Complement Activation Pathways


The complement system is an enzyme cascade that is a collection of blood and cell surface proteins to help the abilities of antibodies to clear pathogens from an organism. The complement system that comprises 30 different proteins, including serum proteins, serosal proteins, and cell membrane receptors is an important part of the innate immune system. Some complement proteins bind to immunoglobulins or to membrane components of cells. Others are proenzymes that, when activated, cleave one or more other complement proteins and initiate an amplifying cascade of further cleavages. The end-result of this cascade is massive amplification of the response and activation of the cell-killing membrane attack complex. The complement system has four major function, including lysis of infectious organisms, activation of inflammation, opsonization and immune clearance.

There are three different complement pathways, the classical complement pathway, the alternative complement pathway, and the mannose-binding lectin pathway. The classic complement pathway is triggered when antibody-antigen complex interact with C1-complex, which consists of C1q, two molecules of C1r, and two molecules of C1s. The C1-complex cleaves C2 and C4, which then form C3 convertase (C4b2a). C3 is then cleaved by the C3 convertase, and forms C5 convertase in association with C4b and C2a. The generation of C5 convertase is the end of the classical pathway. The lectin pathway is very similar to the classical pathway. It is stimulated when the mannose-binding lectin (MBL) binds to mannose residues on the pathogen surface. The MBL-associated serine proteases, MASP-1, and MASP-2, are activated and cleave C4 and C2, which then form the C3 convertase as in the classical pathway. The alternative complement pathway begins with the activation of C3 and requires factor B and factor D. All three pathways merge at C3, which is then converted into C3a and C3b. The further formed C5 convertase from C3b cleaves C5 into C5a and C5b. C5b with C6, C7, C8, and C9 complex to form the membrane attack complex (MAC), which is inserted into the cell membrane, forms a hole in the membrane, and initiates cells lysis.

Activation of the complement system must be tightly regulated, since it has the potential to be extremely damaging to host tissues. The complement system is regulated by complement control proteins, which are present at a higher concentration in the blood plasma than the complement proteins themselves. At least 12 proteins are known involved in regulation of the complement system; examples are Factor H, Factor I, C1 inhibitor, and CD59. Factor H removes Bb from the alternative pathway C3 convertase breaking the positive feedback loop. Factor I inactivates C3b. C1 inhibitor binds to sites on activated C1r and C1s shutting down their proteolytic activity. So when C1 is activated by antigen-antibody complexes, there is only a brief interval during which it can cleave C4 and C2 before it is deactivated by C1 inhibitor. CD59, also known as protectin, inhibits C9 polymerisation during the formation of the membrane attack complex.

Disorders of the complement system are sometimes encountered in humans, since so many proteins are involved and inherited deficiencies of one or another is not surprised. There are four examples of disorders of the complement system. An inherited deficiency of C3 predisposes the person to frequent bouts of bacterial infections. It is curious that the main problems with a deficiency of C2 (or of one of the other “early” complement components like C1q, C1r, C1s, or C4) are immune complex disorders, not bacterial infections. This emphasizes the important role of the complement system in clearing away antigen-antibody complexes. A deficiency of C2 (or one of the other early complement components) is frequently found in patients with the autoimmune disorder system lupus erythematosus (SLE). Another curiosity is that most people who cannot make C9 have no more of a problem with bacterial infections than those who can. Laboratory studies suggest that the C5b-6-7-8 complex by itself is able to lyze bacteria although not as efficiently as C9. A deficiency of C1 inhibitor produces hereditary angioedema. Patients are at risk of occasional explosive triggering of the complement system. The massive release of anaphylatoxins (C3a, C5a) may cause dangerous swelling (edema) of the airways, as well as of the skin and intestine.


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