Activating the complement system: Classical, alternative and lectin pathways

The complement system is part of the innate immune system, meaning it does not “learn” over time by being exposed to organisms, and its behavior is the same throughout life. This system is made up of many small proteins that are manufactured in the liver and then released into the bloodstream. Importantly, these proteins are in an inactive state when they move out of the liver. To be active, these proteins have to be “cleaved” or have pieces of the molecule cut off. This is done by other proteins when specific signals are detected.

The complement system undergoes large scale amplification, meaning many, many proteins can be cleaved to fight infection from only one small signal. Once there are many complement proteins to help, they help to kill microbes by building a tunnel through the cell membrane. This tunnel is called the membrane attack complex (MAC).

There are three methods for activating the complement system, all of which involve several steps and several molecules.  It is crucial that these complements are present in the correct ratio or it can contribute to inflammation and disease.

The classical pathway is activated in one of three ways:

1. Activation:

• An antibody binds to the outside of microbe. This can be done by certain types of IgG (but not IgG4) or IgM.
• The enzyme C1 can also bind to the surface of some microbes.
• C-reactive protein can also activate the classical system by binding to some microbial products.

2. In the blood, C1 is actually made up of three small parts called subunits: C1q, C1r and C1s. The C1q binds to the antibody on the surface of the microbe. This activates the subunits.
3. C1s cleaves C4 into two pieces. C4b binds to the cell surface of the microbes. C4a has no function here and is broken down after being released.
4. C1s cleaves C2 into two pieces. C2b binds to C4b, which is bound to the cell surface. C2a has no function here and is broken down after being released.
5. When C4b and C2b are bound together, they are called C3 convertase and they perform the special function of cleaves C3. C3 is cleaved into two pieces.
6. C3b binds to various places on the cell surface. Macrophages and neutrophils (immune cells) can bind to C3b. When macrophages bind to C3b, it may then phagocytose (or eat) the microbe. C3b can also bind to C5, which allows it to be cleaved by C3/C5 convertase.
7. C3a is an anaphylatoxin. (I have written a previous detailed post on this). It can trigger basophils and mast cells to degranulate.
8. C5 is cleaved by C3/C5 convertase. This release C5a and C5b.
9. C5a is a very strong anaphylatoxin and also attracts neutrophils to fight infections.
10. C5b is the anchor for the membrane attack complex. C6, C7, C8 and several molecules of C9 form a long line on molecules that pokes a whole in the membrane of the microbe. If the membrane is broken, water will rush into the cell and the cell will not function correctly. This results in cell death.

The alternative pathway is activated as follows:

1. C3 can turn itself into the molecule C3b. This is spontaneous and does not require any other molecules. C3b is short lived under normal circumstances.
2. If a microbe is nearby, C3b will bind to a molecule on the microbial surface called Factor B.
3. C3b and Factor B bound together are a different kind of C3 convertase than the one described for classical pathway. This C3 convertase cleaves other molecules.
4. C3b-Factor B, a C3 convertase, cleaves a molecule of C3.
5. The liberated molecule of C3b binds to C3b-Factor B-C3b. This is a C5 convertase, which starts the membrane attack complex.
6. While the MAC is being made, this C5 convertase is still cleaving C3 to release large amounts of C3b.

The lectin pathway is activated as follows:

1. MBL and ficolin bind to microbial surfaces.
2. This activates the molecule MASP-2.
3. MASP-2 cleaves C4 and C2, forming a grouping of molecules called the terminal complement complex (TCC).
4. C1s cleaves C2 into two pieces. C2b binds to C4b, which is bound to the cell surface. C2a has no function here and is broken down after being released.
5. When C4b and C2b are bound together, they are called C3 convertase and they perform the special function of cleaves C3. C3 is cleaved into two pieces.
6. C3b binds to various places on the cell surface. Macrophages and neutrophils (immune cells) can bind to C3b. When macrophages bind to C3b, it may then phagocytose (or eat) the microbe. C3b can also bind to C5, which allows it to be cleaved by C3/C5 convertase.
7. C3a is an anaphylatoxin. (I have written a previous detailed post on this). It can trigger basophils and mast cells to degranulate.
8. C5 is cleaved by C3/C5 convertase. This release C5a and C5b.
9. C5a is a very strong anaphylatoxin and also attracts neutrophils to fight infections.
10. C5b is the anchor for the membrane attack complex. C6, C7, C8 and several molecules of C9 form a long line on molecules that pokes a whole in the membrane of the microbe. If the membrane is broken, water will rush into the cell and the cell will not function correctly. This results in cell death.

 

Some molecules control the complement system so that the amplification does not cause problems.

• Factor H controls the alternative pathway. It helps to degrade the C3b-Factor B-C3b complex.
• Factor I converts C3b to an inactive form.
• C1INH (C1 inhibitor) binds to activated C1r and C1s, making them inactive. This happens quickly, so there is only a brief time before C1INH binds to C1r or C1s during which they can cleave C4 and C2.