Classical Pathway Figure HA30

This forms part of the specific immune response. C1q can bind to the FC regions of aggregates of IgG1 or IgG3 molecules bound to antigen (immune complexes). C1q also attaches to single antigen bound IgM molecules, which are by nature pentameric. C1r and C1s are also components of the C1 complex. Binding of C1q leads to conformation change in the C1

Figure HA.29 Central role of C3 in the complement pathway

Figure HA.30 Classical complement pathway complex resulting in auto-activation of C1r, which in turn activates C1s. The next step is activation of C4 with the production of C4b, which avidly binds surface carbohydrates or proteins, thus complement activation is localized to a surface. Like the coagulation cascade, the large number of steps ensures amplification and offer opportunity for regulation. The C4b2a complex catalyses the central step; the cleavage of C3.

Inhibitors of the classical pathway help ensure localization of complement activation. C1 inhibitor in the serum inactivates C1r and C1s. Complement control proteins (such as decay accelerating factor) are present on the surface of cells and interfere with the C4b-C2 interaction, preventing complement activation and damage to nearby normal cells.

Alternative Pathway (Figure HA.31)

This is a non specific immune function and relies on continual low level complement activation. This is achieved by hydrolysis of C3 to form C3i, which in the presence of magnesium is able to associate with Factor B. The C3iB complex is then itself cleaved by Factor D to form C3iBb and Ba. C3iBb is able to act as a C3 convertase (i.e. catalyses C3 ^ C3b + C3a). The above reactions occur in the fluid phase but C3b attaches itself to any adjacent surface. Autologous cells can inactivate C3b. The surface of micro-organisms, however, stabilize C3b and facilitate C3 binding to Factor B and, as above, Factor D cleaves the resulting complex to form C3bBb and Ba. C3bBb is a C3 convertase and also combines to C3b to act as a C5 convertase, which initiates membrane attack complex formation. Here again is a system in which a large number of reaction steps occurring on a surface produces considerable amplification. Bacteria with surface bound C3b, C3i or C4b (which implies immunoglobulin binding also) are said to be opsonized and are readily phagocytosed by neutrophils or macrophages. This is initiated by binding to complement receptors on the phagocyte's surface. Otherwise lysis may occur as outlined below.

Figure HA.31 Alternative complement pathway

Formation of the Membrane Attack Complex

This is the final common pathway of complement activation. The first step is cleavage of C5 to C5a (a mediator of inflammation) and C5b. C5b can then aggregate with C6 and C7 to produce C5b67 which, being hydrophobic, attaches to plasma membranes. C8 then binds to a site on C5b and penetrates the membrane. The resulting C5b678 complex polymerizes a number of C9 molecules to form the membrane attack complex (C5b6789n) which is essentially a pore in the cell membrane; lysis is thus produced.

Once the C5b67 complex is formed it can attach to any nearby membrane and produce lysis—this is sometimes called 'the innocent bystander' effect. This is prevented in the fluid phase by proteins such as vitronectin inactivating this complex. On cell membranes a protein (MIRL = membrane inhibitor of reactive lysis) performs a similar function against membrane attack complex.

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