| Added by | alainmange |
|---|---|
| Group name | PlateformePP2I |
| Item Type | Journal Article |
| Title | 4C3 Human Monoclonal Antibody: A Proof of Concept for Non-pathogenic Proteinase 3 Anti-neutrophil Cytoplasmic Antibodies in Granulomatosis With Polyangiitis |
| Creator | Granel et al. |
| Author | Jérôme Granel |
| Author | Roxane Lemoine |
| Author | Eric Morello |
| Author | Yann Gallais |
| Author | Julie Mariot |
| Author | Marion Drapeau |
| Author | Astrid Musnier |
| Author | Anne Poupon |
| Author | Martine Pugnière |
| Author | Seda Seren |
| Author | Dalila Nouar |
| Author | Valérie Gouilleux-Gruart |
| Author | Hervé Watier |
| Author | Brice Korkmaz |
| Author | Cyrille Hoarau |
| Abstract | 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 IgG1? anti-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 Fc?RIIA and Fc?RIIIB 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. |
| Publication | Frontiers in Immunology |
| Volume | 11 |
| Pages | 573040 |
| Date | 2020 |
| Journal Abbr | Front Immunol |
| Language | eng |
| DOI | 10.3389/fimmu.2020.573040 |
| ISSN | 1664-3224 |
| Short Title | 4C3 Human Monoclonal Antibody |
| Library Catalog | PubMed |
| Extra | 00000 PMID: 33101296 PMCID: PMC7546423 |
| Tags | anti-neutrophil cytoplasmic antibodies, author, epitope, granulomatosis with polyangiitis, human neutrophils, original, pp2i, proteinase 3 |
| Date Added | 2020/11/05 - 11:17:37 |
| Date Modified | 2021/01/06 - 16:41:27 |
| Notes and Attachments | PubMed entry (Attachment) |
Institut de Recherche en Cancérologie de
