variation at loci that were genetically linked to SpA, but not associated with the IL-23 pathway, did not affect the expression of Th17- and Th1-specific genes, suggesting that these SNPs may contribute to the pathogenesis of SpA through distinct cellular mechanisms. CONCLUSION: These results show that genetic variations at genes associated with the IL-23 signaling pathway may influence the effector functions of Th17 and Th1 cells in patients with SpA. These findings provide a framework to delineate the mechanisms by which genetic variants contribute to pathology.


Assuntos
Linfócitos T CD4-Positivos/metabolismo , Citocinas/metabolismo , Inflamação/metabolismo , Interleucina-23/genética , Espondiloartropatias/metabolismo , Células Th1/metabolismo , Células Th17/metabolismo , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Variação Genética , Genótipo , Humanos , Interleucina-23/metabolismo , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único , Reação em Cadeia da Polimerase em Tempo Real , Transdução de Sinais , Espondiloartropatias/genética , Adulto Jovem
7.
J Immunol ; 186(10): 5758-65, 2011 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-21478400

RESUMO

CD1d-reactive invariant NKT (iNKT) cells have been implicated in a number of experimental models of human pathologies. Given the scope of their immunoregulatory activities mediated through distinct cytokine patterns, it has been proposed that this functional diversity originates from distinct iNKT subpopulations. In this study, we report that human CD161(+) iNKT cells are intrinsically endowed with the capacity to generate IL-17, but require TGF-ß, IL-1ß, and IL-23 to carry out this potential. IL-17-producing iNKT cells are already present in cord blood but, in contrast to peripheral blood iNKT cells, they cannot generate IFN-γ. These IL-17 producers respond to aryl hydrocarbon receptor stimulation and express IL-23 receptor and retinoic acid-related orphan receptor C, similar to conventional T helper 17 cells, from which they differ by their restricted ability to coproduce IL-22. In conclusion, IL-17 production by human iNKT cells depends on two critical parameters, namely an intrinsic program and a proinflammatory environment.


Assuntos
Inflamação/imunologia , Interleucina-17/biossíntese , Células T Matadoras Naturais/metabolismo , Ensaio de Imunoadsorção Enzimática , Humanos , Interferon gama , Interleucina-1beta/biossíntese , Interleucina-23/biossíntese , Interleucinas/biossíntese , Subfamília B de Receptores Semelhantes a Lectina de Células NK/imunologia , Células T Matadoras Naturais/imunologia , Membro 3 do Grupo F da Subfamília 1 de Receptores Nucleares/metabolismo , Reação em Cadeia da Polimerase , Receptores de Hidrocarboneto Arílico/metabolismo , Receptores de Interleucina/metabolismo , Linfócitos T Auxiliares-Indutores/imunologia , Fator de Crescimento Transformador beta/biossíntese , Interleucina 22
8.
J Immunol ; 183(12): 7743-51, 2009 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-19923468

RESUMO

T-bet is a key regulator controlling Th1 cell development. This factor is not expressed in naive CD4(+) T cells, and the mechanisms controlling expression of T-bet are incompletely understood. In this study, we defined regulatory elements at the human T-bet locus and determined how signals originating at the TCR and at cytokine receptors are integrated to induce chromatin modifications and expression of this gene during human Th1 cell differentiation. We found that T cell activation induced two strong DNase I-hypersensitive sites (HS) and rapid histone acetylation at these elements in CD4(+) T cells. Histone acetylation and T-bet expression were strongly inhibited by cyclosporine A, and we detected binding of NF-AT to a HS in vivo. IL-12 and IFN-gamma signaling alone were not sufficient to induce T-bet expression in naive CD4(+) T cells, but enhanced T-bet expression in TCR/CD28-stimulated cells. We detected a third HS 12 kb upstream of the mRNA start site only in developing Th1 cells, which was bound by IL-12-induced STAT4. Our data suggest that T-bet locus remodeling and gene expression are initiated by TCR-induced NF-AT recruitment and amplified by IL-12-mediated STAT4 binding to distinct distal regulatory elements during human Th1 cell differentiation.


