Cutting edge: Complement (C3d)-linked antigens break B cell anergy.
C3dg adducts of Ag can coligate complement receptor type 2 (CR2; CD21) and the B cell Ag receptor. This interaction significantly amplifies BCR-mediated signals in Ag-naive wild-type mice, lowering the threshold for B cell activation and the generation of humoral immune responses as much as 1000-fold. In this study we demonstrate that CR2-mediated complementation of BCR signals can also overcome B cell anergy. Unlike Ag alone, BCR/CR2 costimulation (Ars-CCG/C3dg complexes) of anergic Ars/A1 B cells led to Ca(2+) mobilization in vitro and the production of autoantibodies in vivo. Interestingly, the in vivo immune response of anergic cells occurs without the formation of germinal centers. These results suggest that the Ag unresponsiveness of anergic B cells can be overcome by cross-reactive (self-mimicking) Ags that have been complement-opsonized. This mechanism may place individuals exposed to complement-fixing bacteria at risk for autoimmunity.
Lyubchenko
Taras
T
Division of Rheumatology, Department of Medicine, University of Colorado School of Medicine, Denver, CO 802602, USA.
Dal Porto
Joseph M
JM
Holers
V Michael
VM
Cambier
John C
JC
D000818:Animals; D000941:Antigens / Q000276:immunology / Q000494:pharmacology; D001323:Autoantibodies / Q000276:immunology*; D001402:B-Lymphocytes / Q000187:drug effects / Q000276:immunology*; D002118:Calcium / Q000378:metabolism; D017635:Clonal Anergy / Q000187:drug effects / Q000276:immunology*; D003179:Complement C3b / Q000276:immunology* / Q000494:pharmacology; D003429:Cross Reactions; D051379:Mice; D008810:Mice, Inbred C57BL; D010446:Peptide Fragments / Q000276:immunology* / Q000494:pharmacology; D011947:Receptors, Antigen, B-Cell / Q000819:agonists / Q000276:immunology; D017464:Receptors, Complement 3d / Q000819:agonists* / Q000276:immunology
D000941:Antigens; D001323:Autoantibodies; D010446:Peptide Fragments; D011947:Receptors, Antigen, B-Cell; D017464:Receptors, Complement 3d; C045477:complement C3d,g; D003179:Complement C3b; D002118:Calcium