15 results on '"Seren, Seda"'
Search Results
2. Neutrophil Elastase-Activatable Prodrugs Based on an Alkoxyamine Platform to Deliver Alkyl Radicals Cytotoxic to Tumor Cells
- Author
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Seren, Seda, primary, Joly, Jean-Patrick, additional, Voisin, Pierre, additional, Bouchaud, Véronique, additional, Audran, Gérard, additional, Marque, Sylvain R. A., additional, and Mellet, Philippe, additional
- Published
- 2022
- Full Text
- View/download PDF
3. Constitutive and induced forms of membrane-bound proteinase 3 interact with antineutrophil cytoplasmic antibodies and promote immune activation of neutrophils.
- Author
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Guarino, Carla, Seren, Seda, Lemoine, Roxane, Hummel, Amber M., Margotin, Jean-Edouard, El-Benna, Jamel, Hoarau, Cyrille, Specks, Ulrich, Jenne, Dieter E., and Korkmaz, Brice
- Subjects
- *
ANTINEUTROPHIL cytoplasmic antibodies , *NEUTROPHILS , *PROTEINASES , *ELASTASES - Abstract
Proteinase 3 (PR3) is the main target antigen of antineutrophil cytoplasmic antibodies (ANCAs) in PR3-ANCA-associated vasculitis. A small fraction of PR3 is constitutively exposed on the surface of quiescent blood neutrophils in a proteolytically inactive form. When activated, neutrophils expose an induced form of membrane-bound PR3 (PR3mb) on their surface as well, which is enzymatically less active than unbound PR3 in solution due to its altered conformation. In this work, our objective was to understand the respective role of constitutive and induced PR3mb in the immune activation of neutrophils triggered by murine anti-PR3 mAbs and human PR3-ANCA. We quantified immune activation of neutrophils by the measurement of the production of superoxide anions and secreted protease activity in the cell supernatant before and after treatment of the cells by alpha-1 protease inhibitor that clears induced PR3mb from the cell surface. Incubation of TNFa-primed neutrophils with anti-PR3 antibodies resulted in a significant increase in superoxide anion production, membrane activation marker exposition, and secreted protease activity. When primed neutrophils were first treated with alpha-1 protease inhibitor, we observed a partial reduction in antibody-induced neutrophil activation, suggesting that constitutive PR3mb is sufficient to activate neutrophils. The pretreatment of primed neutrophils with purified antigenbinding fragments used as competitor significantly reduced cell activation by whole antibodies. This led us to the conclusion that PR3mb promoted immune activation of neutrophils. We propose that blocking and/or elimination of PR3mb offers a new therapeutic strategy to attenuate neutrophil activation in patients with PR3-ANCA-associated vasculitis. [ABSTRACT FROM AUTHOR]
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- 2023
- Full Text
- View/download PDF
4. The discovery of the Papillon-Lefèvre syndrome, a rare cathepsin C related lysosomal disease
- Author
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Korkmaz, Brice, primary, Seren, Seda, additional, Kara, Elodie, additional, and Moss, Celia, additional
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- 2022
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- View/download PDF
5. Monitoring Human Neutrophil Activation by a Proteinase 3 Near-Infrared Fluorescence Substrate-Based Probe
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Saidi, Ahlame, primary, Wartenberg, Mylène, additional, Madinier, Jean-Baptiste, additional, Ilango, Guy, additional, Seren, Seda, additional, Korkmaz, Brice, additional, Lecaille, Fabien, additional, Aucagne, Vincent, additional, and Lalmanach, Gilles, additional
- Published
- 2021
