The protease inhibitor C1-INH prevents the spontaneous activation of complement and limits consumption of C2 and C4 by rapidly inactivating C1r, C1s and MASP2. It is the only plasma serine protease inhibitor (Serpin) capable of interacting with and inhibiting activated C1. C1-INH interacts with the catalytic sites of both C1r and C1s. The interaction with activated C1r and C1s is covalent resulting in complexes which are stable to SDS. The binding of C1-INH to activated C1 releases both C1r and C1s from the complex leaving C1q bound to the immune complex. The released complexes contain four molecules: C1-INH-C1r-C1s-C1-INH. The reaction of C1 esterase inhibitor with activated C1 is very fast with the estimated half-life of C1r and C1s being approximately 15 seconds in serum. In fact, at serum concentrations of C1-INH little or no additional C4 or C2 activation occurs 3 min after immune complexes are added because all the C1r and C1s molecules have been inactivated and removed from the C1q which remains bound to the immune complex (Ross, G.D. (1986); Morley, B.J. and Walport, M.J. (2000); Rother, K., et al. (1998); Ziccardi, R.J. (1982a and 1982b); Morgan, B.P. (1990)). C1-INH is thought to bind to and stabilize unactivated C1r and C1s in the C1 complex thus retarding their spontaneous activation (Ziccardi, RJ. (1982b)).
C1-INH plays an important role in suppression of inflammation and control of vascular permeability. Through its ability to inhibit complement proteases (C1r, C1s and MASP2) and to express a variety of other biological functions (Davis III, A.E. et al. (2008)) C1-INH is able to regulate inflammatory reactions in sepsis, endotoxic shock, ischemia-reperfusion injury, transplantation, and other bacterial and parasitic infections. Through its ability to control contact system activation it inhibits bradykinin generation and this controls vascular permeability. This function is most apparent in patients with a physical or functional deficiency of C1-INH. Hereditary angioedema (HAE) patients suffer from enhanced blood vessel permeability and tissue swelling or edema. Most patients are heterozygous and have 15% to 30 % of the normal level of functional C1-INH in blood.
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