13 results on '"Benoit Manfroi"'
Search Results
2. Data from CXCL-8/IL8 Produced by Diffuse Large B-cell Lymphomas Recruits Neutrophils Expressing a Proliferation-Inducing Ligand APRIL
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Bertrand Huard, Nathalie Sturm, Thomas Matthes, Alexandar Tzankov, Pascal Schneider, Mary Callanan, Martin Dyer, Christian Righini, Christian Villiers, Sebastien Moret, Sebastien Tabruyn, Jean Francois Mayol, Thomas McKee, and Benoit Manfroi
- Abstract
Tumor-infiltrating neutrophils have been implicated in malignant development and progression, but mechanisms are ill defined. Neutrophils produce a proliferation-inducing ligand APRIL/TNFSF13, a factor that promotes development of tumors from diverse origins, including diffuse large B-cell lymphoma (DLBCL). High APRIL expression in DLBCL correlates with reduced patient survival, but the pathway(s) dictating APRIL expression are not known. Here, we show that all blood neutrophils constitutively secrete APRIL, and inflammation-associated stimuli, such as TNF, further upregulate APRIL. In a significant fraction of DLBCL patients, tumor cells constitutively produced the ELC-CXC chemokine CXCL-8 (IL8), enabling them to recruit APRIL-producing blood neutrophils. CXCL-8 production in DLBCL was unrelated to the cell of origin, as APRIL-producing neutrophils infiltrated CXCL-8+ DLBCL from both germinal center (GC) and non-GC subtypes. Rather, CXCL-8 production implied events affecting DNA methylation and acetylation. Overall, our results showed that chemokine-mediated recruitment of neutrophils secreting the tumor-promoting factor APRIL mediates DLBCL progression. Cancer Res; 77(5); 1097–107. ©2016 AACR.
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- 2023
3. The microenvironment of DLBCL is characterized by noncanonical macrophages recruited by tumor-derived CCL5
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Michel Aurrand-Lions, Mélanie Quintero, Christian Righini, Jean-François Mayol, Nathalie Sturm, Benoit Manfroi, Sébastien Tabruyn, Jérôme Moreaux, Bertrand Huard, Maria De Grandis, Anthropologie bio-culturelle, Droit, Ethique et Santé (ADES), Aix Marseille Université (AMU)-EFS ALPES MEDITERRANEE-Centre National de la Recherche Scientifique (CNRS), Centre de Recherche en Cancérologie de Marseille (CRCM), Aix Marseille Université (AMU)-Institut Paoli-Calmettes, and Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)
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CCR1 ,Chemokine ,[SDV]Life Sciences [q-bio] ,Biology ,medicine.disease_cause ,CCL5 ,Monocytes ,Leukocyte Count ,stomatognathic system ,immune system diseases ,hemic and lymphatic diseases ,medicine ,Tumor Microenvironment ,Neoplasm ,Humans ,skin and connective tissue diseases ,Chemokine CCL5 ,Lymphoid Neoplasia ,Macrophages ,Hematology ,Gene signature ,Tumor-Derived ,medicine.disease ,Germinal Center ,Lymphoma ,Cancer research ,biology.protein ,Lymphoma, Large B-Cell, Diffuse ,Carcinogenesis ,hormones, hormone substitutes, and hormone antagonists - Abstract
Key Points CCL5 is differentially expressed by DLBCL cells and efficiently recruits TAMs through their expression of CCR1/CCR5.Most DLBCL TAMs have a noncanonical gene signature., Visual Abstract, Tissue invasion by tumor cells induces a host inflammatory response that variably impacts tumorigenesis. This has been well documented for tumor-associated macrophages (TAMs) that could play a pro/M2- or an anti/M1-tumoral function. TAMs frequently infiltrate diffuse large B-cell lymphoma (DLBCL), an aggressive neoplasm arising from germinal center–experienced B cells. However, the pathway leading to the presence of TAMs in DLBCL remains unknown, and their impact is unclear. Here, we show that some DLBCL tumor cells expressed the chemokine CCL5, enabling the differential recruitment of blood monocytes through their expression of CCR1 and CCR5. CCL5 expression by DLBCL was not related to molecular subtypes, and healthy tonsillar B cells did not produce this chemokine, implying a posttransformation event. A single-cell analysis revealed that most DLBCL TAMs had a noncanonical gene signature with the concomitant expression of M1 and M2 genes. The presence of noncanonical TAMs may explain the lack of impact of macrophages on DLBCL development reported in some survival studies.