- Full Text
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6. 4C3 Human Monoclonal Antibody: A Proof of Concept for Non-pathogenic Proteinase 3 Anti-neutrophil Cytoplasmic Antibodies in Granulomatosis With Polyangiitis
- Author
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Granel, Jérôme, Lemoine, Roxane, Morello, Eric, Gallais, Yann, Mariot, Julie, Drapeau, Marion, Musnier, Astrid, Poupon, Anne, Pugnière, Martine, Seren, Seda, Nouar, Dalila, Gouilleux-Gruart, Valérie, Watier, Herve, Korkmaz, Brice, Hoarau, Cyrille, EA4245 - Transplantation, Immunologie, Inflammation [Tours] (T2i), Université de Tours, Infectiologie et Santé Publique (UMR ISP), Université de Tours-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), MAbSilico SAS, Dynamiques de populations multi-échelles pour des systèmes physiologiques (MUSCA), Inria Saclay - Ile de France, Institut National de Recherche en Informatique et en Automatique (Inria)-Institut National de Recherche en Informatique et en Automatique (Inria)-Physiologie de la reproduction et des comportements [Nouzilly] (PRC), Institut Français du Cheval et de l'Equitation [Saumur]-Université de Tours-Centre National de la Recherche Scientifique (CNRS)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Institut Français du Cheval et de l'Equitation [Saumur]-Université de Tours-Centre National de la Recherche Scientifique (CNRS)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Mathématiques et Informatique Appliquées du Génome à l'Environnement [Jouy-En-Josas] (MaIAGE), Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Physiologie de la reproduction et des comportements [Nouzilly] (PRC), Institut Français du Cheval et de l'Equitation [Saumur]-Université de Tours-Centre National de la Recherche Scientifique (CNRS)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Institut de Recherche en Cancérologie de Montpellier (IRCM - U1194 Inserm - UM), CRLCC Val d'Aurelle - Paul Lamarque-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Centre d’Etude des Pathologies Respiratoires (CEPR), UMR 1100 (CEPR), Université de Tours-Institut National de la Santé et de la Recherche Médicale (INSERM), Service de néphrologie et immunologie clinique [CHRU Tours] (EA4245 UT), Centre Hospitalier Régional Universitaire de Tours (CHRU Tours)-Hôpital Bretonneau-Université de Tours, Region Centre-Val-de-Loire (program Ambition Research and Development 'Biopharmaceuticals'), University of Tours, ANR-10-LABX-0053,MAbImprove,Optimization of therapeutic monoclonal antibodies development Better antibodies, better developed AND better used(2010), Université de Tours (UT), Université de Tours (UT)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Institut Français du Cheval et de l'Equitation [Saumur] (IFCE)-Université de Tours (UT)-Centre National de la Recherche Scientifique (CNRS)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Institut Français du Cheval et de l'Equitation [Saumur] (IFCE)-Université de Tours (UT)-Centre National de la Recherche Scientifique (CNRS)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Mathématiques et Informatique Appliquées du Génome à l'Environnement [Jouy-En-Josas] (MaIAGE), Institut Français du Cheval et de l'Equitation [Saumur] (IFCE)-Université de Tours (UT)-Centre National de la Recherche Scientifique (CNRS)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Université de Tours (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service de néphrologie et immunologie clinique [CHRU Tours], Centre Hospitalier Régional Universitaire de Tours (CHRU Tours)-Hôpital Bretonneau-Université de Tours (UT), Institut Français du Cheval et de l'Equitation [Saumur]-Université de Tours (UT)-Centre National de la Recherche Scientifique (CNRS)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Institut Français du Cheval et de l'Equitation [Saumur]-Université de Tours (UT)-Centre National de la Recherche Scientifique (CNRS)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Mathématiques et Informatique Appliquées du Génome à l'Environnement [Jouy-En-Josas] (MaIAGE), and Institut Français du Cheval et de l'Equitation [Saumur]-Université de Tours (UT)-Centre National de la Recherche Scientifique (CNRS)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)
