38 results on '"Presumey, J."'
Search Results
2. A4.4 MIR-146A deficiency in LY6Chigh monocytes contributes to pathogenic bone loss during inflammatory arthritis
- Author
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Ammari, M, Duroux-Richard, I, Presumey, J, Ponsolles, C, Roussignol, G, Roubert, C, Escriou, V, Toupet, K, Mausset-Bonnefont, AL, Georgel, P, Jorgensen, C, and Apparailly, F
- Published
- 2015
- Full Text
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3. Cytosolic phospholipase A2α gene silencing in monocytes alters development of Th1 responses and reduces autoimmune arthritis
- Author
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Scherman D, Van Lent P, Baron M, Escriou V, Presumey J, Courties G, Cantagrel A, Van den Berg W, Jorgensen C, Davignon J-L, and Apparailly F
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Medicine - Published
- 2010
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4. Myeloid cell subsets dynamic during progression of mouse collagen-induced arthritis
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Jorgensen C, Presumey J, Courties G, and Apparailly F
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Medicine - Published
- 2010
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5. BIK is a novel pro-apoptotic target gene for miR-125b in human monocytes
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Fabre S, Pers Y M, Presumey J, Duroux-Richard I, Lecellier C H, Gruen J, Häupl T, Grützkau A, Burmester G, Jorgensen C, and Apparailly F
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Medicine - Published
- 2010
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- View/download PDF
6. Cytosolic phospholipase A2α gene silencing in the myeloid lineage alters development of Th1 responses and reduces disease severity in collagen-induced arthritis
- Author
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Courties, G., Baron, M., Presumey, J., Escriou, V., van Lent, P., Scherman, D., Cantagrel, A., van den Berg, W. B., Jorgensen, C., Apparailly, F., and Davignon, J. -L.
- Published
- 2011
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7. Myeloid cell subsets dynamic during progression of mouse collagen-induced arthritis
- Author
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Presumey, J, Jorgensen, C, Courties, G, and Apparailly, F
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- 2011
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8. RNAi mediated silencing of hnRNP-A2 decreases collagen-induced arthritis by inhibiting proliferation and cytokine production of cells of the mononuclear phagocytic system
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Herman, S, Presumey, J, Pfatschbacher, J, Apparailley, F, and Steiner, G
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- 2011
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9. Inhibition of Inflammation and Bone Erosion by RNA Interference-Mediated Silencing of Heterogeneous Nuclear RNP A2/B1 in Two Experimental Models of Rheumatoid Arthritis
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Herman, S., Fischer, A., Presumey, J., Hoffmann, M., Koenders, M.I., Escriou, V., Apparailly, F., Steiner, G., Medizinische Universität Wien = Medical University of Vienna, Cellules Souches, Plasticité Cellulaire, Médecine Régénératrice et Immunothérapies (IRMB), Université de Montpellier (UM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Radboud University Medical Center [Nijmegen], Unité de Technologies Chimiques et Biologiques pour la Santé (UTCBS - UM 4 (UMR 8258 / U1022)), Ecole Nationale Supérieure de Chimie de Paris - Chimie ParisTech-PSL (ENSCP), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut de Chimie du CNRS (INC), Medical University of Vienna, Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), and Ecole Nationale Supérieure de Chimie de Paris- Chimie ParisTech-PSL (ENSCP)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)
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EXPRESSION ,RA33 ,[SDV.BIO]Life Sciences [q-bio]/Biotechnology ,[SDV]Life Sciences [q-bio] ,PATHOGENESIS ,EFFICIENT ,IMMUNITY ,ALPHA ,ACTIVATION ,RIBONUCLEOPROTEINS ,[SDV.MHEP.RSOA]Life Sciences [q-bio]/Human health and pathology/Rhumatology and musculoskeletal system ,AUTOANTIBODIES ,AUTOREACTIVE T-CELLS ,Inflammatory diseases Radboud Institute for Molecular Life Sciences [Radboudumc 5] ,ComputingMilieux_MISCELLANEOUS - Abstract
Contains fulltext : 153179.pdf (Publisher’s version ) (Closed access) OBJECTIVE: The nuclear protein heterogeneous nuclear RNP A2/B1 (hnRNP A2/B1) is involved in posttranscriptional regulation of gene expression. It is constitutively expressed in lymphoid organs and highly up-regulated in the synovial tissue of patients with rheumatoid arthritis (RA), who may also generate autoantibodies to this protein. This study was undertaken to investigate the potential involvement of hnRNP A2/B1 in the pathogenesis of autoimmune arthritis, by silencing hnRNP A2/B1 expression in 2 animal models of RA. METHODS: Collagen-induced arthritis (CIA) and the K/BxN serum-transfer model were used as animal models of RA. Efficient silencing of hnRNP A2/B1 was achieved using a liposome-based carrier system for delivery of small interfering RNAs. Expression of hnRNP A2/B1 was analyzed by flow cytometry, reverse transcription-quantitative polymerase chain reaction, Western blotting, and immunohistochemistry. The number of osteoclasts was determined by tartrate-resistant acid phosphatase staining. Cytokine levels and anticollagen antibody levels were measured by enzyme-linked immunosorbent assay. RESULTS: Efficient silencing of hnRNP A2/B1 was achieved in all lymphoid organs. In both experimental models, the incidence and severity of arthritis were largely reduced and bone erosion was not detectable as compared to the control groups. Down-modulation of hnRNP A2/B1 significantly interfered with the production of proinflammatory cytokines from monocyte/macrophages, but not from T cells. Consistent with these findings, production of T cell cytokines was not impaired when cells were restimulated in vitro with type II collagen. Furthermore, levels of anticollagen antibodies were not affected by hnRNP A2/B1 silencing. CONCLUSION: Our findings suggest that hnRNP A2/B1 has an important role in regulation of the innate immune system, especially at the level of monocyte/macrophage activation. Therefore, down-modulation of hnRNP A2/B1 seems to affect primarily the effector phase of autoimmune arthritis.
