IgG and complement-mediated tissue damage in the absence of C2: evidence of a functionally active C2-bypass pathway in a guinea pig model

In vitro complement-mediated lysis of heavily sensitized sheep erythrocytes by C4-deficient (C4D) guinea pig and CZ-deficient (C2D) human sera was dem onstrated some years ago. It was postulated that these "complement-bypass'' pathways resulted from activation of C1 and components of the alternative pathway. We used normal, C2D, and C4D guinea pigs in a Forssman shock model to test the in vivo relevance of the C2- and C4-bypass pathways of complem ent activation. High concentrations of both anti-Forssman Ab and C2D or C4D guinea pig serum induced efficient lysis of sheep erythrocytes in vitro, T he most efficient lysis was observed when IgG Ab and C2D guinea pig serum w ere used. Blocking either the classical pathway (treatments with EGTA-Mg2or soluble recombinant complement receptor type 1 (sCR1)) or the alternativ e pathway (treatment with heating at 50 degrees C, sCR1, or soluble recombi nant CR1 lacking the first of the four long homologous repeat sequences (sC R1[desLHR-A])) inhibited lysis; both pathways were required for lysis of sh eep erythrocytes by C2D and C4D guinea pig sera. i.v. injection of anti-For ssman Ab in normal guinea pigs resulted in rapid death from pulmonary shock , whereas C4D guinea pigs had no adverse effect. Surprisingly, C2D guinea p igs either died in a delayed fashion or had a sublethal reaction. sCR1 trea tment prevented Forssman shock in both normal and C2D guinea pigs, whereas sCR1[desLHR-A] prevented Forssman shock only in C2D animals. Our results su ggest that the CZ-bypass pathway occurs in vivo to produce tissue damage. A ctivation of complement in the absence of C2 appears to be far more efficie nt than in the absence of C4.