- Subjects
Male ,Glycosylation ,human neutrophils ,biologie computationnelle ,[SDV]Life Sciences [q-bio] ,Myeloblastin ,Immunology ,Antibody Affinity ,Proof of Concept Study ,Neutrophil Activation ,Antibodies, Antineutrophil Cytoplasmic ,Cell Line ,Epitopes ,immune system diseases ,Antibody Specificity ,Humans ,Immunology and Allergy ,cardiovascular diseases ,skin and connective tissue diseases ,Aged ,Original Research ,B-Lymphocytes ,epitope ,granulomatosis with polyangiitis ,Antibodies, Monoclonal ,Middle Aged ,respiratory tract diseases ,proteinase 3 ,Case-Control Studies ,anti-neutrophil cytoplasmic antibodies ,Female ,Binding Sites, Antibody ,Biomarkers ,Epitope Mapping - Abstract
International audience; Granulomatosis with polyangiitis (GPA) is a severe autoimmune vasculitis associated with the presence of anti-neutrophil cytoplasmic antibodies (ANCA) mainly targeting proteinase 3 (PR3), a neutrophilic serine proteinase.PR3-ANCA binding to membrane-bound PR3 on neutrophils induce their auto-immune activation responsible for vascular lesions. However, the correlation between PR3-ANCA level and disease activity remains inconsistent, suggesting the existence of non-pathogenic PR3-ANCA. In order to prove their existence, we immortalized B lymphocytes from blood samples of GPA patients in remission having persistent PR3-ANCA to isolate non-activating PR3-ANCA. We obtained for the first time a non-activating human IgG1κanti-PR3 monoclonal antibody (mAb) named 4C3. This new mAb binds soluble PR3 with a high affinity and membrane-bound PR3 on an epitope close to the PR3 hydrophobic patch and in the vicinity of the active site. 4C3 is able to bind FcγRIIA and FcγRIIIB and has a G2F glycosylation profile on asparagine 297. 4C3 did not induce activation of neutrophils and could inhibit human polyclonal PR3-ANCA-induced activation suggesting that 4C3 is non-pathogenic This characteristic relies on the recognized epitope on PR3 rather than to the Fc portion properties. The existence of non-pathogenic PR3-ANCA, which do not activate neutrophils, could explain the persistence of high PR3-ANCA levels in some GPA patients in remission and why PR3-ANCA would not predict relapse. Finally, these results offer promising perspectives particularly regarding the understanding of PR3-ANCA pathogenicity and the development of new diagnostic and therapeutic strategies in GPA
- Published
- 2020
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- View/download PDF
7. Proteinase release from activated neutrophils in mechanically ventilated patients with non-COVID-19 and COVID-19 pneumonia
- Author
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Seren, Seda, primary, Derian, Lohann, additional, Keleş, Irem, additional, Guillon, Antoine, additional, Lesner, Adam, additional, Gonzalez, Loïc, additional, Baranek, Thomas, additional, Si-Tahar, Mustapha, additional, Marchand-Adam, Sylvain, additional, Jenne, Dieter E., additional, Paget, Christophe, additional, Jouan, Youenn, additional, and Korkmaz, Brice, additional
- Published
- 2021
- Full Text
- View/download PDF
8. Human proteinase 3 resistance to inhibition extends to alpha‐2 macroglobulin
- Author