- Published
- 2015
10. Schizophrenia risk from complex variation of complement component 4
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Sekar, A, Bialas, AR, de Rivera, H, Davis, A, Hammond, TR, Kamitaki, N, Tooley, K, Presumey, J, Baum, M, Van Doren, V, Genovese, G, Rose, SA, Handsaker, RE, Daly, MJ, Carroll, MC, Stevens, B, McCarroll, SA, Sekar, A, Bialas, AR, de Rivera, H, Davis, A, Hammond, TR, Kamitaki, N, Tooley, K, Presumey, J, Baum, M, Van Doren, V, Genovese, G, Rose, SA, Handsaker, RE, Daly, MJ, Carroll, MC, Stevens, B, and McCarroll, SA
- Abstract
Schizophrenia is a heritable brain illness with unknown pathogenic mechanisms. Schizophrenia's strongest genetic association at a population level involves variation in the major histocompatibility complex (MHC) locus, but the genes and molecular mechanisms accounting for this have been challenging to identify. Here we show that this association arises in part from many structurally diverse alleles of the complement component 4 (C4) genes. We found that these alleles generated widely varying levels of C4A and C4B expression in the brain, with each common C4 allele associating with schizophrenia in proportion to its tendency to generate greater expression of C4A. Human C4 protein localized to neuronal synapses, dendrites, axons, and cell bodies. In mice, C4 mediated synapse elimination during postnatal development. These results implicate excessive complement activity in the development of schizophrenia and may help explain the reduced numbers of synapses in the brains of individuals with schizophrenia.
- Published
- 2016
11. MicroRNAs as new player in rheumatoid arthritis
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Duroux-Richard, I, Presumey, J, Courties, G, Gay, S, Gordeladze, J, Jorgensen, C, Kyburz, D, Apparailly, F, University of Zurich, and Apparailly, F
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2745 Rheumatology ,10051 Rheumatology Clinic and Institute of Physical Medicine ,610 Medicine & health - Published
- 2011
12. A4.4 MIR-146A deficiency in LY6Chighmonocytes contributes to pathogenic bone loss during inflammatory arthritis
- Author
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Ammari, M, primary, Duroux-Richard, I, additional, Presumey, J, additional, Ponsolles, C, additional, Roussignol, G, additional, Roubert, C, additional, Escriou, V, additional, Toupet, K, additional, Mausset-Bonnefont, AL, additional, Georgel, P, additional, Jorgensen, C, additional, and Apparailly, F, additional
- Published
- 2015
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13. OP0220 Innovative anti-inflammatory strategy in arthritis using PBEF sirna-mediated silencing in LY-6CHIGH monocytes
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Presumey, J., primary, Courties, G., additional, Charbonnier, L.-M., additional, Escriou, V., additional, Scherman, D., additional, Pers, Y.-M., additional, Louis-Plence, P., additional, Yssel, H., additional, Pène, J., additional, Kyburz, D., additional, Gay, S., additional, Jorgensen, C., additional, and Apparailly, F., additional
- Published
- 2013
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14. A9.17 Targeting the Expression of miR-146a in Mouse Inflammatory Ly6ChighMonocyte Subset for Therapeutic Intervention in Arthritis
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Ammari, M, primary, Duroux-Richard, I, additional, Presumey, J, additional, Roubert, C, additional, Escriou, V, additional, Jorgensen, C, additional, and Apparailly, F, additional
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- 2013
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15. BIK is a novel pro-apoptotic target gene for miR-125b in human monocytes
- Author
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Duroux-Richard, I, primary, Presumey, J, additional, Pers, Y M, additional, Fabre, S, additional, Lecellier, C H, additional, Gruen, J, additional, Häupl, T, additional, Grützkau, A, additional, Burmester, G, additional, Jorgensen, C, additional, and Apparailly, F, additional
- Published
- 2010
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16. Myeloid cell subsets dynamic during progression of mouse collagen-induced arthritis
- Author
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Presumey, J, primary, Jorgensen, C, additional, Courties, G, additional, and Apparailly, F, additional
- Published
- 2010
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- View/download PDF
17. Cytosolic phospholipase A2α gene silencing in monocytes alters development of Th1 responses and reduces autoimmune arthritis
- Author
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Courties, G, primary, Presumey, J, additional, Baron, M, additional, Escriou, V, additional, Van Lent, P, additional, Scherman, D, additional, Cantagrel, A, additional, Van den Berg, W, additional, Jorgensen, C, additional, Davignon, J-L, additional, and Apparailly, F, additional
- Published
- 2010
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18. Negative regulation of BIK by the micro RNA125B interferes with macrophage apoptosis in rheumatoid arthritis
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Presumey, J., primary, Duroux-Richard, I., additional, Fabre, S., additional, Pers, Y.-M., additional, Courties, G., additional, Jorgensen, C., additional, and Apparailly, F., additional
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- 2010
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19. A liposome-based nanocarrier for preferential targeting of the mononuclear phagocyte system in arthritic mice
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Courties, G, primary, Presumey, J, additional, Escriou, V, additional, Scherman, D, additional, Jorgensen, C, additional, and Apparailly, F, additional
- Published
- 2010
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20. FCGR3A F158V alleles frequency differs in multiple myeloma patients from healthy population.
