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Circulating autoreactive proteinase 3(+) B cells and tolerance checkpoints in ANCA-associated vasculitis
- Source :
- JCI Insight, 6(22):150999. AMER SOC CLINICAL INVESTIGATION INC, JCI Insight
- Publication Year :
- 2021
- Publisher :
- AMER SOC CLINICAL INVESTIGATION INC, 2021.
-
Abstract
- BACKGROUND Little is known about the autoreactive B cells in antineutrophil cytoplasmic antibody–associated (ANCA-associated) vasculitis (AAV). We aimed to investigate tolerance checkpoints of circulating antigen-specific proteinase 3–reactive (PR3+) B cells. METHODS Multicolor flow cytometry in combination with bioinformatics and functional in vitro studies were performed on baseline samples of PBMCs from 154 well-characterized participants of the RAVE trial (NCT00104299) with severely active PR3-AAV and myeloperoxidase-AAV (MPO-AAV) and 27 healthy controls (HCs). Clinical data and outcomes from the trial were correlated with PR3+ B cells (total and subsets). RESULTS The frequency of PR3+ B cells among circulating B cells was higher in participants with PR3-AAV (4.77% median [IQR, 3.98%–6.01%]) than in participants with MPO-AAV (3.16% median [IQR, 2.51%–5.22%]) and participants with AAV compared with HCs (1.67% median [IQR, 1.27%–2.16%], P < 0.001 for all comparisons), implying a defective central tolerance checkpoint in patients with AAV. Only PBMCs from participants with PR3-AAV contained PR3+ B cells capable of secreting PR3-ANCA IgG in vitro, proving they were functionally distinct from those of participants with MPO-AAV and HCs. Unsupervised clustering identified subtle subsets of atypical autoreactive PR3+ memory B cells accumulating through the maturation process in patients with PR3-AAV. PR3+ B cells were enriched in the memory B cell compartment of participants with PR3-AAV and were associated with higher serum CXCL13 levels, suggesting an increased germinal center activity. PR3+ B cells correlated with systemic inflammation (C-reactive protein and erythrocyte sedimentation rate, P < 0.05) and complete remission (P < 0.001). CONCLUSION This study suggests the presence of defective central antigen-independent and peripheral antigen-dependent checkpoints in patients with PR3-AAV, elucidating the selection process of autoreactive B cells. Trial registration ClinicalTrials.gov NCT00104299. Funding The Vasculitis Foundation, the National Institute of Allergy and Infectious Diseases of the NIH, and the Mayo Foundation for Education and Research.
- Subjects :
- Male
Vasculitis
Autoimmune diseases
Immunology
BIOMARKERS
Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis
Autoimmunity
medicine.disease_cause
Peripheral blood mononuclear cell
Flow cytometry
ACTIVATION
WEGENERS-GRANULOMATOSIS
Double-Blind Method
Memory B Cells
Proteinase 3
Medicine
Humans
cardiovascular diseases
RITUXIMAB
SPECIFICITY
biology
medicine.diagnostic_test
business.industry
RECOGNITION
MYELOPEROXIDASE
General Medicine
medicine.disease
Flow Cytometry
PR3
In vitro
Peripheral
Myeloperoxidase
ANTIBODIES
biology.protein
Female
AUTOANTIBODIES
Clinical Medicine
business
Peptide Hydrolases
Subjects
Details
- Language :
- English
- ISSN :
- 23793708 and 00104299
- Volume :
- 6
- Issue :
- 22
- Database :
- OpenAIRE
- Journal :
- JCI Insight
- Accession number :
- edsair.doi.dedup.....4ac6ce95d3a976110d1a0de400e51e18