Studies of complement autoactivatability in hereditary angioedema: Direct relationship to functional C1-INA and the effect of classical pathway activators

It has been observed earlier that the hemolytic complement in diluted sera obtained from patients with hereditary angioedema (HAE) undergoes spontaneous decay when incubated at 37°C. Employing individual serum from patients at different stages of this disease it was demonstrated that this spontaneous loss of hemolytic complement also occurs without dilution and is directly linked to the absence of functional C1-INA. Incubation of HAE serum resulted in a loss of activity which appears to be dependent upon the concentration of functional C1-INA. While C1-INA levels < 50 μg/ml lead to rapid depletion with time, reconstitution of deficient sera with highly purified C1-INA or of undiluted NHS inhibited spontaneous activation. Furthermore, NHS was rendered susceptible to autoactivation when its C1-INA was depleted by passage over an anti-C1-INA Sepharose 4B affinity column in the presence of 10 mM EDTA, indicating that in the absence of functional C1-INA, C1 undergoes an uninhibited spontaneous autoactivation which leads to the consumption of C4 and C2 but not C3. Consumption of C3 was observed, however, in HAE sera that contained a significant amount of immune complexes. Incubation of HAE sera with highly purified Hageman factor fragment (5 μg/ml), or aggregated IgG (2 mg/ml) was found to accelerate the rate of decay when compared to untreated samples while sera from patients under treatment with danazol or Stanozolol failed to autoactive. These results suggest that, the absence of C1-INA, may, by itself trigger the dissociation and autoactivation of C1 in the sera of such patients; however, the presence of other complement activators accelerates the reaction. This inherent property of HAE sera, i.e., spontaneous autoactivation at 37°C, may be a useful screening test but direct determination of C1-INA activity is required to establish the precise diagnosis.