The architecture of the complement system has evolved during the last 600 - 700 million years to become an amazingly efficient and highly versatile alerting and cell killing device. Under physiological conditions, this system acts as a well-regulated cascade, protecting the organism against pathogens and participating during the initial defensive steps of humoral and cellular response.
Complement activation is tightly regulated and designed to kill invading microbes while producing minimal "collateral damage" that could result in the destruction of host tissues. Complement proteins in the circulation are not activated until triggered by an encounter with a bacterial cell, a virus, an immune complex, damaged tissue or other substance not usually present in the body.
Complement activation is a cascading event like the falling of a row of dominoes. It must follow a specific order if the end result is to be achieved. The circulating proteins have been grouped into three activation pathways, based on the types of substances and proteins that initiate the activation.
Complement activation can be divided into four pathways: the classical pathway, the lectin pathway, the alternative pathway and the membrane attack (or lytic) pathway. Both classical and alternative pathways lead to the activation of C5 convertase and result in the production of C5b which is essential for the activation of the membrane attack pathway.
C5 convertase from the classical (C4b2a3b), lectin (C4b2a3b) or alternative (C3bBb3b) pathway cleaves C5 into C5a and C5b. C5a remains in the fluid phase and the C5b rapidly associates with C6 and C7 and inserts into the membrane. Subsequently C8 binds, followed by several molecules of C9. The C9 molecules form a pore in the membrane through which the cellular contents leak and lysis occurs. Lysis is not an enzymatic process; it is thought to be due to physical damage to the membrane. The complex consisting of C5bC6C7C8C9 is referred to as the membrane attack complex (MAC).
C5a generated in the lytic pathway has several potent biological activities. It is the most potent anaphylotoxin. In addition, it is a chemotactic factor for neutrophils and stimulates the respiratory burst in them and it stimulates inflammatory cytokine production by macrophages. Its activities are controlled by inactivation by carboxypeptidase B (C3-INA).
Some of the C5b67 complex formed can dissociate from the membrane and enter the fluid phase. If this were to occur it could then bind to other nearby cells and lead to their lysis. The damage to bystander cells is prevented by Protein S (vitronectin). Protein S binds to soluble C5b67 and prevents its binding to other cells.
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