28 results on '"Coffre, M."'
Search Results
2. Single-cell gene profiling analysis of human regulatory T cell subsets
- Author
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Benecke A, Bianchi E, Placek K, Coffre M, Becavin C, Dong S, Maiella S, and Rogge L
- Subjects
Medicine - Published
- 2010
- Full Text
- View/download PDF
3. Combinatorial control of Th17 and Th1 cell function by genetic variation at genes associated with the IL-23 signaling pathway in spondyloarthritis: W11.004
- Author
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Rogge, L., Coffre, M., Roumier, M., Rybczynska, M., Sechet, E., Law, H., Gossec, L., Dougados, M., and Bianchi, E.
- Published
- 2012
4. Pro-inflammatory environment dictates the IL-17-producing capacity of human invariant NKT cells
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Moreira-Teixeira, L., Resende, M., Coffre, M., Devergne, O., J.P., Herbeuval, Hermine, O., Schneider, E., Rogge, L., F.M., Ruemmele, M., Dy, Cordeiro-Da-Silva, Anabela, de Moraes M.C., Leite, Cytokines, hématopoïèse et réponse immune (CHRI), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Université Paris Descartes - Paris 5 (UPD5) - Institut National de la Santé et de la Recherche Médicale (INSERM) - Centre National de la Recherche Scientifique (CNRS), and Slama, Catherine
- Subjects
ComputingMilieux_MISCELLANEOUS - Abstract
International audience
- Published
- 2011
5. THU0006 Combinatorial control of TH1 and TH17 cell functions by single-nucleotide polymorphisms at genes associated with the IL-23 signaling pathway in spondyloarthritis
- Author
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Rogge, L., primary, Coffre, M., additional, Roumier, M., additional, Rybczynska, M., additional, Sechet, E., additional, Law, H., additional, Gossec, L., additional, Dougados, M., additional, and Bianchi, E., additional
- Published
- 2013
- Full Text
- View/download PDF
6. Single-cell analysis techniques reveal a striking heterogeneity of human CD4+ T cell subsets
- Author
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Coffre, M, primary, Placek, K, additional, Maiella, S, additional, Bianchi, E, additional, and Rogge, L, additional
- Published
- 2010
- Full Text
- View/download PDF
7. Single-cell gene profiling analysis of human regulatory T cell subsets
- Author
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Maiella, S, primary, Dong, S, additional, Becavin, C, additional, Coffre, M, additional, Placek, K, additional, Bianchi, E, additional, Benecke, A, additional, and Rogge, L, additional
- Published
- 2010
- Full Text
- View/download PDF
8. Linking genotype to cell function in chronic inflammation: analysis of the IL-23/Th17 axis in spondylarthropathy
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Roumier, M, primary, Coffre, M, additional, Law, H, additional, Salliot, C, additional, Dougados, M, additional, Bianchi, E, additional, and Rogge, L, additional
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- 2010
- Full Text
- View/download PDF
9. General nature of the STAT3-activated anti-inflammatory response
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El Kasmi, K. C., Jeff Holst, Coffre, M., Mielke, L., Pauw, A., Lhocine, N., Smith, A. M., Rutschman, R., Kaushal, D., Shen, Y., Suda, T., Donnelly, R. P., Myers Jr, M. G., Alexander, W., Vignali, D. A. A., Watowich, S. S., Ernst, M., Hilton, D. J., and Murray, P. J.
10. Single-cell analysis techniques reveal a striking heterogeneity of human CD4+ T cell subsets.
- Author
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Coffre, M., Placek, K., Maiella, S., Bianchi, E., and Rogge, L.
- Subjects
- *
T cells - Abstract
The article presents an abstract of research paper on human T-cell subsets submitted at the 5th European Workshop on Immune-Mediated Inflammatory Diseases held at Barcelona, Spain, on December 1-3, 2010.
- Published
- 2010
- Full Text
- View/download PDF
11. Evidence for Environmental-Human Microbiota Transfer at a Manufacturing Facility with Novel Work-related Respiratory Disease.
