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1.
PLoS Genet ; 15(10): e1008357, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31609978

RESUMO

Nonsyndromic orofacial cleft (NSOFC) is a severe birth defect that occurs early in embryonic development and includes the subtypes cleft palate only (CPO), cleft lip only (CLO) and cleft lip with cleft palate (CLP). Given a lack of specific genetic factor analysis for CPO and CLO, the present study aimed to dissect the landscape of genetic factors underlying the pathogenesis of these two subtypes using 6,986 cases and 10,165 controls. By combining a genome-wide association study (GWAS) for specific subtypes of CPO and CLO, as well as functional gene network and ontology pathway analysis, we identified 18 genes/loci that surpassed genome-wide significance (P < 5 × 10-8) responsible for NSOFC, including nine for CPO, seven for CLO, two for both conditions and four that contribute to the CLP subtype. Among these 18 genes/loci, 14 are novel and identified in this study and 12 contain developmental transcription factors (TFs), suggesting that TFs are the key factors for the pathogenesis of NSOFC subtypes. Interestingly, we observed an opposite effect of the genetic variants in the IRF6 gene for CPO and CLO. Moreover, the gene expression dosage effect of IRF6 with two different alleles at the same single-nucleotide polymorphism (SNP) plays important roles in driving CPO or CLO. In addition, PAX9 is a key TF for CPO. Our findings define subtypes of NSOFC using genetic factors and their functional ontologies and provide a clue to improve their diagnosis and treatment in the future.


Assuntos
Encéfalo/anormalidades , Fenda Labial/genética , Fissura Palatina/genética , Fatores Reguladores de Interferon/genética , Fator de Transcrição PAX9/genética , Alelos , Encéfalo/fisiopatologia , Fenda Labial/fisiopatologia , Fissura Palatina/fisiopatologia , Dosagem de Genes/genética , Regulação da Expressão Gênica/genética , Redes Reguladoras de Genes/genética , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Genótipo , Humanos , Polimorfismo de Nucleotídeo Único/genética
2.
Nature ; 574(7777): 249-253, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31578523

RESUMO

The integrity of the mammalian epidermis depends on a balance of proliferation and differentiation in the resident population of stem cells1. The kinase RIPK4 and the transcription factor IRF6 are mutated in severe developmental syndromes in humans, and mice lacking these genes display epidermal hyperproliferation and soft-tissue fusions that result in neonatal lethality2-5. Our understanding of how these genes control epidermal differentiation is incomplete. Here we show that the role of RIPK4 in mouse development requires its kinase activity; that RIPK4 and IRF6 expressed in the epidermis regulate the same biological processes; and that the phosphorylation of IRF6 at Ser413 and Ser424 primes IRF6 for activation. Using RNA sequencing (RNA-seq), histone chromatin immunoprecipitation followed by sequencing (ChIP-seq) and assay for transposase-accessible chromatin using sequencing (ATAC-seq) of skin in wild-type and IRF6-deficient mouse embryos, we define the transcriptional programs that are regulated by IRF6 during epidermal differentiation. IRF6 was enriched at bivalent promoters, and IRF6 deficiency caused defective expression of genes that are involved in the metabolism of lipids and the formation of tight junctions. Accordingly, the lipid composition of the stratum corneum of Irf6-/- skin was abnormal, culminating in a severe defect in the function of the epidermal barrier. Collectively, our results explain how RIPK4 and IRF6 function to ensure the integrity of the epidermis and provide mechanistic insights into why developmental syndromes that are characterized by orofacial, skin and genital abnormalities result when this axis goes awry.


Assuntos
Diferenciação Celular , Células Epidérmicas/citologia , Epiderme/fisiologia , Fatores Reguladores de Interferon/metabolismo , Proteínas Serina-Treonina Quinases/metabolismo , Transdução de Sinais , Anormalidades Múltiplas/genética , Animais , Fenda Labial/genética , Fissura Palatina/genética , Cistos/genética , Embrião de Mamíferos/citologia , Embrião de Mamíferos/embriologia , Embrião de Mamíferos/metabolismo , Células Epidérmicas/metabolismo , Epiderme/embriologia , Anormalidades do Olho/genética , Feminino , Dedos/anormalidades , Regulação da Expressão Gênica , Fatores Reguladores de Interferon/deficiência , Fatores Reguladores de Interferon/genética , Joelho/anormalidades , Articulação do Joelho/anormalidades , Lábio/anormalidades , Metabolismo dos Lipídeos/genética , Deformidades Congênitas das Extremidades Inferiores/genética , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Fosforilação , Fosfosserina/metabolismo , Proteínas Serina-Treonina Quinases/genética , Sindactilia/genética , Anormalidades Urogenitais/genética
3.
Nat Commun ; 10(1): 3974, 2019 09 03.
Artigo em Inglês | MEDLINE | ID: mdl-31481662

