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Complement
Written by Tim Sheppard MBBS BSc. Last updated 9/11/10

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What is complement?

Complement is a whole system of proteins which act in a cascade a bit like the clotting cascade. It's called complement because it complements what antibodies do. It has several effects, all designed to remove the threat, and it achieves these in three different ways:

- The Classical Pathway
- The Mannan-Binding Lectin Pathway
- The Alternate Complement Pathway


These pathways are made up of 12 of the complement proteins, while the rest of them make adjustments to the way in which the process develops. These proteins are kicking about all over the body - they're found everywhere, and they're ready to do their stuff when a threat makes an appearance.


What is the classical pathway?

The classical pathway is activated by antibodies, which are bound to antigens. One of the many things that an antibody does is alert the immune system to the presence of a threat. This is exactly what an antibody does to start off the classical pathway.

When the antibody is bound to an antigen, the C1q protein binds to the Fc region of the antibody. This then offers an opportunity for two more complement proteins to bind: C1r and C1s.

This combination of three proteins produces an enzyme, which is the first one in a whole series which will be produced during the course of complement's pathway. It is, rather appropriately, called C1.

Unfortunately the next few proteins don't run in number order, but the processes which occur each time are pretty similar. We get C4 next - a protein which is inactive when it's left all on its own, but which takes advantage of the fact that C1 is an enzyme.

Indeed, C1 is an enzyme which causes C4 to split into its two parts: C4a and C4b. C4a is of little interest to use at the moment, but C4b is particularly useful as it leads us into the next step. Having been split from C4a, C4b binds with other proteins and carbohydrates on the surface of the invading threat, and most importantly with the next protein in the pathway, C2.

C2 is similar to C4 in that it is not activate in its current form, but rather it needs to be turned into something else. This is rather handily achieved again by the C1 enzyme, which breaks it up into C2a and C2b. This time it is the 'a' component which we're interested in, because C2a and C4b together form an enzyme known as C3 convertase.

It doesn't really take a genius to work out the an enzyme called C3 convertase has something to do with converting C3, and of course that's exactly what it does. And, in the same way that C4 and C2 were split apart, C3 is split apart. Again, it forms two components - C3a and C3b, and this time we're looking for the C3b part. The C3b part is involved in opsonisation, which involves binding to the surface of things such as bacteria to make them more easily engulfed by cells such as macrophages and neutrophils. Binding of C3b to the surface makes them more easily eaten, enabling these phagocytic cells to destroy what they've eaten.

C3b is also useful for continuing this cascade, as it joins the C3 convertase complex to form C5 convertase.

C5 convertase is used in exactly the same way as C3 convertase, except that the product we want here (again the 'b' part) has an entirely different function. Having separated C5 into C5a and C5b, the C5b part is used as part of the killing machine, the membrane attack complex - the very thing which leads to death of the invading cell.

So, a long cascade of enzymes and proteins all culminates in this final complex which is used to destroy the offending article.


What is the membrane attack complex?

The classical pathway produces a cascade of reactions leading to the production of C5b, an important protein in leading to the death of an imposing threat. A bacterium, invading the body and hoping to evade defences, apparently didn't count on the fact that complement proteins exist all around, and the reactions are set off very quickly.

C5b is needed in combination with four other complement proteins: C6-9 inclusive. C9 forms the outside of a pore, a hole in the membrane of the invader. The assembly of these proteins together is therefore catastrophic for the cell which tried to make its way into the body.

There is a much higher concentration of sodium ions (Na+) outside cells than inside. There is also a much higher concentration of potassium and chloride ions inside the cell than outside. With the leaking of ions out of the cell, and the leaking of sodium in, the careful balance of ions which is necessary to maintain the integrity of the cell is lost. In other words, it all goes a bit wrong for the cell!

Water follows the sodium into the cell by osmosis. The cell swells and eventually bursts - which is obviously not all that great. Indeed, it dies. The membrane attack complex does exactly what it says on the tin - it attacks the membrane, forming channels that ruin the osmotic and electrochemical gradient across the membrane, and causing it to burst.

A helpful and easy (though not entirely accurate) way of thinking about it is as though the MAC is just a complex of proteins that punch holes in the membrane of a cell, which will obviously cause it to die.


