The Experts below are selected from a list of 297 Experts worldwide ranked by ideXlab platform
Betsy J Barnes - One of the best experts on this subject based on the ideXlab platform.
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b cell intrinsic role for irf5 in tlr9 bcr induced human b cell activation proliferation and plasmablast differentiation
Frontiers in Immunology, 2018Co-Authors: Baohong Zhang, Betsy J Barnes, Aaron Winkler, Tiffany Shih, Sukhwinder Singh, Robert DonnellyAbstract:Upon recognition of antigen, B cells undergo rapid proliferation followed by differentiation to specialized antibody secreting cells (ASCs). During this transition, B cells are reliant upon a multilayer transcription factor network to achieve a dramatic remodeling of the B cell transcriptional landscape. Increased levels of ASCs are often seen in autoimmune diseases and it is believed that altered expression of Regulatory transcription factors play a role in this imbalance. The transcription factor Interferon Regulatory factor 5 (IRF5) is one such candidate as polymorphisms in IRF5 associate with risk of numerous autoimmune diseases and correlate with elevated IRF5 expression. IRF5 genetic risk has been widely replicated in systemic lupus erythematosus (SLE), and loss of Irf5 ameliorates disease in murine lupus models, in part, through the lack of pathogenic autoantibody secretion. It remains unclear, however, whether IRF5 is contributing to autoantibody production through a B cell-intrinsic function. To date, IRF5 function in healthy human B cells has not been characterized. Using human primary naive B cells, we define a critical intrinsic role for IRF5 in B cell activation, proliferation, and plasmablast differentiation. Targeted IRF5 knockdown resulted in significant immunoglobulin (Ig) D retention, reduced proliferation, plasmablast differentiation, and IgG secretion. The observed decreases were due to impaired B cell activation and clonal expansion. Distinct from murine studies, we identify and confirm new IRF5 target genes, IRF4, ERK1, and MYC, and pathways that mediate IRF5 B cell-intrinsic function. Together, these results identify IRF5 as an early regulator of human B cell activation and provide the first dataset in human primary B cells to map IRF5 dysfunction in SLE.
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Interferon Regulatory factor 5 irf5 suppresses hepatitis c virus hcv replication and hcv associated hepatocellular carcinoma
Journal of Biological Chemistry, 2017Co-Authors: Betsy J Barnes, Dan Li, Erica Maria Pimenta, Ozge Cevik, Erdene Baljinnyam, Dinesh Manvar, Gulam WarisAbstract:Abstract Hepatitis C virus (HCV) infection is a major risk factor for the development of chronic liver disease. The disease typically progresses from chronic HCV to fibrosis, cirrhosis, hepatocellular carcinoma (HCC), and death. Chronic inflammation associated with HCV infection is implicated in cirrhosis and HCC, but the molecular players and signaling pathways contributing to these processes remain largely unknown. Interferon Regulatory factor 5 (IRF5) is a molecule of interest in HCV-associated HCC because it has critical roles in virus-, Tolllike receptor (TLR)-, and Interferon (IFN)- induced signaling pathways. IRF5 is also a tumor suppressor, and its expression is dysregulated in several human cancers. Here, we present first evidence that IRF5 expression and signaling are modulated during HCV infection. Using HCV infection of human hepatocytes and cells with autonomously replicating HCV RNA, we found that levels of IRF5 mRNA and protein expression were downregulated. Of note, reporter assays indicated that IRF5 re-expression inhibited HCV protein translation and RNA replication. Gene expression analysis revealed significant differences in the expression of cancer pathway mediators and autophagy proteins rather than in cytokines between IRF5- and empty vector-transfected HCV replicon cells. IRF5 reexpression induced apoptosis via loss in mitochondrial membrane potential, downregulated autophagy, and inhibited hepatocyte cell migration/invasion. Analysis of clinical HCC specimens support a pathologic role for IRF5 in HCV-induced HCC, as IRF5 expression was down-regulated in livers from HCV-positive versus HCV-negative HCC patients or healthy donor livers. These results identify IRF5 as an important suppressor of HCV replication and HCC pathogenesis.
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Interferon Regulatory factor 5 (IRF5) suppresses hepatitis C virus (HCV) replication and HCV-associated hepatocellular carcinoma.
Journal of Biological Chemistry, 2017Co-Authors: Ozge Cevik, Betsy J Barnes, Erica Maria Pimenta, Erdene Baljinnyam, Dinesh Manvar, Gulam Waris, Neerja Kaushik-basuAbstract:Hepatitis C virus (HCV) infection is a major risk factor for the development of chronic liver disease. The disease typically progresses from chronic HCV to fibrosis, cirrhosis, hepatocellular carcinoma (HCC), and death. Chronic inflammation associated with HCV infection is implicated in cirrhosis and HCC, but the molecular players and signaling pathways contributing to these processes remain largely unknown. Interferon Regulatory factor 5 (IRF5) is a molecule of interest in HCV-associated HCC because it has critical roles in virus-, Toll-like receptor (TLR)-, and IFN-induced signaling pathways. IRF5 is also a tumor suppressor, and its expression is dysregulated in several human cancers. Here, we present first evidence that IRF5 expression and signaling are modulated during HCV infection. Using HCV infection of human hepatocytes and cells with autonomously replicating HCV RNA, we found that levels of IRF5 mRNA and protein expression were down-regulated. Of note, reporter assays indicated that IRF5 re-expression inhibited HCV protein translation and RNA replication. Gene expression analysis revealed significant differences in the expression of cancer pathway mediators and autophagy proteins rather than in cytokines between IRF5- and empty vector-transfected HCV replicon cells. IRF5 re-expression induced apoptosis via loss in mitochondrial membrane potential, down-regulated autophagy, and inhibited hepatocyte cell migration/invasion. Analysis of clinical HCC specimens supports a pathologic role for IRF5 in HCV-induced HCC, as IRF5 expression was down-regulated in livers from HCV-positive versus HCV-negative HCC patients or healthy donor livers. These results identify IRF5 as an important suppressor of HCV replication and HCC pathogenesis.
