B cell resistance to Fas-mediated apoptosis contributes to their ineffective control by regulatory T cells in rheumatoid arthritis

• Published in: Annals of the rheumatic diseases Vol. 74; no. 1; pp. 294 - 302
• Main Authors: Rapetti, Laetitia, Chavele, Konstantia-Maria, Evans, Catherine M, Ehrenstein, Michael R
• Format: Journal Article
• Language: English
• Published: United States Elsevier Limited 01.01.2015
• Subjects: Apoptosis - physiology; Arthritis, Rheumatoid - immunology; B-Lymphocytes - immunology; B-Lymphocytes - metabolism; Case-Control Studies; Colleges & universities; fas Receptor - metabolism; Female; Flow Cytometry; Humans; Leukocytes, Mononuclear - immunology; Lymphocyte Activation - immunology; Lymphocyte receptors; Male; Rheumatoid arthritis; Rodents; T cell receptors; T-Lymphocytes, Regulatory - immunology; Autoimmunity; T Cells; B cells; Rheumatoid Arthritis
• ISSN: 0003-4967; 1468-2060; 1468-2060
• DOI: 10.1136/annrheumdis-2013-204049

Objective To investigate whether regulatory T cells (Treg) can control B cell function in rheumatoid arthritis (RA) and if not to explore the basis for this defect. Methods Suppression of B cell responses by Treg was analysed in vitro by flow cytometry and ELISA using peripheral blood mononuclear cells from 65 patients with RA and 41 sex-matched and aged-matched healthy volunteers. Blocking and agonistic antibodies were used to define the role of Fas-mediated apoptosis in B cell regulation. Results Treg failed to restrain B cell activation, proinflammatory cytokine and antibody production in the presence of responder T cells in RA patients. This lack of suppression was not only caused by impaired Treg function but was also due to B cell resistance to regulation. In healthy donors, control by Treg was associated with increased B cell death and relied upon Fas-mediated apoptosis. In contrast, RA B cells had reduced Fas expression compared with their healthy counterparts and were resistant to Fas-mediated apoptosis. Conclusions These studies demonstrate that Treg are unable to limit B cell responses in RA. This appears to be primarily due to B cell resistance to suppression, but Treg defects also contribute to this failure of regulation. Our data identify the Fas pathway as a novel target for Treg-mediated suppression of B cells and highlight a potential therapeutic approach to restore control of B cells by Treg in RA patients.