- Author
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Wu BG, Kapoor B, Cummings KJ, Stanton ML, Nett RJ, Kreiss K, Abraham JL, Colby TV, Franko AD, Green FHY, Sanyal S, Clemente JC, Gao Z, Coffre M, Meyn P, Heguy A, Li Y, Sulaiman I, Borbet TC, Koralov SB, Tallaksen RJ, Wendland D, Bachelder VD, Boylstein RJ, Park JH, Cox-Ganser JM, Virji MA, Crawford JA, Edwards NT, Veillette M, Duchaine C, Warren K, Lundeen S, Blaser MJ, and Segal LN
- Subjects
- Adult, Air Microbiology, Cross-Sectional Studies, Female, Humans, Male, Middle Aged, Respiration Disorders etiology, United States, Aerosols adverse effects, Air Pollutants, Occupational adverse effects, Manufacturing and Industrial Facilities, Microbiota, Pseudomonas pseudoalcaligenes, Respiration Disorders physiopathology
- Abstract
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.
- Published
- 2020
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12. miR-29 Sustains B Cell Survival and Controls Terminal Differentiation via Regulation of PI3K Signaling.
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Hines MJ, Coffre M, Mudianto T, Panduro M, Wigton EJ, Tegla C, Osorio-Vasquez V, Kageyama R, Benhamou D, Perez O, Bajwa S, McManus MT, Ansel KM, Melamed D, and Koralov SB
- Subjects
- Animals, Cell Differentiation, Humans, Mice, Signal Transduction, Survival Analysis, B-Lymphocytes metabolism, MicroRNAs metabolism, Phosphatidylinositol 3-Kinases metabolism
- Abstract
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., Competing Interests: Declaration of Interests The authors declare no competing interests., (Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.)
- Published
- 2020
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13. Targeting leukocidin-mediated immune evasion protects mice from Staphylococcus aureus bacteremia.
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Tam K, Lacey KA, Devlin JC, Coffre M, Sommerfield A, Chan R, O'Malley A, Koralov SB, Loke P, and Torres VJ
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- Animals, Antibodies, Neutralizing immunology, Antibody Formation immunology, Bacteremia blood, Bacteremia microbiology, CD4-Positive T-Lymphocytes immunology, Cytokines blood, Host-Pathogen Interactions immunology, Immunity, Immunization, Immunoglobulin G blood, Inflammation pathology, Methicillin-Resistant Staphylococcus aureus immunology, Mice, Models, Biological, Organ Specificity, Recurrence, Spleen pathology, Staphylococcal Infections blood, Toxoids immunology, Bacteremia immunology, Bacteremia prevention & control, Immune Evasion, Leukocidins metabolism, Staphylococcal Infections immunology, Staphylococcal Infections prevention & control, Staphylococcus aureus immunology
- Abstract
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., Competing Interests: Disclosures: V.J. Torres reported grants from Janssen Biotech Inc. during the conduct of the study outside the submitted work; in addition, V.J. Torres has patents to use leukocidins as S. aureus vaccine antigens, which are licensed to Janssen Biotech Inc. No other disclosures were reported., (© 2020 Tam et al.)
- Published
- 2020
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14. Distinct Requirements of CHD4 during B Cell Development and Antibody Response.
- Author
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Yen WF, Sharma R, Cols M, Lau CM, Chaudhry A, Chowdhury P, Yewdell WT, Vaidyanathan B, Sun A, Coffre M, Pucella JN, Chen CC, Jasin M, Sun JC, Rudensky AY, Koralov SB, and Chaudhuri J
- Subjects
- Animals, B-Lymphocytes cytology, B-Lymphocytes physiology, Cell Differentiation, Cells, Cultured, Chromatin Assembly and Disassembly, DNA Helicases metabolism, Genes, Immunoglobulin Heavy Chain, Mice, Tumor Suppressor Protein p53 genetics, Tumor Suppressor Protein p53 metabolism, B-Lymphocytes immunology, Cell Proliferation, DNA Helicases genetics, Immunoglobulin Class Switching
- Abstract
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., (Copyright © 2019 The Author(s). Published by Elsevier Inc. All rights reserved.)
- Published
- 2019
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15. Staphylococcus aureus Leukocidins Target Endothelial DARC to Cause Lethality in Mice.