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Constantinides M, Robert N, Multrier C, Coënon L, Campos-Mora M, Jacquard C, Gao F, Zemiti S, Presumey J, Cartron G, Moreaux J, and Villalba M
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- Humans, Male, Female, Middle Aged, Aged, Monoclonal Gammopathy of Undetermined Significance genetics, Monoclonal Gammopathy of Undetermined Significance immunology, Genotype, Receptors, IgG genetics, Multiple Myeloma genetics, Multiple Myeloma drug therapy, Multiple Myeloma immunology, Polymorphism, Single Nucleotide, Gene Frequency
- Abstract
FCGR3A presents a single nucleotide polymorphism at location 158 (V/F), which affects its binding to the fragment crystallizable (Fc) of antibodies (Abs). FcγRIIIa-158 V allotype has the highest affinity and is associated with a better clinical response to IgG1 monoclonal Abs (mAb) treatment. We compared the allele frequency of FCGR3A- F158V polymorphism in cohorts of patients with B-cell lymphoproliferative disorders, including multiple myeloma (MM), monoclonal gammopathy of undetermined significance (MGUS), non-Hodgkin lymphoma (NHL), and B-cell chronic leukemia (B-CLL). FCGR3A -158F homozygous were enriched and tended to be in MM and MGUS patients, respectively; but neither in B-CLL nor in NHL patients. We identified a significantly lower concentration of CD8 T-cells and resting memory CD4 T-cells in MM patients bone marrow with the F/F genotype, associated with an increase in the macrophage percentage. In contrast, natural killer cells increased in V/V homozygous patients. This suggests a deregulation of the immune microenvironment in FCGR3A -F/F homozygous patients. However, we did not observe difference in response following treatment combining chemotherapy associated or not with daratumumab, an IgG1 mAb direct against CD38. Our findings suggest that FCGR3A F158V polymorphism can regulate the immune environment and affect the development of tumor plasma cells., Competing Interests: No potential conflict of interest was reported by the authors., (© 2024 The Author(s). Published with license by Taylor & Francis Group, LLC.)
- Published
- 2024
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21. Generation of non-genetically modified, CAR-like, NK cells.
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Coënon L, Rigal E, Courot H, Multrier C, Zemiti S, Lambour J, Pugnière M, de Toledo M, Bossis G, Cartron G, Robert B, Martineau P, Fauvel B, Presumey J, and Villalba M
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- Humans, Animals, Mice, Immunotherapy, Adoptive methods, Cell Line, Tumor, Antigens, CD19 immunology, Antibody-Dependent Cell Cytotoxicity, Receptors, Chimeric Antigen immunology, Receptors, Chimeric Antigen genetics, Receptors, Chimeric Antigen metabolism, Xenograft Model Antitumor Assays, Antibodies, Monoclonal therapeutic use, Antibodies, Monoclonal pharmacology, Killer Cells, Natural immunology, Killer Cells, Natural metabolism, Receptors, IgG metabolism, Receptors, IgG immunology
- Abstract
Background: Natural killer (NK) cell therapy is considered an attractive and safe strategy for anticancer therapy. Nevertheless, when autologous or allogenic NK cells are used alone, the clinical benefit has been disappointing. This is partially due to the lack of target specificity. Recently, CD19-specific chimeric antigen receptor (CAR)-NK cells have proven to be safe and potent in patients with B-cell tumors. However, the generation of CAR-NK cells is a complicated manufacturing process. We aim at developing a targeted NK cell therapy without the need for cellular genetic modifications. We took advantage of the natural expression of the IgG Fc receptor CD16a (FcγRIIIa) to induce strong antigen-specific effector functions through antibody-dependent cell-mediated cytotoxicity (ADCC). We have generated the new technology "Pin", which enables the arming of modified monoclonal antibodies (mAbs) onto the CD16a of ex vivo expanded NK (eNK) cells. Methods Ex vivo eNK were prepared from umbilical cord blood cells and expanded using interleukin (IL)-2/IL-15 and Epstein-Barr virus (EBV)-transformed B-lymphoblastoid feeder cells. mAbs were engineered with four substitutions called Pin mutations to increase their affinity to CD16a. eNK were incubated with anti-CD20 or anti-CD19 Pin-mAbs to generate "armed" eNK and were used to assess effector functions in vitro on cancer cell lines, lymphoma patient cells and in vivo., Results: CD16a/Pin-mAb interaction is stable for several days and Pin-mAb eNK inherit the mAb specificity and exclusively induce ADCC against targets expressing the cognate antigen. Hence, Pin-mAbs confer long-term selectivity to eNK, which allows specific elimination of the target cells in several in vivo mouse models. Finally, we showed that it is possible to arm eNK with at least two Pin-mAbs simultaneously, to increase efficacy against heterogenous cancer cell populations., Conclusions: The Pin technology provides an off-the-shelf NK cell therapy platform to generate CAR-like NK cells, without genetic modifications, that easily target multiple tumor antigens., Competing Interests: Competing interests: The patent of PINTM technology has been licensed to CYTEA BIO (WO2022023581A1 “Armed NK cells for universal cell therapy”). ER, HC, BF and JP are currently employees of CYTEA BIO. BR, PM and MV were initial creators of CYTEA BIO., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)
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- 2024
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22. Novel trehalose-based excipients for stabilizing nebulized anti-SARS-CoV-2 antibody.
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Noverraz F, Robin B, Passemard S, Fauvel B, Presumey J, Rigal E, Cookson A, Chopineau J, Martineau P, Villalba M, Jorgensen C, Aubert-Pouëssel A, Morille M, and Gerber-Lemaire S
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- Mice, Animals, Trehalose chemistry, SARS-CoV-2, Antibodies, Viral, Excipients chemistry, COVID-19
- Abstract
COVID-19 is caused by the infection of the lungs by SARS-CoV-2. Monoclonal antibodies, such as sotrovimab, showed great efficiency in neutralizing the virus before its internalization by lung epithelial cells. However, parenteral routes are still the preferred route of administration, even for local infections, which requires injection of high doses of antibody to reach efficacious concentrations in the lungs. Lung administration of antibodies would be more relevant requiring lower doses, thus reducing the costs and the side effects. But aerosolization of therapeutic proteins is very challenging, as the different processes available are harsh and trigger protein aggregation and conformational changes. This decreases the efficiency of the treatment, and can increase its immunogenicity. To address those issues, we developed a series of new excipients composed of a trehalose core, a succinyl side chain and a hydrophobic carbon chain (from 8 to 16 carbons). Succinylation increased the solubility of the excipients, allowing their use at relevant concentrations for protein stabilization. In particular, the excipient with 16 carbons (C
16 TreSuc) used at 5.6 mM was able to preserve colloidal stability and antigen-binding ability of sotrovimab during the nebulization process. It could also be used as a cryoprotectant, allowing storage of sotrovimab in a lyophilized form during weeks. Finally, we demonstrated that C16 TreSuc could be used as an excipient to stabilize antibodies for the treatment against COVID-19, by in vitro and in vivo assays. The presence of C16 TreSuc during nebulization preserved the neutralization capacity of sotrovimab against SARS-CoV-2 in vitro; an increase of its efficacy was even observed, compared to the non-nebulized control. The in vivo study also showed the wide distribution of sotrovimab in mice lungs, after nebulization with 5.6 mM of excipient. This work brings a solution to stabilize therapeutic proteins during storage and nebulization, making pulmonary immunotherapy possible in the treatment of COVID-19 and other lung diseases., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 The Author(s). Published by Elsevier B.V. All rights reserved.)- Published
- 2023
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23. Author Correction: Schizophrenia risk from complex variation of complement component 4.