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Abstract 4141: Role of Interferon Regulatory factor 5 in anti-tumor immunity: Orchestration of a functional tertiary lymphoid structure
Tumor Biology, 2016Co-Authors: Erica Maria Pimenta, Ryan Weiss, Betsy J BarnesAbstract:The ability of breast cancer cells to metastasize is due to intrinsic intratumoral and extrinsic microenvironment changes. Many breast cancers are heavily infiltrated by immune cells and these infiltrating leukocytes are commonly observed around tumors in patients with invasive ductal carcinoma. Several recent studies show that the presence of tumor infiltrating leukocytes in human breast cancer tissue is associated with improved outcome, suggesting that the immune system is participating in the control and elimination of tumor cells. One way in which epithelial-derived cancers evade immunity is through dysregulation of cytokines and chemokines that “call in” specific immune cells to form a functional ectopic lymphoid-like structure termed a tertiary lymphoid structure (TLS) near the tumor. TLS are important for cell-mediated and humoral immunity and are extremely efficient immunological tools as the presentation of antigen occurs to both B and T cells. Although very little is known about the processes that drive TLS formation, data indicate that the presence of a TLS next to a solid cancer, including breast cancer, is a strong positive prognostic indicator. Recent data from our lab and others show that expression of the transcription factor Interferon Regulatory factor 5 (IRF5) in a human breast cancer molecular signature predicts increased survival and lower incidence of metastasis. We recently identified IRF5 as an important intrinsic regulator of mammary epithelial cell migration and metastasis. We also found that IRF5 within a breast tumor regulates the expression of cytokines/chemokines, such as CXCL13, that mediate immune cell trafficking. We previously reported that tumor-conditioned media (TCM) from IRF5-positive breast tumor cells contains CXCL13 and induces trafficking of CD19+CXCR5+ B cells and CD3+CD4+CXCR5+ T follicular helper-like (Tfh) cells to the TCM. CXCL13 is a key player in the formation of a TLS as it recruits in the specific cells and activates the B cells to produce immunoglobulins. Further analysis of immune cell trafficking to TCM from IRF5+ and IRF5- breast tumor cells reveals specificity for the trafficking of anti-tumorigenic B and T cell subsets to IRF5-positive TCM, such as transitional, memory, and plasmablast/plasma B cells, along with Th1 and Tfh cells, rather than pro-tumorigenic, immunosuppressive Bregs, Th2, and Tregs that were found to specifically migrate to IRF5-negative TCM. Analysis of formalin-fixed paraffin-embedded breast tumors by immunofluorescence microscopy revealed a significant correlation between IRF5 intratumoral expression and the presence of a TLS. Furthermore, preliminary data from a murine model of invasive mammary tumorigenesis supports a critical role for IRF5 in anti-tumor immunity. Together, these data implicate IRF5 in the generation of a functional TLS and as a critical mediator of anti-tumor immunity. Citation Format: Erica Pimenta, Ryan Weiss, Dan Li, Betsy Barnes. Role of Interferon Regulatory factor 5 in anti-tumor immunity: Orchestration of a functional tertiary lymphoid structure. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4141.
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irf5 is a novel regulator of cxcl13 expression in breast cancer that regulates cxcr5 b and t cell trafficking to tumor conditioned media
Immunology and Cell Biology, 2015Co-Authors: Erica Maria Pimenta, Ryan Weiss, Di Feng, Saurav De, Kelly Hall, Sarah Kilic, Gyan Bhanot, Shridar Ganesan, Betsy J BarnesAbstract:Clinical studies using prognostic and predictive signatures have shown that an immune signal emanating from whole tumors reflects the level of immune cell infiltration—a high immune signal linked to improved outcome. Factors regulating immune cell trafficking to the tumor, however, are not known. Previous work has shown that expression of Interferon Regulatory factor 5 (IRF5), a critical immune regulator, is lost in ~80% of invasive ductal carcinomas examined. We postulated that IRF5-positive and -negative breast tumors would differentially regulate immune cell trafficking to the tumor. Using a focused tumor inflammatory array, differences in cytokine and chemokine expression were examined between IRF5-positive and -negative MDA-MB-231 cells grown in three-dimensional culture. A number of cytokines/chemokines were found to be dysregulated between cultures. CXCL13 was identified as a direct target of IRF5 resulting in the enhanced recruitment of B and T cells to IRF5-positive tumor-conditioned media. The ability of IRF5 to regulate mediators of cell migration was confirmed by enzyme-linked immunosorbent assay, chromatin immunoprecipitation assay, small interfering RNA knockdown and immunofluorescence staining of human breast tumor tissues. Analysis of primary immune cell subsets revealed that IRF5 specifically recruits CXCR5+ B and T cells to the tumor; CXCR5 is the receptor for CXCL13. Analysis of primary breast tumor tissues revealed a significant correlation between IRF5 and CXCL13 expression providing clinical relevance to the study. Together, these data support that IRF5 directly regulates a network of genes that shapes a tumor immune response and may, in combination with CXCL13, serve as a novel prognostic marker for antitumor immunity.