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Lubkin A, Lee WL, Alonzo F 3rd, Wang C, Aligo J, Keller M, Girgis NM, Reyes-Robles T, Chan R, O'Malley A, Buckley P, Vozhilla N, Vasquez MT, Su J, Sugiyama M, Yeung ST, Coffre M, Bajwa S, Chen E, Martin P, Kim SY, Loomis C, Worthen GS, Shopsin B, Khanna KM, Weinstock D, Lynch AS, Koralov SB, Loke P, Cadwell K, and Torres VJ
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- Animals, Bacterial Proteins metabolism, Bacterial Toxins metabolism, Cell Survival drug effects, Cells, Cultured, Disease Models, Animal, Exotoxins metabolism, Hemolysin Proteins metabolism, Humans, Mice, Mice, Knockout, Models, Biological, Staphylococcus aureus metabolism, Survival Analysis, Bacterial Proteins toxicity, Bacterial Toxins toxicity, Duffy Blood-Group System metabolism, Endothelial Cells drug effects, Exotoxins toxicity, Hemolysin Proteins toxicity, Receptors, Cell Surface metabolism, Staphylococcal Infections pathology, Staphylococcus aureus pathogenicity
- Abstract
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., (Copyright © 2019 Elsevier Inc. All rights reserved.)
- Published
- 2019
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16. B Cell Defects Observed in Nod2 Knockout Mice Are a Consequence of a Dock2 Mutation Frequently Found in Inbred Strains.
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Wong SY, Coffre M, Ramanan D, Hines MJ, Gomez LE, Peters LA, Schadt EE, Koralov SB, and Cadwell K
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- Animals, B-Lymphocytes pathology, Guanine Nucleotide Exchange Factors, Mice, Mice, Knockout, Nod2 Signaling Adaptor Protein immunology, B-Lymphocytes immunology, GTPase-Activating Proteins genetics, GTPase-Activating Proteins immunology, Immune System Diseases genetics, Immune System Diseases immunology, Immune System Diseases pathology, Mutation, Nod2 Signaling Adaptor Protein deficiency
- Abstract
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., (Copyright © 2018 by The American Association of Immunologists, Inc.)- Published
- 2018
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17. miRNAs in B Cell Development and Lymphomagenesis.
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Coffre M and Koralov SB
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- Animals, B-Lymphocytes pathology, Cell Transformation, Neoplastic pathology, Humans, Lymphoma, B-Cell pathology, B-Lymphocytes metabolism, Cell Transformation, Neoplastic metabolism, Lymphoma, B-Cell metabolism, MicroRNAs metabolism, RNA, Neoplasm metabolism
- Abstract
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., (Copyright © 2017 Elsevier Ltd. All rights reserved.)
- Published
- 2017
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18. miRNAs Are Essential for the Regulation of the PI3K/AKT/FOXO Pathway and Receptor Editing during B Cell Maturation.
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Coffre M, Benhamou D, Rieß D, Blumenberg L, Snetkova V, Hines MJ, Chakraborty T, Bajwa S, Jensen K, Chong MMW, Getu L, Silverman GJ, Blelloch R, Littman DR, Calado D, Melamed D, Skok JA, Rajewsky K, and Koralov SB
- Subjects
- Animals, Down-Regulation, Forkhead Transcription Factors metabolism, Immunoglobulin Light Chains genetics, Mice, Phosphatidylinositol 3-Kinases metabolism, Proto-Oncogene Proteins c-akt metabolism, Proto-Oncogene Proteins c-bcl-2 metabolism, RNA Interference, RNA-Binding Proteins metabolism, Ribonuclease III metabolism, Spleen cytology, Transgenes, B-Lymphocytes cytology, B-Lymphocytes metabolism, Cell Differentiation genetics, Gene Expression Regulation, MicroRNAs metabolism, RNA Editing genetics, Receptors, Antigen, B-Cell metabolism, Signal Transduction genetics
- Abstract
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., (Copyright © 2016 The Author(s). Published by Elsevier Inc. All rights reserved.)
- Published
- 2016
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19. IL35-Producing B Cells Promote the Development of Pancreatic Neoplasia.
- Author
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Pylayeva-Gupta Y, Das S, Handler JS, Hajdu CH, Coffre M, Koralov SB, and Bar-Sagi D
- Subjects
- Animals, Biomarkers, Carcinoma, Pancreatic Ductal, Disease Models, Animal, Humans, Immunohistochemistry, Lymphocytes, Tumor-Infiltrating immunology, Lymphocytes, Tumor-Infiltrating metabolism, Mice, Mice, Knockout, Pancreatic Neoplasms pathology, Phenotype, Pancreatic Neoplasms, B-Lymphocytes immunology, B-Lymphocytes metabolism, Cell Transformation, Neoplastic immunology, Cell Transformation, Neoplastic metabolism, Interleukins biosynthesis, Pancreatic Neoplasms immunology, Pancreatic Neoplasms metabolism
- Abstract
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., (©2015 American Association for Cancer Research.)
