The Complement System

The complement system consists of a group of glycoproteins in the extracellular space that can be stimulated in a cascading fashion to produce biologically active fragments that either directly attack foreign substances or enhance the functions of certain types of inflammatory leukocytes. The complement system consists of two recognition-stimulation pathways that are designated as the classical and alternative pathways, either of which may lead to the formation of a cell membrane attack complex (Fig. 1-20).

Figure 1-20

The complement system. Activation of either wing of the system leads to the formation of peptide fragments that function on leukocytes and forms the membrane attack complex.

Activation of either wing of the system leads to the formation of peptide fragments that function on leukocytes and forms the membrane attack complex.

The Classical Pathway

The classical pathway of the complement system may be activated by antigen-antibody complexes of the IgG, IgG3, or IgM isotypes by their binding to the C1q subunit of the first component of complement (Fig. 1-20). Consequently, the C1qrs subunits of C1 form an esterase that cleaves the next component, C4, to two fragments, the larger of which, C4b, binds covalently to hydroxyl or amino groups on cellular membranes. The next component, C2, after binding to C4b is partially digested by C1s esterase to form C2b. The resultant membrane-bound complex, C4b2a, is an enzyme (C3 convertase) that cleaves C3 into two biologically active fragments, C3a and C3b.

The Alternative Pathway

The alternative pathway of the complement system is activated independently of antigen-antibody complexes (Fig. 1-20). The major exogenous activators of the pathway are microbial agents and their products. The major components of the pathway are the serum protein factors B, D, and P (properdin). A small amount of C3 in the fluid phase, which normally is spontaneously activated, interacts with factor B to form C3Bb, which cleaves other C3 molecules to form C3b. C3b in turn attaches to surfaces and binds factor B. The resultant C3bB is then cleaved by factor D to form C3bBb, the C3 convertase of the alternative pathway. That enzyme is distinct from the one generated from the classical pathway but serves the same purpose. This complex then is stabilized by factor P.
The binding of C3 to factor B is prevented, particularly in the fluid phase, by a regulatory molecule, factor H. The more vigorous activation of this pathway occurs when the host is exposed to microorganisms that are poor in sialic acid. In those circumstances, the binding of factor B to C3 is favored, and the activation of the alternative pathway is not readily inhibited by factor H. Therefore, more C3b is generated and a positive amplification loop that generates more C3bBb (C3 convertase) is created. In contrast, sialic acid-rich encapsulated microorganisms such as Streptococcus pneumoniae, Haemophilus influenzae, and Niesseria meningitides are incapable of activating the alternative pathway and require binding to specific IgG or IgM antibodies to activate the classical pathway and generate the C3b for phagocytosis and the formation of the membrane attack complex. The receptors for activated complement fragments are 1) CR1, principally on phagocytic cells for C3b; 2) CR2, principally on B cells for a fragment called C3d (receptor for EBV); and CR3 (Mac-1), on phagocytic and NK cells for inactivated C3b (C3bi) and C3d-g fragments.

The Membrane Attack Complex

The activation of the complement system eventually leads to the formation of the membrane attack complex that consequently lyses cells. The membrane attack complex is formed in the following manner. As a result of the formation of C3b, C5 is cleaved into two fragment, C5b and C5a. The larger fragment, C5b, combines with C6 and the complex attaches to the cell surface, where it forms the foundation for the sequential binding of C7, 8 and 9, e.g., the membrane attack complex (Fig. 1-20). C3b and its degradation product, C3bi, are opsonins. C3a and C5a are chemotaxins and anaphylotoxins; C5a is the more potent of the two factors.
Once the membrane attack complex is formed, discrete holes are created in the surface membranes of the target cells. Consequently, extracellular fluid accumulates in the target cell, eventually leading to its lysis.