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Sekar A, Bialas AR, de Rivera H, Davis A, Hammond TR, Kamitaki N, Tooley K, Presumey J, Baum M, Van Doren V, Genovese G, Rose SA, Handsaker RE, Daly MJ, Carroll MC, Stevens B, and McCarroll SA
- Published
- 2022
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24. Overexpression of schizophrenia susceptibility factor human complement C4A promotes excessive synaptic loss and behavioral changes in mice.
- Author
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Yilmaz M, Yalcin E, Presumey J, Aw E, Ma M, Whelan CW, Stevens B, McCarroll SA, and Carroll MC
- Subjects
- Animals, Complement C4 biosynthesis, Dendritic Spines pathology, Depression psychology, Female, Gene Dosage, Male, Mice, Mice, Inbred C57BL, Mice, Knockout, Mice, Transgenic, Microglia pathology, Nerve Net pathology, Psychomotor Performance, Schizophrenia pathology, Synaptosomes pathology, Behavior, Animal, Complement C4 genetics, Schizophrenia genetics, Schizophrenic Psychology, Synapses pathology
- Abstract
The complement component 4 (C4) gene is linked to schizophrenia and synaptic refinement. In humans, greater expression of C4A in the brain is associated with an increased risk of schizophrenia. To investigate this genetic finding and address how C4A shapes brain circuits in vivo, here, we generated a mouse model with primate-lineage-specific isoforms of C4, human C4A and/or C4B. Human C4A bound synapses more efficiently than C4B. C4A (but not C4B) rescued the visual system synaptic refinement deficits of C4 knockout mice. Intriguingly, mice without C4 had normal numbers of cortical synapses, which suggests that complement is not required for normal developmental synaptic pruning. However, overexpressing C4A in mice reduced cortical synapse density, increased microglial engulfment of synapses and altered mouse behavior. These results suggest that increased C4A-mediated synaptic elimination results in abnormal brain circuits and behavior. Understanding pathological overpruning mechanisms has important therapeutic implications in disease conditions such as schizophrenia.
- Published
- 2021
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25. Complement C4A Regulates Autoreactive B Cells in Murine Lupus.
- Author
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Simoni L, Presumey J, van der Poel CE, Castrillon C, Chang SE, Utz PJ, and Carroll MC
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- Amino Acid Sequence, Animals, Apoptosis, Autoantibodies metabolism, Autoantigens metabolism, Base Sequence, Complement C4a chemistry, Complement C4b chemistry, Complement C4b metabolism, Disease Models, Animal, Gene Editing, Humans, Immune Tolerance, Mice, Inbred C57BL, Mice, Transgenic, B-Lymphocytes immunology, Complement C4a metabolism, Lupus Erythematosus, Systemic immunology
- Abstract
Systemic lupus erythematosus (SLE) is a severe autoimmune disease mediated by pathogenic autoantibodies. While complement protein C4 is associated with SLE, its isoforms (C4A and C4B) are not equal in their impact. Despite being 99% homologous, genetic studies identified C4A as more protective than C4B. By generating gene-edited mouse strains expressing either human C4A or C4B and crossing these with the 564lgi lupus strain, we show that, overall, C4A-like 564Igi mice develop less humoral autoimmunity than C4B-like 564Igi mice. This includes a decrease in the number of GCs, autoreactive B cells, autoantibodies, and memory B cells. The higher efficiency of C4A in inducing self-antigen clearance is associated with the follicular exclusion of autoreactive B cells. These results explain how the C4A isoform is protective in lupus and suggest C4A as a possible replacement therapy in lupus., 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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26. An Ultrahigh-Affinity Complement C4b-Specific Nanobody Inhibits In Vivo Assembly of the Classical Pathway Proconvertase.
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Zarantonello A, Presumey J, Simoni L, Yalcin E, Fox R, Hansen A, Olesen HG, Thiel S, Johnson MB, Stevens B, Laursen NS, Carroll MC, and Andersen GR
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- Animals, Antibody Affinity, Antigen-Antibody Complex metabolism, Cell Differentiation, Cells, Cultured, Complement Activation, Complement C4b genetics, Complement C4b immunology, Humans, Mice, Mice, Knockout, Protein Multimerization, Up-Regulation, Complement C3 metabolism, Complement C3-C5 Convertases, Classical Pathway metabolism, Complement C4b metabolism, Induced Pluripotent Stem Cells physiology, Neurons physiology, Schizophrenia metabolism, Single-Domain Antibodies metabolism
- Abstract
The classical and lectin pathways of the complement system are important for the elimination of pathogens and apoptotic cells and stimulation of the adaptive immune system. Upon activation of these pathways, complement component C4 is proteolytically cleaved, and the major product C4b is deposited on the activator, enabling assembly of a C3 convertase and downstream alternative pathway amplification. Although excessive activation of the lectin and classical pathways contributes to multiple autoimmune and inflammatory diseases and overexpression of a C4 isoform has recently been linked to schizophrenia, a C4 inhibitor and structural characterization of the convertase formed by C4b is lacking. In this study, we present the nanobody hC4Nb8 that binds with picomolar affinity to human C4b and potently inhibits in vitro complement C3 deposition through the classical and lectin pathways in human serum and in mouse serum. The crystal structure of the C4b:hC4Nb8 complex and a three-dimensional reconstruction of the C4bC2 proconvertase obtained by electron microscopy together rationalize how hC4Nb8 prevents proconvertase assembly through recognition of a neoepitope exposed in C4b and reveals a unique C2 conformation compared with the alternative pathway proconvertase. On human induced pluripotent stem cell-derived neurons, the nanobody prevents C3 deposition through the classical pathway. Furthermore, hC4Nb8 inhibits the classical pathway-mediated immune complex delivery to follicular dendritic cells in vivo. The hC4Nb8 represents a novel ultrahigh-affinity inhibitor of the classical and lectin pathways of the complement cascade under both in vitro and in vivo conditions., (Copyright © 2020 by The American Association of Immunologists, Inc.)