- Published
- 2016
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20. Limited miR-17-92 overexpression drives hematologic malignancies.
- Author
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Danielson LS, Reavie L, Coussens M, Davalos V, Castillo-Martin M, Guijarro MV, Coffre M, Cordon-Cardo C, Aifantis I, Ibrahim S, Liu C, Koralov SB, and Hernando E
- Subjects
- Animals, Blotting, Western, Cell Proliferation, Hematologic Neoplasms genetics, Hematologic Neoplasms metabolism, Immunoenzyme Techniques, Integrases metabolism, Mice, RNA, Messenger genetics, Real-Time Polymerase Chain Reaction, Reverse Transcriptase Polymerase Chain Reaction, Tumor Cells, Cultured, Cell Transformation, Neoplastic pathology, Gene Expression Regulation, Neoplastic, Hematologic Neoplasms pathology, MicroRNAs physiology, Microfilament Proteins physiology, Muscle Proteins physiology
- Abstract
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., (Copyright © 2014 Elsevier Ltd. All rights reserved.)
- Published
- 2015
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21. VH replacement in primary immunoglobulin repertoire diversification.
- Author
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Sun A, Novobrantseva TI, Coffre M, Hewitt SL, Jensen K, Skok JA, Rajewsky K, and Koralov SB
- Subjects
- Animals, B-Lymphocytes immunology, Cell Compartmentation, Mice, Mice, Transgenic, Stochastic Processes, Immunoglobulin Variable Region genetics
- Abstract
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.
- Published
- 2015
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22. Antibody repertoire deep sequencing reveals antigen-independent selection in maturing B cells.
- Author
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Kaplinsky J, Li A, Sun A, Coffre M, Koralov SB, and Arnaout R
- Subjects
- Animals, Complementarity Determining Regions genetics, Female, High-Throughput Nucleotide Sequencing, Immunoglobulin Heavy Chains genetics, Mice, B-Lymphocytes immunology, Complementarity Determining Regions immunology, Immunoglobulin Heavy Chains immunology
- Abstract
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.
- Published
- 2014
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23. T cell-derived IL-17 mediates epithelial changes in the airway and drives pulmonary neutrophilia.
- Author
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Fogli LK, Sundrud MS, Goel S, Bajwa S, Jensen K, Derudder E, Sun A, Coffre M, Uyttenhove C, Van Snick J, Schmidt-Supprian M, Rao A, Grunig G, Durbin J, Casola S, Rajewsky K, and Koralov SB
- Subjects
- Animals, Asthma metabolism, Cell Separation, Disease Models, Animal, Enzyme-Linked Immunosorbent Assay, Flow Cytometry, Interleukin-17 metabolism, Mice, Mice, Inbred C57BL, Pneumonia immunology, Pneumonia metabolism, Real-Time Polymerase Chain Reaction, Respiratory Mucosa metabolism, Th17 Cells immunology, Th17 Cells metabolism, Transfection, Asthma immunology, Immune System Diseases immunology, Interleukin-17 immunology, Leukocyte Disorders immunology, Neutrophils immunology, Respiratory Mucosa immunology
- Abstract
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.
- Published
- 2013
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24. Combinatorial control of Th17 and Th1 cell functions by genetic variations in genes associated with the interleukin-23 signaling pathway in spondyloarthritis.
- Author
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Coffre M, Roumier M, Rybczynska M, Sechet E, Law HK, Gossec L, Dougados M, Bianchi E, and Rogge L
- Subjects
- Adult, Aged, Aged, 80 and over, Female, Genetic Variation, Genotype, Humans, Interleukin-23 metabolism, Male, Middle Aged, Polymorphism, Single Nucleotide, Real-Time Polymerase Chain Reaction, Signal Transduction, Spondylarthropathies genetics, Young Adult, CD4-Positive T-Lymphocytes metabolism, Cytokines metabolism, Inflammation metabolism, Interleukin-23 genetics, Spondylarthropathies metabolism, Th1 Cells metabolism, Th17 Cells metabolism
- Abstract
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., (Copyright © 2013 by the American College of Rheumatology.)
