Activation of the alternative complement pathway due to resistance of zymosan-bound amplification convertase to endogenous regulatory mechanisms.
The surface of zymosan (Zy), by affording a protected microenvironment for C3b and the amplification convertase stabilized by properdin, P,C3b,Bb, shifts the alternative complement pathway from slow fluid phase turnover to the amplification phase of its expression. This mode of activation is in contradistinction to that of the classical pathway, which follows conversion of a proenzyme, Cl, to its active form, C1. Under conditions in which the control proteins, C3b inactivator (C3bINA) and beta1H, completely, inactivated C3b on the sheep erythrocyte intermediate, EAC4b,3b, the activity of C3b bound to Zy,ZyC3b, was diminished by only one-third. Further, when ZyC3b was converted to ZyC3b,Bb,P there was an additional point of deregulation in that the convertase was resistant to beta1H-mediated decay-dissociation while P,C3b,Bb on the sheep erythrocyte exhibited the usual susceptibility to beta1H. That Zy alone could indeed promote rapid C3 cleavage by the alternative pathway through assembly and protection of the amplification convertase on its surface was demonstrated with a mixture of alternative pathway proteins, C3,B,D,P, C3bINA, and beta1H, that had each been purified to homogeneity. Interaction of these proteins at one-tenth their relative serum concentrations with Zy permitted low-grade inactivation of C3 and B to advance to the level of amplification after a 15 min lag period. Because the reaction of the purified proteins proceeded spontaneously when either regulatory protein was deleted, the effect of Zy was attributed to deregulation rather than to conversion of one of the proteins to a specific initiating state. The alternative pathway, through the normal presence of D, interacts with a microbial surface, such as Zy, to amplify deposition of C3b by circumvention of endogenous regulatory mechanisms, thereby augmenting host defense.
D000818:Animals; D003176:Complement C3 / Q000502:physiology*; D003165:Complement System Proteins / Q000502:physiology*; D004912:Erythrocytes / Q000187:drug effects / Q000502:physiology; D004950:Esterases / Q000378:metabolism*; D006461:Hemolysis; D006801:Humans; D007700:Kinetics; D011414:Properdin / Q000494:pharmacology; D012756:Sheep; D015054:Zymosan / Q000502:physiology*
D003176:Complement C3; D011414:Properdin; D003165:Complement System Proteins; D015054:Zymosan; D004950:Esterases
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