The Complement System

Every living thing needs to fight off other things that want to feast on it. So, as multicellular life evolved, it found a way to defend itself. Today, humans have a sophisticated defensive network, like physical barriers, defence cells, and weapons factories. But one of the most important defence systems in the human body is largely unknown: the Complement System. It evolved over 700 million years ago and is an army of over 30 different proteins that work to stop intruders. All in all, there is about 15 quintillion of them saturating every fluid in your body right now. Guided by nothing but chemistry, these proteins are one of the most powerful weapons we have against invaders. Many other parts of the immune system are just tools that are used to activate the Complementary System. But it’s also really dangerous. Imagine having thousands of tiny bombs in your blood that could go off at any moment. So, our cells use various methods to prevent the Complementary System from accidentally attacking them. Okay, what exactly does it do, and why is it so dangerous?

Simply, the Complement System does three things: it cripples enemies, activates the immune system and rips holes in things until they die. But how? After all, these are mindless little proteins that randomly drift around without will or direction. Well, this is actually part of the strategy. Complement proteins float around in a sort of passive mode. They do nothing until they are activated and change their shape. In the world of proteins, your shape determines what you can or cannot do. Because shape determines what you can interact with and in what way. For example, in your passive shape, you might do nothing. In your active shape, however, you might change the shape of other proteins, activating them so that they can activate others. Mechanisms like this can start cascades that spread very quickly. Imagine the complement proteins as being like millions of matches very close together. Once one catches fire, it ignites the ones around it. They ignite more and, suddenly, you have a big fire.

So, imagine you cut yourself and a bunch of bacteria enter the surrounding tissue. Our complement attack begins with C3. C3 is the first match, the initial spark that will start our fire. And, to do that, C3 needs to switch from passive to active. How this happens is complex, but let’s just say it happens randomly through other complement proteins that bind to enemies, or through antibodies. C3 breaks into two smaller proteins: C3a and C3b. C3b is like a seeker missile that is specialized for bacteria, fungi and viruses. It has a fraction of a second to find a victim, or it will be neutralized by water molecules. If C3b does find a target, it anchors itself firmly to its surface. By doing so, the protein changes its shape again. In its new shape, it can grab other proteins and start a small cascade, changing its shape multiple times and attaching more proteins to itself. Finally, it transforms itself into a recruiting platform known as C3 Convertase. This platform is an expert at activating new proteins that start the whole cycle anew. An amplification loop begins. Soon, thousands of proteins cover the bacteria. For the bacteria, this is very bad. It can cripple the bacteria and make them helpless, or slow them down.

But there’s more. Remember the other part of C3 -- the C3a protein? C3a is like a distress beacon. Thousands of them stream away from the battle scene, screaming for attention. Passive immune cells notice the C3a proteins and wake from their slumber to follow the protein tracks to the site of infection. The more alarm the proteins encounter, the more aggressive they get. So far, the Complement System has slowed down the invaders and called for help. Now, it’s actively beginning to help kill the bacteria. The first immune cells to arrive at the battlefield are phagocytes. Phagocytes are cells that swallow you whole, trap you in a tiny prison, and kill you with acid. But, to swallow an enemy, they need to capture it first. This is not easy because bacteria prefer not to get caught and are sort of slippery. But now, the complements that have attached themselves to the bacteria act as a kind of glue that makes it easy for the cells to catch their victims. But it gets even better.

Another cascade is about to begin. On the surface of the bacteria, the C3 recruitment platform changes its shape again and begins to recruit new proteins. Together, they begin the construction of a bigger structure: a Membrane Attack Complex. New proteins shaped like long spears anchor themselves deep into the bacteria’s membranes until they rip a hole that cannot be closed again. Fluids rush into the bacteria, and their insides spill out. They bleed to death. The remaining bacteria are maimed and distracted and are quickly taken care of by the arriving immune cells. The invasion is stopped completely before it has a chance to become dangerous. You probably didn’t even notice it.

But, while bacteria are not happy about the Complement System, it is most useful against viruses. Viruses have one problem: they need to travel from cell to cell. Outside of cells, they’re basically hoping to bump against one by pure chance. Here, they’re completely defenceless. And here, the Complement System can intercept and cripple them, and guide the immune system to devour them. Without the Complement System, virus infections would be a lot more deadly.

But, if we have such an effective weapon, why do we ever get sick? The problem is, both sides can adapt. For example, when the vaccinia virus infects a cell, it forces the cell to release a protein that shuts the Complement System down. This way, the virus creates safe zones around the cell it infects. When it kills the cell and tries to infect more, it has more chance of succeeding. So, the Complement System, while being extremely important, is only one player in our complex immune system.