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- 2021
4. Toll-like receptor signalling in B cells during systemic lupus erythematosus
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Benoit Manfroi, Simon Fillatreau, and Thomas Dörner
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Autoimmune diseases ,Immunology ,Review Article ,Autoantigens ,Mice ,Rheumatology ,Antigen ,immune system diseases ,medicine ,Animals ,Humans ,Lupus Erythematosus, Systemic ,skin and connective tissue diseases ,B cell ,Autoantibodies ,Toll-like receptor ,B-Lymphocytes ,Lupus erythematosus ,business.industry ,Effector ,Toll-Like Receptors ,Autoantibody ,TLR9 ,TLR7 ,medicine.disease ,medicine.anatomical_structure ,Toll-Like Receptor 7 ,Toll-Like Receptor 9 ,business ,Signal Transduction - Abstract
B lymphocytes have a central role in autoimmune diseases, which are often defined by specific autoantibody patterns and feature a loss of B cell tolerance. A prototypic disease associated with B cell hyperactivity is systemic lupus erythematosus (SLE). In patients with SLE, the loss of B cell tolerance to autoantigens is controlled in a cell-intrinsic manner by Toll-like receptors (TLRs), which sense nucleic acids in endosomes. TLR7 drives the extrafollicular B cell response and the germinal centre reaction that are involved in autoantibody production and disease pathogenesis. Surprisingly, TLR9 seems to protect against SLE, even though it is required for the production of autoantibodies recognizing double-stranded DNA-associated antigens, which are abundant in SLE and are a hallmark of this disease. The protective function of TLR9 is at least partly mediated by its capacity to limit the stimulatory activity of TLR7. The roles of TLR7 and TLR9 in the effector function of B cells in lupus-like disease and in patients with SLE, and the unique features of TLR signalling in B cells, suggest that targeting TLR signalling in SLE might be therapeutically beneficial., Loss of B cell tolerance to autoantigens in systemic lupus erythematosus (SLE) is driven by TLR7, whereas TLR9 appears to protect against SLE by limiting the stimulatory activity of TLR7. The unique features of Toll-like receptor signalling in B cells implicate it as a therapeutic target in SLE., Key points Intrinsic TLR7 and TLR9 signalling in B cells plays an important role in the development and pathogenesis of systemic lupus erythematosus (SLE).In patients with SLE, effector plasma cells are generated via the extrafollicular response and via the formation of spontaneous germinal centres.TLR7 plays key roles in the extrafollicular response and the response mediated by germinal centres.Some plasma cells produce IL-10 and can have protective roles in lupus-like disease.
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- 2020
5. CXCL-8/IL-8 produced by diffuse large B-cell lymphomas recruits neutrophils expressing a proliferation inducing ligand APRIL
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Mary Callanan, Martin J. S. Dyer, Alexandar Tzankov, Thomas Alexander Mckee, Pascal Schneider, Sebastien Moret, Bertrand Huard, Jean Francois Mayol, Nathalie Sturm, Christian Righini, Benoit Manfroi, Sébastien Tabruyn, Christian L. Villiers, and Thomas Matthes
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0301 basic medicine ,Cancer Research ,Chemokine ,Neutrophils ,Tumor Necrosis Factor Ligand Superfamily Member 13 ,Lymphoma, Large B-Cell, Diffuse/genetics/immunology/metabolism/pathology ,Animals ,Humans ,Interleukin-8/biosynthesis ,Interleukin-8/immunology ,Ligands ,Lymphoma, Large B-Cell, Diffuse/genetics ,Lymphoma, Large B-Cell, Diffuse/immunology ,Lymphoma, Large B-Cell, Diffuse/metabolism ,Lymphoma, Large B-Cell, Diffuse/pathology ,Mice ,Neutrophils/immunology ,Neutrophils/metabolism ,Neutrophils/pathology ,Tumor Microenvironment/immunology ,Tumor Necrosis Factor Ligand Superfamily Member 13/biosynthesis ,Tumor Necrosis Factor Ligand Superfamily Member 13/genetics ,Tumor Necrosis Factor Ligand Superfamily Member 13/immunology ,Interleukin-8/biosynthesis/immunology ,03 medical and health sciences ,0302 clinical medicine ,Neutrophils/immunology/metabolism/pathology ,hemic and lymphatic diseases ,medicine ,Tumor Microenvironment ,Interleukin 8 ,B cell ,ddc:616 ,biology ,business.industry ,Interleukin-8 ,Germinal center ,Cancer ,medicine.disease ,Lymphoma ,030104 developmental biology ,medicine.anatomical_structure ,Oncology ,Tumor Necrosis Factor Ligand Superfamily Member 13/biosynthesis/genetics/immunology ,Immunology ,DNA methylation ,biology.protein ,Tumor necrosis factor alpha ,Lymphoma, Large B-Cell, Diffuse ,business ,030215 immunology - Abstract
