Human F(ab')2-containing immune complexes together with anti-hinge natural antibodies stimulate complement amplification in vitro and in vivo.
The systemic inflammatory response syndrome (SIRS) is triggered by C5a generation following an excessive complement amplification, but it has remained unclear how complement amplification is stimulated. It is known that neutrophilic elastase can cleave IgG to F(ab')(2) and that F(ab')(2)-containing immune complexes (F(ab')(2)-IC) stimulate complement amplification together with an unidentified plasma factor. We show that absorption of plasma on F(ab')(2) from human IgG removed this factor and prevented F(ab')(2)-IC from stimulating complement amplification. The required factor was purified from pooled whole human IgG (IVIG) as those naturally occurring antibodies (NAbs) that bind to F(ab')(2), but not to intact IgG. These "anti-hinge NAbs" restored complement amplification by F(ab')(2)-IC in absorbed plasma. Anti-hinge NAbs must have formed secondary, rigidified IC from F(ab')(2)-IC, because the F(ab')(2) fragments evidently captured dimeric C3b, known as a potent C3 convertase precursor. This process may also stimulate complement amplification in vivo, because plasma from septic patients at the onset of SIRS indeed contained F(ab')(2) fragments. The concentrations of F(ab')(2) and that of factor Bb, an unbiased measure of complement amplification, correlated linearly with that of released elastase. Moreover, the F(ab')(2) fragments migrated on gelfiltration columns together with anti-hinge NAbs as ICs with MW of up to approximately 750kDa, as verified on plasma of each of the nine patients studied. These findings provide for the first time a plausible mechanism of how F(ab')(2)-containing immune complexes stimulate complement amplification together with anti-hinge NAbs. The same mechanism may contribute to complement overreaction at the onset of SIRS.
Fumia
Sandra
S
Institute of Biochemistry, ETH Zurich, Schafmattstrasse 18, Zurich, Switzerland.
Goede
Jeroen S
JS
Fischler
Manuel
M
Luginbühl
Alexander
A
Frick
Sonia
S
Fodor
Patricia
P
Lutz
Hans U
HU
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000906:Antibodies / Q000276:immunology*; D000936:Antigen-Antibody Complex / Q000276:immunology*; D003167:Complement Activation / Q000276:immunology*; D003179:Complement C3b / Q000276:immunology; D005260:Female; D006801:Humans; D007140:Immunoglobulin Fab Fragments / Q000097:blood / Q000276:immunology*; D008297:Male; D008875:Middle Aged; D018448:Models, Immunological; D008970:Molecular Weight; D010196:Pancreatic Elastase; D018746:Systemic Inflammatory Response Syndrome / Q000097:blood
D000906:Antibodies; D000936:Antigen-Antibody Complex; D007140:Immunoglobulin Fab Fragments; D003179:Complement C3b; D010196:Pancreatic Elastase