RESUMO

Tumor-associated macrophages (TAMs) usually express an M2 phenotype, which enables them to perform immunosuppressive and tumor-promoting functions. Reprogramming these TAMs toward an M1 phenotype could thwart their pro-cancer activities and unleash anti-tumor immunity, but efforts to accomplish this are nonspecific and elicit systemic inflammation. Here we describe a targeted nanocarrier that can deliver in vitro-transcribed mRNA encoding M1-polarizing transcription factors to reprogram TAMs without causing systemic toxicity. We demonstrate in models of ovarian cancer, melanoma, and glioblastoma that infusions of nanoparticles formulated with mRNAs encoding interferon regulatory factor 5 in combination with its activating kinase IKKß reverse the immunosuppressive, tumor-supporting state of TAMs and reprogram them to a phenotype that induces anti-tumor immunity and promotes tumor regression. We further establish that these nanoreagents are safe for repeated dosing. Implemented in the clinic, this immunotherapy could enable physicians to obviate suppressive tumors while avoiding systemic treatments that disrupt immune homeostasis.


Assuntos
Macrófagos/imunologia , Nanopartículas , Neoplasias/imunologia , RNA Mensageiro/administração & dosagem , Animais , Linhagem Celular Tumoral , Reprogramação Celular , Feminino , Glioblastoma/imunologia , Glioblastoma/patologia , Glioblastoma/terapia , Humanos , Quinase I-kappa B/genética , Quinase I-kappa B/metabolismo , Imunossupressão , Fatores Reguladores de Interferon/genética , Fatores Reguladores de Interferon/metabolismo , Ativação de Macrófagos , Melanoma Experimental/imunologia , Melanoma Experimental/patologia , Melanoma Experimental/terapia , Camundongos , Metástase Neoplásica , Neoplasias/genética , Neoplasias/patologia , Neoplasias Ovarianas/imunologia , Neoplasias Ovarianas/patologia , Neoplasias Ovarianas/terapia , RNA Mensageiro/genética , Linfócitos T/imunologia , Fatores de Transcrição/genética , Transfecção
4.
Forensic Sci Int Genet ; 42: 252-259, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31400656

RESUMO

Freckles or ephelides are hyperpigmented spots observed on skin surface mainly in European and Asian populations. Easy recognition and external visibility make prediction of ephelides, the potentially useful target in the field of forensic DNA phenotyping. Prediction of freckles would be a step forward in sketching the physical appearance of unknown perpetrators or decomposed cadavers for the forensic DNA intelligence purposes. Freckles are especially common in people with pale skin and red hair and therefore it is expected that predisposition to freckles may partially share the genetic background with other pigmentation traits. The first proposed freckle prediction model was developed based on investigation that involved variation of MC1R and 8 SNPs from 7 genes in a Spanish cohort [19]. In this study we examined 113 DNA variants from 46 genes previously associated with human pigmentation traits and assessed their impact on freckles presence in a group of 960 individuals from Poland. Nineteen DNA variants revealed associations with the freckle phenotype and the study also revealed that females have ∼1.8 higher odds of freckles presence comparing to males (p-value = 9.5 × 10-5). Two alternative prediction models were developed using regression methods. A simplified binomial 12-variable model predicts the presence of ephelides with cross-validated AUC = 0.752. A multinomial 14-variable model predicts one of three categories - non-freckled, medium freckled and heavily freckled. The two extreme categories, non-freckled and heavily freckled were predicted with moderately high accuracy of cross-validated AUC = 0.754 and 0.792, respectively. Prediction accuracy of the intermediate category was lower, AUC = 0.657. The study presents novel DNA models for prediction of freckles that can be used in forensic investigations and emphasizes significance of pigmentation genes and sex in predictive DNA analysis of freckles.


Assuntos
Melanose/genética , Modelos Genéticos , Miosinas Cardíacas/genética , Estudos de Coortes , Proteínas de Ligação a DNA/genética , Proteínas da Matriz Extracelular/genética , Feminino , Glicoproteínas/genética , Fatores de Troca do Nucleotídeo Guanina/genética , Ribonucleoproteínas Nucleares Heterogêneas Grupo C/genética , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Fatores Reguladores de Interferon/genética , Modelos Logísticos , Masculino , Proteínas de Membrana Transportadoras/genética , Monofenol Mono-Oxigenase/genética , Cadeias Pesadas de Miosina/genética , Proteínas Nucleares/genética , Coativadores de Receptor Nuclear/genética , Fenótipo , Polimorfismo de Nucleotídeo Único , Receptor Tipo 1 de Melanocortina/genética , Sensibilidade e Especificidade , Análise de Sequência de DNA , Fatores Sexuais , Pigmentação da Pele
5.
Nat Immunol ; 20(9): 1161-1173, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31406378

