C1- inactivator: its efficiency as a regulator of classical complement pathway activation by soluble IgG aggregates.

The role of C1- inactivator (C1(-)-In) during activation of the classical complement pathway by soluble immune complexes was studied using purified human complement components C1, C4 and C1(-)-In, and stabilized soluble aggregates of normal human IgG as a model for soluble immune complexes. The C4-consuming ability that could be generated by incubation of precursor C1 with IgG aggregates was abolished completely by the presence of a large excess of C1(-)-In during the C1 activation step. Kinetic studies confirmed that this inhibition was due to a second-order reaction between C1- and C1(-)-In resulting in the irreversible inactivation of C1-. When aggregates of various sizes were enabled to induce C4 conversion in mixtures of C1, C4 and a variable concentration of C1(-)-In, the presence of C1(-)-In had two effects. Firstly, the efficiency of the aggregates in causing C4 consumption was reduced remarkably. At a C1(-)-In:C1 ratio of 8, which can be found in normal human serum, approximately eight to ten times as many aggregates were required for a given level of C4 consumption as when no C1(-)-In was present. Secondly, C1(-)-In diminished the maximum C4 consumption that could be achieved, especially with smaller aggregates. Thus, a complete or partial C1(-)-In deficiency probably facilitates complement activation by soluble immune complexes in two ways: it may enhance the efficiency of classical pathway activation by all C1-activating complexes, and it may enable small complexes, which normally cannot overcome the C1(-)-In barrier, to activate the classical pathway to the C4 level.