- Published
- 2020
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27. Retraction Note: Microglia-dependent synapse loss in type I interferon-mediated lupus.
- Author
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Bialas AR, Presumey J, Das A, van der Poel CE, Lapchak PH, Mesin L, Victora G, Tsokos GC, Mawrin C, Herbst R, and Carroll MC
- Abstract
An amendment to this paper has been published and can be accessed via a link at the top of the paper.
- Published
- 2020
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28. Glucocorticoids Regulate Bone Marrow B Lymphopoiesis After Stroke.
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Courties G, Frodermann V, Honold L, Zheng Y, Herisson F, Schloss MJ, Sun Y, Presumey J, Severe N, Engblom C, Hulsmans M, Cremer S, Rohde D, Pittet MJ, Scadden DT, Swirski FK, Kim DE, Moskowitz MA, and Nahrendorf M
- Subjects
- Aged, Animals, B-Lymphocytes cytology, Bone Marrow metabolism, Bone Marrow Cells cytology, Female, Humans, Hypothalamo-Hypophyseal System physiopathology, Male, Mice, Inbred C57BL, Mice, Knockout, Mice, Transgenic, Middle Aged, Pituitary-Adrenal System physiopathology, Receptors, Glucocorticoid genetics, Receptors, Glucocorticoid metabolism, Stroke genetics, Stroke physiopathology, Adrenal Cortex Hormones blood, B-Lymphocytes metabolism, Bone Marrow Cells metabolism, Lymphopoiesis, Receptors, Glucocorticoid blood, Stroke blood
- Abstract
Rationale: After a stroke, patients frequently experience altered systemic immunity resulting in peripheral immunosuppression and higher susceptibility to infections, which is at least partly attributed to lymphopenia. The mechanisms that profoundly change the systemic leukocyte repertoire after stroke are incompletely understood. Emerging evidence indicates that stroke alters hematopoietic output of the bone marrow., Objective: To explore the mechanisms that lead to defects of B lymphopoiesis after ischemic stroke., Methods and Results: We here report that ischemic stroke triggers brain-bone marrow communication via hormonal long-range signals that regulate hematopoietic B lineage decisions. Bone marrow fluorescence-activated cell sorter analyses and serial intravital microscopy indicate that transient middle cerebral artery occlusion in mice arrests B-cell development beginning at the pro-B-cell stage. This phenotype was not rescued in Myd88
-/- and TLR4-/- mice with disrupted TLR (Toll-like receptor) signaling or after blockage of peripheral sympathetic nerves. Mechanistically, we identified stroke-induced glucocorticoid release as the main instigator of B lymphopoiesis defects. B-cell lineage-specific deletion of the GR (glucocorticoid receptor) in CD19-Cre loxP Nr3c1 mice attenuated lymphocytopenia after transient middle cerebral artery. In 20 patients with acute stroke, increased cortisol levels inversely correlated with blood lymphocyte numbers., Conclusions: Our data demonstrate that the hypothalamic-pituitary-adrenal axis mediates B lymphopoiesis defects after ischemic stroke.- Published
- 2019
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29. Delivery of miR-146a to Ly6C high Monocytes Inhibits Pathogenic Bone Erosion in Inflammatory Arthritis.
- Author
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Ammari M, Presumey J, Ponsolles C, Roussignol G, Roubert C, Escriou V, Toupet K, Mausset-Bonnefont AL, Cren M, Robin M, Georgel P, Nehmar R, Taams L, Grün J, Grützkau A, Häupl T, Pers YM, Jorgensen C, Duroux-Richard I, Courties G, and Apparailly F
- Subjects
- Animals, Arthritis chemically induced, Arthritis therapy, Arthritis, Rheumatoid pathology, Disease Models, Animal, Flow Cytometry, Humans, Mice, Inbred C57BL, Mice, Inbred DBA, Mice, Knockout, MicroRNAs administration & dosage, Monocytes chemistry, Antigens, Ly analysis, Arthritis pathology, Bone and Bones pathology, Cell Differentiation, MicroRNAs analysis, Monocytes physiology, Osteoclasts physiology
- Abstract
Rationale: Monocytes play critical roles in the pathogenesis of arthritis by contributing to the inflammatory response and bone erosion. Among genes involved in regulating monocyte functions, miR-146a negatively regulates the inflammatory response and osteoclast differentiation of monocytes. It is also the only miRNA reported to differentially regulate the cytokine response of the two classical Ly6C
high and non-classical Ly6Clow monocyte subsets upon bacterial challenge. Although miR-146a is overexpressed in many tissues of arthritic patients, its specific role in monocyte subsets under arthritic conditions remains to be explored. Methods: We analyzed the monocyte subsets during collagen-induced arthritis (CIA) development by flow cytometry. We quantified the expression of miR-146a in classical and non-classical monocytes sorted from healthy and CIA mice, as well as patients with rheumatoid arthritis (RA). We monitored arthritis features in miR-146a-/- mice and assessed in vivo the therapeutic potential of miR-146a mimics delivery to Ly6Chigh monocytes. We performed transcriptomic and pathway enrichment analyses on both monocyte subsets sorted from wild type and miR-146a-/- mice. Results: We showed that the expression of miR-146a is reduced in the Ly6Chigh subset of CIA mice and in the analogous monocyte subset (CD14+ CD16- ) in humans with RA as compared with healthy controls. The ablation of miR-146a in mice worsened arthritis severity, increased osteoclast differentiation in vitro and bone erosion in vivo . In vivo delivery of miR-146a to Ly6Chigh monocytes, and not to Ly6Clow monocytes, rescues bone erosion in miR-146a-/- arthritic mice and reduces osteoclast differentiation and pathogenic bone erosion in CIA joints of miR-146a+/+ mice, with no effect on inflammation. Silencing of the non-canonical NF-κB family member RelB in miR-146a-/- Ly6Chigh monocytes uncovers a role for miR-146a as a key regulator of the differentiation of Ly6Chigh , and not Ly6Clow , monocytes into osteoclasts under arthritic conditions. Conclusion: Our results show that classical monocytes play a critical role in arthritis bone erosion. They demonstrate the theranostics potential of manipulating miR-146a expression in Ly6Chigh monocytes to prevent joint destruction while sparing inflammation in arthritis., Competing Interests: Competing Interests: The authors have declared that no competing interest exists.- Published
- 2018
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30. Microglia-dependent synapse loss in type I interferon-mediated lupus.