RESUMO

Induction of the transcription factor Irf8 in the common dendritic cell progenitor (CDP) is required for classical type 1 dendritic cell (cDC1) fate specification, but the mechanisms controlling this induction are unclear. In the present study Irf8 enhancers were identified via chromatin profiling of dendritic cells and CRISPR/Cas9 genome editing was used to assess their roles in Irf8 regulation. An enhancer 32 kilobases (kb) downstream of the Irf8 transcriptional start site (+32-kb Irf8) that was active in mature cDC1s was required for the development of this lineage, but not for its specification. Instead, a +41-kb Irf8 enhancer, previously thought to be active only in plasmacytoid dendritic cells, was found to also be transiently accessible in cDC1 progenitors, and deleting this enhancer prevented the induction of Irf8 in CDPs and abolished cDC1 specification. Thus, cryptic activation of the +41-kb Irf8 enhancer in dendritic cell progenitors is responsible for cDC1 fate specification.


Assuntos
Células Dendríticas/citologia , Elementos Facilitadores Genéticos/genética , Fatores Reguladores de Interferon/metabolismo , Macrófagos/citologia , Monócitos/citologia , Animais , Sistemas CRISPR-Cas/genética , Diferenciação Celular , Linhagem da Célula , Células Dendríticas/imunologia , Regulação da Expressão Gênica , Fatores Reguladores de Interferon/genética , Macrófagos/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Monócitos/metabolismo , Células-Tronco/citologia , Células Tumorais Cultivadas
7.
Biomed Res Int ; 2019: 1050285, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31380412

RESUMO

Background: Th17/Treg balance skews towards Th17 in ITP patient. IRF4 has been highlighted for its close relationship to the immunosuppressive function of Treg cells and the IL-17 synthesis in CD4+ T cells. This study was aimed at examining the effects of IRF4 to the Th17/Treg cells in patients with ITP. Methods: Treg and Teff cells were isolated from PBMCs of newly diagnosed ITP patients. The percentages of CD4+CD25hiFoxp3+Treg cells and the CD3+CD4+IL-17+Th17 cells were detected by flow cytometry. After being cultured, the supernatants of Tregs were collected for IL-10 concentration test. The IRF4 levels of Tregs were measured. Teffs were cultured alone or with Tregs for 24 hours. Then the supernatants were collected for IL-17 concentration test. The binding intensity of IRF4 to the gene IL-10 in Treg cells was detected by ChIP-qPCR. Metabolic assays for Teffs and Tregs were performed with Agilent Seahorse XF96 Analyzer. Results: The secretion of IL-10 by Tregs was decreased in ITP patients. The intensity of IRF4 binding to IL-10 DNA of Tregs in patients was higher than that of normal controls and Teffs in ITP patients. The expressions of IRF4 of Tregs in ITP patients were remarkably lower than that of healthy controls. The percentage of Th17 cells in healthy controls was significantly increased after IRF4 mRNA silencing. Abnormal metabolism of Treg and Teff cells was found in ITP patients. Conclusion: The skewed ratio of Th17/Treg cells and dysfunction of Treg cells in newly diagnosed ITP patients was at least partly caused by IRF4 dysfunction. The underlying mechanism might be the impact of IRF4 on the metabolism of Treg and Teff cells.


Assuntos
Fatores Reguladores de Interferon/genética , Interleucina-10/genética , Púrpura Trombocitopênica Idiopática/genética , Linfócitos T Reguladores/imunologia , Adulto , Idoso , Linfócitos T CD4-Positivos/imunologia , Feminino , Regulação da Expressão Gênica , Humanos , Imunossupressão/métodos , Fatores Reguladores de Interferon/imunologia , Masculino , Pessoa de Meia-Idade , Ligação Proteica/imunologia , Púrpura Trombocitopênica Idiopática/imunologia , Púrpura Trombocitopênica Idiopática/patologia , Linfócitos T Reguladores/metabolismo , Células Th17/imunologia , Células Th17/metabolismo
8.
J Craniofac Surg ; 30(5): e465-e467, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31299817

RESUMO

Van der Woude syndrome (VWS) is a rare autosomal dominant disease, first reported in the literature in 1845 by Demarquay and subsequently thoroughly described in 1954 by Van der Woude. Van der Woude Syndrome is the most common form of syndromic orofacial clefting and individuals with this syndrome account for 2% of all cleft cases. Van der Woude syndrome clinically presents with congenital lip pits. These lip pits occur on paramedian portion of the vermillion border of the lip. In VWS, congenital lip pits occur in concurrence with cleft lip and/or cleft palate and represent the most common clinical problem occurring in 80% of the patients. Lip pits result due to notching of the lips at an early stage of development with fixation of tissues at the base of the notch or they may result from a failure of complete union of embryonic lateral sulci of lip. Single lip sinuses without any cleft syndrome are rare; lower lip fistulas in VWS are generally asymptomatic, and surgical management is usually accomplished because of aesthetic concerns. However, in some cases, patients may complain of watery drainage or hypotonia of the lower lip. Herein, the authors report a novel frameshift mutation in IRF6 gene which may contribute to better understanding the genetic aspect of VWS.


