CLEAVAGE AND INACTIVATION OF HUMAN C1-INHIBITOR BY THE HUMAN-LEUKOCYTE PROTEINASE, PROTEINASE-3

Incubation of highly purified human C1 inhibitor with equally pure hum an leukocyte proteinase 3, resulted in a dose- and time-dependent inac tivation of C1 inhibitor hemolytic activity. Furthermore, this inactiv ation was accompanied by proteinase 3-dependent cleavage of the C1 inh ibitor into an 83 000 molecular weight fragment. The formation of the 83 000 molecular weight fragment followed a time course which was simi lar to that observed for the inactivation of hemolytic activity. Withi n 120 minutes more than 90% of the hemolytic activity was lost. This i nactivation of C1 inhibitor appeared to be selective as purified human C1q was not degraded in a similar time period. Moreover, when 100 mu g IgG, isolated from each of 21 Wegener's granulomatosis patients with cytoplasmic anti-nuclear antibodies immunofluoresent titers to protei nase 3 greater then 1:64, was incubated with 3 milliunits of proteinas e 3, little to no cleavage of C1 inhibitor was observed. In contrast, 100 mu g of IgG isolated from 14 normal donors was ineffective in affo rding protection to C1 inhibitor upon incubation with proteinase 3. Ou r results suggest that neutrophil infiltration and activation could le ad to local complement consumption at the tissue sites.