Circulating autoreactive proteinase 3+ B cells and tolerance checkpoints in ANCA-associated vasculitis
Year: 2021
Type: article
Abstract: BACKGROUNDLittle 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.METHODSMulticolor 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).RESULTSThe 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).CONCLUSIONThis 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 registrationClinicalTrials.gov NCT00104299.FundingThe Vasculitis Foundation, the National Institute of Allergy and Infectious Diseases of the NIH, and the Mayo Foundation for Education and Research.
Source: JCI Insight
Authors: Alvise Berti, Sophie Hillion, Amber M. Hummel, Young Min Son, Nedra Chriti, Tobias Peikert, Eva M. Carmona, Wayel H. Abdulahad, Peter Heeringa, Kristina M. Harris, E. William St. Clair, Paul Brunetta, Fernando C. Fervenza, Carol A. Langford, Cees G.M. Kallenberg, Peter A. Merkel, Paul A. Monach, Philip Seo, Robert F. Spiera, John H. Stone, Guido Grandi, Jie Sun, Jacques-Olivier Pers, Ulrich Specks, Divi Cornec
Institutions: Mayo Clinic, University of Trento, Ospedale Santa Chiara, Inserm, Centre Hospitalier Régional Universitaire de Brest, University of Groningen, Immune Tolerance Network, Duke Medical Center, Genentech, Cleveland Clinic, University of Pennsylvania, Brigham and Women's Hospital, VA Boston Healthcare System, Johns Hopkins University, Hospital for Special Surgery, Massachusetts General Hospital
Language: English
Subfield: Pulmonary and Respiratory Medicine
Field: Medicine
Domain: Health Sciences
Open Access status: gold
Estimated APC paid: $4,100
Funders: Arthritis Foundation, Biogen, Mayo Foundation for Medical Education and Research, Vasculitis Foundation, Immune Tolerance Network, National Institutes of Health, Genentech, Vasculitis Clinical Research Consortium, National Institute of Allergy and Infectious Diseases, National Institute of Arthritis and Musculoskeletal and Skin Diseases
Awards: G210009881, Roles of tissue-resident helper T cells in mucosal immunity against influenzainfection, Immune tolerance network: liver transplantation, G4555365247, G482277048, IDENTIFICATION AND VALIDATION OF BIOMARKERS FOR VASCULITIS, G554752038, G6247097663, G6823653762, G7589514649, G8463206173, G9000035275, G9000057425, G9000284116, Host cellular network governing the development of post SARS-CoV-2 tissue sequelae
OpenAlex ID: W3204763137