Assuntos
Anormalidades Múltiplas/genética , Fenda Labial/genética , Fissura Palatina/genética , Cistos/genética , Fatores Reguladores de Interferon/genética , Lábio/anormalidades , Mutação , Pré-Escolar , Humanos , Masculino
9.
Virology ; 534: 132-142, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31255797

RESUMO

The chicken upper respiratory tract is the portal of entry for respiratory pathogens including avian influenza virus (AIV). There is a paucity of information about the role of airway epithelial cells in the induction of antiviral responses in the chicken trachea. A better understanding of the role of these cells in the initiation of innate responses may improve prophylactic or therapeutic strategies for control of viral infections. The present study aimed to characterize antiviral innate responses in chicken tracheal epithelial cells (cTECs) induced by TLR ligands. The results demonstrated that stimulation of cTECs with TLR ligands induced antiviral responses, and subsequently reduced the replication of AIV in cTECs. Additionally, stimulated cTECs were able to influence the function of other cells such as macrophages. Overall, these results provided evidence that cTECs mount antiviral responses after stimulation with TLR ligands through IRF7 and NF-κB signaling pathways, leading to activation of other cells, such as macrophages.


Assuntos
Células Epiteliais/imunologia , Vírus da Influenza A/fisiologia , Influenza Aviária/imunologia , Macrófagos/imunologia , Doenças das Aves Domésticas/imunologia , Traqueia/virologia , Animais , Proteínas Aviárias/genética , Proteínas Aviárias/imunologia , Galinhas , Células Epiteliais/virologia , Imunidade Inata , Vírus da Influenza A/genética , Influenza Aviária/genética , Influenza Aviária/virologia , Fatores Reguladores de Interferon/genética , Fatores Reguladores de Interferon/imunologia , Interleucina-1beta/genética , Interleucina-1beta/imunologia , Interleucina-8/genética , Interleucina-8/imunologia , Ligantes , Macrófagos/virologia , Poli I-C/imunologia , Doenças das Aves Domésticas/genética , Doenças das Aves Domésticas/virologia , Receptor 3 Toll-Like/genética , Receptor 3 Toll-Like/imunologia , Receptor 4 Toll-Like/genética , Receptor 4 Toll-Like/imunologia , Traqueia/citologia , Traqueia/imunologia
10.
Fish Shellfish Immunol ; 92: 821-832, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31299462

RESUMO

Interferon regulatory factors (IRFs) were originally identified as transcriptional regulators of type I interferon (IFN) expression. Recent studies have widely identified the roles of IRFs as central mediators in immune defence against pathogen infection. However, the functional roles and expression profiles of IRFs are still unclear in Chinese soft-shelled turtle (Pelodiscus sinensis). In this study, eight members of the PsIRF family were identified in P. sinensis through a genome-wide search. These PsIRF genes contained the conserved domains of this group of proteins, including the N-terminal DNA-binding domain and C-terminal IRF-associated domain. Phylogenetic analyses among IRF homologs showed that the PsIRFs shared the closest phylogenetic relationships with IRFs of other turtle species. Further molecular evolutionary analyses revealed evolutionary conservation of the PsIRF genes. Moreover, expression profiling demonstrated that eight PsIRF genes exhibited constitutive expression in different tissues of P. sinensis. Several genes, such as PsIRF1, PsIRF2 and PsIRF4, showed predominant expression in the spleen and were significantly upregulated upon Aeromonas hydrophila infection. Remarkably, PsIRF1, PsIRF2 and PsIRF4 exhibited rapid increases in their protein expression levels post-infection and were mainly expressed in the splenic red pulp according to immunohistochemistry analysis. These results provide rich resources for further exploration of the roles of PsIRFs in immune regulation in P. sinensis and other turtles.


