OBJECTIVE: Anti-citrullinated protein antibodies (ACPAs) are a hallmark of rheumatoid arthritis (RA). Aside from autoantibody production, the function of autoantigen-specific B cells remains poorly understood in the context of this disease. This study set out to elucidate autoantigen-specific B cell functions through the isolation and immortalization of unique citrullinated protein/peptide (CP)-reactive B cell clones from RA patients. METHODS: B cell clones from either the blood or synovial fluid of cyclic citrullinated peptide 2 (CCP2) antibody-positive RA patients were immortalized by genetic reprogramming with Bcl-6 and Bcl-xL. Enzyme-linked immunosorbent assay and flow cytometry were used to identify CCP2-reactive clones and to further characterize surface marker and cytokine expression as well as B cell receptor signaling competence. Global gene expression profiles were interrogated by RNA sequencing. RESULTS: Three unique CP-reactive memory B cell clones were generated from the blood or synovial fluid of 2 RA patients. CP-reactive memory B cells did not appear to be broadly cross-reactive, but rather had a fairly restricted epitope recognition profile. These clones were able to secrete both pro- and antiinflammatory cytokines and had a unique surface profile of costimulatory molecules and receptors, including CD40 and C5a receptor type 1, when compared to non-CP-reactive clones from the same patient. In addition, CP-reactive clones bound citrullinated protein, but not native protein, and could mobilize calcium in response to antigen binding. CONCLUSION: CP-reactive memory B cells comprise a rare, seemingly oligoclonal population with restricted epitope specificity and distinct phenotypic and molecular characteristics suggestive of antigen-presenting cells. Cloning by genetic reprogramming opens new avenues to study the function of autoreactive memory B cells, especially in terms of antigen processing, presentation, and subsequent T cell polarization.
OBJECTIVE: Anti-citrullinated protein antibodies (ACPAs) are a hallmark of rheumatoid arthritis (RA). Aside from autoantibody production, the function of autoantigen-specific B cells remains poorly understood in the context of this disease. This study set out to elucidate autoantigen-specific B cell functions through the isolation and immortalization of unique citrullinated protein/peptide (CP)-reactive B cell clones from RApatients. METHODS: B cell clones from either the blood or synovial fluid of cyclic citrullinated peptide 2 (CCP2) antibody-positive RApatients were immortalized by genetic reprogramming with Bcl-6 and Bcl-xL. Enzyme-linked immunosorbent assay and flow cytometry were used to identify CCP2-reactive clones and to further characterize surface marker and cytokine expression as well as B cell receptor signaling competence. Global gene expression profiles were interrogated by RNA sequencing. RESULTS: Three unique CP-reactive memory B cell clones were generated from the blood or synovial fluid of 2 RApatients. CP-reactive memory B cells did not appear to be broadly cross-reactive, but rather had a fairly restricted epitope recognition profile. These clones were able to secrete both pro- and antiinflammatory cytokines and had a unique surface profile of costimulatory molecules and receptors, including CD40 and C5a receptor type 1, when compared to non-CP-reactive clones from the same patient. In addition, CP-reactive clones bound citrullinated protein, but not native protein, and could mobilize calcium in response to antigen binding. CONCLUSION: CP-reactive memory B cells comprise a rare, seemingly oligoclonal population with restricted epitope specificity and distinct phenotypic and molecular characteristics suggestive of antigen-presenting cells. Cloning by genetic reprogramming opens new avenues to study the function of autoreactive memory B cells, especially in terms of antigen processing, presentation, and subsequent T cell polarization.
Authors: Hendy Kristyanto; Miles D Holborough-Kerkvliet; Lianne Lelieveldt; Yvonne Bartels; Roel Hammink; Karin A J van Schie; Rene E M Toes; Kimberly M Bonger; Hans Ulrich Scherer Journal: ACS Biomater Sci Eng Date: 2022-03-08
Authors: Uta Hardt; Konstantin Carlberg; Erik Af Klint; Peter Sahlström; Ludvig Larsson; Annika van Vollenhoven; Susana Hernandez Machado; Lena Israelsson; Khaled Amara; Karine Chemin; Marina Korotkova; Gunilla B Karlsson Hedestam; Anca I Catrina; Sarah A Teichmann; Patrik L Ståhl; Vivianne Malmström Journal: Sci Rep Date: 2022-07-13 Impact factor: 4.996
Authors: Caroline Grönwall; Lisa Liljefors; Holger Bang; Aase H Hensvold; Monika Hansson; Linda Mathsson-Alm; Lena Israelsson; Vijay Joshua; Anna Svärd; Ragnhild Stålesen; Philip J Titcombe; Johanna Steen; Luca Piccoli; Natalia Sherina; Cyril Clavel; Elisabet Svenungsson; Iva Gunnarsson; Saedis Saevarsdottir; Alf Kastbom; Guy Serre; Lars Alfredsson; Vivianne Malmström; Johan Rönnelid; Anca I Catrina; Karin Lundberg; Lars Klareskog Journal: Front Immunol Date: 2021-05-20 Impact factor: 7.561
Authors: Andrea Cossarizza; Hyun-Dong Chang; Andreas Radbruch; Andreas Acs; Dieter Adam; Sabine Adam-Klages; William W Agace; Nima Aghaeepour; Mübeccel Akdis; Matthieu Allez; Larissa Nogueira Almeida; Giorgia Alvisi; Graham Anderson; Immanuel Andrä; Francesco Annunziato; Achille Anselmo; Petra Bacher; Cosima T Baldari; Sudipto Bari; Vincenzo Barnaba; Joana Barros-Martins; Luca Battistini; Wolfgang Bauer; Sabine Baumgart; Nicole Baumgarth; Dirk Baumjohann; Bianka Baying; Mary Bebawy; Burkhard Becher; Wolfgang Beisker; Vladimir Benes; Rudi Beyaert; Alfonso Blanco; Dominic A Boardman; Christian Bogdan; Jessica G Borger; Giovanna Borsellino; Philip E Boulais; Jolene A Bradford; Dirk Brenner; Ryan R Brinkman; Anna E S Brooks; Dirk H Busch; Martin Büscher; Timothy P Bushnell; Federica Calzetti; Garth Cameron; Ilenia Cammarata; Xuetao Cao; Susanna L Cardell; Stefano Casola; Marco A Cassatella; Andrea Cavani; Antonio Celada; Lucienne Chatenoud; Pratip K Chattopadhyay; Sue Chow; Eleni Christakou; 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Authors: Yan Wang; Katy A Lloyd; Ioannis Melas; Diana Zhou; Radha Thyagarajan; Joakim Lindqvist; Monika Hansson; Anna Svärd; Linda Mathsson-Alm; Alf Kastbom; Karin Lundberg; Lars Klareskog; Anca I Catrina; Stephen Rapecki; Vivianne Malmström; Caroline Grönwall Journal: Sci Rep Date: 2019-12-27 Impact factor: 4.379