- Published
- 2013
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25. Proinflammatory environment dictates the IL-17-producing capacity of human invariant NKT cells.
- Author
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Moreira-Teixeira L, Resende M, Coffre M, Devergne O, Herbeuval JP, Hermine O, Schneider E, Rogge L, Ruemmele FM, Dy M, Cordeiro-da-Silva A, and Leite-de-Moraes MC
- Subjects
- Enzyme-Linked Immunosorbent Assay, Humans, Interferon-gamma, Interleukin-1beta biosynthesis, Interleukin-23 biosynthesis, Interleukins biosynthesis, NK Cell Lectin-Like Receptor Subfamily B immunology, Natural Killer T-Cells immunology, Nuclear Receptor Subfamily 1, Group F, Member 3 metabolism, Polymerase Chain Reaction, Receptors, Aryl Hydrocarbon metabolism, Receptors, Interleukin metabolism, T-Lymphocytes, Helper-Inducer immunology, Transforming Growth Factor beta biosynthesis, Interleukin-22, Inflammation immunology, Interleukin-17 biosynthesis, Natural Killer T-Cells metabolism
- Abstract
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-β, IL-1β, 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.
- Published
- 2011
- Full Text
- View/download PDF
26. Integration of distinct intracellular signaling pathways at distal regulatory elements directs T-bet expression in human CD4+ T cells.
- Author
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Placek K, Gasparian S, Coffre M, Maiella S, Sechet E, Bianchi E, and Rogge L
- Subjects
- CD28 Antigens physiology, CD4-Positive T-Lymphocytes cytology, Cell Differentiation genetics, Cell Differentiation immunology, Cytokines physiology, Deoxyribonuclease I metabolism, Deoxyribonuclease I physiology, Humans, Intracellular Signaling Peptides and Proteins physiology, Jurkat Cells, NFATC Transcription Factors metabolism, Protein Binding genetics, Protein Binding immunology, Receptors, Antigen, T-Cell physiology, T-Box Domain Proteins antagonists & inhibitors, Th1 Cells cytology, Th1 Cells immunology, Th1 Cells metabolism, Th2 Cells cytology, Th2 Cells immunology, Th2 Cells metabolism, CD4-Positive T-Lymphocytes immunology, CD4-Positive T-Lymphocytes metabolism, Intracellular Signaling Peptides and Proteins genetics, Intracellular Signaling Peptides and Proteins metabolism, Regulatory Sequences, Nucleic Acid immunology, Signal Transduction immunology, T-Box Domain Proteins biosynthesis, T-Box Domain Proteins genetics
- Abstract
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.
- Published
- 2009
- Full Text
- View/download PDF
27. Genetic and epigenetic networks controlling T helper 1 cell differentiation.
- Author
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Placek K, Coffre M, Maiella S, Bianchi E, and Rogge L
- Subjects
- Cell Differentiation genetics, Cell Differentiation immunology, Gene Expression Regulation immunology, Humans, Interferon-gamma genetics, Interleukin-12 genetics, Interleukin-12 immunology, Protein Biosynthesis, Receptors, Notch immunology, Signal Transduction genetics, Signal Transduction immunology, T-Box Domain Proteins immunology, Epigenesis, Genetic immunology, Th1 Cells immunology
- Abstract
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.
- Published
- 2009
- Full Text
- View/download PDF
28. General nature of the STAT3-activated anti-inflammatory response.
- Author
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El Kasmi KC, Holst J, Coffre M, Mielke L, de Pauw A, Lhocine N, Smith AM, Rutschman R, Kaushal D, Shen Y, Suda T, Donnelly RP, Myers MG Jr, Alexander W, Vignali DA, Watowich SS, Ernst M, Hilton DJ, and Murray PJ
- Subjects
- Animals, Enzyme-Linked Immunosorbent Assay, Immunoblotting, Mice, Oligonucleotide Array Sequence Analysis, Receptors, Interleukin-10 metabolism, Reverse Transcriptase Polymerase Chain Reaction, Suppressor of Cytokine Signaling 3 Protein, Suppressor of Cytokine Signaling Proteins metabolism, Gene Expression, Inflammation, Interleukin-10 metabolism, Interleukin-6 metabolism, STAT3 Transcription Factor metabolism, Signal Transduction immunology
- Abstract
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.
- Published
- 2006
- Full Text
- View/download PDF
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