Assuntos
Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD4-Positivos/metabolismo , Peptídeos e Proteínas de Sinalização Intracelular/genética , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Sequências Reguladoras de Ácido Nucleico/imunologia , Transdução de Sinais/imunologia , Proteínas com Domínio T/biossíntese , Proteínas com Domínio T/genética , Antígenos CD28/fisiologia , Linfócitos T CD4-Positivos/citologia , Diferenciação Celular/genética , Diferenciação Celular/imunologia , Citocinas/fisiologia , Desoxirribonuclease I/metabolismo , Desoxirribonuclease I/fisiologia , Humanos , Peptídeos e Proteínas de Sinalização Intracelular/fisiologia , Células Jurkat , Fatores de Transcrição NFATC/metabolismo , Ligação Proteica/genética , Ligação Proteica/imunologia , Receptores de Antígenos de Linfócitos T/fisiologia , Proteínas com Domínio T/antagonistas & inibidores , Células Th1/citologia , Células Th1/imunologia , Células Th1/metabolismo , Células Th2/citologia , Células Th2/imunologia , Células Th2/metabolismo
9.
J Exp Med ; 217(9)2020 09 07.
Artigo em Inglês | MEDLINE | ID: mdl-32602902

RESUMO

Staphylococcus aureus is responsible for various diseases in humans, and recurrent infections are commonly observed. S. aureus produces an array of bicomponent pore-forming toxins that target and kill leukocytes, known collectively as the leukocidins. The contribution of these leukocidins to impair the development of anti-S. aureus adaptive immunity and facilitate reinfection is unclear. Using a murine model of recurrent bacteremia, we demonstrate that infection with a leukocidin mutant results in increased levels of anti-S. aureus antibodies compared with mice infected with the WT parental strain, indicating that leukocidins negatively impact the generation of anti-S. aureus antibodies in vivo. We hypothesized that neutralizing leukocidin-mediated immune subversion by vaccination may shift this host-pathogen interaction in favor of the host. Leukocidin-immunized mice produce potent leukocidin-neutralizing antibodies and robust Th1 and Th17 responses, which collectively protect against bloodstream infections. Altogether, these results demonstrate that blocking leukocidin-mediated immune evasion can promote host protection against S. aureus bloodstream infection.


Assuntos
Bacteriemia/imunologia , Bacteriemia/prevenção & controle , Evasão da Resposta Imune , Leucocidinas/metabolismo , Infecções Estafilocócicas/imunologia , Infecções Estafilocócicas/prevenção & controle , Staphylococcus aureus/imunologia , Animais , Anticorpos Neutralizantes/imunologia , Formação de Anticorpos/imunologia , Bacteriemia/sangue , Bacteriemia/microbiologia , Linfócitos T CD4-Positivos/imunologia , Citocinas/sangue , Interações Hospedeiro-Patógeno/imunologia , Imunidade , Imunização , Imunoglobulina G/sangue , Inflamação/patologia , Staphylococcus aureus Resistente à Meticilina/imunologia , Camundongos , Modelos Biológicos , Especificidade de Órgãos , Recidiva , Baço/patologia , Infecções Estafilocócicas/sangue , Toxoides/imunologia
10.
Cell Rep ; 33(9): 108436, 2020 12 01.
Artigo em Inglês | MEDLINE | ID: mdl-33264610

RESUMO

The phosphatidylinositol 3-kinase (PI3K) signaling cascade downstream of the B cell receptor (BCR) signalosome is essential for B cell maturation. Proper signaling strength is maintained through the PI3K negative regulator phosphatase and tensin homolog (PTEN). Although a role for microRNA (miRNA)-dependent control of the PTEN-PI3K axis has been described, the contribution of individual miRNAs to the regulation of this crucial signaling modality in mature B lymphocytes remains to be elucidated. Our analyses reveal that ablation of miR-29 specifically in B lymphocytes results in an increase in PTEN expression and dampening of the PI3K pathway in mature B cells. This dysregulation has a profound impact on the survival of B lymphocytes and results in increased class switch recombination and decreased plasma cell differentiation. Furthermore, we demonstrate that ablation of one copy of Pten is sufficient to ameliorate the phenotypes associated with miR-29 loss. Our data suggest a critical role for the miR-29-PTEN-PI3K regulatory axis in mature B lymphocytes.