Snaevar Sigurdsson - One of the best experts on this subject based on the ideXlab platform.
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genome wide profiling of target genes for the systemic lupus erythematosus associated transcription factors irf5 and stat4
Annals of the Rheumatic Diseases, 2013Co-Authors: Chuan Wang, Snaevar Sigurdsson, Johanna K. Sandling, Maija-leena Eloranta, Lars Ronnblom, Niklas Hagberg, Olof Berggren, Olof Karlberg, Annchristine SyvanenAbstract:Background The transcription factors Interferon Regulatory factor 5 (IRF5) and signal transducer and activator of transcription 4 (STAT4) are encoded by two of the strongest susceptibility genes for systemic lupus erythematosus (SLE). Objective To investigate the target genes and functional roles of IRF5 and STAT4 in human peripheral blood mononuclear cells (PBMCs). Methods Chromatin immunoprecipitation-sequencing (ChIP-seq) was performed in PBMCs stimulated to activate IRF5 and STAT4. The expression of the target genes of IRF5 and STAT4 was investigated in a publicly available dataset generated from PBMCs from patients with SLE and healthy controls. The genomic regions bound by the transcription complexes mediated by IRF5 and STAT4 were examined for transcription factor binding motifs and SLE-associated sequence variants. Results More than 7000 target genes for IRF5 and STAT4 were identified in stimulated PBMCs. These genes were enriched to functional pathways in the type I Interferon system, and have key roles in the inflammatory response. The expression patterns of the target genes were characteristic for patients with SLE. The transcription factors high mobility group-I/Y, specificity protein 1, and paired box 4 may function cooperatively with IRF5 and STAT4 in transcriptional regulation. Eight of the target regions for IRF5 and STAT4 contain SLE-associated sequence variants. Conclusions By participating in transcription complex with other co-factors, IRF5 and STAT4 harbour the potential of regulating a large number of target genes, which may contribute to their strong association with SLE.
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genetic variants and disease associated factors contribute to enhanced Interferon Regulatory factor 5 expression in blood cells of patients with systemic lupus erythematosus
Arthritis & Rheumatism, 2010Co-Authors: Di Feng, Snaevar Sigurdsson, Maija-leena Eloranta, Gunnel Nordmark, Chuan Wang, Rivka C Stone, Niquiche Sangsterguity, Gunnar V Alm, Annchristine Syvanen, Lars RonnblomAbstract:Objective Genetic variants of the Interferon (IFN) Regulatory factor 5 gene (IRF5) are associated with susceptibility to systemic lupus erythematosus (SLE). The contribution of these variants to IRF-5 expression in primary blood cells of SLE patients has not been addressed, nor has the role of type I IFNs. The aim of this study was to determine the association between increased IRF-5 expression and the IRF5 risk haplotype in SLE patients. Methods IRF-5 transcript and protein levels in 44 Swedish patients with SLE and 16 healthy controls were measured by quantitative real-time polymerase chain reaction, minigene assay, and flow cytometry. Single-nucleotide polymorphisms rs2004640, rs10954213, and rs10488631 and the CGGGG insertion/deletion were genotyped in these patients. Genotypes of these polymorphisms defined both a common risk haplotype and a common protective haplotype. Results IRF-5 expression and alternative splicing were significantly up-regulated in SLE patients compared with healthy donors. Enhanced transcript and protein levels were associated with the risk haplotype of IRF5; rs10488631 displayed the only significant independent association that correlated with increased transcription from the noncoding first exon 1C. Minigene experiments demonstrated an important role for rs2004640 and the CGGGG insertion/deletion, along with type I IFNs, in regulating IRF5 expression. Conclusion This study provides the first formal proof that IRF-5 expression and alternative splicing are significantly up-regulated in primary blood cells of patients with SLE. Furthermore, the risk haplotype is associated with enhanced IRF-5 transcript and protein expression in patients with SLE.
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a risk haplotype of stat4 for systemic lupus erythematosus is over expressed correlates with anti dsdna and shows additive effects with two risk alleles of irf5
Human Molecular Genetics, 2008Co-Authors: Snaevar Sigurdsson, Maija-leena Eloranta, Gunnel Nordmark, Iva Gunnarsson, Sophie Garnier, Elin Grundberg, Tony Kwan, Olof Nilsson, Elisabet Svenungsson, Gunnar SturfeltAbstract:Systemic lupus erythematosus (SLE) is the prototype autoimmune disease where genes regulated by type I Interferon (IFN) are over-expressed and contribute to the disease pathogenesis. Because signal transducer and activator of transcription 4 (STAT4) plays a key role in the type I IFN receptor signaling, we performed a candidate gene study of a comprehensive set of single nucleotide polymorphism (SNPs) in STAT4 in Swedish patients with SLE. We found that 10 out of 53 analyzed SNPs in STAT4 were associated with SLE, with the strongest signal of association (P = 7.1 x 10(-8)) for two perfectly linked SNPs rs10181656 and rs7582694. The risk alleles of these 10 SNPs form a common risk haplotype for SLE (P = 1.7 x 10(-5)). According to conditional logistic regression analysis the SNP rs10181656 or rs7582694 accounts for all of the observed association signal. By quantitative analysis of the allelic expression of STAT4 we found that the risk allele of STAT4 was over-expressed in primary human cells of mesenchymal origin, but not in B-cells, and that the risk allele of STAT4 was over-expressed (P = 8.4 x 10(-5)) in cells carrying the risk haplotype for SLE compared with cells with a non-risk haplotype. The risk allele of the SNP rs7582694 in STAT4 correlated to production of anti-dsDNA (double-stranded DNA) antibodies and displayed a multiplicatively increased, 1.82-fold risk of SLE with two independent risk alleles of the IRF5 (Interferon Regulatory factor 5) gene.
