Factor I co-factor activity of CR1 overcomes the protective effect of IgG on covalently bound C3b residues.
We have shown previously that C3b resides in a protected site when it is covalently bound to IgG (C3b-IgG). Such C3b displays a reduced affinity for factor H, with consequent enhanced survival in the presence of factors H and I and increased capacity for promoting alternative pathway consumption of C3. Because erythrocyte CR1 may be a major co-factor for factor I-mediated inactivation of immune complex-borne C3b in blood, we have examined the effect of covalently bound IgG on the C3b-CR1 interaction. Binding of monomeric C3b and C3b-IgG to human erythrocyte CR1 demonstrates identical ionic strength dependence for both species. Identical numbers of binding sites with indistinguishable affinities are detected by both ligands. Cleavage of the alpha'-chain of C3b and the alpha'-heavy chain of C3b-IgG proceeds at the same rate when erythrocyte CR1 serves as co-factor for factor I. Unlike factor H, CR1 supports a second cleavage of fluid-phase iC3b alpha'1 chain (free or bound to IgG) that generates C3c and a 33,000 m.w. fragment, which bears antigenic markers characteristic of C3g. Inactivation of C3b and C3b-IgG by CR1 and factor I also occurs at physiologic ionic strength, but proceeds very slowly relative to rates attainable with sub-physiologic inputs of factor H. CR1 does not recognize IgG-bound C3b as being in a protected site but, because of low binding affinity at physiologic ionic strength, is probably highly dependent on multivalent ligand-receptor interactions to efficiently exert its co-factor functions. Thus, inactivation of C3b-IgG heterodimers or small immune complexes bearing limited numbers of C3b residues may remain largely factor H-dependent in vivo, with resultant enhanced C3b survival.
Fries
L F
LF
Prince
G M
GM
Gaither
T A
TA
Frank
M M
MM
D000936:Antigen-Antibody Complex / Q000378:metabolism; D001665:Binding Sites; D003179:Complement C3b / Q000378:metabolism*; D003180:Complement C3b Inactivator Proteins / Q000378:metabolism* / Q000502:physiology; D017242:Complement Factor H; D017244:Complement Factor I; D010450:Endopeptidases / Q000378:metabolism / Q000502:physiology*; D004912:Erythrocytes / Q000378:metabolism; D006801:Humans; D007074:Immunoglobulin G / Q000378:metabolism / Q000502:physiology*; D007700:Kinetics; D009994:Osmolar Concentration; D011951:Receptors, Complement / Q000378:metabolism*; D017463:Receptors, Complement 3b
D000936:Antigen-Antibody Complex; C493495:CFH protein, human; D003180:Complement C3b Inactivator Proteins; D007074:Immunoglobulin G; D011951:Receptors, Complement; D017463:Receptors, Complement 3b; D003179:Complement C3b; D017242:Complement Factor H; D010450:Endopeptidases; D017244:Complement Factor I