Complement

It's a while until the next midterm, but I figured that I better start writing a bit about immunology so that I don't get swamped with having to write about lots of topics at once. So here goes!

Describe components of the complement system

The complement system is so-called because it complements other aspects of the immune system, like antibodies and so forth. Complement proteins themselves are secreted by monocytes, macrophages and hepatocytes, and are involved in a diverse array of immunology-related processes such as lysis of pathogens, opsonisation, activation of inflammatory responses and clearance of immune complexes. They are heat labile so don't set them on fire or they won't work.

Describe pathways of activation of the complement system

There are three main pathways of complement activation: the classical pathway, the lectin pathway and the alternative pathway. All of these result in a C3 convertase, then a C5 convertase, and finally a membrane attack complex (MAC). (Don't worry- this will all make sense in a bit!)

The classical pathway starts off with the C1 complex, which is made up of 3 different components: C1q, C1r and C1s. C1q binds to antibody-antigen complexes, which activates C1r, which activates C1s, which is a serine protease (i.e. a protease with serine in its active site- see my earlier post for BIOC2001). C1s is then able to cleave C4 and C2 into C4a, C4b, C2a and C2b. The "a" parts are smaller and serve other purposes in inflammation and so forth, and we'll get back to them in a bit. The "b" parts, on the other hand, are larger and stick to the cell membrane. C4b and C2b can bind to form C4b2b, which is a C3 convertase. (Note: some textbooks may call this one C4bC2a. That is an older nomenclature that is still used by a lot of people.) I'm going to leave it there for now, and go on to talking about the lectin pathway.

The lectin pathway starts off with MBL (mannose-binding lectin), which binds to mannose residues (a.k.a. mannan) on the surface of microbes. (Mannose, which I've mentioned on an earlier post, is generally not present on the cell surface of mammalian cells.) MBL is an acute phase protein, which means that it is produced more during inflammation. MBL is associated with MBL-associated serine proteases, called MASP1 and MASP2 for short, which are pretty similar to C1r and C1s of the classical pathway. They perform the same function too: cleaving C4 and C2 and ultimately resulting in the formation of the C3 convertase C4b2b (or C4bC2a, if you'd rather call it that).

The alternative pathway is a little bit different. Essentially C3 floating around might become activated by binding to microbial particles, causing cleavage into C3a and C3b (again, C3b is the larger part that sticks). C3b can bind to another complement molecule called Bb to produce C3bBb, which is also a C3 convertase.

So what does C3 convertase do? Well, C3 convertase cleaves C3 to form C3a and C3b. C3b can stick to existing C3 convertases to form C5 convertases. These C5 convertases can be either C4b2b3b (from the classical or lectin pathways), or C3bBb3b (from the alternative pathway). C5 convertase, as its name suggests, can cleave C5 into C5a and C5b.

Now for the main attack! C5b can recruit C6, C7, C8 and C9, forming a membrane attack complex (MAC), which is essentially just a pore in the cell membrane. This causes the cell to lyse. Victory!

Describe the immunological consequences of complement activation

Aside from formation of MAC, complement can have several other effects, as I mentioned earlier.

First, let's talk about anaphylatoxins. Some of the smaller complement molecules, notably C3a and C5a, fall into this category. These are small molecules that can bind to receptors like the C3aR and C5aR (R = receptor) on granulocytes and macrophages, stimulating the release of proinflammatory cytokines. They can also help stimulate chemotaxis, causing more immune cells to move to the site of infection. If this process is uncontrolled, however, then anaphylaxis can result. In anaphylaxis, the airways constrict and the blood vessels dilate and become super permeable, resulting in reduced oxygen uptake and low blood pressure. This can lead to death if medical attention isn't sought quickly.

Secondly, as I mentioned earlier, complement molecules like C3b can aid in opsonisation, along with antibodies. (As I alluded to earlier, complement complements the action of antibodies.) Hence complement means that more things can become opsonised or the effectiveness of opsonisation is increased, which in turn means that more things can be phagocytosed by macrophages and so forth.

It becomes more obvious how important complement is when somebody doesn't have enough. They are more likely to be sick for long periods of time due to reduced lysis, opsonisation etc. However, it is possible to have too much of a good thing.

C1r and C1s are usually inhibited by an acute phase plasma protein called C1-INH (which just stands for "C1 inhibitor"). This stops the immune response from going overboard. A deficiency in C1-INH can lead to a condition called hereditary angioedema (HAE). Patients with this condition have cutaneous angioedema (i.e. oedema/swelling under the skin) and severe abdominal pain. The treatment for this is Cinryze, which is a drug made up of C1-INH concentrate from donor blood. It is given twice a week to prevent the swelling.