- Author
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Bialas AR, Presumey J, Das A, van der Poel CE, Lapchak PH, Mesin L, Victora G, Tsokos GC, Mawrin C, Herbst R, and Carroll MC
- Subjects
- Animals, Antibodies, Monoclonal therapeutic use, Antibodies, Monoclonal, Humanized, Behavior, Animal, Disease Models, Animal, Female, Hippocampus metabolism, Hippocampus pathology, Humans, Interferon Type I antagonists & inhibitors, Lupus Vasculitis, Central Nervous System psychology, Male, Mice, Microglia metabolism, Phenotype, Signal Transduction, Synapses immunology, Transcriptome, Interferon Type I immunology, Lupus Vasculitis, Central Nervous System immunology, Lupus Vasculitis, Central Nervous System pathology, Microglia immunology, Microglia pathology, Synapses pathology
- Abstract
Systemic lupus erythematosus (SLE) is an incurable autoimmune disease characterized by autoantibody deposition in tissues such as kidney, skin and lungs. Notably, up to 75% of patients with SLE experience neuropsychiatric symptoms that range from anxiety, depression and cognitive impairment to seizures and, in rare cases, psychosis-collectively this is referred to as central nervous system (CNS) lupus. In some cases, certain autoantibodies, such as anti-NMDAR or anti-phospholipid antibodies, promote CNS lupus. However, in most patients, the mechanisms that underlie these symptoms are unknown. CNS lupus typically presents at lupus diagnosis or within the first year, suggesting that early factors contributing to peripheral autoimmunity may promote CNS lupus symptoms. Here we report behavioural phenotypes and synapse loss in lupus-prone mice that are prevented by blocking type I interferon (IFN) signalling. Furthermore, we show that type I IFN stimulates microglia to become reactive and engulf neuronal and synaptic material in lupus-prone mice. These findings and our observation of increased type I IFN signalling in post-mortem hippocampal brain sections from patients with SLE may instruct the evaluation of ongoing clinical trials of anifrolumab, a type I IFN-receptor antagonist. Moreover, identification of IFN-driven microglia-dependent synapse loss, along with microglia transcriptome data, connects CNS lupus with other CNS diseases and provides an explanation for the neurological symptoms observed in some patients with SLE.
- Published
- 2017
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31. microRNA target prediction programs predict many false positives.
- Author
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Pinzón N, Li B, Martinez L, Sergeeva A, Presumey J, Apparailly F, and Seitz H
- Subjects
- 3' Untranslated Regions genetics, Algorithms, Animals, Binding Sites, Computational Biology, Humans, Mice, MicroRNAs metabolism, Gene Expression Regulation genetics, MicroRNAs genetics, RNA, Messenger genetics
- Abstract
According to the current view, each microRNA regulates hundreds of genes. Computational tools aim at identifying microRNA targets, usually selecting evolutionarily conserved microRNA binding sites. While the false positive rates have been evaluated for some prediction programs, that information is rarely put forward in studies making use of their predictions. Here, we provide evidence that such predictions are often biologically irrelevant. Focusing on miR-223-guided repression, we observed that it is often smaller than inter-individual variability in gene expression among wild-type mice, suggesting that most predicted targets are functionally insensitive to that microRNA. Furthermore, we found that human haplo-insufficient genes tend to bear the most highly conserved microRNA binding sites. It thus appears that biological functionality of microRNA binding sites depends on the dose-sensitivity of their host gene and that, conversely, it is unlikely that every predicted microRNA target is dose-sensitive enough to be functionally regulated by microRNAs. We also observed that some mRNAs can efficiently titrate microRNAs, providing a reason for microRNA binding site conservation for inefficiently repressed targets. Finally, many conserved microRNA binding sites are conserved in a microRNA-independent fashion: Sequence elements may be conserved for other reasons, while being fortuitously complementary to microRNAs. Collectively, our data suggest that the role of microRNAs in normal and pathological conditions has been overestimated due to the frequent overlooking of false positive rates., (© 2017 Pinzón et al.; Published by Cold Spring Harbor Laboratory Press.)
- Published
- 2017
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32. Complement System in Neural Synapse Elimination in Development and Disease.
- Author
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Presumey J, Bialas AR, and Carroll MC
- Subjects
- Animals, Autistic Disorder genetics, Autistic Disorder immunology, Autistic Disorder pathology, Complement System Proteins genetics, Epilepsy genetics, Epilepsy immunology, Epilepsy pathology, Gene Expression Regulation, Developmental, Humans, Microglia immunology, Microglia pathology, Nerve Net pathology, Nerve Tissue Proteins genetics, Nerve Tissue Proteins immunology, Neurogenesis genetics, Neuronal Plasticity genetics, Neurons immunology, Neurons pathology, Schizophrenia genetics, Schizophrenia immunology, Schizophrenia pathology, Synapses genetics, Synapses pathology, Synaptic Transmission, Complement System Proteins immunology, Nerve Net immunology, Neurogenesis immunology, Neuronal Plasticity immunology, Synapses immunology
- Abstract
Recent discoveries implicate the classical complement cascade in normal brain development and in disease. Complement proteins C1q, C3, and C4 participate in synapse elimination, tagging inappropriate synaptic connections between neurons for removal by phagocytic microglia that exist in a special, highly phagocytic state during the synaptic pruning period. Several neurodevelopmental disorders, such as schizophrenia and autism, are thought to be caused by an imbalance in synaptic pruning, and recent studies suggest that dysregulation of complement could promote this synaptic pruning imbalance. Moreover, in the mature brain, complement can be aberrantly activated in early stages of neurodegenerative diseases to stimulate synapse loss. Similar pathways can also be activated in response to inflammation, as in West Nile Virus infection or in lupus, where peripheral inflammation can promote microglia-mediated synapse loss. Whether synapse loss in disease is a true reactivation of developmental synaptic pruning programs remains unclear; nonetheless, complement proteins represent potential therapeutic targets for both neurodevelopmental and neurodegenerative diseases., (© 2017 Elsevier Inc. All rights reserved.)
