Every living being needs to fight off other living beings that want to feast on them. So as multicellular life evolved over billions of years, it came up with ways to find itself. Today humans have a sophisticated defence network, like physical barriers (skin), defense cells (macrophages), and weapons factories (B-cells). But one of the most important defenses of our body is largely unknown: THE COMPLEMENT SYSTEM.
Complement was discovered many years ago as a heat-labile component of normal plasma that augments the opsonization of bacteria by antibodies and allows antibodies to kill some bacteria. This activity was said to ‘complement’ the antibacterial activity of antibody, hence the name. Although first discovered as an effector arm of the antibody response, complement can also be activated early in infection in the absence of antibodies. Indeed, it now seems clear that complement first evolved as part of the innate immune system, where it still plays an important role.
The complement system is made up of a large number of distinct plasma proteins that react with one another to opsonize pathogens and induce a series of inflammatory responses that help to fight infection. A number of complement proteins are proteases that are themselves activated by proteolytic cleavage. Such enzymes are called zymogens and were first found in the gut. The digestive enzyme pepsin, for example, is stored inside cells and secreted as an inactive precursor enzyme, pepsinogen, which is only cleaved to pepsin in the acid environment of the stomach. The advantage to the host of not being autodigested is obvious.
It evolved over 700 million years ago and is an army of over 30 different proteins that work together in a complex and elegant dance to stop intruders. All in all, about 15 quintillion of them are saturating every fluid in your body right now. Guided by nothing but chemistry, these proteins are one of them most effective weapons we have against invaders. Many other parts of the immune system are just tools to activate the Complement system. But it's also really dangerous. Imagine having trillions of little bombs inside your blood that could go off at any moment. So our cells use numerous mechanisms to prevent complement from accidentally attacking them. Okay, what exactly does it do and what makes it so dangerous ?
In a nutshell, The complement system does three things: it cripples enemies, it activates the immune system, and it rips holes in things until they die. But, how ? After all, these are mindless proteins randomly drifting 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 get activated and change their shape. In the world of proteins, your shape determines what you can and 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 your active shape, however, you might, for example, change the shape of other proteins, activating them so they can activate others. