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)
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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 |
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Status: | Published |
Refereed: | Yes |
Glasgow Author(s) Enlighten ID: | Harnett, Professor Margaret and Michie, Professor 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 > School of Cancer Sciences College of Medical Veterinary and Life Sciences > School of Infection & Immunity |
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. |
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