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.
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-Fas(lpr) 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.
Institute of Infection, Immunity and Inflammation, University of Glasgow, Glasgow G12 8TA, UK.
Verica
V
Paunovic
Natalie A
NA
Carter
Theresa
T
Thalhamer
Derek
D
Blair
Brian
B
Gordon
Erica
E
Lacey
Alison M
AM
Michie
Margaret M
MM
Harnett
D000818:Animals; D000936:Antigen-Antibody Complex / Q000235:genetics / Q000276:immunology*; D017209:Apoptosis; D001402:B-Lymphocytes / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D051023:BH3 Interacting Domain Death Agonist Protein / Q000235:genetics / Q000276:immunology; D053181:Caspase 8 / Q000235:genetics / Q000276:immunology; D004195:Disease Models, Animal; D053222:Fas Ligand Protein / Q000235:genetics / Q000276:immunology; D005786:Gene Expression Regulation / Q000276:immunology; D006801:Humans; D008181:Lupus Nephritis / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D008247:Lysosomes / Q000276:immunology / Q000473:pathology; D008297:Male; D051379:Mice; D019463:Mice, Inbred MRL lpr; D018345:Mice, Knockout; D008928:Mitochondria / Q000276:immunology / Q000473:pathology; D011947:Receptors, Antigen, B-Cell / Q000235:genetics / Q000276:immunology*; D017452:Receptors, IgG / Q000235:genetics / Q000276:immunology*; D015398:Signal Transduction / Q000235:genetics / Q000276:immunology; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000276:immunology; D051025:bcl-Associated Death Protein / Q000235:genetics / Q000276:immunology; D019014:fas Receptor / Q000235:genetics / Q000276:immunology*
D000936:Antigen-Antibody Complex; D051023:BH3 Interacting Domain Death Agonist Protein; C494820:Bad protein, mouse; C494815:Bid protein, mouse; D053222:Fas Ligand Protein; C491899:Fas protein, mouse; C505658:Fasl protein, mouse; C499172:Fcgr2b protein, mouse; D011947:Receptors, Antigen, B-Cell; D017452:Receptors, IgG; D016159:Tumor Suppressor Protein p53; D051025:bcl-Associated Death Protein; D019014:fas Receptor; D053181:Caspase 8