Tumor-infiltrating neutrophils have been implicated in malignant development and progression, but mechanisms are ill defined. Neutrophils produce a proliferation-inducing ligand APRIL/TNFSF13, a factor that promotes development of tumors from diverse origins, including diffuse large B-cell lymphoma (DLBCL). High APRIL expression in DLBCL correlates with reduced patient survival, but the pathway(s) dictating APRIL expression are not known. Here, we show that all blood neutrophils constitutively secrete APRIL, and inflammation-associated stimuli, such as TNF, further upregulate APRIL. In a significant fraction of DLBCL patients, tumor cells constitutively produced the ELC-CXC chemokine CXCL-8 (IL8), enabling them to recruit APRIL-producing blood neutrophils. CXCL-8 production in DLBCL was unrelated to the cell of origin, as APRIL-producing neutrophils infiltrated CXCL-8+ DLBCL from both germinal center (GC) and non-GC subtypes. Rather, CXCL-8 production implied events affecting DNA methylation and acetylation. Overall, our results showed that chemokine-mediated recruitment of neutrophils secreting the tumor-promoting factor APRIL mediates DLBCL progression. Cancer Res; 77(5); 1097–107. ©2016 AACR.
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- 2017
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6. Toll-Like Receptor 9 Stimulation Induces Aberrant Expression of a Proliferation-Inducing Ligand by Tonsillar Germinal Center B Cells in IgA Nephropathy
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Hitoshi Suzuki, Yasuhiko Tomino, Masahiro Muto, Sachiko Wakai, Kensuke Joh, Masaaki Nagai, Masayuki Maiguma, Yusuke Suzuki, Christian Righini, Bertrand Huard, Shozo Izui, and Benoit Manfroi
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Adult ,Male ,0301 basic medicine ,Palatine Tonsil ,Tumor Necrosis Factor Ligand Superfamily Member 13 ,B-cell receptor ,Tonsillitis ,030232 urology & nephrology ,Biology ,urologic and male genital diseases ,Palatine tonsil ,Pathogenesis ,03 medical and health sciences ,0302 clinical medicine ,stomatognathic system ,Downregulation and upregulation ,medicine ,Humans ,B-Lymphocytes ,Germinal center ,TLR9 ,Glomerulonephritis, IGA ,General Medicine ,Germinal Center ,medicine.disease ,Molecular biology ,030104 developmental biology ,medicine.anatomical_structure ,Nephrology ,Toll-Like Receptor 9 ,Immunology ,biology.protein ,Female ,Antibody - Abstract
The TNF family member a proliferation-inducing ligand (APRIL; also known as TNFSF13), produced by myeloid cells, participates in the generation and survival of antibody-producing plasma cells. We studied the potential role of APRIL in the pathogenesis of IgA nephropathy (IgAN). We found that a significant proportion of germinal centers (GCs) in tonsils of patients with IgAN contained cells aberrantly producing APRIL, contributing to an overall upregulation of tonsillar APRIL expression compared with that in tonsils of control patients with tonsillitis. In IgAN GC, antigen-experienced IgD-CD38+/-CD19+ B cells expressing a switched IgG/IgA B cell receptor produced APRIL. Notably, these GC B cells expressed mRNA encoding the common cleavable APRIL-α but also, the less frequent APRIL-δ/ζ mRNA, which encodes a protein that lacks a furin cleavage site and is, thus, the uncleavable membrane-bound form. Significant correlation between TLR9 and APRIL expression levels existed in tonsils from patients with IgAN. In vitro, repeated TLR9 stimulation induced APRIL expression in tonsillar B cells from control patients with tonsillitis. Clinically, aberrant APRIL expression in tonsillar GC correlated with greater proteinuria, and patients with IgAN and aberrant APRIL overexpression in tonsillar GC responded well to tonsillectomy, with parallel decreases in serum levels of galactose-deficient IgA1. Taken together, our data indicate that antibody disorders in IgAN associate with TLR9-induced aberrant expression of APRIL in tonsillar GC B cells.