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Interferon Regulatory factor 5 irf5 gene variants are associated with multiple sclerosis in three distinct populations
Journal of Medical Genetics, 2008Co-Authors: Gudlaug Kristjansdottir, Snaevar Sigurdsson, Johanna K. Sandling, Lili Milani, Alessandro Bonetti, Izaura M Roos, Chuan Wang, Sigrun M Gustafsdottir, Anders Lundmark, Pentti J TienariAbstract:Background: IRF5 is a transcription factor involved both in the type I Interferon and the toll-like receptor signalling pathways. Previously, IRF5 has been found to be associated with systemic lupus erythematosus, rheumatoid arthritis and inflammatory bowel diseases. Here we investigated whether polymorphisms in the IRF5 gene would be associated with yet another disease with features of autoimmunity, multiple sclerosis. Materials and methods: We genotyped nine single nucleotide polymorphisms and one insertion-deletion polymorphism in the IRF5 gene in a collection of 2337 patients with MS and 2813 controls from three populations: two case-control cohorts from Spain and Sweden, and a set of MS trio families from Finland. Results: Two SNPs (rs4728142, rs3807306) and a 5 bp insertion-deletion polymorphism located in the promoter and first intron of the IRF5 gene, showed association signals with p-values <0.001 when the data from all cohorts were combined. The predisposing alleles were present on the same common haplotype in all populations. Using electrophoretic mobility shift assays we observed allele-specific differences in protein binding for the SNP rs4728142 and the 5 bp indel, and by a proximity ligation assay we demonstrated increased binding of the transcription factor SP1 to the risk allele of the 5 bp indel. Conclusion: These findings add IRF5 to the short list of genes shown to be associated with MS in more than one population. Our study adds to the evidence that there might be genes or pathways that are common in multiple autoimmune diseases, and that the type I Interferon system is likely to be involved in the development of these diseases.
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an insertion deletion polymorphism in the Interferon Regulatory factor 5 irf5 gene confers risk of inflammatory bowel diseases
Human Molecular Genetics, 2007Co-Authors: Vinciane Dideberg, Snaevar Sigurdsson, Ann-christin Wiman, Gudlaug Kristjansdottir, Lili Milani, Cecile Libioulle, Edouard Louis, Severine Vermeire, Paul Rutgeerts, Jacques BelaicheAbstract:The Interferon Regulatory factor 5 (IRF5) gene encodes a transcription factor that plays an important role in the innate as well as in the cell-mediated immune responses. The IRF5 gene has been shown to be associated with systemic lupus erythematosus and rheumatoid arthritis. We studied whether the IRF5 gene is also associated with inflammatory bowel diseases (IBD), Crohn disease (CD) and ulcerative colitis (UC). Twelve polymorphisms in the IRF5 gene were genotyped in a cohort of 1007 IBD patients (748 CD and 254 UC) and 241 controls from Wallonia, Belgium. The same polymorphisms were genotyped in a confirmatory cohort of 311 controls and 687 IBD patients (488 CD and 192 UC) from Leuven, Belgium. A strong signal of association [P = 1.9 x 10(-5), odds ratio (OR) 1.81 (1.37-2.39)] with IBD was observed for a 5 bp indel (CGGGG) polymorphism in the promoter region of the IRF5 gene. The association was detectable also in CD patients (P = 6.8 x 10(-4)) and was particularly strong among the UC patients [P = 5.3 x 10(-8), OR = 2.42 (1.76-3.34)]. The association of the CGGGG indel was confirmed in the second cohort [P = 3.2 x 10(-5), OR = 1.59 (1.28-1.98)]. The insertion of one CGGGG unit is predicted to create an additional binding site for the transcription factor SP1. Using an electrophoretic mobility shift assay, we show allele-specific differences in protein binding to this repetitive DNA-stretch, which suggest a potential function role for the CGGGG indel.
Erica Maria Pimenta - One of the best experts on this subject based on the ideXlab platform.
