Approximately 100 years ago complement, a bacteriolytic activity identified in serum, was distinguished from antibodies specific for microorganisms. Classical enzyme kinetic studies coupled with advances in protein chemistry subsequently resulted in the discovery, isolation and characterization of the more than 20 proteins of the complement system. These are responsible for bacteriolysis as well as many other features of the inflammatory response, including changes in vascular permeability, smooth muscle contraction, chemotaxis of phagocytic leukocytes, opsonization of microorganisms, modulation of specific immune responses and viral neutralization. The sequential activation of the complement cascade generates an effector of antigenantibody interactions and is an amplification system for defenses against infection especially in the immunologically naive host. The complement system may also promote adverse reactions since several components mediate pathophysiological effects associated with disorders of immune regulation such as arthritis, systemic lupus erythematosus, nephritis and others. Two distinct but homologous pathways initiate the complement activation sequence. The classical pathway is triggered by interaction of the first component of complement (C1) with immunoglobulins of the IgG and IgM classes in complex with antigen. When the antigen is surface bound or an integral membrane constituent, a single IgM molecule or IgG doublets (separated by 150 nm) bind a single C 1 molecule. The stoichiometry of C 1-immunoglobulin interaction differs in fluid phase reactions, i.e. in the case of soluble immune complexes. Immunoglobulins of the IgA, IgE and IgD classes and IgG of the G4 subclass do not bind C 1 under physiological conditions. Hence only certain antibodies are capable of activating the complement cascade; i.e. are 'complement fixing' antibodies. C1 is a macromolecule consisting of three noncovalently bound subcomponents, Clq, Clr and Cls (Fig. 1). The Clq subcomponent is a 460,000 dalton protein composed of 18 polypeptides organized as six collagen-like triple helical units (A, B and C chains) with carboxyl terminal globular regions which serve as the immunoglobulin-binding domains. The collagen-like regions of Clq bind dimers of the Clr and Cls subcomponents, zymogen-forms of these two serine proteinases (reviewed in Reid, 1983). Activation is the result of cleavage of C 1 r (90,000 daltons) which generates an amino terminal 60,000 dalton peptide disulfide linked to a 30,000 dalton fragment. The latter bears the active enzymatic site. The active Clr enzyme cleaves zymogen Cls to activate this subcomponent (Sire et al., 1977). Cls and Clr are structurally and functionally homologous proteins. The natural substrates of the Cls enzyme are the fourth (C4) and second (C2) components of complement. A 10,000 dalton amino terminal peptide (C4a) is cleaved from the alpha chain of C4 to generate C4b. The C4b complexes with the carboxyl terminal (60,000 dalton) C2a fragment liberated from C2 by the action of C ls. The C4b2a complex is an unstable enzyme that facilitates cleavage at the Arg77-Ser78 bond of a 9000 dalton peptide (C3a) from the alpha chain of the third component (C3). Dissociation of the C4b2a enzyme is facilitated on cell surfaces by an interesting protein designated decay-accelerating factor (DAF). This