- Published
- 2017
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33. Schizophrenia risk from complex variation of complement component 4.
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Sekar A, Bialas AR, de Rivera H, Davis A, Hammond TR, Kamitaki N, Tooley K, Presumey J, Baum M, Van Doren V, Genovese G, Rose SA, Handsaker RE, Daly MJ, Carroll MC, Stevens B, and McCarroll SA
- Subjects
- Alleles, Amino Acid Sequence, Animals, Axons metabolism, Base Sequence, Brain metabolism, Brain pathology, Complement C4 chemistry, Complement Pathway, Classical, Dendrites metabolism, Gene Dosage genetics, Gene Expression Regulation genetics, Haplotypes genetics, Humans, Major Histocompatibility Complex genetics, Mice, Models, Animal, Neuronal Plasticity genetics, Neuronal Plasticity physiology, Polymorphism, Single Nucleotide genetics, RNA, Messenger analysis, RNA, Messenger genetics, Risk Factors, Schizophrenia pathology, Synapses metabolism, Complement C4 genetics, Genetic Predisposition to Disease genetics, Genetic Variation genetics, Schizophrenia genetics
- Abstract
Schizophrenia is a heritable brain illness with unknown pathogenic mechanisms. Schizophrenia's strongest genetic association at a population level involves variation in the major histocompatibility complex (MHC) locus, but the genes and molecular mechanisms accounting for this have been challenging to identify. Here we show that this association arises in part from many structurally diverse alleles of the complement component 4 (C4) genes. We found that these alleles generated widely varying levels of C4A and C4B expression in the brain, with each common C4 allele associating with schizophrenia in proportion to its tendency to generate greater expression of C4A. Human C4 protein localized to neuronal synapses, dendrites, axons, and cell bodies. In mice, C4 mediated synapse elimination during postnatal development. These results implicate excessive complement activity in the development of schizophrenia and may help explain the reduced numbers of synapses in the brains of individuals with schizophrenia.
- Published
- 2016
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34. Inhibition of Inflammation and Bone Erosion by RNA Interference-Mediated Silencing of Heterogeneous Nuclear RNP A2/B1 in Two Experimental Models of Rheumatoid Arthritis.
- Author
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Herman S, Fischer A, Presumey J, Hoffmann M, Koenders MI, Escriou V, Apparailly F, and Steiner G
- Subjects
- Animals, Arthritis, Rheumatoid immunology, Autoantibodies immunology, Disease Models, Animal, Heterogeneous-Nuclear Ribonucleoprotein Group A-B immunology, Inflammation genetics, Inflammation immunology, Macrophage Activation immunology, Mice, Monocytes immunology, T-Lymphocytes immunology, Arthritis, Experimental genetics, Arthritis, Rheumatoid genetics, Cytokines immunology, Gene Silencing, Heterogeneous-Nuclear Ribonucleoprotein Group A-B genetics, Macrophages immunology, RNA Interference
- Abstract
Objective: The nuclear protein heterogeneous nuclear RNP A2/B1 (hnRNP A2/B1) is involved in posttranscriptional regulation of gene expression. It is constitutively expressed in lymphoid organs and highly up-regulated in the synovial tissue of patients with rheumatoid arthritis (RA), who may also generate autoantibodies to this protein. This study was undertaken to investigate the potential involvement of hnRNP A2/B1 in the pathogenesis of autoimmune arthritis, by silencing hnRNP A2/B1 expression in 2 animal models of RA., Methods: Collagen-induced arthritis (CIA) and the K/BxN serum-transfer model were used as animal models of RA. Efficient silencing of hnRNP A2/B1 was achieved using a liposome-based carrier system for delivery of small interfering RNAs. Expression of hnRNP A2/B1 was analyzed by flow cytometry, reverse transcription-quantitative polymerase chain reaction, Western blotting, and immunohistochemistry. The number of osteoclasts was determined by tartrate-resistant acid phosphatase staining. Cytokine levels and anticollagen antibody levels were measured by enzyme-linked immunosorbent assay., Results: Efficient silencing of hnRNP A2/B1 was achieved in all lymphoid organs. In both experimental models, the incidence and severity of arthritis were largely reduced and bone erosion was not detectable as compared to the control groups. Down-modulation of hnRNP A2/B1 significantly interfered with the production of proinflammatory cytokines from monocyte/macrophages, but not from T cells. Consistent with these findings, production of T cell cytokines was not impaired when cells were restimulated in vitro with type II collagen. Furthermore, levels of anticollagen antibodies were not affected by hnRNP A2/B1 silencing., Conclusion: Our findings suggest that hnRNP A2/B1 has an important role in regulation of the innate immune system, especially at the level of monocyte/macrophage activation. Therefore, down-modulation of hnRNP A2/B1 seems to affect primarily the effector phase of autoimmune arthritis., (© 2015, American College of Rheumatology.)
- Published
- 2015
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35. MicroRNAs as new player in rheumatoid arthritis.