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Interferon Regulatory factor 5 irf5 suppresses hepatitis c virus hcv replication and hcv associated hepatocellular carcinoma
Journal of Biological Chemistry, 2017Co-Authors: Betsy J Barnes, Dan Li, Erica Maria Pimenta, Ozge Cevik, Erdene Baljinnyam, Dinesh Manvar, Gulam WarisAbstract:Abstract Hepatitis C virus (HCV) infection is a major risk factor for the development of chronic liver disease. The disease typically progresses from chronic HCV to fibrosis, cirrhosis, hepatocellular carcinoma (HCC), and death. Chronic inflammation associated with HCV infection is implicated in cirrhosis and HCC, but the molecular players and signaling pathways contributing to these processes remain largely unknown. Interferon Regulatory factor 5 (IRF5) is a molecule of interest in HCV-associated HCC because it has critical roles in virus-, Tolllike receptor (TLR)-, and Interferon (IFN)- induced signaling pathways. IRF5 is also a tumor suppressor, and its expression is dysregulated in several human cancers. Here, we present first evidence that IRF5 expression and signaling are modulated during HCV infection. Using HCV infection of human hepatocytes and cells with autonomously replicating HCV RNA, we found that levels of IRF5 mRNA and protein expression were downregulated. Of note, reporter assays indicated that IRF5 re-expression inhibited HCV protein translation and RNA replication. Gene expression analysis revealed significant differences in the expression of cancer pathway mediators and autophagy proteins rather than in cytokines between IRF5- and empty vector-transfected HCV replicon cells. IRF5 reexpression induced apoptosis via loss in mitochondrial membrane potential, downregulated autophagy, and inhibited hepatocyte cell migration/invasion. Analysis of clinical HCC specimens support a pathologic role for IRF5 in HCV-induced HCC, as IRF5 expression was down-regulated in livers from HCV-positive versus HCV-negative HCC patients or healthy donor livers. These results identify IRF5 as an important suppressor of HCV replication and HCC pathogenesis.
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Interferon Regulatory factor 5 (IRF5) suppresses hepatitis C virus (HCV) replication and HCV-associated hepatocellular carcinoma.
Journal of Biological Chemistry, 2017Co-Authors: Ozge Cevik, Betsy J Barnes, Erica Maria Pimenta, Erdene Baljinnyam, Dinesh Manvar, Gulam Waris, Neerja Kaushik-basuAbstract:Hepatitis C virus (HCV) infection is a major risk factor for the development of chronic liver disease. The disease typically progresses from chronic HCV to fibrosis, cirrhosis, hepatocellular carcinoma (HCC), and death. Chronic inflammation associated with HCV infection is implicated in cirrhosis and HCC, but the molecular players and signaling pathways contributing to these processes remain largely unknown. Interferon Regulatory factor 5 (IRF5) is a molecule of interest in HCV-associated HCC because it has critical roles in virus-, Toll-like receptor (TLR)-, and IFN-induced signaling pathways. IRF5 is also a tumor suppressor, and its expression is dysregulated in several human cancers. Here, we present first evidence that IRF5 expression and signaling are modulated during HCV infection. Using HCV infection of human hepatocytes and cells with autonomously replicating HCV RNA, we found that levels of IRF5 mRNA and protein expression were down-regulated. Of note, reporter assays indicated that IRF5 re-expression inhibited HCV protein translation and RNA replication. Gene expression analysis revealed significant differences in the expression of cancer pathway mediators and autophagy proteins rather than in cytokines between IRF5- and empty vector-transfected HCV replicon cells. IRF5 re-expression induced apoptosis via loss in mitochondrial membrane potential, down-regulated autophagy, and inhibited hepatocyte cell migration/invasion. Analysis of clinical HCC specimens supports a pathologic role for IRF5 in HCV-induced HCC, as IRF5 expression was down-regulated in livers from HCV-positive versus HCV-negative HCC patients or healthy donor livers. These results identify IRF5 as an important suppressor of HCV replication and HCC pathogenesis.
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Abstract 4141: Role of Interferon Regulatory factor 5 in anti-tumor immunity: Orchestration of a functional tertiary lymphoid structure
Tumor Biology, 2016Co-Authors: Erica Maria Pimenta, Ryan Weiss, Betsy J BarnesAbstract:The ability of breast cancer cells to metastasize is due to intrinsic intratumoral and extrinsic microenvironment changes. Many breast cancers are heavily infiltrated by immune cells and these infiltrating leukocytes are commonly observed around tumors in patients with invasive ductal carcinoma. Several recent studies show that the presence of tumor infiltrating leukocytes in human breast cancer tissue is associated with improved outcome, suggesting that the immune system is participating in the control and elimination of tumor cells. One way in which epithelial-derived cancers evade immunity is through dysregulation of cytokines and chemokines that “call in” specific immune cells to form a functional ectopic lymphoid-like structure termed a tertiary lymphoid structure (TLS) near the tumor. TLS are important for cell-mediated and humoral immunity and are extremely efficient immunological tools as the presentation of antigen occurs to both B and T cells. Although very little is known about the processes that drive TLS formation, data indicate that the presence of a TLS next to a solid cancer, including breast cancer, is a strong positive prognostic indicator. Recent data from our lab and others show that expression of the transcription factor Interferon Regulatory factor 5 (IRF5) in a human breast cancer molecular signature predicts increased survival and lower incidence of metastasis. We recently identified IRF5 as an important intrinsic regulator of mammary epithelial cell migration and metastasis. We also found that IRF5 within a breast tumor regulates the expression of cytokines/chemokines, such as CXCL13, that mediate immune cell trafficking. We previously reported that tumor-conditioned media (TCM) from IRF5-positive breast tumor cells contains CXCL13 and induces trafficking of CD19+CXCR5+ B cells and CD3+CD4+CXCR5+ T follicular helper-like (Tfh) cells to the TCM. CXCL13 is a key player in the formation of a TLS as it recruits in the specific cells and activates the B cells to produce immunoglobulins. Further analysis of immune cell trafficking to TCM from IRF5+ and IRF5- breast tumor cells reveals specificity for the trafficking of anti-tumorigenic B and T cell subsets to IRF5-positive TCM, such as transitional, memory, and plasmablast/plasma B cells, along with Th1 and Tfh cells, rather than pro-tumorigenic, immunosuppressive Bregs, Th2, and Tregs that were found to specifically migrate to IRF5-negative TCM. Analysis of formalin-fixed paraffin-embedded breast tumors by immunofluorescence microscopy revealed a significant correlation between IRF5 intratumoral expression and the presence of a TLS. Furthermore, preliminary data from a murine model of invasive mammary tumorigenesis supports a critical role for IRF5 in anti-tumor immunity. Together, these data implicate IRF5 in the generation of a functional TLS and as a critical mediator of anti-tumor immunity. Citation Format: Erica Pimenta, Ryan Weiss, Dan Li, Betsy Barnes. Role of Interferon Regulatory factor 5 in anti-tumor immunity: Orchestration of a functional tertiary lymphoid structure. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4141.
