Effect of plicatic acid on human serum complement includes interference with C1 inhibitor function

In an earlier study, we presented evidence that plicatic acid (PA) activated C in normal human serum (NHS) by an immunoglobulin-independent mechanism that did not involve factor B of the alternative pathway and that required Ca++ for initiation. The present paper further verifies that PA acts through the classical pathway. In PA-treated NHS, titers of C1, C4, C3, and C5 decreased after incubation at 37 degrees C, but in C2-deficient serum, only the titers of C1 and C4 were decreased after identical PA treatment. Activation of purified precursor C1 did not occur when it was incubated with PA at concentrations that would have produced C1 consumption in serum. Thus, PA added to serum initiates activation of the classical pathway, but is incapable of activating C1 directly. PA added to a mixture of native C4 and activated C1s did not alter the kinetics or the extent of C4 inactivation by the C1s. However, when mixtures of C4, C1s, and C1-In were incubated with PA, the ability of the inhibitor to inactivate the C1s was markedly reduced. These data indicate that the mechanism by which PA activates C in serum may involve interference with the normal regulatory mechanism that controls C1 activity.