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Complement receptor is an inhibitor of the complement cascade
Insights
Complement receptor 1 (CR1) on human erythrocytes inhibits both classical and alternative complement pathways. This glycoprotein protects cells from damage by preventing excessive complement activation when binding C3b- and C4b-coated substrates.
Area of Science:
- Immunology
- Complement System
- Cell Biology
Background:
- Complement receptor 1 (CR1) is a glycoprotein found on human erythrocytes.
- CR1 is known to bind C3b and C4b, mediating adherence of complement-opsonized particles.
- The complement system comprises classical and alternative pathways crucial for innate immunity.
Purpose of the Study:
- To investigate the inhibitory functions of CR1 beyond its role in adherence.
- To determine CR1's effect on complement convertases of both classical and alternative pathways.
- To elucidate CR1's mechanism in protecting cells from complement-mediated damage.
Main Methods:
- Biochemical assays to measure CR1's enzymatic inhibitory activity.
- Radioligand binding studies using 125I-CR1 to assess C4b interaction.
- Functional assays to evaluate CR1's cofactor activity in C4b cleavage.
Main Results:
- CR1 promotes dissociation of the alternative pathway C3 convertase (C3b,Bb) and C3b cleavage.
- CR1 inactivates classical pathway C3 (EAC142) and C5 convertases, inhibiting C3 consumption and enhancing C4b,2a decay.
- CR1 is a more potent inhibitor of C4b,2a than C4 binding protein and competes with C2 for binding to C4b.
Conclusions:
- CR1 acts as a potent inhibitor of complement cascade amplification enzymes on cell surfaces.
- CR1 provides a protective mechanism against complement-mediated cellular damage during substrate binding.
- CR1's dual role in adherence and inhibition highlights its importance in regulating complement activation.
Abstract:
A glycoprotein from the membrane of human erythrocytes has been identified as a receptor for C3b (CR1). It promotes the dissociation of the alternative pathway C3 convertase C3b,Bb and the cleavage of C3b by C3b/C4b inactivator. We find that CR1 also inactivates the C3 and C5 convertases of the classical pathway. CR1 inhibits the consumption of C3 by C3 convertase EAC142 and enhances the decay of C4b,2a sites. On a weight basis, CR1 is approximately 5-10 times more active than C4 binding protein, a serum inhibitor of C4b,2a. The binding of 125I-CR1 to EAC14 cells is inhibited by C2. Therefore, it is likely that CR1 and C2 compete for a site on C4b. CR1 inhibited C5 convertase even more effectively, but had no effect on the assembly of the late complement components. At high concentrations, CR1 alone has no irreversible effects on cell-bound C4b. In the fluid phase, CR1 can function as a cofactor for the cleavage of the alpha' chain of C4b by C3b/C4b inactivator. A well-known function of CR1 is to promote adherence of microbes or immune complexes bearing C3b and C4b to cells. This interaction could result in a microenvironment damaging to the plasma membrane of the responding cell because the extrinsic C3b and C4b fragments can serve as additional sites of assembly of enzymes of the cascade. We therefore wish to propose that CR1 on the surface of cells supplies an increased local concentration of a strong inhibitor of the amplifying enzymes of the complement system and provides cells with a mechanism for circumventing damage when they bind C3b- and C4b-bearing substrates.