Citations 1
Circulating autoreactive proteinase 3+ B cells and tolerance checkpoints in ANCA-associated vasculitis
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. , Clair, E. William St. , Brunetta, Paul , Langford, Carol A. , Kallenberg, Cees G. M., Stone, John H. , Grandi, Guido , Cornec, Divi, Carmona, Eva M , Berti, Alvise , Fervenza, Fernando C. , Merkel, Peter A. , Monach, Paul A. , Seo, Philip , Spiera, Robert , Sun, Jie , Pers, Jacques-Olivier , Specks, Ulrich , Cornec, Divi
JCI Insight | October 7, 2021 | Volume: 6 | Issue: 22 | Pages: No page available
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.