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- 2016
7. IL-10-producing regulatory B cells and plasmocytes: Molecular mechanisms and disease relevance
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Catia Cerqueira, Simon Fillatreau, Benoit Manfroi, Institut Necker Enfants-Malades (INEM - UM 111 (UMR 8253 / U1151)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), CCSD, Accord Elsevier, and Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Paris (UP)
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0301 basic medicine ,medicine.medical_treatment ,Regulatory B cells ,[SDV]Life Sciences [q-bio] ,Immunology ,Biology ,Plasma cell ,Autoimmune Diseases ,03 medical and health sciences ,0302 clinical medicine ,Antigen ,medicine ,Immunology and Allergy ,Animals ,Humans ,B cell ,B-Lymphocytes, Regulatory ,Autoantibody ,3. Good health ,Interleukin-10 ,[SDV] Life Sciences [q-bio] ,Interleukin 10 ,030104 developmental biology ,medicine.anatomical_structure ,Cytokine ,030220 oncology & carcinogenesis ,biology.protein ,Antibody - Abstract
It has long been assumed that the functions of B cells reflected the roles of antibodies. However, B cells also decisively influence immunity via antibody-independent mechanisms including the presentation of antigen to T cells and the secretion of cytokines. In fact, B cell depletion therapy improves the course of autoimmune diseases such as multiple sclerosis by removing pro-inflammatory cytokine-producing B cells rather than by reducing autoantibody levels. Remarkably, B cells can also produce anti-inflammatory cytokines, and subsequently suppress immunity, providing protection from autoimmune diseases while interfering with beneficial responses against pathogens and cancers. A major mediator of this B cell regulatory function is their secretion of IL-10. There is considerable interest in identifying the mechanisms inducing the expression of IL-10 in B cells during the course of their activation. Here, we review the molecular mechanisms controlling IL-10 expression in B cells, and the evidence that IL-10-producing B cells play a protective role in human autoimmune diseases, underlying the relevance of this immunosuppressive axis for therapy.
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- 2019
8. A proliferation‐inducing ligand–mediated anti‐inflammatory response of astrocytes in multiple sclerosis
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Mahdia Benkhoucha, Mashal Claude Ahmed, Dominique Baeten, Romain Marignier, Jose Boucraut, Olivier Casez, Michael Hahne, Jean Boutonnat, Corinne Sonrier, Benoit Manfroi, Laurie Baert, Patrice N. Marche, Nathalie Sturm, Marine Tessier, Patrice H. Lalive, Romain R. Vivès, Bertrand Huard, Cyril Rivat, Catherine Ghezzi, Hans Lassmann, Pascal Schneider, Natalia Popa, Gilda Raguenez, Alexis Broisat, Hugues Lortat-Jacob, Mitra Ahmadi, Institute for Advanced Biosciences / Institut pour l'Avancée des Biosciences (Grenoble) (IAB), Centre Hospitalier Universitaire [Grenoble] (CHU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Etablissement français du sang - Auvergne-Rhône-Alpes (EFS)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019]), Department of Pathology and Immunology [Geneva, Switzerland] (Clinical Pathology Division), University of Geneva [Switzerland]-Geneva University Hospitals - HUG [Switzerland], Centre de recherche en neurobiologie - neurophysiologie de Marseille (CRN2M), Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Département d'anatomie et cythologie pathologique, CHU Grenoble-Hôpital Michallon, Centre Hospitalier Universitaire [Grenoble] (CHU), Centre de recherche en neurosciences de Lyon (CRNL), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Université Jean Monnet [Saint-Étienne] (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Radiopharmaceutiques biocliniques (LRB), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019]), Institut des Neurosciences de Montpellier - Déficits sensoriels et moteurs (INM), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Institut de