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

Background Little is known about the autoreactive B cells in anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV). We aimed to investigate tolerance checkpoints of circulating antigen-specific proteinase 3 (PR3+) B cells. Methods Multicolor flow cytometry in combination with bioinformatics and functional in vitro studies were performed on baseline samples of peripheral blood mononuclear cells from 154 well-characterized participants of the RAVE trial (NCT00104299) with severely active PR3-AAV and myeloperoxidase (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 PR3-AAV (4.77% [3.98%-6.01%]), than in MPO-AAV (3.16% [2.51%-5.22%]), and in AAV compared to HCs (1.67% [1.27%-2.16%], p Conclusions This study suggests the presence of defective central antigen-independent and peripheral antigen-dependent checkpoints in patients in PR3-AAV, elucidating the selection process of autoreactive B cells.