Complement activation by interaction of polyanions and polycations.

Interactions between heparin and protamine in normal human serum previously were found to activate the primary complement pathway and deplete the early-acting complement components. In the present investigation, the role of heparin-protamine complexes, immunoglobulins, C1q and C1-INH in this interaction was studied. Heparin and protamine, like antibody and antigen, were found to combine in multiple proportions; those proportions which resulted in optimal precipitation also induced maximal C consumption. Complexes formed in serum contained C1q and IgG, but the amount of C1q was insufficient to account for the total depletion of C1 haemolytic activity, and immunoglobulins were not required for activation of complement to occur: maximal consumption was observed in immunoabsorbed hypogammaglobulinaemic sera in which IgG, IgM and IgA were undetectable (less than 5, less than 10 and less than 7 mug/ml, respectively). Purified C1q aggregated heparin-protamine complexes formed or forming in the presence or absence of serum. The ability to induce maximal C consumption was rapidly lost as heparin and protamine interacted, and complexes preformed either in serum or buffer, or supernates thereof, were relatively ineffective in complement consumption. Thus, the consumption of complement seems to occur via transient reactivity with C1,probably at the level of C1q. It seems to be limited by the ability of free heparin to potentiate the activity of C1-INH, and perhaps also by its direct effect upon the early acting C components. These experiments support the concept that complement activation by interactions between polyelectrolytes such as heparin and protamine, like interactions between the antibodies and antigens, may have a role in the initiation of inflammatory reactions by direct activation of the complement system.