There are three major pathways that activate complement: the classical pathway, alternative pathway, and MBL path way (Figure 1). Each of these pathways results in the formation of the MAC. All three pathways lead to the release of C5 convertase, which breaks down C5 into C5a and C5b. As mentioned previously, C5a is an anaphylatoxin as well as a chemotactic factor. C5b binds to C6 and C7 to form a complex that inserts into the membrane bilayer. C8 then binds to the C5b–C6–C7 complex followed by polymerization of up to 16 C9 molecules to produce the MAC. The MAC now generates a pore in the membrane and causes cytolysis by allowing free passage of water across the cell membrane.

Fig1. Complement reaction sequence.

The Classical Pathway

 C1, which binds to the Fc region of an immunoglobulin, is composed of three proteins: C1q, C1r, and C1s. C1q is an aggregate of polypeptides that bind to the Fc portion of IgG and IgM. The antibody–antigen immune complex bound to C1 activates C1s, which cleaves C4 and C2 to form C4b2b. The latter protein (C4b2b) is an active C3 convertase, which splits C3 molecules into two fragments: C3a and C3b. As mentioned earlier, C3a is a potent anaphylatoxin. C3b forms a complex with C4b2b, producing a new enzyme, C5 convertase, which cleaves C5 to form C5a and C5b. C5b is now available to bind to C6 and C7 and form the C5b/C6/C7 complex. Finally, C9 binds to this newly formed complex to produce the formation of the MAC. Once the MAC is formed, cell lysis ensues shortly thereafter. Only IgM and IgG fix complement via the classic pathway. Furthermore, only IgG subclass 1, 2, and 3 fix complement whereas IgG4 does not.

An example of the classical complement pathway in action can be observed in herpes simplex virus (HSV) infections. HSV replication within cells is accompanied by the insertion of virus proteins into the cell surface membrane. A specific anti-HSV antibody can bind to the surface of the infected cell by its Fab site. The Fc portion of the antigen antibody complex is now exposed and ready for C1 to attach. The classical pathway is now activated, and the infected cell is destroyed by the MAC.

The Alternative Pathway

The alternative pathway of complement can be activated by infectious agents that activate the complement system by triggering the cellular production of factors B, D, and proper din. These factors cleave C3 and generate C3 convertase. C3 convertase (C3bBb) that was generated during the alternative pathway produces more C3b. The additional C3b binds to the C3 convertase to form C3bBbC3b. This enzyme is the alternative pathway C5 convertase that generates C5b, leading to production of the MAC described earlier.

Mannose-Binding Lectin Pathway

The lectin pathway is an important component of the innate immune response and is similar to the classical pathway at the point of cleavage of C4. However, the major difference is that it is initiated by the binding of mannose-binding lectin (MBL) to polysaccharides on bacterial surfaces. The binding of MBL to a pathogen results in the formation of a tricomplex of MBL with two serine proteases (MASP-1 and MASP-2). This tricomplex is now activated to cleave C4 into C4a and C4b and C2 into C2a and C2b. The new complex C4bC2a is a C3 convertase and proceeds to cascade as the classic pathway.

A. Regulation of the Complement System

In order to avoid constant complement activation, a regulatory network exits to terminate complement activity. Several serum proteins regulate the complement system at different stages: (1) C1-inhibitor protein binds to and inactivates the serine protease activity of C1r and C1s, causing them to dis sociate from C1q; (2) factor I cleaves C3b and C4b, thereby reducing the amount of C5 convertase available; (3) factor H enhances the effect of factor I on C3b; and (4) factor P (properdin) protects C3b and stabilizes the C3 convertase of the alternative pathway. Regulation is also provided by proteins that have the ability to accelerate the decay of the complement proteins, such as decay-accelerating factor (DAF expressed on blood and endothelial cells) that can act to accelerate dissociation of the C3 convertases of all three pathways.

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مواضيع ذات صلة

Cytokines

Complement Deficiencies and Pathogen Evasion

T Cells

Antibody Responses

Immunoglobulin Genes and Generation of Diversity

Immunoglobulin Classes

Immunofluorescence

Chemiluminescence

Enzyme Immunoassay

Capillary Electrophoresis

Antibody Structure and Function

B Cell Receptor for Antigen