Assuntos
Linfócitos B/metabolismo , MicroRNAs/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Animais , Diferenciação Celular , Humanos , Camundongos , Transdução de Sinais , Análise de Sobrevida
11.
Immunology ; 127(2): 155-62, 2009 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-19476511

RESUMO

Significant progress has been made during the past years in our understanding of the mechanisms that control the differentiation of naïve CD4(+) T cells into effector T-cell subsets with distinct functional properties. Previous work allowed the identification of key molecules involved in regulating this highly complex process, such as cytokines and their receptors, signal transducers and transcription factors. More recently, the emphasis of research in this field has been to elucidate how the multiplicity of signals is integrated to shape a T helper subset-specific gene-expression program controlling differentiation and effector functions. In this review we will highlight advances that have been made in unravelling the genetic and epigenetic networks controlling differentiation of naïve CD4(+) T cells into interferon-gamma(IFN-gamma)-secreting T helper type 1 (Th1) cells.


Assuntos
Epigênese Genética/imunologia , Células Th1/imunologia , Diferenciação Celular/genética , Diferenciação Celular/imunologia , Regulação da Expressão Gênica/imunologia , Humanos , Interferon gama/genética , Interleucina-12/genética , Interleucina-12/imunologia , Biossíntese de Proteínas , Receptores Notch/imunologia , Transdução de Sinais/genética , Transdução de Sinais/imunologia , Proteínas com Domínio T/imunologia
12.
Cell Rep ; 27(5): 1472-1486.e5, 2019 04 30.
Artigo em Inglês | MEDLINE | ID: mdl-31042474

RESUMO

The immunoglobulin heavy chain (Igh) locus features a dynamic chromatin landscape to promote class switch recombination (CSR), yet the mechanisms that regulate this landscape remain poorly understood. CHD4, a component of the chromatin remodeling NuRD complex, directly binds H3K9me3, an epigenetic mark present at the Igh locus during CSR. We find that CHD4 is essential for early B cell development but is dispensable for the homeostatic maintenance of mature, naive B cells. However, loss of CHD4 in mature B cells impairs CSR because of suboptimal targeting of AID to the Igh locus. Additionally, we find that CHD4 represses p53 expression to promote B cell proliferation. This work reveals distinct roles for CHD4 in B cell development and CSR and links the H3K9me3 epigenetic mark with AID recruitment to the Igh locus.


Assuntos
Linfócitos B/imunologia , Proliferação de Células , DNA Helicases/genética , Switching de Imunoglobulina , Animais , Linfócitos B/citologia , Linfócitos B/fisiologia , Diferenciação Celular , Células Cultivadas , Montagem e Desmontagem da Cromatina , DNA Helicases/metabolismo , Genes de Cadeia Pesada de Imunoglobulina , Camundongos , Proteína Supressora de Tumor p53/genética , Proteína Supressora de Tumor p53/metabolismo
13.
Cell Host Microbe ; 25(3): 463-470.e9, 2019 Mar 13.
Artigo em Inglês | MEDLINE | ID: mdl-30799265

RESUMO

The pathogenesis of Staphylococcus aureus is thought to depend on the production of pore-forming leukocidins that kill leukocytes and lyse erythrocytes. Two leukocidins, Leukocidin ED (LukED) and γ-Hemolysin AB (HlgAB), are necessary and sufficient to kill mice upon infection and toxin challenge. We demonstrate that LukED and HlgAB cause vascular congestion and derangements in vascular fluid distribution that rapidly cause death in mice. The Duffy antigen receptor for chemokines (DARC) on endothelial cells, rather than leukocytes or erythrocytes, is the critical target for lethality. Consistent with this, LukED and HlgAB injure primary human endothelial cells in a DARC-dependent manner, and mice with DARC-deficient endothelial cells are resistant to toxin-mediated lethality. During bloodstream infection in mice, DARC targeting by S. aureus causes increased tissue damage, organ dysfunction, and host death. The potential for S. aureus leukocidins to manipulate vascular integrity highlights the importance of these virulence factors.