Génétique Moléculaire de Montpellier (IGMM), Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM), Department of Clinical Immunology and Rheumatology [Academic Medical Center, Amsterdam], University of Amsterdam [Amsterdam] (UvA), Institut de biologie structurale (IBS - UMR 5075 ), Université Grenoble Alpes [2016-2019] (UGA [2016-2019])-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Centre National de la Recherche Scientifique (CNRS), Department of Biochemistry [Lausanne], Université de Lausanne (UNIL), University of Vienna [Vienna], Department of Clinical Neurosciences [Geneva, Switzerland], Unit of Neuroimmunology and Neuromuscular Diseases [Geneva, Switzerland] (Division of Neurology), Geneva University Hospitals - HUG [Switzerland]-Geneva University Hospitals - HUG [Switzerland], This work was supported by Grenoble Alpes University (B.H.), the National Institute of Health and Medical Research (B.H.), the Association for Aid to Multiple Sclerosis Research (B.H.), the National Agency for Research (program center of excellence in neurodegeneration obtained within the Grenoble excellence in neurodegeneration network, B.H.), the Swiss National Science Foundation (310030_156961/310030_176256 to PS and 310030_153164/310030_176678 to PL), and the Swiss Multiple Sclerosis Society (P.L.)., Clinical Immunology and Rheumatology, AII - Inflammatory diseases, Centre Hospitalier Universitaire [Grenoble] (CHU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Etablissement français du sang - Auvergne-Rhône-Alpes (EFS)-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019]), Université de Genève = University of Geneva (UNIGE)-Geneva University Hospitals - HUG [Switzerland], Centre de recherche en neurosciences de Lyon - Lyon Neuroscience Research Center (CRNL), Université de Lyon-Université de Lyon-Université Jean Monnet - Saint-Étienne (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Institut des Neurosciences de Montpellier (INM), Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019])-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Université de Lausanne = University of Lausanne (UNIL), Grenoble Alpes University, the National Institute of Health and Medical Research, the Association for Aid to Multiple Sclerosis Research), the National Agency for Research (program center of excellence in neurodegeneration obtained within the Grenoble excellence in neurodegeneration network, the Swiss National Science Foundation (310030_156961/310030_176256 to PS and 310030_153164/310030_176678 )The Swiss Multiple Sclerosis Society, and MARCHE, Patrice
- Subjects
Male ,0301 basic medicine ,T-Lymphocytes ,Mice ,chemistry.chemical_compound ,0302 clinical medicine ,B-Cell Activating Factor ,Medicine ,Mice, Knockout ,Reverse Transcriptase Polymerase Chain Reaction ,Chondroitin Sulfates ,Middle Aged ,Immunohistochemistry ,Interleukin-10 ,3. Good health ,Interleukin 10 ,Neurology ,Adult ,Aged ,Animals ,Astrocytes/immunology ,Astrocytes/metabolism ,Astrocytes/pathology ,B-Cell Activating Factor/metabolism ,Cell Proliferation ,Chondroitin Sulfate Proteoglycans/metabolism ,Chondroitin Sulfates/metabolism ,Cytokines/immunology ,Disease Models, Animal ,Encephalomyelitis, Autoimmune, Experimental/immunology ,Encephalomyelitis, Autoimmune, Experimental/metabolism ,Encephalomyelitis, Autoimmune, Experimental/pathology ,Female ,Humans ,Interleukin-10/immunology ,Macrophages/pathology ,Multiple Sclerosis/immunology ,Multiple Sclerosis/metabolism ,Multiple Sclerosis/pathology ,T-Lymphocytes/immunology ,Tumor Necrosis Factor Ligand Superfamily Member 13/genetics ,Tumor Necrosis Factor Ligand Superfamily Member 13/metabolism ,Tumor Necrosis Factor Ligand Superfamily Member 13/pharmacology ,Cytokines ,[SDV.IMM]Life Sciences [q-bio]/Immunology ,Tumor necrosis factor alpha ,medicine.symptom ,Encephalomyelitis, Autoimmune, Experimental ,Multiple Sclerosis ,[SDV.IMM] Life Sciences [q-bio]/Immunology ,Tumor Necrosis Factor Ligand Superfamily Member 13 ,Inflammation ,03 medical and health sciences ,[SDV.BBM] Life Sciences [q-bio]/Biochemistry, Molecular Biology ,[SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology ,B-cell activating factor ,Autoimmune encephalitis ,business.industry ,Macrophages ,Multiple sclerosis ,medicine.disease ,030104 developmental biology ,Chondroitin Sulfate Proteoglycans ,chemistry ,Chondroitin sulfate proteoglycan ,Astrocytes ,Immunology ,Cytokine secretion ,Neurology (clinical) ,business ,030217 neurology & neurosurgery - Abstract
