Acquired Angioedema Research Articles

Mechanism of Action of Anti-C1-Inhibitor Autoantibodies: Prevention of the Formation of Stable C1s-C1-inh Complexes

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). 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. 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. 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).

Activation of the Coagulation Cascade in C1-Inhibitor Deficiencies

AbstractActivation of the contact and complement systems in C1-inhibitor deficiencies is thought to contribute to the pathogenesis of angioedema attacks by releasing kinins. Trigger stimuli of attacks may also activate coagulation. This is particularly important because experimental data suggest that thrombin, the main enzyme of the coagulation cascade, increases vascular permeability and can thus influence edema formation. We have studied 19 patients with hereditary angioedema (HAE) during remission, 5 HAE patients during acute attacks, and 6 patients with acquired angioedema (AAE) during remission and during seven attacks. Thirty normal subjects, matched for sex and age, served as controls. Generation of thrombin was measured by enzyme-linked immunosorbent assay (ELISA) as plasma levels of the prothrombin fragment 1 + 2 (F1 + 2); the initiators of the tissue factor and contact coagulation pathways were investigated by measuring plasma levels of activated factor VII (FVIIa) coagulometrically and activated factor XII (FXIIa) by ELISA. Cleavage of high molecular weight kininogen (HK) was evaluated by immunoblotting analysis. F1 + 2 was slightly increased during remission and further significantly increased during attacks in both HAE (P = .0115) and AAE. FVIIa and FXIIa, normal during remission, increased strikingly during attacks in both HAE (P = .0022 and P = .0044) and AAE. During remission, cleaved HK was normal in HAE and high in AAE; during attacks it increased in HAE (P = .0008) and remained elevated in AAE. Our data indicate that in C1-inhibitor deficient patients there is increased generation of thrombin during attacks, with signs of activation of both the contact and tissue factor coagulation pathways. In conclusion, C1-inhibitor deficiency, whether hereditary or acquired, has demonstrable activation of the coagulation and kinin-forming cascades during attacks and that thrombin should be considered a possible contributing factor in the pathogenesis of edema in HAE and AAE.

Acquired angioedema

Acquired angioedema (AAE) is a rare disorder that has been categorized into two forms, AAE-I and AAE-II. AAE-I is associated with other diseases, most commonly B-cell lymphoproliferative disorders. AAE-II is defined by the presence of an autoantibody directed against the C1-inhibitor molecule. Differentiating AAE-I from AAE-II is vital because different therapeutic interventions are required for each type. This review summarizes the clinical aspects, pathophysiology, and management of AAE compared with the types of hereditary angioedema. (J Am Acad Dermatol 1997;36:611-5.)

Autoimmune C1 inhibitor deficiency: Report of eight patients

purpose: In this study, we investigated the clinical and biochemical features and the responses to treatment of eight patients with auto-antibody-mediated Cl inhibitor (C1-INH) deficiency and symptoms of angioedema. patients and methods: In addition to the 8 patients with acquired angioedema (AAE), we also studied 36 subjects with hereditary angioedema (HAE), 15 of them treated with C1-INH plasma concentrate, and 26 patients with different autoantibodies in their plasma (10 with systemic lupus erythematosus, 6 with lupus-like anticoagulant, and 10 with chronic liver disease). Functional C1-INH was measured with the reagent kit of Immuno (Vienna, Austria); C1-INH, C4, and Clq antigen were determined by radial immunodiffusion; and autoantibodies to C1-INH were detected by an enzyme-linked immunosorbent assay method. results: Four patients with AAE had no other diseases, one had breast cancer, one liver hydatidosis, one Waldenstrom's disease, and one a benign M component. Functional C1-INH levels were below 30% of normal, and Clq plasma levels were low in seven patients but normal in one. Autoantibodies to C1-INH were detectable in all eight AAE patients but in none of the others. Prophylactic treatment with attenuated androgens was successful in one of four patients, and with antifibrinolytic agents (tranexamic acid) in six of seven patients. Laryngeal attacks in five patients were treated with C1-INH plasma concentrate; two patients had marked clinical and biochemical responses. In three, the symptoms resolved only with high doses, and the biochemical parameters did not significantly increase. conclusions: Our results suggest that patients with autoimmune AAE are clinically and biochemically heterogeneous. They have different responses to treatment that seem to be related to variable C1-INH consumption.