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N’Guessan, Koffi, primary, Grzywa, Renata, additional, Seren, Seda, additional, Gabant, Guillaume, additional, Juliano, Maria A., additional, Moniatte, Marc, additional, van Dorsselaer, Alain, additional, Bieth, Joseph G., additional, Kellenberger, Christine, additional, Gauthier, Francis, additional, Wysocka, Magdalena, additional, Lesner, Adam, additional, Sienczyk, Marcin, additional, Cadene, Martine, additional, and Korkmaz, Brice, additional
- Published
- 2020
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- View/download PDF
9. Processing and Maturation of Cathepsin C Zymogen: A Biochemical and Molecular Modeling Analysis
- Author
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Lamort, Anne-Sophie, primary, Hamon, Yveline, additional, Czaplewski, Cezary, additional, Gieldon, Artur, additional, Seren, Seda, additional, Coquet, Laurent, additional, Lecaille, Fabien, additional, Lesner, Adam, additional, Lalmanach, Gilles, additional, Gauthier, Francis, additional, Jenne, Dieter, additional, and Korkmaz, Brice, additional
- Published
- 2019
- Full Text
- View/download PDF
10. Consequences of cathepsin C inactivation for membrane exposure of proteinase 3, the target antigen in autoimmune vasculitis
- Author
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Seren, Seda, Rashed Abouzaid, Maha, Eulenberg-Gustavus, Claudia, Hirschfeld, Josefine, Nasr Soliman, Hala, Jerke, Uwe, N'Guessan, Koffi, Dallet-Choisy, Sandrine, Lesner, Adam, Lauritzen, Conni, Schacher, Beate, Eickholz, Peter, Nagy, Nikoletta, Szell, Marta, Croix, Cécile, Viaud-Massuard, Marie-Claude, Al Farraj Aldosari, Abdullah, Ragunatha, Shivanna, Ibrahim Mostafa, Mostafa, Giampieri, Francesca, Battino, Maurizio, Cornillier, Hélène, Lorette, Gérard, Stephan, Jean-Louis, Goizet, Cyril, Pedersen, John, Gauthier, Francis, Jenne, Dieter E., Marchand-Adam, Sylvain, Chapple, Iain L., Kettritz, Ralph, Korkmaz, Brice, Pathologies Respiratoires : Protéolyse et Aérosolthérapie, Université de Tours (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM), National Research Center, Helmholtz-Gemeinschaft = Helmholtz Association, University of Birmingham, Medical & Molecular Genetics, University of Birmingham, School of Clinical and Experimental Medicine, Faculty of Chemistry, Technion - Israel Institute of Technology [Haifa], Unizyme Laboratories A/S, Partenaires INRAE, Department of Periodontology, People's Liberation Army No. 309 Hospital, Department of Medical Genetics, University Hospital of North-Norway, Centre National de la Recherche Scientifique (CNRS), King Saud University [Riyadh] (KSU), Department of Dermatology, Venereology, and Leprosy, Sri Siddhartha Medical College, Department of Clinical Sciences, Swedish University of Agricultural Sciences (SLU), Service de dermatologie, Infectiologie et Santé Publique (UMR ISP), Institut National de la Recherche Agronomique (INRA)-Université de Tours (UT), Centre Hospitalier Universitaire de Saint-Etienne (CHU de Saint-Etienne), Laboratoire Maladies Rares: Génétique et Métabolisme (Bordeaux) (U1211 INSERM/MRGM), Université de Bordeaux (UB)-Groupe hospitalier Pellegrin-Institut National de la Santé et de la Recherche Médicale (INSERM), German Centre for Lung Research, Max Planck Institute of Neurobiology, Charité - UniversitätsMedizin = Charité - University Hospital [Berlin], Ministère de l'Enseignement Supérieur et de la Recherche, the 'Région Centre-Val de Loire' (Project BPCO-Lyse), European Project: 668036,H2020,H2020-PHC-2015-two-stage,RELENT(2015), ProdInra, Migration, RELapses prevENTion in chronic autoimmune disease: common mechanisms and co-morbidities - RELENT - - H20202015-11-01 - 2020-04-30 - 668036 - VALID, Université de Tours-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre Hospitalier Régional Universitaire de Tours (CHRU TOURS), Institut National de la Recherche Agronomique (INRA)-Université de Tours, Centre Hospitalier Universitaire de Saint-Etienne [CHU Saint-Etienne] (CHU ST-E), and Centre Hospitalier Régional Universitaire de Tours (CHRU Tours)