International audience; OBJECTIVE:The two related tumor necrosis factor members a proliferation-inducing ligand (APRIL) and B-cell activation factor (BAFF) are currently targeted in autoimmune diseases as B-cell regulators. In multiple sclerosis (MS), combined APRIL/BAFF blockade led to unexpected exacerbated inflammation in the central nervous system (CNS) of patients. Here, we investigate the role of the APRIL/BAFF axis in the CNS.METHODS:APRIL expression was analyzed in MS lesions by immunohistochemistry. The in vivo role of APRIL was assessed in the murine MS model, experimental autoimmune encephalitis (EAE). Functional in vitro studies were performed with human and mouse astrocytes.RESULTS:APRIL was expressed in lesions from EAE. In its absence, the disease was worst. Lesions from MS patients also showed APRIL expression upon infiltration of macrophages. Notably, all the APRIL secreted by these macrophages specifically targeted astrocytes. The upregulation of chondroitin sulfate proteoglycan, sometimes bearing chondroitin sulfate of type E sugar moieties, binding APRIL, in reactive astrocytes explained the latter selectivity. Astrocytes responded to APRIL by producing a sufficient amount of IL-10 to dampen antigen-specific T-cell proliferation and pathogenic cytokine secretion. Finally, an intraspinal delivery of recombinant APRIL before disease onset, shortly reduced EAE symptoms. Repeated intravenous injections of recombinant APRIL before and even at disease onset also had an effect.INTERPRETATION:Our data show that APRIL mediates an anti-inflammatory response from astrocytes in MS lesions. This protective activity is not shared with BAFF. ANN NEUROL 2019;85:406-420.© 2019 American Neurological Association.
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- 2019
9. Tumor-associated neutrophils correlate with poor prognosis in diffuse large B-cell lymphoma patients
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Christian Righini, Nathalie Sturm, Jérôme Moreaux, Benoit Manfroi, François Ghiringhelli, Bertrand Huard, Institute for Advanced Biosciences / Institut pour l'Avancée des Biosciences (Grenoble) (IAB), Centre Hospitalier Universitaire [Grenoble] (CHU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Etablissement français du sang - Auvergne-Rhône-Alpes (EFS)-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019]), Institut de génétique humaine (IGH), Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), Centre Hospitalier Universitaire [Grenoble] (CHU), Département d'oncologie médicale [Centre Georges-François Leclerc], Centre Régional de Lutte contre le cancer Georges-François Leclerc [Dijon] (UNICANCER/CRLCC-CGFL), UNICANCER-UNICANCER, Lipides - Nutrition - Cancer [Dijon - U1231] (LNC), and Université de Bourgogne (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement
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0301 basic medicine ,Poor prognosis ,Neutrophils ,[SDV.CAN]Life Sciences [q-bio]/Cancer ,lcsh:RC254-282 ,Immunophenotyping ,03 medical and health sciences ,Text mining ,Correspondence ,medicine ,Humans ,ComputingMilieux_MISCELLANEOUS ,business.industry ,Gene Expression Profiling ,Hematology ,Prognosis ,lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,medicine.disease ,3. Good health ,Phenotype ,030104 developmental biology ,Oncology ,Cancer research ,Lymphoma, Large B-Cell, Diffuse ,Transcriptome ,business ,Diffuse large B-cell lymphoma ,Biomarkers - Abstract
International audience
- Published
- 2018
10. Myelopoiesis dysregulation associated to sustained APRIL production in multiple myeloma-infiltrated bone marrow