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irf5 is a novel regulator of cxcl13 expression in breast cancer that regulates cxcr5 b and t cell trafficking to tumor conditioned media
Immunology and Cell Biology, 2015Co-Authors: Erica Maria Pimenta, Ryan Weiss, Di Feng, Saurav De, Kelly Hall, Sarah Kilic, Gyan Bhanot, Shridar Ganesan, Betsy J BarnesAbstract:Clinical studies using prognostic and predictive signatures have shown that an immune signal emanating from whole tumors reflects the level of immune cell infiltration—a high immune signal linked to improved outcome. Factors regulating immune cell trafficking to the tumor, however, are not known. Previous work has shown that expression of Interferon Regulatory factor 5 (IRF5), a critical immune regulator, is lost in ~80% of invasive ductal carcinomas examined. We postulated that IRF5-positive and -negative breast tumors would differentially regulate immune cell trafficking to the tumor. Using a focused tumor inflammatory array, differences in cytokine and chemokine expression were examined between IRF5-positive and -negative MDA-MB-231 cells grown in three-dimensional culture. A number of cytokines/chemokines were found to be dysregulated between cultures. CXCL13 was identified as a direct target of IRF5 resulting in the enhanced recruitment of B and T cells to IRF5-positive tumor-conditioned media. The ability of IRF5 to regulate mediators of cell migration was confirmed by enzyme-linked immunosorbent assay, chromatin immunoprecipitation assay, small interfering RNA knockdown and immunofluorescence staining of human breast tumor tissues. Analysis of primary immune cell subsets revealed that IRF5 specifically recruits CXCR5+ B and T cells to the tumor; CXCR5 is the receptor for CXCL13. Analysis of primary breast tumor tissues revealed a significant correlation between IRF5 and CXCL13 expression providing clinical relevance to the study. Together, these data support that IRF5 directly regulates a network of genes that shapes a tumor immune response and may, in combination with CXCL13, serve as a novel prognostic marker for antitumor immunity.
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Loss of Interferon Regulatory factor 5 (IRF5) expression in human ductal carcinoma correlates with disease stage and contributes to metastasis.
Breast Cancer Research, 2011Co-Authors: Meera Hameed, Erica Maria Pimenta, Neena Mirani, Jason B. Anari, Betsy J BarnesAbstract:Introduction New signaling pathways of the interleukin (IL) family, Interferons (IFN) and Interferon Regulatory factors (IRF) have recently been found within tumor microenvironments and in metastatic sites. Some of these cytokines stimulate while others inhibit breast cancer proliferation and/or invasion. IRFs, a family of nine mammalian transcription factors, have multiple biologic functions that when dysregulated may contribute to tumorigenesis; most well-known are their roles in regulating/initiating host immunity. Some IRF family members have been implicated in tumorigenesis yet little is still known of their expression in primary human tumors or their role(s) in disease development/progression. IRF5 is one of the newer family members to be studied and has been shown to be a critical mediator of host immunity and the cellular response to DNA damage. Here, we examined the expression of IRF5 in primary breast tissue and determined how loss of expression may contribute to breast cancer development and/or progression.
Ozge Cevik - One of the best experts on this subject based on the ideXlab platform.
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Interferon Regulatory factor 5 irf5 suppresses hepatitis c virus hcv replication and hcv associated hepatocellular carcinoma
Journal of Biological Chemistry, 2017Co-Authors: Betsy J Barnes, Dan Li, Erica Maria Pimenta, Ozge Cevik, Erdene Baljinnyam, Dinesh Manvar, Gulam WarisAbstract:Abstract Hepatitis C virus (HCV) infection is a major risk factor for the development of chronic liver disease. The disease typically progresses from chronic HCV to fibrosis, cirrhosis, hepatocellular carcinoma (HCC), and death. Chronic inflammation associated with HCV infection is implicated in cirrhosis and HCC, but the molecular players and signaling pathways contributing to these processes remain largely unknown. Interferon Regulatory factor 5 (IRF5) is a molecule of interest in HCV-associated HCC because it has critical roles in virus-, Tolllike receptor (TLR)-, and Interferon (IFN)- induced signaling pathways. IRF5 is also a tumor suppressor, and its expression is dysregulated in several human cancers. Here, we present first evidence that IRF5 expression and signaling are modulated during HCV infection. Using HCV infection of human hepatocytes and cells with autonomously replicating HCV RNA, we found that levels of IRF5 mRNA and protein expression were downregulated. Of note, reporter assays indicated that IRF5 re-expression inhibited HCV protein translation and RNA replication. Gene expression analysis revealed significant differences in the expression of cancer pathway mediators and autophagy proteins rather than in cytokines between IRF5- and empty vector-transfected HCV replicon cells. IRF5 reexpression induced apoptosis via loss in mitochondrial membrane potential, downregulated autophagy, and inhibited hepatocyte cell migration/invasion. Analysis of clinical HCC specimens support a pathologic role for IRF5 in HCV-induced HCC, as IRF5 expression was down-regulated in livers from HCV-positive versus HCV-negative HCC patients or healthy donor livers. These results identify IRF5 as an important suppressor of HCV replication and HCC pathogenesis.