Assuntos
Regulação da Expressão Gênica/imunologia , Imunidade Inata/genética , Fatores Reguladores de Interferon/genética , Fatores Reguladores de Interferon/imunologia , Tartarugas/genética , Tartarugas/imunologia , Aeromonas hydrophila/fisiologia , Animais , Perfilação da Expressão Gênica/veterinária , Infecções por Bactérias Gram-Negativas/imunologia , Infecções por Bactérias Gram-Negativas/veterinária , Família Multigênica/imunologia , RNA Mensageiro/genética , Proteínas de Répteis/genética , Proteínas de Répteis/imunologia
11.
Cell Physiol Biochem ; 53(1): 1-18, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31162913

RESUMO

BACKGROUND/AIMS: Innate immune toll-like receptors (TLRs) are emerging as nutrient sensors. Oxidative stress in the adipose tissue in obesity acts as a critical early trigger of altered pathophysiology. TLR2/TLR4 adipose upregulation has been associated with insulin resistance in humans; however, it remains unclear whether oxidative stress can modulate expression of TLR2/4 and related immune-metabolic regulators (IRF3/5) in immune cells. We, therefore, assessed their expression along with proinflammatory cytokines in the human PBMC following induction of oxidative stress. METHODS: PBMC were isolated from blood of healthy donors using Ficoll-Paque method and cells were treated with H2O2 to induce oxidative stress. ROS was measured by DCFH-DA assay. Target gene and protein expression was determined using real-time RT-PCR and flow cytometry/confocal microscopy, respectively. TLR2/4 expression by H2O2 in presence of ROS-inhibitors or leptin/LPS/fatty acids was also assessed. Expression of phosphorylated/total ERK1/2, c-Jun, p38, and NF-κB was determined by western blotting. The data (mean±SEM) were compared using unpaired student's t-test or ANOVA; all P-values <0.05 were considered significant. RESULTS: TLR2/4 mRNA/protein expression was elevated by oxidative stress in PBMC compared to controls (P<0.001). This induction was abrogated by apocynin/N-acetyl cysteine treatments (P<0.01). H2O2-induced TLR2/4 gene expression was further enhanced by leptin, LPS, oleate, or palmitate (P<0.05). Oxidative stress also promoted expression of IRF3/5 and proinflammatory cytokines including IFN-γ, IL-1ß, IL-6, TNF-α, and MCP-1/CCL2. This oxidative stress in PBMC involved MAPK/NF-κB dependent signaling. CONCLUSION: Taken together, oxidative stress upregulates expression of TLR2/4, IRF3/5 and signature proinflammatory cytokines in PBMC, involving MAPK/NF-κB dependent signaling, all of which may have implications for metabolic inflammation.


Assuntos
Inflamação/genética , Estresse Oxidativo , Receptor 2 Toll-Like/genética , Receptor 4 Toll-Like/genética , Regulação para Cima , Células Cultivadas , Humanos , Inflamação/metabolismo , Fator Regulador 3 de Interferon/genética , Fatores Reguladores de Interferon/genética , Leucócitos Mononucleares/metabolismo , Espécies Reativas de Oxigênio/metabolismo
12.
Hematol Oncol ; 37 Suppl 1: 53-61, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31187530

RESUMO

Pediatric-type follicular lymphoma (PTFL), pediatric nodal marginal zone lymphoma (pnMZL), and large B-cell lymphoma (LBCL) with IRF4 rearrangement have been introduced into the current World Health Organization (WHO) classification. They account for 5% to 10% of mature B-cell lymphomas in children and adolescents. Both PTFL and pnMZL predominantly affect male adolescents and usually present with localized lymphadenopathy in the head and neck region. The cells within the follicles of PTFL typically show high-grade cytology, IGH monoclonality and lack the t(14;18) chromosomal alteration. In contrast, pnMZL is characterized by progressive transformation of germinal center (PTGC)-like features and interfollicular proliferation of the cells with expansion of the marginal zones with diffuse areas. Watch and wait after complete resection seems an adequate therapy with chemotherapy restricted to incompletely resected disease. All children with PTFL and pnMZL reported, so far, survived. B-cell lymphomas presenting in the Waldeyer's ring are characterized by the expression of IRF4/MUM1 and often associated with IRF4 rearrangements. Because of the frequent diffuse component, treatment often follows current protocols for mature B-NHL. The prognosis is excellent.


