OK. I've learned, and I have informed you, that the complement system works via a proteolytic cascade. One proteolytic enzyme clips and activates another. In turn, the newly active enzyme cuts the next inactive enzyme in line and activates it. It's a positive feedback loop, an avalanche, a nuclear chain reaction. And, like the Chernobyl disaster, it can get out of control. There are, in fact, many pathologies that can result from a too energetic or a too prolonged complement reaction. I'll briefly mention some of these conditions in the next post. For now, I'll describe what I learned about some of the details of how the complement system gets going and one of the many major functions it serves when its fully deployed.
At the heart of complement initiation is a protein called C3. It's made in the liver and present in high concentrations in the blood. It cruises along without doing much, but it's a time bomb waiting to be set. As mentioned in the previous post, there are three ways for turning the complement cascade on, all involving the activation of C3. One mechanism is via the adaptive immune system and I'll not discuss it here. One of the other ways that the system is activated takes place via the innate immune system and is called the "alternative pathway".
The Alternative Pathway
Thank goodness that the scientists who work on the complement system use a system of nomenclature that is rational and relatively easy to understand. They simply add a lower case letter as a suffix to the name of the uncut protein when they give a name to the cleavage products. For example, when C3 is cut (or breaks) into two pieces, the fragments are called C3a and C3b. The lower case "a" always designates the smaller of the two pieces; the larger one, of course, bearing a "b" suffix. Two other examples just to be clear: There's a protein called "B" that is sliced into Ba and Bb, and another called C5 cut into C5a and C5b. (Further reading revealed that the nomenclature isn't as consistent as I thought. There is a C2 protein in the innate pathway. When it gets cleaved its larger fragment is called C2a rather then the other way around. So much for consistency. Go figure.)
Here's how the complement cascade gets activated. As C3 circulates in the blood, a tiny percentage is continually breaking apart spontaneously into C3a and b. When that happens, C3b changes its shape and become capable of binding to an invading microbe. Most of the time, there will be no intruders to bind to and C3b will rapidly become inactive. In this way the complement cascade never initiates. However, when a foreign organism is present, C3b can bind to it. C3b become more stable and it changes its shape so that it now becomes the subject of binding by another protein, called "B", also dissolved in the blood.
Now comes the Rube Goldberg part. When B binds to C3b, another proteolytic enzyme called "D", beaks it apart into, of course, Ba and Bb. The result is that the microbe now bears on its surface a complex of C3b and Bb. This duo now transforms into a proteolytic enzyme with the particular property of being able to cut more C3. The result is a large amount of C3b bound to the surface of the invader (What about the C3a? It gets released and has an important function, but more on that in next post).
But wait, there's more. Some of the C3b formed as a result of this activity binds to the C3bBb complex forming another proteolytic enzyme with the tripartite composition C3bBbC3b. This new enzyme is capable of cutting yet another complement component called "C5" (naturally into C5a and C5b). In turn, C5b attaches to C6, C7, C8, and C9 to form a device that opens up holes in invaders like bacteria and destroys them. Wow!
It's clear that an illustration is in order since a written description is hard to follow.
The nomenclature is pretty straightforward, but there appear to be some terms missing. Where are C1, C2, and C4? Simple. They're in the other two pathways. And what's the role of the small fragments, C3a, Ba, and C5a? I'll cover that question, the other functions that complement carries out, and the pathology that results when the complement system goes awry, in the next post.