Assuntos
Proteínas de Bactérias/toxicidade , Toxinas Bacterianas/toxicidade , Sistema do Grupo Sanguíneo Duffy/metabolismo , Células Endoteliais/efeitos dos fármacos , Exotoxinas/toxicidade , Proteínas Hemolisinas/toxicidade , Receptores de Superfície Celular/metabolismo , Infecções Estafilocócicas/patologia , Staphylococcus aureus/patogenicidade , Animais , Proteínas de Bactérias/metabolismo , Toxinas Bacterianas/metabolismo , Sobrevivência Celular/efeitos dos fármacos , Células Cultivadas , Modelos Animais de Doenças , Exotoxinas/metabolismo , Proteínas Hemolisinas/metabolismo , Humanos , Camundongos , Camundongos Knockout , Modelos Biológicos , Staphylococcus aureus/metabolismo , Análise de Sobrevida
14.
Trends Mol Med ; 23(8): 721-736, 2017 08.
Artigo em Inglês | MEDLINE | ID: mdl-28694140

RESUMO

B lymphocytes are essential for an efficient immune response against a variety of pathogens. A large fraction of hematologic malignancies is of B cell origin, suggesting that the development and activation of B cells need to be tightly regulated. In recent years, increasing evidence has emerged demonstrating that microRNAs (miRNAs) - a class of non-coding RNAs that control gene expression - are involved in the regulation of B cell development and function. We provide here an overview of the current knowledge on the role of miRNAs and their relevant targets in B cell development, B cell activation, and B cell malignant transformation.


Assuntos
Linfócitos B/metabolismo , Transformação Celular Neoplásica/metabolismo , Linfoma de Células B/metabolismo , MicroRNAs/metabolismo , RNA Neoplásico/metabolismo , Animais , Linfócitos B/patologia , Transformação Celular Neoplásica/patologia , Humanos , Linfoma de Células B/patologia
15.
Cancer Discov ; 6(3): 247-55, 2016 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-26715643

RESUMO

UNLABELLED: A salient feature of pancreatic ductal adenocarcinoma (PDAC) is an abundant fibroinflammatory response characterized by the recruitment of immune and mesenchymal cells and the consequent establishment of a protumorigenic microenvironment. Here, we report the prominent presence of B cells in human pancreatic intraepithelial neoplasia and PDAC lesions as well as in oncogenic Kras-driven pancreatic neoplasms in the mouse. The growth of orthotopic pancreatic neoplasms harboring oncogenic Kras was significantly compromised in B-cell-deficient mice (µMT), and this growth deficiency could be rescued by the reconstitution of a CD1d(hi)CD5(+) B-cell subset. The protumorigenic effect of B cells was mediated by their expression of IL35 through a mechanism involving IL35-mediated stimulation of tumor cell proliferation. Our results identify a previously unrecognized role for IL35-producing CD1d(hi)CD5(+) B cells in the pathogenesis of pancreatic cancer and underscore the potential significance of a B-cell/IL35 axis as a therapeutic target. SIGNIFICANCE: This study identifies a B-cell subpopulation that accumulates in the pancreatic parenchyma during early neoplasia and is required to support tumor cell growth. Our findings provide a rationale for exploring B-cell-based targeting approaches for the treatment of pancreatic cancer.


Assuntos
Linfócitos B/imunologia , Linfócitos B/metabolismo , Transformação Celular Neoplásica/imunologia , Transformação Celular Neoplásica/metabolismo , Interleucinas/biossíntese , Neoplasias Pancreáticas/imunologia , Neoplasias Pancreáticas/metabolismo , Animais , Biomarcadores , Carcinoma Ductal Pancreático , Modelos Animais de Doenças , Humanos , Imuno-Histoquímica , Linfócitos do Interstício Tumoral/imunologia , Linfócitos do Interstício Tumoral/metabolismo , Camundongos , Camundongos Knockout , Neoplasias Pancreáticas/patologia , Fenótipo , Neoplasias Pancreáticas
16.
Cell Rep ; 17(9): 2271-2285, 2016 11 22.
Artigo em Inglês | MEDLINE | ID: mdl-27880903

