High doses of immunoglobulin G attenuate immune aggregate-mediated complement activation by enhancing physiologic cleavage of C3b in C3bn-IgG complexes.
Intravenously applied human IgG has beneficial effects in treating inflammatory diseases, presumably because it has a complement attenuating role. This role of IgG was studied in vitro by following C3 activation and inactivation in sera that were supplemented with exogenous human IgG and incubated with immune aggregates. IgG added at 2 to 10 mg/mL stimulated the physiologic inactivation of C3b-containing complexes twofold to threefold in 20% sera. This, in turn, lowered the overall C3 activation by 28%, as new C3 convertases primarily assembled on C3b-containing complexes. Exogenous IgG (5 mg/mL) also stimulated inactivation of purified C3b2-IgG complexes, whereby their half-life dropped from 3-4 to 1.5 minutes in 20% serum. IgG appeared to act like a modulator of factor H and I because it did not stimulate inactivation of C3b-containing complexes in factor I-deficient serum. Thus, the known partial protection of C3bn-IgG complexes from inactivation by factor H and I was downregulated by high concentrations of IgG. The ability of high doses of IgG to stimulate complement inactivation is a novel regulatory role of IgG. This may be one of the molecular principles for its therapeutic efficacy in treating complement-mediated inflammations.
Lutz
H U
HU
Laboratory for Biochemistry, Swiss Federal Institute of Technology, ETH-Zentrum, Zurich, Switzerland.
Stammler
P
P
Jelezarova
E
E
Nater
M
M
Späth
P J
PJ
D000936:Antigen-Antibody Complex / Q000276:immunology* / Q000378:metabolism; D001667:Binding, Competitive; D003167:Complement Activation / Q000187:drug effects*; D003179:Complement C3b / Q000378:metabolism*; D017242:Complement Factor H / Q000378:metabolism; D017244:Complement Factor I / Q000378:metabolism; D015180:Electrophoresis, Gel, Two-Dimensional; D006207:Half-Life; D006801:Humans; D007074:Immunoglobulin G / Q000008:administration & dosage / Q000378:metabolism / Q000494:pharmacology*; D007249:Inflammation / Q000276:immunology; D046911:Macromolecular Substances
D000936:Antigen-Antibody Complex; C493495:CFH protein, human; D007074:Immunoglobulin G; D046911:Macromolecular Substances; D003179:Complement C3b; D017242:Complement Factor H; D017244:Complement Factor I