Immune complex-mediated co-ligation of the BCR with FcγRIIB results in homeostatic apoptosis of B cells involving Fas signalling that is defective in the MRL/Lpr model of systemic lupus erythematosus

Paunovic, V., Carter, N. A., Thalhamer, T., Blair, D., Gordon, B., Lacey, E., Michie, A. M. and Harnett, M. M. (2012) Immune complex-mediated co-ligation of the BCR with FcγRIIB results in homeostatic apoptosis of B cells involving Fas signalling that is defective in the MRL/Lpr model of systemic lupus erythematosus. Journal of Autoimmunity, 39(4), pp. 332-346. (doi:10.1016/j.jaut.2012.04.006)

[img]
Preview
Text
75658.pdf - Accepted Version

1MB

Publisher's URL: http://dx.doi.org/10.1016/j.jaut.2012.04.006

Abstract

Negative regulation of B cell activation by cognate immune complexes plays an important homeostatic role in suppressing B cell hyperactivity and preventing consequent autoimmunity. Immune complexes co-ligate the BCR and FcγRIIB resulting in both growth arrest and apoptosis. We now show that such apoptotic signalling involves induction and activation of p53 and its target genes, the pro-apoptotic Bcl-2 family members, Bad and Bid, as well as nuclear export of p53. Collectively, these events result in destabilisation of the mitochondrial and lysosomal compartments with consequent activation and interplay of executioner caspases and endosomal-derived proteases. In addition, the upregulation of Fas and FasL with consequent activation of caspase 8-dependent death receptor signalling is required to facilitate efficient apoptosis of B cells. Consistent with this role for Fas death receptor signalling, apoptosis resulting from co-ligation of the BCR and FcγRIIB is defective in B cells from Fas-deficient MRL/MpJ-Faslpr mice. As these mice develop spontaneous, immune complex-driven lupus-like glomerulonephritis, targeting this FcγRIIB-mediated apoptotic pathway may therefore have novel therapeutic implications for systemic autoimmune disease.

Item Type:Articles
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Harnett, Professor Margaret and Michie, Dr Alison and Paunovic, Dr Verica and Lacey, Ms Erica
Authors: Paunovic, V., Carter, N. A., Thalhamer, T., Blair, D., Gordon, B., Lacey, E., Michie, A. M., and Harnett, M. M.
College/School:College of Medical Veterinary and Life Sciences > Institute of Cancer Sciences
College of Medical Veterinary and Life Sciences > Institute of Infection Immunity and Inflammation
Journal Name:Journal of Autoimmunity
Publisher:Elsevier
ISSN:0896-8411
ISSN (Online):1095-9157
Published Online:28 May 2012
Copyright Holders:Copyright © 2012 Elsevier
First Published:First published in Journal of Autoimmunity 39(04):332-346
Publisher Policy:Reproduced in accordance with the copyright policy of the publisher.
Related URLs:

University Staff: Request a correction | Enlighten Editors: Update this record

Project CodeAward NoProject NamePrincipal InvestigatorFunder's NameFunder RefLead Dept
480081Unique ErkMAPkinase checkpoint signatures drive differential responses during the immature-mature B cell transition?Margaret HarnettMedical Research Council (MRC)G0800167III -IMMUNOLOGY