MODULATION OF NATURAL IGM BINDING AND COMPLEMENT ACTIVATION BY NATURAL IGG ANTIBODIES - A ROLE FOR IGG ANTI-GAL-ALPHA-1-3GAL ANTIBODIES

The most abundant natural IgG Abs in human serum are thought to be Abs specific for Gal alpha 1-3Gal, a carbohydrate expressed in lower mamm als. IgG Abs specific for Gal alpha 1-3Gal have been postulated to con tribute to host defense and to participate in the rejection of intersp ecies organ grafts. Our previous studies indicated, however, that IgM and not IgG anti-Gal alpha 1-3Gal Abs activate complement on foreign s urfaces, and thus the physiologic role of IgG anti-Gal alpha 1-3Gal re mains uncertain. We tested whether the IgG anti-Gal alpha 1-3Gal in a human serum might in fact compete with IgM for binding and thus modula te complement fixation by IgM. Several lines of evidence suggested suc h competition might occur. First, the functional avidity of IgG and Ig M for Gal alpha 1-3Gal on cell surfaces were nearly within the same or der of magnitude, and in some sera the molar concentrations of IgG and IgM anti-Gal alpha 1-3Gal were comparable. Second, binding of human I gM to Gal alpha 1-3Gal on cell surfaces was inversely correlated with the concentration of IgG anti-Gal alpha 1-3Gal in serum. Third, combin ation of IgG and IgM Abs specific for Gal alpha 1-3Gal demonstrated di rect competition for binding. The presence of IgG anti-Gal alpha 1-3Ga l, which was predominantly lgG2, attenuated by up to 80% the fixation of C1q mediated by IgM, presumably by competing for antigenic sites re cognized by IgM Abs that fix complement. Thus, IgG Abs specific for Ga l alpha 1-3Gal modulate complement activation by IgM specific for that structure and might in this way modulate the consequences that ensue when human blood is brought into contact with foreign organisms or xen ogenic cells.