How is Complement Activated in Classical Pathway

Overview of the Classical Pathway

The complement system provides a critical first-line defense against infection. The classical pathway is one of the main pathways of complement activation. It is primarily triggered by the binding of C1 to antigen-antibody complexes containing IgG or IgM) in the presence of complement components C1, C4, C2, Ca²⁺ and Mg²⁺ cations. IgG and IgM are the most effective activators of this pathway. They combine with antigens to form antigen-antibody complexes, which react in the order of C1q, C1r, C1s, C4, C2, C3, C5, C6, C7, C8 and C9. Different IgG subclasses have different abilities to activate the classical pathway. Although IgG1, IgG2, and IgG3 (most effective) can activate complement, IgG4 is not able to activate at all.

How is Complement Activated in Classical Pathway

The classical pathway begins with the formation and activation of C1qr2s2 by the antigen-antibody complex and ends with the formation of a membrane attack complex (MAC). The whole process can be divided into the following parts:

1. Initiation:
1. C1 is the first complement component involved in the classical pathway. It is a complex composed of three polypeptide chains (C1q, C1r and C1s). The entire molecule looks like a bunch of six tulips. Each globular head contains a binding site for the Fc fragment of the antibody. Two molecules each of C1r and C1s bind to C1q in space between the heads and stems. The overall molecular structure of the C1 complex is C1qr2s2.
2. The activation of the classical pathway begins with the binding of at least two globular heads of the C1qr2s2 complex to the antigen-antibody complex through the Fc fragment of the antibody.

1. Formation of C3 Convertase
1. The binding of the Cqr2s2 globular head results in a conformational change in the C1q stem. This change is transmitted to C1r2 and C1s2 in turn, causing C1r to be activated by auto cleavage and cleaving C1s. At this stage, the Cqr2s2 complex has been fully activated.
2. The cleaved C1s can cleave C4 and C2. Activated C1s cleaves C4 into C4a and C4b, where C4b binds to antigen-bearing particle or cell membrane, while C4a retains bioactive peptides at the reaction site.
3. C1s binds to C2 and cleaves it into C2a and C2b. C2a and C4b exist as complexes, whereas C2b is released. C4b2a complex is also known as the C3 convertase.

1. Formation of C5 Convertase
1. In the presence of Mg²⁺, C3 convertase cleaves C3 into C3a and C3b. C3b binds to the membrane to form C4b2a3b complex while C3a remains in the microenvironment. The C4b2a3b complex functions as C5 convertase, which cleaves C5 into C5a and C5b. The production of the C5 convertase marks the end of the classical pathway. C5b initiates the formation of membrane attack complex (MAC).

1. Formation of MAC
1. The C3b components of C5 convertase bind C5 and cuts it into C5a and C5b fragments. The C5a diffuses away and the C5b combines with the C5 convertase to form a C4b2a3b5b complex, which acts as the catalyst to form the MAC.
2. The C5b is extremely unstable unless stabilized by binding to C6 and immobilized by binding to the cell membrane. Therefore, C5b binds to C6 and C7 sequentially to form the complex C5b67. This binding exposes a hydrophobic region on C7, which can penetrate the cell membrane. The membrane-bound C5b67 serves as a receptor for C8 and binds to it. C8 also inserts itself into the membrane.
3. The membrane-inserted complex C5b678 bind the C9 molecule and polymerize it into a 12-15 unit tubular channel of about 10 nm diameter. This structure penetrates into the cell membrane and forms channels or pores in the cell membrane, which allows the free passage of water into the cell resulting in cell swelling and lysis.
4. Because the C5b6789 complex destroys the cell by attacking cell membranes, it is also called the membrane attack complex. This form of cytolysis is referred to as complement-mediated cytotoxicity.

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