A recently defined subgroup of patients with acquired angioedema (AAE) were found to elaborate autoantibodies to Cl inhibitor (Cl- Inh). The Cl-Inh molecule is important in regulating Cl activation, but also represents the major control mechanism influencing the enzymes of the contact system: activated Hageman factor (XIIa), Hageman factor fragment (XIIf), and plasma kallikrein (KK). Since uncontrolled action of these enzymes could promote both Cl-Inh consumption and generation of the vasoactive peptide bradykinin, we have examined the impact of the AAE Cl-Inh autoantibodies on the control of the contact enzymes KK and XIIf by normal plasma Cl-Inh. Endogenous plasma kallikrein showed enhanced survival in AAE plasmas similar to that seen in untreated hereditary angioedema (HAE) plasmas. Mixing HAE or AAE plasmas with normal plasma revealed partial correction of the HAE plasma defect but little or no change of the AAE plasma defect. This finding implies active inhibition of Cl-Inh function by AAE plasmas. When immunoglobulin concentrates from AAE plasmas were mixed with normal plasmas the kinetics of exogenous KK inhibition demonstrated progressive, dose responsive retardation and the concentrates induced KK inhibitory defects like those observed in HAE plasmas. In marked contrast defects in XIIf inhibition obtained at immunoglobulin doses simulating patient plasmas were small relative to those found in HAE plasma and in general there was less than a two-fold prolongation of XIIf survival. Enzyme-linked differential antibody immunoabsorbent assays confirmed that all three patient antibodies had more profound effects on KK-CI-Inh complex formation than on complex formation between Cl-Inh and factor XII-derived enzymes. These studies indicate that the autoantibodies elaborated by AAE patients can cause dysregulation of the contact system as well as the complement cascade this derangement in control of the contact system could contribute to the consumption of Cl-Inh and production of angioedema in these patients.
