Role of complement-binding CD21/CD19/CD81 in enhancing human B cell protection from Fas-mediated apoptosis.
Defective expression of Fas leads to B cell autoimmunity, indicating the importance of this apoptotic pathway in eliminating autoreactive B cells. However, B cells with anti-self specificities occasionally escape such regulation in individuals with intact Fas, suggesting ways of precluding this apoptosis. Here, we examine whether coligation of the B cell Ag receptor (BCR) with the complement (C3)-binding CD21/CD19/CD81 costimulatory complex can enhance the escape of human B cells from Fas-induced death. This was warranted given that BCR-initiated signals induce resistance to Fas apoptosis, some (albeit not all) BCR-triggered events are amplified by coligation of BCR and the co-stimulatory complex, and several self Ags targeted in autoimmune diseases effectively activate complement. Using a set of affinity-diverse surrogate Ags (receptor-specific mAb:dextran conjugates) with varying capacity to engage CD21, it was established that BCR:CD21 coligation lowers the BCR engagement necessary for inducing protection from Fas apoptosis. Enhanced protection was associated with altered expression of several molecules known to regulate Fas apoptosis, suggesting a unique molecular model for how BCR:CD21 coligation augments protection. BCR:CD21 coligation impairs the generation of active fragments of caspase-8 via dampened expression of membrane Fas and augmented expression of FLIP(L). This, in turn, diminishes the generation of cells that would be directly triggered to apoptosis via caspase-8 cleavage of caspase 3 (type I cells). Any attempt to use the mitochondrial apoptotic protease-activating factor 1 (Apaf-1)-dependent pathway for apoptosis (as type II cells) is further blocked because BCR:CD21 coligation promotes up-regulation of the mitochondrial antiapoptotic molecule, Bcl-2.
Mongini
Patricia K A
PK
Department of Rheumatology, Hospital for Joint Diseases, New York, NY 10003, USA. patricia.mongini@med.nyu.edu
Jackson
Anna E
AE
Tolani
Sonia
S
Fattah
Rasem J
RJ
Inman
John K
JK
D048868:Adaptor Proteins, Signal Transducing; D000276:Adjuvants, Immunologic / Q000378:metabolism / Q000502:physiology*; D000293:Adolescent; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D015703:Antigens, CD / Q000378:metabolism / Q000502:physiology*; D018941:Antigens, CD19 / Q000378:metabolism / Q000502:physiology*; D017209:Apoptosis / Q000276:immunology*; D051017:Apoptosis Regulatory Proteins; D001402:B-Lymphocytes / Q000166:cytology / Q000276:immunology* / Q000378:metabolism; D001665:Binding Sites / Q000276:immunology; D019013:CD40 Antigens / Q000494:pharmacology; D023201:CD40 Ligand / Q000494:pharmacology; D002352:Carrier Proteins / Q000096:biosynthesis; D053181:Caspase 8; D020169:Caspases / Q000096:biosynthesis / Q000378:metabolism; D002470:Cell Survival / Q000276:immunology; D002478:Cells, Cultured; D002648:Child; D002675:Child, Preschool; D056970:Co-Repressor Proteins; D003176:Complement C3 / Q000378:metabolism*; D053938:DNA Fragmentation / Q000276:immunology; D053222:Fas Ligand Protein; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D008024:Ligands; D046911:Macromolecular Substances; D008562:Membrane Glycoproteins / Q000096:biosynthesis / Q000378:metabolism; D008565:Membrane Proteins / Q000378:metabolism / Q000502:physiology*; D018832:Molecular Chaperones; D009687:Nuclear Proteins / Q000096:biosynthesis; D011485:Protein Binding / Q000276:immunology; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000096:biosynthesis; D011947:Receptors, Antigen, B-Cell / Q000378:metabolism; D017464:Receptors, Complement 3d / Q000378:metabolism / Q000502:physiology*; D053221:TNF-Related Apoptosis-Inducing Ligand; D060225:Tetraspanin 28; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis; D051020:bcl-X Protein; D019014:fas Receptor / Q000096:biosynthesis / Q000276:immunology / Q000378:metabolism / Q000502:physiology*
D048868:Adaptor Proteins, Signal Transducing; D000276:Adjuvants, Immunologic; D000911:Antibodies, Monoclonal; D015703:Antigens, CD; D018941:Antigens, CD19; D051017:Apoptosis Regulatory Proteins; C494811:BCL2L1 protein, human; D019013:CD40 Antigens; C554798:CD81 protein, human; D002352:Carrier Proteins; D056970:Co-Repressor Proteins; D003176:Complement C3; C106985:DAXX protein, human; C505661:FASLG protein, human; D053222:Fas Ligand Protein; D047908:Intracellular Signaling Peptides and Proteins; D008024:Ligands; D046911:Macromolecular Substances; D008562:Membrane Glycoproteins; D008565:Membrane Proteins; D018832:Molecular Chaperones; D009687:Nuclear Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D011947:Receptors, Antigen, B-Cell; D017464:Receptors, Complement 3d; D053221:TNF-Related Apoptosis-Inducing Ligand; C505653:TNFSF10 protein, human; D060225:Tetraspanin 28; D014409:Tumor Necrosis Factor-alpha; D051020:bcl-X Protein; D019014:fas Receptor; D023201:CD40 Ligand; C505530:CASP8 protein, human; D053181:Caspase 8; D020169:Caspases