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Interferon Regulatory factor 5 (IRF5) suppresses hepatitis C virus (HCV) replication and HCV-associated hepatocellular carcinoma.
Journal of Biological Chemistry, 2017Co-Authors: Ozge Cevik, Betsy J Barnes, Erica Maria Pimenta, Erdene Baljinnyam, Dinesh Manvar, Gulam Waris, Neerja Kaushik-basuAbstract:Hepatitis C virus (HCV) infection is a major risk factor for the development of chronic liver disease. The disease typically progresses from chronic HCV to fibrosis, cirrhosis, hepatocellular carcinoma (HCC), and death. Chronic inflammation associated with HCV infection is implicated in cirrhosis and HCC, but the molecular players and signaling pathways contributing to these processes remain largely unknown. Interferon Regulatory factor 5 (IRF5) is a molecule of interest in HCV-associated HCC because it has critical roles in virus-, Toll-like receptor (TLR)-, and IFN-induced signaling pathways. IRF5 is also a tumor suppressor, and its expression is dysregulated in several human cancers. Here, we present first evidence that IRF5 expression and signaling are modulated during HCV infection. Using HCV infection of human hepatocytes and cells with autonomously replicating HCV RNA, we found that levels of IRF5 mRNA and protein expression were down-regulated. Of note, reporter assays indicated that IRF5 re-expression inhibited HCV protein translation and RNA replication. Gene expression analysis revealed significant differences in the expression of cancer pathway mediators and autophagy proteins rather than in cytokines between IRF5- and empty vector-transfected HCV replicon cells. IRF5 re-expression induced apoptosis via loss in mitochondrial membrane potential, down-regulated autophagy, and inhibited hepatocyte cell migration/invasion. Analysis of clinical HCC specimens supports a pathologic role for IRF5 in HCV-induced HCC, as IRF5 expression was down-regulated in livers from HCV-positive versus HCV-negative HCC patients or healthy donor livers. These results identify IRF5 as an important suppressor of HCV replication and HCC pathogenesis.
Maija-leena Eloranta - One of the best experts on this subject based on the ideXlab platform.
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genome wide profiling of target genes for the systemic lupus erythematosus associated transcription factors irf5 and stat4
Annals of the Rheumatic Diseases, 2013Co-Authors: Chuan Wang, Snaevar Sigurdsson, Johanna K. Sandling, Maija-leena Eloranta, Lars Ronnblom, Niklas Hagberg, Olof Berggren, Olof Karlberg, Annchristine SyvanenAbstract:Background The transcription factors Interferon Regulatory factor 5 (IRF5) and signal transducer and activator of transcription 4 (STAT4) are encoded by two of the strongest susceptibility genes for systemic lupus erythematosus (SLE). Objective To investigate the target genes and functional roles of IRF5 and STAT4 in human peripheral blood mononuclear cells (PBMCs). Methods Chromatin immunoprecipitation-sequencing (ChIP-seq) was performed in PBMCs stimulated to activate IRF5 and STAT4. The expression of the target genes of IRF5 and STAT4 was investigated in a publicly available dataset generated from PBMCs from patients with SLE and healthy controls. The genomic regions bound by the transcription complexes mediated by IRF5 and STAT4 were examined for transcription factor binding motifs and SLE-associated sequence variants. Results More than 7000 target genes for IRF5 and STAT4 were identified in stimulated PBMCs. These genes were enriched to functional pathways in the type I Interferon system, and have key roles in the inflammatory response. The expression patterns of the target genes were characteristic for patients with SLE. The transcription factors high mobility group-I/Y, specificity protein 1, and paired box 4 may function cooperatively with IRF5 and STAT4 in transcriptional regulation. Eight of the target regions for IRF5 and STAT4 contain SLE-associated sequence variants. Conclusions By participating in transcription complex with other co-factors, IRF5 and STAT4 harbour the potential of regulating a large number of target genes, which may contribute to their strong association with SLE.
