Acquired angioedema: observations on the mechanism of action of autoantibodies directed against C1 esterase inhibitor.

We describe a mechanism of action of autoantibodies reactive with the C1 esterase inhibitor (C1EI) molecule found in three patients with acquired angioedema without associated diseases. All of these patients have a circulating C1EI of lower molecular weight than that of normal control subjects. When native C1EI was added to patient, but not control, plasmas, it was cleaved to a lower molecular weight fragment under conditions that allowed contact system activation. In a partially purified system, patient immunoglobulin preparations impaired stable complex formation between plasmin and C1EI and exaggerated the cleavage of the latter to a lower molecular weight fragment. We propose that the autoantibody does not interfere with the cleavage of the bait sequence of the inhibitor but reduces the availability of the reactive center of the molecule in a way that interferes with the irreversible inhibition of target enzymes. In this way unregulated activation of the kinin and complement pathways occurs, leading to disease manifestations via as yet uncharacterized mediators.