- Subjects
Adult ,Male ,neutrophile ,Adolescent ,Neutrophils ,cathepsin C ,Myeloblastin ,Papillon-Lefèvre syndrome ,Médecine humaine et pathologie ,cathepsine ,autoimmune disease ,Cysteine Proteinase Inhibitors ,activation cellulaire ,protease inhibitor ,Young Adult ,antigen ,genetic disease ,cellule souche ,Humans ,cardiovascular diseases ,Child ,hématopoïèse ,aminopeptidase ,granulomatosis with polyangiitis ,neutrophil ,protease ,proteinase 3 ,maladie autoimmune ,[SDV.MHEP] Life Sciences [q-bio]/Human health and pathology ,Cell Membrane ,inhibiteur pharmacologique ,Case-Control Studies ,Child, Preschool ,Proteolysis ,Enzymology ,Female ,Human health and pathology ,[SDV.MHEP]Life Sciences [q-bio]/Human health and pathology - Abstract
International audience; Membrane-bound proteinase 3 (PR3m) is the main target antigen of anti-neutrophil cytoplasmic autoantibodies (ANCA) in granulomatosis with polyangiitis, a systemic small-vessel vasculitis. Binding of ANCA to PR3m triggers neutrophil activation with the secretion of enzymatically active PR3 and related neutrophil serine proteases, thereby contributing to vascular damage. PR3 and related proteases are activated from pro-forms by the lysosomal cysteine protease cathepsin C (CatC) during neutrophil maturation. We hypothesized that pharmacological inhibition of CatC provides an effective measure to reduce PR3m and therefore has implications as a novel therapeutic approach in granulomatosis with polyangiitis. We first studied neutrophilic PR3 from 24 patients with Papillon-Lefèvre syndrome (PLS), a genetic form of CatC deficiency. PLS neutrophil lysates showed a largely reduced but still detectable (0.5-4%) PR3 activity when compared with healthy control cells. Despite extremely low levels of cellular PR3, the amount of constitutive PR3m expressed on the surface of quiescent neutrophils and the typical bimodal membrane distribution pattern were similar to what was observed in healthy neutrophils. However, following cell activation, there was no significant increase in the total amount of PR3m on PLS neutrophils, whereas the total amount of PR3m on healthy neutrophils was significantly increased. We then explored the effect of pharmacological CatC inhibition on PR3 stability in normal neutrophils using a potent cell-permeable CatC inhibitor and a CD34+ hematopoietic stem cell model. Human CD34+ hematopoietic stem cells were treated with the inhibitor during neutrophil differentiation over 10 days. We observed strong reductions in PR3m, cellular PR3 protein, and proteolytic PR3 activity, whereas neutrophil differentiation was not compromised.
- Published
- 2018
11. Therapeutic targeting of cathepsin C: from pathophysiology to treatment
- Author
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Korkmaz, Brice, primary, Caughey, George H., additional, Chapple, Iain, additional, Gauthier, Francis, additional, Hirschfeld, Josefine, additional, Jenne, Dieter E., additional, Kettritz, Ralph, additional, Lalmanach, Gilles, additional, Lamort, Anne-Sophie, additional, Lauritzen, Conni, additional, Łȩgowska, Monika, additional, Lesner, Adam, additional, Marchand-Adam, Sylvain, additional, McKaig, Sarah J., additional, Moss, Celia, additional, Pedersen, John, additional, Roberts, Helen, additional, Schreiber, Adrian, additional, Seren, Seda, additional, and Thakker, Nalin S., additional