Assuntos
Linfoma de Células B/diagnóstico , Adolescente , Fatores Etários , Biópsia , Criança , Terapia Combinada , Humanos , Imuno-Histoquímica , Fatores Reguladores de Interferon/genética , Fatores Reguladores de Interferon/metabolismo , Linfoma de Células B/epidemiologia , Linfoma de Células B/etiologia , Linfoma de Células B/terapia , Linfoma de Zona Marginal Tipo Células B/diagnóstico , Linfoma de Zona Marginal Tipo Células B/epidemiologia , Linfoma de Zona Marginal Tipo Células B/terapia , Linfoma Folicular/diagnóstico , Linfoma Folicular/epidemiologia , Linfoma Folicular/terapia , Técnicas de Diagnóstico Molecular , Gradação de Tumores , Estadiamento de Neoplasias , Resultado do Tratamento
13.
PLoS Pathog ; 15(5): e1007743, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-31059555

RESUMO

Kaposi's sarcoma-associated herpesvirus (KSHV; human herpesvirus 8) belongs to the subfamily of Gammaherpesvirinae and is the etiological agent of Kaposi's sarcoma as well as of two lymphoproliferative diseases: primary effusion lymphoma and multicentric Castleman disease. The KSHV life cycle is divided into a latent and a lytic phase and is highly regulated by viral immunomodulatory proteins which control the host antiviral immune response. Among them is a group of proteins with homology to cellular interferon regulatory factors, the viral interferon regulatory factors 1-4. The KSHV vIRFs are known as inhibitors of cellular interferon signaling and are involved in different oncogenic pathways. Here we characterized the role of the second vIRF protein, vIRF2, during the KSHV life cycle. We found the vIRF2 protein to be expressed in different KSHV positive cells with early lytic kinetics. Importantly, we observed that vIRF2 suppresses the expression of viral early lytic genes in both newly infected and reactivated persistently infected endothelial cells. This vIRF2-dependent regulation of the KSHV life cycle might involve the increased expression of cellular interferon-induced genes such as the IFIT proteins 1, 2 and 3, which antagonize the expression of early KSHV lytic proteins. Our findings suggest a model in which the viral protein vIRF2 allows KSHV to harness an IFN-dependent pathway to regulate KSHV early gene expression.


Assuntos
Endotélio Vascular/virologia , Regulação Viral da Expressão Gênica , Herpesvirus Humano 8/fisiologia , Proteínas Imediatamente Precoces/metabolismo , Fatores Reguladores de Interferon/metabolismo , Interferons/metabolismo , Sarcoma de Kaposi/virologia , Proteínas Virais/metabolismo , Ativação Viral , Células Cultivadas , Endotélio Vascular/metabolismo , Endotélio Vascular/patologia , Humanos , Proteínas Imediatamente Precoces/genética , Fatores Reguladores de Interferon/genética , Interferons/genética , Sarcoma de Kaposi/genética , Sarcoma de Kaposi/metabolismo , Proteínas Virais/genética , Latência Viral
14.
Gene ; 706: 181-187, 2019 Jul 20.
Artigo em Inglês | MEDLINE | ID: mdl-31082500

RESUMO

Systemic lupus erythematous (SEL) is a heterogeneous, systemic autoimmune disorder which is defined by its autoantibody pattern. Transcriptomic data analysis has shown pathways and immune system responses associated with SLE. Eight up-regulated genes (SOCE, MMP9, CXCL8, JUN, IL1B, NFKBIA, TNF and FOS) have been examined with four interactions among different pathways. These genes are associated with SNPs which have been identified through two datasets from SLE genome-wide association studies (GWAS). In this investigation, the GWAS results were integrated with pathway analysis of transcriptomes and several genes were detected with known SLE-related variations (TYK2, C5, SH2B, IRF5, IL2RA, STAT4, FCGR2A, IL7R, LYN, HLA-DRB and TNFAIP3). Pathway-based analysis on the Wikipathway Human Collection allowed the identification of prioritized variants in the relevant pathways, such as thymic stromal lymphopoietin (TSLP) signaling pathway linked to LYN, IL7R, STAT4 and rs7574865. Analysis of existing transcriptomes and GWAS data identified eight up-regulated candidate genes with more than four relationships among the different pathways associated with SNPs to pinpoint the relevant loci linked to SLE. The results of this investigation have expanded the number of candidate genes related to SLE and have highlighted possible pathways and GWAS-based methods for gene detection. Identification of the fundamental genes would assist in revealing the mechanisms responsible for SLE.


Assuntos
Perfilação da Expressão Gênica/métodos , Lúpus Eritematoso Sistêmico/genética , Estudos de Casos e Controles , Bases de Dados Genéticas , Ontologia Genética , Redes Reguladoras de Genes/genética , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla/métodos , Genótipo , Humanos , Fatores Reguladores de Interferon/genética , Lúpus Eritematoso Sistêmico/fisiopatologia , Polimorfismo de Nucleotídeo Único/genética , Receptores de IgG/genética , Fator de Transcrição STAT4/genética , Proteína 3 Induzida por Fator de Necrose Tumoral alfa/genética
15.
Tuberculosis (Edinb) ; 116S: S131-S137, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-31085128

