Properdin: initiation of alternative complement pathway

Abstract

Activation of the classical complement (C) system involves conversion of C1 to its active state with subsequent cleavage of C4 and C2 so as to form the classical C3 convertase, activated C42 which sequentially cleaves C3 and C5 to initiate the cytolytic event associated with the complete reaction. An alternative, or properidin dependent, pathway to complement activation generates a C3 convertase, activated C3B, that is formed by cleavage of B with activated D in the presence of C3b, the major cleavage fragment of C3. C3b is capable of binding activated properidin (P) with resultant stabilization of C3b, which otherwise rapidly decays by loss of b activity. Initial cleavage of C3, a prerequisite for formation of activated C3b, is demonstrated to occur through the interaction of native C3 and B in the presence of either activated D or activated P alone, or together. The effect of activated P on the interaction of activated D, B, and C3 is attributed to stabilization of C3B, as has been shown for activated C3B. Larger amounts of activated P and B with C3 in the absence of activated D form a C3 convertase that is designated activated (P)C3B to indicate that demonstrable cleavage of B does not occur although the active site is available. The generation of this initial convertase, as assessed by C3 inactivation, is dose related to P and B inputs. The presence of both activated P and activated D greatly augments initial cleavage of C3 with activated D fully uncovering the active site of B and activated P stabilizing that site.