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4C3 Human Monoclonal Antibody: A Proof of Concept for Non-pathogenic Proteinase 3 Anti-neutrophil Cytoplasmic Antibodies in Granulomatosis With Polyangiitis
- Source :
- Frontiers in Immunology, Frontiers in Immunology, Frontiers, 2020, 11, 17 p. ⟨10.3389/fimmu.2020.573040⟩, Frontiers in Immunology, 2020, 11, 17 p. ⟨10.3389/fimmu.2020.573040⟩
- Publication Year :
- 2020
- Publisher :
- Frontiers Media SA, 2020.
-
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
- 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
Subjects
Details
- Language :
- English
- ISSN :
- 16643224
- Volume :
- 11
- Database :
- OpenAIRE
- Journal :
- Frontiers in Immunology
- Accession number :
- edsair.pmid.dedup....b331ad503aa4d9bcf3a4796d1315143f
- Full Text :
- https://doi.org/10.3389/fimmu.2020.573040