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Complement activation

We have alluded to complement before and it is described in detail below. Complement is a group of molecules that will attack and destroy bacteria and other pathogens. The complement system has been around in some shape or form for a long time in terms of evolutionary history, testament to the fact that it is a highly effective defense mechanism. The complement system can be observed operating in many invertebrates long before the development of the adaptive immune system, B cells and antibody production.

Complement can work on its own in invertebrates and still has that ability under certain circumstances in ourselves and other vertebrates. However, it has teamed up with the adaptive immune system and antibodies to be even more potent in its defense activity. Antibodies can act as a marker for complement molecules. If a high concentration of antibodies bind to something antigenic (bacteria etc.) then complement will preferentially bind alongside the antibody. Once complement is bound to the surface of a cell wall it is activated into its destructive form (see below).


Complement

The complement system is part of our innate immune defense. The complement system, like antibodies, can operate independently of the rest of the immune system to defend against a limited range of microorganisms but more frequently it works in conjunction with antibodies and immune cells to remove a pathogenic threat. The complement system is made up of numerous serum soluble protein molecules each with particular functions. The system involves a cascade of reactions between these proteins that must occur in sequence to have an effect. The complement system is present in some form in most vertebrates and can be seen to resemble functions observed in many higher invertebrates too.

The complement system is quite complex and understanding the process is not helped by the obscure method used to name the different proteins involved. There are at least 11 different proteins involved and sometimes more depending on how the process develops with each pathogenic challenge. A typical complement process would involve (in order) proteins C1q, C1r, C1s, C4, C2, C3, C5, C6, and lastly C7. The complex naming is a consequence of the way in which the proteins were discovered. Different components of the complement system have been discovered over a time span of 50 years from around 1907 to the mid 1950s. C2 was discovered before C4 although it works in the system after C4 has been activated. The potency of the complement system was first recognized in 1895 when it was known that mixing purified serum with antibody and applying this to a suspension of bacteria will result in their rapid destruction. I'm going to avoid discussing the particular components of the complement system as there are so many and each can have more than one function.

The complement system has three several roles. 1) We described antibodies as opsonizers, coating microorganisms and damaged cells to flag them as suitable for attack and destruction. Some proteins of the complement system can do the same thing, they are also opsonizers indicating what particles should be destroyed. 2) Binding of complement proteins to particles results in small fragments of complement being broken off. These fragments diffuse away from the site of pathogenic challenge and act as stimulators of immune cells. Many immune cell types will migrate towards a high concentration of these complement fragments. In other words immune cells move up a concentration gradient of complement fragments towards their source of release, the cells indulge in chemotaxis. 3) Many immune system cells have receptors for complement proteins and are able to recognize complement bound to tissue. Immune cells will attach to the bound complement which then activates the cells into antigen destroyers. 4) The complement proteins themselves are capable of destroying microorganisms. The proteins can come together in such a way as to break up the integrity of a cell wall and cause lysis (bursting) of the microorganism.


Activation pathways

To add to the confusion, when we talk about the complement system we are really talking about two very different mechanisms, the "classic" pathway and the "alternative" pathway.

The classic pathway is the most common method of complement activation. It usually involves antibody as the dictator of what happens where. The complement protein C1q favors binding to both IgM and IgG, but only if the antibodies are themselves bound to a target. When C1q is unattached it is inactive and innocuous. When it binds to an antibody it changes its molecular shape and this exposes a binding site for another complement protein C1r. This leads to a cascade of complement proteins binding in sequence to each other and with binding each protein is activated. C1q can also bind directly to a minority of pathogens without the help of antibodies. Some types of retro virus are favorite targets for C1q.

The alternative pathway of complement activation does not involve the binding of C1 proteins. It starts with a C3 molecule. C3 breaks into two molecules on binding and becomes active to elicit a cascade of complement protein interactions similar, but not the same as the classical pathway.

In the alternative activation pathway the complement system is capable of acting independently of other parts of the immune system. Typically antibodies are not involved in the alternative pathway. For complement to be activated without using bound antibodies as an initial trigger complement must take on the ability of distinguishing between self and non self antigens. The protein called "C3" is the key to distinguishing between different antigens. Self cells and tissues prohibit binding of C3 to their surface. It's not fully understood how the mechanism works but self cell membranes promote binding of two proteins (C3b and factor H). These proteins are entirely innocuous but they physically block the binding sites for other complement proteins. Bacterial and viral cell walls cannot bind C3b or factor H and so are exposed to the alternative pathway of activation. Any foreign cells that do have a coating of protective proteins can still be destroyed using antibodies and the classic pathway of complement activation.

Both the alternative and classic activation pathways ultimately lead to the formation of a "membrane attack complex". A group of complement proteins link together to form a cylinder which is then punched through the cell surface. The mechanism is very similar to the method used by cytotoxic T cells to destroy cells. Punching a hole in a cell wall means the cell can no longer regulate the concentration of water and salts inside, they can flow freely through the hole. Cells have a high concentration of salts inside, much higher than in the fluid which bathes tissue. When a hole is made in a cell membrane water molecules rush in to even up the salt concentration and make it the same as the external fluid. The water molecules blow the cell up until it bursts (lysis).


In the classical pathway of complement activation, complement proteins take their cue from antibodies. Complement recognizes material to which large amounts of antibody has bound. Complement proteins preferentially bind to the material alongside the antibodies. A cascade of events leads to formation of a membrane attack complex alongside the complement protein. The attack complex is simply a hollow tube that is pushed into the membrane creating a hole through which water enters. Water will swell the organism until it bursts.

I have glossed over much of the complex complement system but I think this brief overview will be enough to understand how it acts independently and in conjunction with antibodies and immune cells to form a potent defense mechanism.

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