%0 Journal Article %T 4C3 Human Monoclonal Antibody: A Proof of Concept for Non-pathogenic Proteinase 3 Anti-neutrophil Cytoplasmic Antibodies in Granulomatosis With Polyangiitis %+ EA4245 - Transplantation, Immunologie, Inflammation [Tours] (T2i) %+ Infectiologie et Santé Publique (UMR ISP) %+ MAbSilico SAS %+ Dynamiques de populations multi-échelles pour des systèmes physiologiques (MUSCA) %+ Physiologie de la reproduction et des comportements [Nouzilly] (PRC) %+ Institut de Recherche en Cancérologie de Montpellier (IRCM - U1194 Inserm - UM) %+ Centre d’Etude des Pathologies Respiratoires (CEPR), UMR 1100 (CEPR) %+ Service de néphrologie et immunologie clinique [CHRU Tours] %+ Université de Tours (UT) %A Granel, Jérôme %A Lemoine, Roxane %A Morello, Eric %A Gallais, Yann %A Mariot, Julie %A Drapeau, Marion %A Musnier, Astrid %A Poupon, Anne %A Pugnière, Martine %A Seren, Seda %A Nouar, Dalila %A Gouilleux-Gruart, Valérie %A Watier, Herve %A Korkmaz, Brice %A Hoarau, Cyrille %Z Region Centre-Val-de-Loire (program Ambition Research and Development "Biopharmaceuticals"), University of Tours %< avec comité de lecture %Z MICA, BRMF %@ 1664-3224 %J Frontiers in Immunology %I Frontiers %V 11 %P 17 p. %8 2020-09-25 %D 2020 %R 10.3389/fimmu.2020.573040 %M 33101296 %K epitope %K granulomatosis with polyangiitis %K anti-neutrophil cytoplasmic antibodies %K proteinase 3 %K human neutrophils %K biologie computationnelle %Z Life Sciences [q-bio]Journal articles %X 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 %G English %2 https://cnrs.hal.science/hal-03039822/document %2 https://cnrs.hal.science/hal-03039822/file/granel2020.pdf %L hal-03039822 %U https://cnrs.hal.science/hal-03039822 %~ UNIV-TOURS %~ CNRS %~ INRIA %~ INRIA-SACLAY %~ INRIA_TEST %~ FNCLCC %~ VALDAURELLE %~ TESTALAIN1 %~ INRIA2 %~ UNIV-PARIS-SACLAY %~ BS %~ UNIV-MONTPELLIER %~ IRCM %~ INRAE %~ INRAE-UPSACLAY %~ ANR %~ GS-MATHEMATIQUES %~ GS-COMPUTER-SCIENCE %~ GS-BIOSPHERA %~ INFECTIOLOGIE-SANTE-PUBLIQUE %~ PRC %~ PHASE %~ MICA-UNITES %~ INRAEVALDELOIRE %~ CEPR %~ UM-2015-2021 %~ INRIAARTDOI %~ TEST3-HALCNRS %~ MATHNUM