Complement is a family of more than 20 plasma proteins that includes enzymes, proenzymes, enzyme inhibitors, and glycoproteins. Components interact in cascades and assist in the resolution of a microbial infection. For example, fragments indirectly render the microbe insoluble and draw phagocytic cells to the area of infection. Other fragments coat the microbe and act as opsonins, which promote phagocytosis. In a third function, complement components create lesions in the microbial cell wall that result in osmotic lysis. Complement fragments also provide the second signal necessary for B cell activation.

Three different complement cascades have been described—classical, alternative, and the mannose-binding lectin (MBL) pathways (see Chapter 2). Only the classic pathway requires an antibody for complement activation. In the MBL and alternative pathways, complement components are directly activated by highly conserved microbial antigens.

Classic Complement Pathway

The classic pathway was the first described using sheep red blood cells (SRBCs) coated with anti-SRBC immunoglobulin M (IgM). Over a number of years, nine complement proteins were found to be involved in the cascade. These proteins interact in the following sequence: Ab:C142356789. On the basis of function, the classic cascade is subdivided into recognition, activation, and membrane attack complexes.

Recognition Complex

The recognition complex consists of antibody (Ab) and C1. The C1 component is a complex of three proteins (C1q, r, and s). C1q is composed of polypeptide chains with a triple helix “collagen-like” amino terminus and a globular structure at the carboxyl terminus (Figure 11-1). C1r and C1s are inactive serine esterases.

Figure 11-1 Structure of C1. C1q consists of six identical subunits arranged to form a central core and symmetrically projecting radial arms. The globular heads at the end of each arm, designated H, are the contact regions for immunoglobulin. C1r and C1s form a tetramer composed of two C1r and two C1s molecules. The ends of C1r and C1s contain the catalytic domains of these proteins. One C1r₂s₂ tetramer wraps around the radial arms of the C1q complex in a manner that juxtaposes the catalytic domains of C1r and C1s. (From Abbas AK, Lichtman AH, Pillai S: Cellular and molecular immunology, ed 6 [updated edition], Philadelphia, 2010, Saunders.)

When the antibody binds to the antigen, a conformational change occurs in the hinge region, which exposes complement receptors. Although both IgG and IgM can activate the complement cascade, IgM is more efficient because of the proximity of multiple hinge regions. In the initial step of complement activation, C1q bridges two hinge regions. In the next step, C1r and C1s associate to form a tetrameric complex (two molecules of each protein), which binds to C1q. In the presence of calcium, C1r activates the serine esterase activity of C1s.

Activation Complex

Activated C1s cleaves multiple C4 and C2 molecules. C4 is a large 210-kDal trimeric polypeptide, which contains an unusual thioester group. C4 is cleaved into C42a and C4b. C4a is a soluble protein that attracts phagocytic cells into the area where complement is being fixed. The C4b fragment is coupled to the microbial cell. Cleavage of C2 results in the production of C2a and C2b. The larger C2a (75-kDal) fragment remains in contact with C4b to create an AbC4b2a complex on the cell surface. Plasmin cleavage of the smaller, soluble C2b fragment creates a kinin, which causes leakage of fluid from vessels and tissue edema.

C3 Convertase

The C4b2a complex, or C3 convertase, catalyzes the cleavage of C3 into C3a and C3b. This is the most important step in the complement cascade and occurs in the classic, alternative, and MBL pathways. C3b is a highly unstable molecule that has a unique thioester that allows covalent binding to a microbial cell. Some C3b fragments bind to the target cell, where they act as opsonins. In the classic pathway, most C3b is found in an AbC4bC2aC3b complex on the cell surface, which is called the C5 convertase.

The soluble C3a fragment acts as an anaphylatoxin. By definition, an anaphylatoxin is a molecule that induces the movement of eosinophils and phagocytic cells (chemotaxis) toward increasing concentrations of C3a (Figure 11-2). Anaphylatoxins also release histamine and heparin from basophils and mast cells. Histamine and heparin cause vasoconstriction and increased vascular permeability, which reduce the solubility of microbes or antigen–antibody complexes.