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genetic variants and disease associated factors contribute to enhanced Interferon Regulatory factor 5 expression in blood cells of patients with systemic lupus erythematosus
Arthritis & Rheumatism, 2010Co-Authors: Di Feng, Snaevar Sigurdsson, Maija-leena Eloranta, Gunnel Nordmark, Chuan Wang, Rivka C Stone, Niquiche Sangsterguity, Gunnar V Alm, Annchristine Syvanen, Lars RonnblomAbstract:Objective Genetic variants of the Interferon (IFN) Regulatory factor 5 gene (IRF5) are associated with susceptibility to systemic lupus erythematosus (SLE). The contribution of these variants to IRF-5 expression in primary blood cells of SLE patients has not been addressed, nor has the role of type I IFNs. The aim of this study was to determine the association between increased IRF-5 expression and the IRF5 risk haplotype in SLE patients. Methods IRF-5 transcript and protein levels in 44 Swedish patients with SLE and 16 healthy controls were measured by quantitative real-time polymerase chain reaction, minigene assay, and flow cytometry. Single-nucleotide polymorphisms rs2004640, rs10954213, and rs10488631 and the CGGGG insertion/deletion were genotyped in these patients. Genotypes of these polymorphisms defined both a common risk haplotype and a common protective haplotype. Results IRF-5 expression and alternative splicing were significantly up-regulated in SLE patients compared with healthy donors. Enhanced transcript and protein levels were associated with the risk haplotype of IRF5; rs10488631 displayed the only significant independent association that correlated with increased transcription from the noncoding first exon 1C. Minigene experiments demonstrated an important role for rs2004640 and the CGGGG insertion/deletion, along with type I IFNs, in regulating IRF5 expression. Conclusion This study provides the first formal proof that IRF-5 expression and alternative splicing are significantly up-regulated in primary blood cells of patients with SLE. Furthermore, the risk haplotype is associated with enhanced IRF-5 transcript and protein expression in patients with SLE.
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a risk haplotype of stat4 for systemic lupus erythematosus is over expressed correlates with anti dsdna and shows additive effects with two risk alleles of irf5
Human Molecular Genetics, 2008Co-Authors: Snaevar Sigurdsson, Maija-leena Eloranta, Gunnel Nordmark, Iva Gunnarsson, Sophie Garnier, Elin Grundberg, Tony Kwan, Olof Nilsson, Elisabet Svenungsson, Gunnar SturfeltAbstract:Systemic lupus erythematosus (SLE) is the prototype autoimmune disease where genes regulated by type I Interferon (IFN) are over-expressed and contribute to the disease pathogenesis. Because signal transducer and activator of transcription 4 (STAT4) plays a key role in the type I IFN receptor signaling, we performed a candidate gene study of a comprehensive set of single nucleotide polymorphism (SNPs) in STAT4 in Swedish patients with SLE. We found that 10 out of 53 analyzed SNPs in STAT4 were associated with SLE, with the strongest signal of association (P = 7.1 x 10(-8)) for two perfectly linked SNPs rs10181656 and rs7582694. The risk alleles of these 10 SNPs form a common risk haplotype for SLE (P = 1.7 x 10(-5)). According to conditional logistic regression analysis the SNP rs10181656 or rs7582694 accounts for all of the observed association signal. By quantitative analysis of the allelic expression of STAT4 we found that the risk allele of STAT4 was over-expressed in primary human cells of mesenchymal origin, but not in B-cells, and that the risk allele of STAT4 was over-expressed (P = 8.4 x 10(-5)) in cells carrying the risk haplotype for SLE compared with cells with a non-risk haplotype. The risk allele of the SNP rs7582694 in STAT4 correlated to production of anti-dsDNA (double-stranded DNA) antibodies and displayed a multiplicatively increased, 1.82-fold risk of SLE with two independent risk alleles of the IRF5 (Interferon Regulatory factor 5) gene.
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Comprehensive evaluation of the genetic variants of Interferon Regulatory factor 5 (IRF5) reveals a novel 5 bp length polymorphism as strong risk factor for systemic lupus erythematosus
Human Molecular Genetics, 2007Co-Authors: Snaevar Sigurdsson, Johanna K. Sandling, Niquiche Sangster-guity, Gudlaug Kristjansdottir, Lili Milani, Di Feng, Maija-leena Eloranta, Harald H.h. Göring, Gunnel Nordmark, Iva GunnarssonAbstract:We analyzed a comprehensive set of single-nucleotide polymorphisms (SNPs) and length polymorphisms in the Interferon Regulatory factor 5 (IRF5) gene for their association with the autoimmune disease systemic lupus erythematosus (SLE) in 485 Swedish patients and 563 controls. We found 16 SNPs and two length polymorphisms that display association with SLE (P 1.4). Using a Bayesian model selection and averaging approach we identified parsimonious models with exactly two variants of IRF5 that are independently associated with SLE. The variants of IRF5 with the highest posterior probabilities (1.00 and 0.71, respectively) of being causal in SLE are a SNP (rs10488631) located 3' of IRF5, and a novel CGGGG insertion-deletion (indel) polymorphism located 64 bp upstream of the first untranslated exon (exon 1A) of IRF5. The CGGGG indel explains the association signal from multiple SNPs in the IRF5 gene, including rs2004640, rs10954213 and rs729302 previously considered to be causal variants in SLE. The CGGGG indel contains three or four repeats of the sequence CGGGG with the longer allele containing an additional SP1 binding site as the risk allele for SLE. Using electrophoretic mobility shift assays we show increased binding of protein to the risk allele of the CGGGG indel and using a minigene reporter assay we show increased expression of IRF5 mRNA from a promoter containing this allele. Increased expression of IRF5 protein was observed in peripheral blood mononuclear cells from SLE patients carrying the risk allele of the CGGGG indel. We have found that the same IRF5 allele also confers risk for inflammatory bowel diseases and multiple sclerosis, suggesting a general role for IRF5 in autoimmune diseases.