- Published
- 2018
- Full Text
- View/download PDF
12. Human proteinase 3 resistance to inhibition extends to alpha‐2 macroglobulin.
- Author
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N'Guessan, Koffi, Grzywa, Renata, Seren, Seda, Gabant, Guillaume, Juliano, Maria A., Moniatte, Marc, Dorsselaer, Alain, Bieth, Joseph G., Kellenberger, Christine, Gauthier, Francis, Wysocka, Magdalena, Lesner, Adam, Sienczyk, Marcin, Cadene, Martine, and Korkmaz, Brice
- Subjects
ELASTASES ,SERINE proteinases ,MASS spectrometry ,LEUCOCYTE elastase ,GRANULOMATOSIS with polyangiitis ,ENDOPEPTIDASES ,PROTEINASES ,PEPTIDASE - Abstract
Polymorphonuclear neutrophils contain at least four serine endopeptidases, namely neutrophil elastase (NE), proteinase 3 (PR3), cathepsin G (CatG), and NSP4, which contribute to the regulation of infection and of inflammatory processes. In physiological conditions, endogenous inhibitors including α2‐macroglobulin (α2‐M), serpins [α1‐proteinase inhibitor (α1‐PI)], monocyte neutrophil elastase inhibitor (MNEI), α1‐antichymotrypsin, and locally produced chelonianins (elafin, SLPI) control excessive proteolytic activity of neutrophilic serine proteinases. In contrast to human NE (hNE), hPR3 is weakly inhibited by α1‐PI and MNEI but not by SLPI. α2‐M is a large spectrum inhibitor that traps a variety of proteinases in response to cleavage(s) in its bait region. We report here that α2‐M was more rapidly processed by hNE than hPR3 or hCatG. This was confirmed by the observation that the association between α2‐M and hPR3 is governed by a kass in the ≤ 105 m−1·s−1 range. Since α2‐M‐trapped proteinases retain peptidase activity, we first predicted the putative cleavage sites within the α2‐M bait region (residues 690–728) using kinetic and molecular modeling approaches. We then identified by mass spectrum analysis the cleavage sites of hPR3 in a synthetic peptide spanning the 39‐residue bait region of α2‐M (39pep‐α2‐M). Since the 39pep‐α2‐M peptide and the corresponding bait area in the whole protein do not contain sequences with a high probability of specific cleavage by hPR3 and were indeed only slowly cleaved by hPR3, it can be concluded that α2‐M is a poor inhibitor of hPR3. The resistance of hPR3 to inhibition by endogenous inhibitors explains at least in part its role in tissue injury during chronic inflammatory diseases and its well‐recognized function of major target autoantigen in granulomatosis with polyangiitis. [ABSTRACT FROM AUTHOR]
- Published
- 2020
- Full Text
- View/download PDF
13. Pharmacological Cathepsin C Inactivation Eliminates Proteinase 3, the Antigen in Autoimmune Vasculitis
- Author
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seren, seda, primary, Dallet‐Choisy, Sandrine, additional, Marchand‐Adam, Sylvain, additional, and Korkmaz, Brice, additional
- Published
- 2018
- Full Text
- View/download PDF
14. Constitutive and induced forms of membrane-bound proteinase 3 interact with antineutrophil cytoplasmic antibodies and promote immune activation of neutrophils.
- Author
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Carla Guarino, Seren S, Lemoine R, Hummel AM, Margotin JE, El-Benna J, Hoarau C, Specks U, Jenne DE, and Korkmaz B
- Subjects
- Animals, Humans, Mice, Neutrophils metabolism, Protease Inhibitors metabolism, Superoxides metabolism, Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis metabolism, Antibodies, Antineutrophil Cytoplasmic, Myeloblastin immunology, Myeloblastin metabolism
- Abstract
Proteinase 3 (PR3) is the main target antigen of antineutrophil cytoplasmic antibodies (ANCAs) in PR3-ANCA-associated vasculitis. A small fraction of PR3 is constitutively exposed on the surface of quiescent blood neutrophils in a proteolytically inactive form. When activated, neutrophils expose an induced form of membrane-bound PR3 (PR3
mb ) on their surface as well, which is enzymatically less active than unbound PR3 in solution due to its altered conformation. In this work, our objective was to understand the respective role of constitutive and induced PR3mb in the immune activation of neutrophils triggered by murine anti-PR3 mAbs and human PR3-ANCA. We quantified immune activation of neutrophils by the measurement of the production of superoxide anions and secreted protease activity in the cell supernatant before and after treatment of the cells by alpha-1 protease inhibitor that clears induced PR3mb from the cell surface. Incubation of TNFα-primed neutrophils with anti-PR3 antibodies resulted in a significant increase in superoxide anion production, membrane activation marker exposition, and secreted protease activity. When primed neutrophils were first treated with alpha-1 protease inhibitor, we observed a partial reduction in antibody-induced neutrophil activation, suggesting that constitutive PR3mb is sufficient to activate neutrophils. The pretreatment of primed neutrophils with purified antigen-binding fragments used as competitor significantly reduced cell activation by whole antibodies. This led us to the conclusion that PR3mb promoted immune activation of neutrophils. We propose that blocking and/or elimination of PR3mb offers a new therapeutic strategy to attenuate neutrophil activation in patients with PR3-ANCA-associated vasculitis., Competing Interests: Conflict of interest The authors declare that they have no conflicts of interest with the contents of this article., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)- Published
- 2023
- Full Text
- View/download PDF
15. Consequences of cathepsin C inactivation for membrane exposure of proteinase 3, the target antigen in autoimmune vasculitis.