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Duroux-Richard I, Presumey J, Courties G, Gay S, Gordeladze J, Jorgensen C, Kyburz D, and Apparailly F
- Subjects
- Humans, Inflammation genetics, Inflammation immunology, Arthritis, Rheumatoid genetics, Arthritis, Rheumatoid immunology, Autoimmunity genetics, Autoimmunity immunology, MicroRNAs immunology
- Abstract
MicroRNAs (miRNAs) are small noncoding RNA molecules that negatively regulate gene expression at the post-transcriptional level. Currently, there are 939 mature human miRNA sequences listed in the Sanger updated miRNA registry. There are approximately 1500 predicted miRNAs in the human genome that may regulate the expression of one third of our genes. By controlling the accumulation of the target protein(s) in cells, these regulatory RNA molecules participate in key functions in many physiological networks and their deregulation has been implicated in the pathogenesis of serious human disorders, such as cancer and infection. The implication of miRNAs in immune-mediated disorders such as rheumatoid arthritis (RA) has recently emerged suggesting that miRNA-based therapeutic approaches may have a promising potential in these diseases. Here, we provide an overview of the state-of-the-art on miRNAs in RA, focusing on both systemic and local features of the pathology., (Copyright © 2010 Société française de rhumatologie. Published by Elsevier SAS. All rights reserved.)
- Published
- 2011
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36. In vivo RNAi-mediated silencing of TAK1 decreases inflammatory Th1 and Th17 cells through targeting of myeloid cells.
- Author
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Courties G, Seiffart V, Presumey J, Escriou V, Scherman D, Zwerina J, Ruiz G, Zietara N, Jablonska J, Weiss S, Hoffmann A, Jorgensen C, Apparailly F, and Gross G
- Subjects
- Animals, Arthritis therapy, Cell Line, Inflammation therapy, JNK Mitogen-Activated Protein Kinases immunology, Lipopolysaccharides immunology, MAP Kinase Kinase Kinases immunology, Mice, Mice, Inbred BALB C, Mitogen-Activated Protein Kinases immunology, Monocytes immunology, NF-kappa B immunology, Tumor Necrosis Factor-alpha immunology, MAP Kinase Kinase Kinases genetics, Myeloid Cells immunology, RNA Interference, Th1 Cells immunology, Th17 Cells immunology
- Abstract
Cells from the mononuclear phagocyte system (MPS) act as systemic and local amplifiers that contribute to the progression of chronic inflammatory disorders. Transforming growth factor-β-activated kinase 1 (TAK1) is a pivotal upstream mitogen-activated protein kinase-kinase-kinase acting as a mediator of cytokine expression. It remains critical to determine in vivo the implication of TAK1 in controlling the innate immune system. Here, we describe a vehicle tailored to selectively deliver siRNAs into MPS cells after intravenous administration, and validate in vivo the potential of the RNAi-mediated TAK1 knock down for immunomodulation. In a mouse model of immune-mediated inflammatory disorder, we show that anti-TAK1 siRNA lipoplexes efficiently alleviate inflammation, severely impair the downstream c-Jun N-terminal kinase and nuclear factor-κB signaling pathways, and decrease the expression of proinflammatory mediators. Importantly, the systemic TAK1 gene silencing decreases the frequency of Th1 and Th17 cells, both mediating autoimmunity in experimental arthritis, demonstrating the immunomodulatory potential of TAK1. Finally, in vitro inhibition of TAK1 in myeloid cells decreases interferon-γ-producing T cells, suggesting that a delivery system able to target MPS cells and to silence TAK1 impacts on pathogenic T effector cells in autoimmunity.
- Published
- 2010
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37. Cationic liposome formulations for RNAi-based validation of therapeutic targets in rheumatoid arthritis.
- Author
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Presumey J, Duroux-Richard I, Courties G, and Apparailly F
- Subjects
- Biological Therapy adverse effects, Chemistry, Pharmaceutical, Dosage Forms, Humans, Inflammation complications, Inflammation drug therapy, Inflammation therapy, Liposomes therapeutic use, Macrophages immunology, RNA Interference, RNA, Small Interfering therapeutic use, Arthritis, Rheumatoid drug therapy, Arthritis, Rheumatoid immunology, Arthritis, Rheumatoid therapy
- Abstract
Several molecules have been identified as critical mediators of chronic inflammation in immune system-mediated disorders such as rheumatoid arthritis (RA), and biological therapies targeting these molecules have been developed during the past two decades. Compared with conventional therapies, anti-TNF biotherapies have greatly improved the treatment of patients with RA, and several biological agents with distinct mechanisms of action are under development. Despite significant advances in this field, unmet medical needs remain. RA is the prototype disease for the evaluation of targeted therapies, and various novel genes have been described as being critically involved in disease pathogenesis. Thus, a novel area of research has recently emerged in the field of RA therapy, involving the genetic screening and validation of novel candidates in vivo using RNAi. Among the vehicles for the efficient targeting of macrophages, which play a critical role in disease chronicity, cationic liposomes represent the most promising option for the safe and specific use of RNAi in vivo. This review discusses the role of cationic liposomes as a mechanism for the systemic administration of siRNAs in the validation of RA therapeutic targets.
- Published
- 2010
38. RNA interference-based gene therapy for successful treatment of rheumatoid arthritis.
- Author
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Courties G, Presumey J, Duroux-Richard I, Jorgensen C, and Apparailly F
- Subjects
- Animals, Genetic Therapy trends, Humans, Arthritis, Rheumatoid genetics, Arthritis, Rheumatoid therapy, Genetic Therapy methods, RNA Interference physiology, RNA, Small Interfering therapeutic use
- Abstract
Background: RNA interference (RNAi) is a powerful endogenous process initiated by short double-stranded RNAs, which results in sequence-specific posttranscriptional gene silencing. The possibility of blocking the expression of any protein carries huge expectations for potential therapeutic applications in a wide range of diseases. For clinical development, however, the use of RNAi-based therapeutics has to overcome major obstacles, mainly targeted delivery and safety issues., Objective/methods: In this short review, we provide an overview of specifications for RNAi-based gene therapy in rheumatoid arthritis (RA) and discuss recent progresses in the development of efficient silencing, focusing on expression of short hairpin RNAs., Results/conclusions: Combining advances in RNAi methodology with gene therapy technology opens avenues for rapid applications to RA.
- Published
- 2009
- Full Text
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