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Circulating autoreactive proteinase 3(+) B cells and tolerance checkpoints in ANCA-associated vasculitis

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...

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Detalles Bibliográficos
Autores principales: Berti, Alvise, Hillion, Sophie, Hummel, Amber M., Son, Young Min, Chriti, Nedra, Peikert, Tobias, Carmona, Eva M., Abdulahad, Wayel H., Heeringa, Peter, Harris, Kristina M., St. Clair, E. William, Brunetta, Paul, Fervenza, Fernando C., Langford, Carol A., Kallenberg, Cees G.M., Merkel, Peter A., Monach, Paul A., Seo, Philip, Spiera, Robert F., Stone, John H., Grandi, Guido, Sun, Jie, Pers, Jacques-Olivier, Specks, Ulrich, Cornec, Divi
Formato: Online Artículo Texto
Lenguaje:English
Publicado: American Society for Clinical Investigation 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8663783/
https://www.ncbi.nlm.nih.gov/pubmed/34618687
http://dx.doi.org/10.1172/jci.insight.150999
Descripción
Sumario: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.