RESUMO

Mycobacterium tuberculosis (Mtb) is a facultative intracellular pathogen that infects macrophages where it avoids elimination by interfering with host defense mechanisms, including phago-lysosome fusion. Endosomal Toll-like receptors (TLRs) generate Type I Interferons (IFNs), which are associated with active tuberculosis (TB). We aimed to explore if DNA from different Mtb lineages lead to differences in the inflammatory response of human monocytic/macrophage cells. THP-1 cells which express two inducible reporter constructs for interferons (IFNs) as well as for NF-κB, were stimulated via endosomal delivery of Mtb DNA as a nanocomplex with PEI. DNA from different Mtb phylogenetic lineages elicited differential inflammatory responses in human macrophages. An initial relatively weak IRF-mediated response to DNA from HN878 and H37Rv increased if the cells were pre-treated with Vitamin D (Vit D) for 72 h. RNAseq of THP-1 under different transformation conditions showed that pre-treatment with Vit D upregulated several TLR9 variants, as well as genes involved in inflammatory immune response to infection, immune cell activation, Type I IFN regulation, and regulation of inflammation. Vit D appears to be important in increasing low IRF responses to DNA from certain lineages of Mtb. Variations in the IRF-mediated response to DNA derived from different Mtb genotypes are potentially important in the pathogenesis of tuberculosis since Type I IFN responses are associated with active disease. The role of Vit D in these responses could also translate into future therapeutic approaches.


Assuntos
Calcitriol/farmacologia , DNA Bacteriano/metabolismo , Macrófagos/efeitos dos fármacos , Mycobacterium tuberculosis/metabolismo , Proteínas de Bactérias/metabolismo , DNA Bacteriano/genética , Interações Hospedeiro-Patógeno , Humanos , Fatores Reguladores de Interferon/genética , Fatores Reguladores de Interferon/metabolismo , Interferon gama/farmacologia , Macrófagos/metabolismo , Macrófagos/microbiologia , Mycobacterium tuberculosis/genética , NF-kappa B/genética , NF-kappa B/metabolismo , Células THP-1 , Receptor Toll-Like 9/genética , Receptor Toll-Like 9/metabolismo
16.
J Immunol ; 202(10): 3033-3040, 2019 05 15.
Artigo em Inglês | MEDLINE | ID: mdl-30988114

RESUMO

Studies have demonstrated the importance of a GM-CSF→IFN regulatory factor 4 (IRF4)→CCL17 pathway, first identified in monocytes/macrophages, for arthritic pain and disease development. In this study, we further investigated the involvement of this new pathway in shaping the inflammatory response using the zymosan-induced peritonitis (ZIP) model. ZIP (8 mg of zymosan, i.p., day 0) was induced in C57BL/6 wild-type (WT), GM-CSF-/- , Irf4-/- , and Ccl17E/E mice. In comparison with WT mice, GM-CSF-/- and Irf4-/- mice had a reduced ZIP response, as judged by a reduced number of neutrophils and macrophages in the peritoneal cavity. Moreover, the phenotype of the ZIP macrophages was altered by a lack of GM-CSF or IRF4 (increased IL-10 secretion and Arg1 mRNA expression), with IRF4 levels being lower in GM-CSF-/- ZIP macrophages than in the WT cells. In addition, GM-CSF ̶IRF4 signaling upregulated MHC class II expression in ZIP macrophages and bone marrow-derived macrophages. Although Ccl17 mRNA expression was reduced in ZIP macrophages in the absence of either GM-CSF or IRF4, thus supporting the presence of the new pathway in inflammatory macrophages, CCL17 did not modulate the inflammatory response, both in terms of number of myeloid cells or the macrophage phenotype. Thus, during an inflammatory response, both macrophage numbers and their phenotype can depend on GM-CSF- and IRF4-dependent signaling independently of CCL17.


Assuntos
Fator Estimulador de Colônias de Granulócitos e Macrófagos/imunologia , Fatores Reguladores de Interferon/imunologia , Macrófagos/imunologia , Transdução de Sinais/imunologia , Animais , Quimiocina CCL17/genética , Quimiocina CCL17/imunologia , Fator Estimulador de Colônias de Granulócitos e Macrófagos/genética , Antígenos de Histocompatibilidade Classe II/genética , Antígenos de Histocompatibilidade Classe II/imunologia , Inflamação/genética , Inflamação/imunologia , Inflamação/patologia , Fatores Reguladores de Interferon/genética , Macrófagos/patologia , Camundongos , Camundongos Knockout , Transdução de Sinais/genética , Regulação para Cima/imunologia
17.
Lupus ; 28(6): 740-747, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-31018759