RESUMO

B cell development is a tightly regulated process dependent on sequential rearrangements of immunoglobulin loci that encode the antigen receptor. To elucidate the role of microRNAs (miRNAs) in the orchestration of B cell development, we ablated all miRNAs at the earliest stage of B cell development by conditionally targeting the enzymes critical for RNAi in early B cell precursors. Absence of any one of these enzymes led to a block at the pro- to pre-B cell transition due to increased apoptosis and a failure of pre-B cells to proliferate. Expression of a Bcl2 transgene allowed for partial rescue of B cell development, however, the majority of the rescued B cells had low surface immunoglobulin expression with evidence of ongoing light chain editing. Our analysis revealed that miRNAs are critical for the regulation of the PTEN-AKT-FOXO1 pathway that in turn controls Rag expression during B cell development.


Assuntos
Linfócitos B/citologia , Linfócitos B/metabolismo , Diferenciação Celular/genética , Regulação da Expressão Gênica , MicroRNAs/metabolismo , Edição de RNA/genética , Receptores de Antígenos de Linfócitos B/metabolismo , Transdução de Sinais/genética , Animais , Regulação para Baixo , Fatores de Transcrição Forkhead/metabolismo , Cadeias Leves de Imunoglobulina/genética , Camundongos , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Interferência de RNA , Proteínas de Ligação a RNA/metabolismo , Ribonuclease III/metabolismo , Baço/citologia , Transgenes
17.
Leuk Res ; 39(3): 335-41, 2015 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-25597017

RESUMO

The overexpression of microRNA cluster miR-17-92 has been implicated in development of solid tumors and hematological malignancies. The role of miR-17-92 in lymphomagenesis has been extensively investigated; however, because of the developmental defects caused by miR-17-92 dysregulation, its ability to drive tumorigenesis has remained undetermined until recently. Here we demonstrate that overexpression of miR-17-92 in a limited number of hematopoietic cells is sufficient to cause B cell malignancies. In sum, our study provides a novel and physiologically relevant model that exposes the potent ability of miR-17-92 to act as a driver of tumorigenesis.


Assuntos
Transformação Celular Neoplásica/patologia , Regulação Neoplásica da Expressão Gênica , Neoplasias Hematológicas/patologia , MicroRNAs/fisiologia , Proteínas dos Microfilamentos/fisiologia , Proteínas Musculares/fisiologia , Animais , Western Blotting , Proliferação de Células , Neoplasias Hematológicas/genética , Neoplasias Hematológicas/metabolismo , Técnicas Imunoenzimáticas , Integrases/metabolismo , Camundongos , RNA Mensageiro/genética , Reação em Cadeia da Polimerase em Tempo Real , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Células Tumorais Cultivadas
18.
J Immunol ; 177(11): 7880-8, 2006 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-17114459

RESUMO

Although many cytokine receptors generate their signals via the STAT3 pathway, the IL-10R appears unique in promoting a potent anti-inflammatory response (AIR) via STAT3 to antagonize proinflammatory signals that activate the innate immune response. We found that heterologous cytokine receptor systems that activate STAT3 but are naturally refractory (the IL-22R), or engineered to be refractory (the IL-6, leptin, and erythropoietin receptors), to suppressor of cytokine signaling-3-mediated inhibition activate an AIR indistinguishable from IL-10. We conclude that the AIR is a generic cytokine signaling pathway dependent on STAT3 but not unique to the IL-10R.


Assuntos
Expressão Gênica , Inflamação , Interleucina-10/metabolismo , Interleucina-6/metabolismo , Fator de Transcrição STAT3/metabolismo , Transdução de Sinais/imunologia , Animais , Ensaio de Imunoadsorção Enzimática , Immunoblotting , Camundongos , Análise de Sequência com Séries de Oligonucleotídeos , Receptores de Interleucina-10/metabolismo , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Proteína 3 Supressora da Sinalização de Citocinas , Proteínas Supressoras da Sinalização de Citocina/metabolismo
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