Activation of Complement by Endotoxin

Ovine erythrocytes (E) coated with endotoxin (LPS) from Salmonella typhosa 0901 have been used for characterization of the nature of a pathway by which LPS activates complement (C). E-LPS consumed C in normal guinea-pig serum in a manner identical to that in which C is consumed by LPS, that is, with marked consumption of C3–C9 and little depletion of C1, C4, and C2. A “natural” γ2-globulin, isolated from serum by ion-exchange chromatography, was required for C-mediated lysis of E-LPS in dilute serum. When it was reacted with guinea-pig γ2-globulin, Cl , C4, and C2, followed by C-EDTA, E-LPS was lysed. Deletion of γ2-globulin, Cl, C4, or C2 from the reaction prevented lysis. The small amounts of the early-acting components of C used indicated that it would be difficult to measure their loss in whole serum after incubation with LPS. This hypothesis could explain the earlier findings of a relative sparing of C1, C4, and C2 during consumption of C3–C9 by LPS in normal serum. Our present concepts of C activation by LPS must consider two pathways: a conventional pathway involving “natural” antibody (γ2-globulin) and the formation of the C3 convertase (C4̅2̅) and an alternate pathway involving the formation of a C3 activator, which proceeds without obvious participation of Cl, C4, or C2. The significance of either or both of these pathways to the induction of tissue injury by endotoxin awaits further investigation.