RESUMO

OBJECTIVE: The aim of this study is to determine whether the functional interferon regulatory factor 5 ( IRF5) polymorphism rs2004640 is associated with susceptibility to systemic lupus erythematosus (SLE) in multiple ethnic populations. METHODS: A meta-analysis was conducted on the T allele of the IRF5 rs2004640 polymorphism in all study participants as well as each ethnic population. RESULTS: Twenty research articles that included 28 comparative studies of 20,892 patients and 24,930 controls were included in the meta-analysis. The Asian population had a much lower prevalence of the T allele than any other study population at 28%, and the European population had the highest prevalence of the T allele at 52%. Meta-analysis showed an association between the IRF5 rs2004640 polymorphism and SLE in all participants (odds ratio = 1.472, 95% confidence interval = 1.370-1.582, p < 0.001). Analysis after stratification by ethnicity indicated that the IRF5 rs2004640 T allele is significantly associated with SLE in Europeans, Asians, Latin Americans and Arabs. CONCLUSIONS: This meta-analysis confirms that the IRF5 rs2004640 polymorphism is associated with SLE susceptibility in different ethnic groups, and that its prevalence is ethnicity dependent.


Assuntos
Fatores Reguladores de Interferon/genética , Lúpus Eritematoso Sistêmico/genética , Polimorfismo Genético , Alelos , Ásia/epidemiologia , Grupo com Ancestrais do Continente Asiático/genética , Estudos de Casos e Controles , Grupos Étnicos/genética , Europa (Continente)/epidemiologia , Grupo com Ancestrais do Continente Europeu/genética , Frequência do Gene , Predisposição Genética para Doença , Humanos , América Latina/epidemiologia , Lúpus Eritematoso Sistêmico/epidemiologia , Prevalência
18.
Nat Commun ; 10(1): 1903, 2019 04 23.
Artigo em Inglês | MEDLINE | ID: mdl-31015418

RESUMO

Single-cell transcriptomic assays have enabled the de novo reconstruction of lineage differentiation trajectories, along with the characterization of cellular heterogeneity and state transitions. Several methods have been developed for reconstructing developmental trajectories from single-cell transcriptomic data, but efforts on analyzing single-cell epigenomic data and on trajectory visualization remain limited. Here we present STREAM, an interactive pipeline capable of disentangling and visualizing complex branching trajectories from both single-cell transcriptomic and epigenomic data. We have tested STREAM on several synthetic and real datasets generated with different single-cell technologies. We further demonstrate its utility for understanding myoblast differentiation and disentangling known heterogeneity in hematopoiesis for different organisms. STREAM is an open-source software package.


Assuntos
Algoritmos , Linhagem da Célula/genética , Genômica/métodos , Células-Tronco Hematopoéticas/metabolismo , Análise de Célula Única/estatística & dados numéricos , Transcriptoma , Animais , Diferenciação Celular , Proteínas de Ligação a DNA/genética , Proteínas de Ligação a DNA/metabolismo , Células Eritroides/citologia , Células Eritroides/metabolismo , Fator de Transcrição GATA1/genética , Fator de Transcrição GATA1/metabolismo , Regulação da Expressão Gênica no Desenvolvimento , Células-Tronco Hematopoéticas/citologia , Fatores Reguladores de Interferon/genética , Fatores Reguladores de Interferon/metabolismo , Linfócitos/citologia , Linfócitos/metabolismo , Camundongos , Redução Dimensional com Múltiplos Fatores , Células Mieloides/citologia , Células Mieloides/metabolismo , Mioblastos/citologia , Mioblastos/metabolismo , Transdução de Sinais , Análise de Célula Única/métodos , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo
19.
Pediatr Blood Cancer ; 66(8): e27770, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31012208

RESUMO

Large B-cell lymphoma with IRF4 rearrangement is a provisional entity in the 2017 World Health Organization classification. In order to characterize these lymphomas in children from the United States, IRF4 FISH and immunohistochemical stains were performed on 32 follicular lymphoma and diffuse large B-cell lymphoma (DLBCL) from Children's Oncology Group studies. Two DLBCLs (6%) had IRF4 rearrangements, one involving the ileocecal valve and another involving the tonsil and cerebrospinal fluid. Both cases had strong, diffuse IRF4/MUM1 immunohistochemical staining, which may be a pathologic clue to the diagnosis. Reclassification of these cases may have prognostic and therapeutic implications.


Assuntos
Biomarcadores Tumorais/genética , Rearranjo Gênico , Fatores Reguladores de Interferon/genética , Linfoma Folicular/genética , Linfoma Difuso de Grandes Células B/genética , Translocação Genética , Adolescente , Protocolos de Quimioterapia Combinada Antineoplásica , Criança , Feminino , Seguimentos , Humanos , Linfoma Folicular/tratamento farmacológico , Linfoma Folicular/patologia , Linfoma Difuso de Grandes Células B/tratamento farmacológico , Linfoma Difuso de Grandes Células B/patologia , Masculino , Prognóstico
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