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Jakob Passweg, Bertrand Huard, Benoit Manfroi, Isabelle Dunand-Sauthier, Thomas Matthes, Sungmee Park, and Thomas Alexander Mckee
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Cancer Research ,Pathology ,medicine.medical_specialty ,Myeloid ,Tumor Necrosis Factor Ligand Superfamily Member 13 ,Gene Expression ,ddc:616.07 ,CD16 ,Immunophenotyping ,Bone Marrow ,Precursor cell ,Paracrine Communication ,medicine ,Animals ,Humans ,Myeloid Cells ,Multiple myeloma ,Mice, Knockout ,Myelopoiesis ,business.industry ,Hematology ,medicine.disease ,Molecular biology ,Disease Models, Animal ,Haematopoiesis ,Cell Transformation, Neoplastic ,medicine.anatomical_structure ,Oncology ,Bone marrow ,Multiple Myeloma ,business ,Infiltration (medical) ,Protein Binding - Abstract
Multiple myeloma (MM) is a non-curable tumor developing in the bone marrow (BM). The BM microenvironment rich in hematopoietic precursors is suspected to have a role in MM development. Here we show that a proliferation-inducing ligand (APRIL) mediated in vivo MM promotion. In MM-infiltrated BM, APRIL originated from differentiating myeloid cells with an expression peak in precursor cells. Notably, APRIL expression stayed stable in BM despite MM infiltration. The pool of APRIL-producing cells changed upon MM infiltration. Although CD16(+) mature myeloid cells constituted about half of the APRIL-producing cells in healthy BM, CD16(-) Elastase(+) myeloid precursor cells were predominant in MM-infiltrated BM. Myeloid precursor cells secreted all the APRIL they produced, and binding of secreted APRIL to MM cells, strictly dependent of heparan sulfate carried by CD138, resulted in an in situ internalization by tumor cells. This indicated APRIL consumption by MM in BM. Taken together, our data show that myelopoiesis dysregulation characterized by an increased proportion of precursor cells occurs in MM patients. Such dysregulation correlates with a stable expression of the MM-promoting factor APRIL in infiltrated BM.
- Published
- 2015
11. Revisiting IL-6 antagonism in multiple myeloma
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Benoit Manfroi, Thomas Matthes, and Bertrand Huard
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0301 basic medicine ,Myeloid ,medicine.medical_treatment ,Plasma Cells ,Inflammation ,Plasma cell ,03 medical and health sciences ,Paracrine signalling ,0302 clinical medicine ,Bone Marrow ,medicine ,Humans ,Autocrine signalling ,Multiple myeloma ,ddc:616 ,business.industry ,Interleukin-6 ,Hematology ,medicine.disease ,030104 developmental biology ,medicine.anatomical_structure ,Cytokine ,Oncology ,030220 oncology & carcinogenesis ,Immunology ,Bone marrow ,medicine.symptom ,business ,Multiple Myeloma - Abstract
IL-6, a cytokine with broad functions in inflammation and immunity, has been extensively studied for its role on normal antibody-producing plasma cells. In addition, IL-6 is recognized as a proliferative factor for multiple myeloma (MM), a malignant plasma cell tumor developing in the bone marrow. Blocking IL-6 signaling was thus developed into a therapeutic approach for MM already early after its discovery, in 1991. Unfortunately, the first clinical trials did not demonstrate a clear benefit, but despite this apparent failure hopes on IL-6 antagonism are still high and trials ongoing. The cellular source of IL-6 has long been a matter of debate. IL-6 was first recognized as an autocrine factor produced by the malignant plasma cells themselves, but later reports clearly showed that IL-6 was a paracrine factor, produced by the microenvironment, mostly by cells from the myeloid lineage. Recently, we have confirmed that IL-6 originates from myeloid lineage cells, mainly from myeloid precursors. We have also demonstrated that IL-6 amplifies the pool of myeloid cells producing a second key factor for MM, a proliferation inducing ligand (APRIL). These findings form a new rationale for IL-6 inhibition in MM and for new ways to use IL-6 blocking in the clinics.
