322 MULLER-EBERHARD function either as enzymes or as binding proteins. The wider complement system includes multiple distinct cell-surface receptors that exhibit specificity for physiological fragments of complement proteins and that occur on inн flammatory cells and cells of the immune system. In addition, there are regulatory membrane proteins that prevent autologous complement activation and protect host cells from accidental complement attack. The system is organized in two activation pathways, designated" classical" and" alternative," and in the cytolytic pathway of membrane attack (Figure 1). Both activation pathways contain an initial enzyme that catalyzes the formation of the target cell-bound C3 convertase which in tum generates the C5 convertase. Binding of antibody molecules to a foreign particle results in activation of the classical pathway, which is antibody-dependent. In contrast, the alternative pathway does not require antibody for its activation. It exists in an activated state at all times due to the spontaneous reaction of its major component, C3, with water. Native C3 is endowed with an internal thioester that undergoes hydrolysis at a slow rate giving rise to a functionally active C3 molecule, C3 (H20). When, as a result of formation of the initial enzyme, native C3 is cleaved and the fragment C3b is deposited on the surface of particles, the alternative pathway is enabled to distinguish between self and nonself. Only on particles recognized as foreign will amplification of C3b deposition occur and membrane attack be initiated. Both activation pathways eventuate in proteolytic cleavage of the protein C5 and thus in assembly of the membrane attack complex (MAC) from five hydrophilic precursor proteins. Through its metastable membrane-binding site, the forming MAC binds f. irmly to target membranes owing to hydrophoн bic interaction with the lipid bilayer. The final events of MAC assembly are unfolding and polymerization of the protein C9 within the target membrane, which cause weakening of membrane structure and formation of transmemн brane channels. Cytotoxic lymphocytes kill their target cells using a protein that resembles in some respects C9. It undergoes polymerization in target membranes to form transmembrane channels and it shows an immunochemiн cal relationship to C9. Whereas this C9-related protein (C9RP) is constitutive in natural killer (NK) cells, it is newly synthesized upon activation of resting cytotoxic T lymphocytes (CTL).

C3 is pivotal in the organization and function of the complement system. It is the precursor of biologically active fragments that function by associating with other complement proteins or by binding to cell-surface receptors. C3 harbors at least 10 distinct binding sites, one of which, the thioester, enables the molecule to bind covalently to target cells and particles such as immune complexes. The cellular receptors for fragments of C3 have assumed increasн ing importance. One has been identified with the Epstein-Barr virus receptor on B lymphocytes; two others have been shown to belong structurally to the LFA-I family of leukocyte surface-adhesive molecules.