Abstract
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.
Highlights
C3dg adducts of Ag can coligate complement receptor type 2 (CR2; CD21) and the B cell Ag receptor
C3dg is a ligand for complement receptor 2 (CR2)3 (CD21) on the B cell surface, and CR2-C3dg interaction greatly amplifies signals elicited by the binding of a C3dg-attached Ag with its specific BCR [11, 12]
Similar to other well-established murine models of B cell anergy such as HyHEL [15], Ars/A1 B cells that reach later transitional stages are capable of binding Ag; their receptors fail to transduce proximal biochemical signaling events as indicated by intracellular Ca2ϩ mobilization or tyrosine phosphorylation
Summary
C3dg adducts of Ag can coligate complement receptor type 2 (CR2; CD21) and the B cell Ag receptor. The Ars/A1 murine model of B cell anergy offers an optimal setting in which to study the effects of complement-mediated signaling in anergic B cells [14]. In this report we describe the ability of C3dg augmentation of BCR signals to overcome proximal inhibitory mechanisms responsible for the Ag unresponsiveness of anergic B cells.
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