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BACKGROUND: Acquired C1-inhibitor (C1-inh) deficiency is usually associated with the presence of circulating C1-inh autoantibodies. These autoantibodies have been shown previously to bind to two synthetic peptides corresponding to C1-inh amino acid residues 438-449 (peptide 2) and 448-459 (peptide 3) but not to peptide 1 (residues 428-440). MATERIALS AND METHODS: Affinity-purified C1-inh autoantibodies from two patients with acquired C1-inh deficiency were studied for their effects on the inhibition of C1s activity by C1-inh using SDS-PAGE and hydrolysis of a synthetic ester. RESULTS: Functional studies confirmed that the anti-C1-inh autoantibodies abrogated C1-inh activity, and their maximum effect was produced when the concentrations of C1-inh and autoantibody were approximately equimolar. The autoantibodies prevent the formation of the C1s-C1-inh complex, but they do not dissociate the preformed complex, suggesting that the autoantibodies act prior to the formation of the enzyme-inhibitor complex. In the presence of autoantibodies, C1s cleaves C1-inh, and a stable covalent bond between C1s and C1-inh does not form. Peptides 2 and 3, but not peptide 1 inhibited autoantibody activity, thus C1-inh inhibitory activity for C1s was expressed fully. CONCLUSIONS: Our data indicate that the anti-C1-inh autoantibodies convert C1-inh to a substrate by preventing the formation of the stable covalent protease-serpin complex. The data also suggest a possible therapeutic use for peptides 2 and 3 or their derivatives in the management of patients with type II acquired angioedema (AAE).