- Author
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Seren S, Rashed Abouzaid M, Eulenberg-Gustavus C, Hirschfeld J, Nasr Soliman H, Jerke U, N'Guessan K, Dallet-Choisy S, Lesner A, Lauritzen C, Schacher B, Eickholz P, Nagy N, Szell M, Croix C, Viaud-Massuard MC, Al Farraj Aldosari A, Ragunatha S, Ibrahim Mostafa M, Giampieri F, Battino M, Cornillier H, Lorette G, Stephan JL, Goizet C, Pedersen J, Gauthier F, Jenne DE, Marchand-Adam S, Chapple IL, Kettritz R, and Korkmaz B
- Subjects
- Adolescent, Adult, Case-Control Studies, Child, Child, Preschool, Female, Granulomatosis with Polyangiitis drug therapy, Granulomatosis with Polyangiitis genetics, Granulomatosis with Polyangiitis metabolism, Humans, Male, Myeloblastin genetics, Neutrophils enzymology, Proteolysis, Young Adult, Cathepsin C antagonists & inhibitors, Cell Membrane metabolism, Cysteine Proteinase Inhibitors pharmacology, Granulomatosis with Polyangiitis pathology, Myeloblastin metabolism
- Abstract
Membrane-bound proteinase 3 (PR3
m ) is the main target antigen of anti-neutrophil cytoplasmic autoantibodies (ANCA) in granulomatosis with polyangiitis, a systemic small-vessel vasculitis. Binding of ANCA to PR3m triggers neutrophil activation with the secretion of enzymatically active PR3 and related neutrophil serine proteases, thereby contributing to vascular damage. PR3 and related proteases are activated from pro-forms by the lysosomal cysteine protease cathepsin C (CatC) during neutrophil maturation. We hypothesized that pharmacological inhibition of CatC provides an effective measure to reduce PR3m and therefore has implications as a novel therapeutic approach in granulomatosis with polyangiitis. We first studied neutrophilic PR3 from 24 patients with Papillon-Lefèvre syndrome (PLS), a genetic form of CatC deficiency. PLS neutrophil lysates showed a largely reduced but still detectable (0.5-4%) PR3 activity when compared with healthy control cells. Despite extremely low levels of cellular PR3, the amount of constitutive PR3m expressed on the surface of quiescent neutrophils and the typical bimodal membrane distribution pattern were similar to what was observed in healthy neutrophils. However, following cell activation, there was no significant increase in the total amount of PR3m on PLS neutrophils, whereas the total amount of PR3m on healthy neutrophils was significantly increased. We then explored the effect of pharmacological CatC inhibition on PR3 stability in normal neutrophils using a potent cell-permeable CatC inhibitor and a CD34+ hematopoietic stem cell model. Human CD34+ hematopoietic stem cells were treated with the inhibitor during neutrophil differentiation over 10 days. We observed strong reductions in PR3m , cellular PR3 protein, and proteolytic PR3 activity, whereas neutrophil differentiation was not compromised., (© 2018 Seren et al.)- Published
- 2018
- Full Text
- View/download PDF
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