What is Mannan-Binding Lectin pathway?

The mannan-binding lectin pathway works in a very similar way to the classical pathway - indeed, most of its steps work the same, and the ultimate intention is production of the membrane attack complex.

However, rather than beginning with an antibody-dependent production of the C1 enzyme, this pathway starts with production of a slightly different enzyme.

First of all, the mannan-binding protein or MBP binds to mannose groups on the surface of the invador. Many bacteria, for example, are covered with carbohydrates including this mannose group. This in turn allows two further proteins - MASP1 and MASP2 - to bind, producing the first enzyme.

This then works in the same way that C1 did, in causing conversion of C4 and C2, allowing their active forms to produce the complex C3 convertase, which is again used to convert C3, and so and and so on (as in the classical pathway) until the MAC is produced. Importantly this provides an innate mechanism which has no involvement of acquired immunity.

Put simply the Mannan-binding lectin pathway is just another complement pathway which leads to destruction of the cell. Importantly, though, it has a different starting point from the classical pathway, and therefore it gives the body more flexibility and versatility when fighting infections.


What is the alternate complement pathway?

Both the Classical Pathway and the Lectin Pathway produce the enzyme C3 convertase which is required to split C3 into C3a and C3b. C3i, a molecule which works in the same way as C3b, can also be produced by hydrolysis of C3.

It is to this C3b (or C3i) that Factor B (a protein required for this pathway) binds, creating the component C3bB. A reaction then occurs with the help of another factor - this time, Factor D - which separates the Factor B into its two parts, 'a' and 'b'. The Bb part stays attached to the C3b (or C3i), forming C3bBb.

Just in case you were looking for a few more letters, the next step complicates things further. The C3bBb complex is not quite sufficient for the function that we're driving at. Rather, we need the addition of another protein: properdin. When this binds, we get C3bBbP, and this is the complex we've been aiming for, since it acts as a C3 convertase. With this in tow, we're able to produce a whole lot more C3b; this then binds to the C3 convertase as before to produce C5 convertase, and thence C5b needed for the membrane attack complex.

Essentially, then, the alternate complement pathway isn't its own pathway - it needs something to provide it with C3b in the first place. However, once this is done, it is able to produce a complex that will quickly split up more C3, so that it can repay its debt and much more besides.


What else does complement do?

Forming the membrane attack complex is obviously a very important feature of complement, but as we've seen, the process of its formation produces splitting up of lots of proteins, with lots of 'waste' products. The body, however, has been cleverly designed so that much of this 'waste' helps out...

Opsonisation - when something binds to a cell to make it easier to gobble up (or phagocytose), this is called opsonisation or enhanced attachment. C4b, and particularly C3b, are good opsonins, with one part binding to a common feature of a cell, and another part attaching to the white blood cells which are to phagocytose the invader. To prevent phagocytosis of normal cells, factor H binds to C3b and allows Factor I to inactivate it. Bacteria produce lipopolysaccharide (LPS - a molecule with both fat and sugar in it) that encourages factor B to bind to C3b (as seen in the alternate complement pathway), which prevents factor I from inactivating it.

Chemotaxis - The immune system does not just randomly send things to attack invading cells. As well as many other mechanisms discussed already and elsewhere on this site, the immune system sends signals to let white blood cells know where the problem is; this is known as chemotaxis - using chemicals to inform cells of the direction to travel in. C5a is one of these chemicals, released to show that something is going on. Cells attracted by C5a will then target cells which have C3b bound to them.

Inflammation - C3a, C4a and most especially C5a are involved in promoting inflammation. C5a particularly causes mast cells to release histamine, an important chemical involved in inflammation, as well as causing white blood cells and the cells lining blood vessels to increase their stickiness (by increasing the expression of adhesion molecules) so that they can access the site where something has invaded. They also cause neutrophils to release chemicals that help out with killing.

Waste disposal - immune complexes (e.g. antibodies bound to viruses) could easily kick around in the blood stream for ages and potentially cause problems if they are attacked by immune defences in the wrong place. However, with C3b (and also C4b) binding to them, they are able to get carried by red blood cells to the spleen and the liver. Here they are removed and destroyed.


Further Reading