- Published
- 2016
12. AKT activity orchestrates marginal zone B cell development in mice and humans
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Eva-Maria Cox, Mohamed El-Behi, Stefanie Ries, Johannes F. Vogt, Vivien Kohlhaas, Thomas Michna, Benoît Manfroi, Mona Al-Maarri, Florian Wanke, Boaz Tirosh, Corinne Pondarre, Harry Lezeau, Nir Yogev, Romy Mittenzwei, Marc Descatoire, Sandra Weller, Jean-Claude Weill, Claude-Agnès Reynaud, Pierre Boudinot, Luc Jouneau, Stefan Tenzer, Ute Distler, Anne Rensing-Ehl, Christoph König, Julian Staniek, Marta Rizzi, Aude Magérus, Frederic Rieux-Laucat, F. Thomas Wunderlich, Nadine Hövelmeyer, and Simon Fillatreau
- Subjects
CP: Immunology ,CP: Developmental biology ,Biology (General) ,QH301-705.5 - Abstract
Summary: The signals controlling marginal zone (MZ) and follicular (FO) B cell development remain incompletely understood. Here, we show that AKT orchestrates MZ B cell formation in mice and humans. Genetic models that increase AKT signaling in B cells or abolish its impact on FoxO transcription factors highlight the AKT-FoxO axis as an on-off switch for MZ B cell formation in mice. In humans, splenic immunoglobulin (Ig) D+CD27+ B cells, proposed as an MZ B cell equivalent, display higher AKT signaling than naive IgD+CD27− and memory IgD−CD27+ B cells and develop in an AKT-dependent manner from their precursors in vitro, underlining the conservation of this developmental pathway. Consistently, CD148 is identified as a receptor indicative of the level of AKT signaling in B cells, expressed at a higher level in MZ B cells than FO B cells in mice as well as humans.
- Published
- 2023
- Full Text
- View/download PDF
13. Autocrine amplification of immature myeloid cells by IL-6 in multiple myeloma-infiltrated bone marrow
- Author
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Thomas Matthes, Isabelle Dunand-Sauthier, A Zeller, Benoit Manfroi, Bertrand Huard, and Bjarne Bogen
- Subjects
Cancer Research ,Myeloid ,medicine.medical_treatment ,Tumor Necrosis Factor Ligand Superfamily Member 13 ,Biology ,Models, Biological ,Immunophenotyping ,Mice ,Bone Marrow ,Cell Line, Tumor ,Precursor cell ,medicine ,Animals ,Myeloid Cells ,Myeloid Progenitor Cells ,Cell Proliferation ,ddc:616 ,Interleukin-6 ,RANK Ligand ,Hematology ,medicine.disease ,Autocrine Communication ,Haematopoiesis ,Cytokine ,medicine.anatomical_structure ,Oncology ,Cell culture ,Immunology ,Cancer research ,Female ,Bone marrow ,Multiple Myeloma ,Infiltration (medical) ,Signal Transduction - Abstract
Multiple myeloma (MM) invariably develops in the bone marrow (BM), indicating the strong requirement of this tumor for the peculiar BM microenvironment, rich in cytokine and hematopoietic precursor cells. Interleukin-6 (IL-6) and a proliferation inducing ligand (APRIL) are key cytokines implicated in MM development. Here, we show that MM cells changed the hematopoietic microenvironment early upon BM infiltration by strongly downregulating hematopoietic precursor cells from all lineages except myeloid precursor cells. Myeloid precursor cells constituted a major source of APRIL in MM-infiltrated BM, and their proliferative response to IL-6 upregulation explained their relative resistance to MM infiltration. The osteolytic molecule receptor activator of NF-kB ligand (RANK-L) expressed by MM cells started this myeloid proliferation by inducing in a contact-dependent manner IL-6 production by myeloid precursor cells themselves. Taken together, our data demonstrate that MM cells do not simply displace hematopoietic cells upon BM infiltration, but rather selectively modulate the BM microenvironment to preserve a pool of high APRIL-producing myeloid precursor cells. Our data also identify a positive regulation of APRIL by IL-6 in myeloid precursor cells.
- Published
- 2015
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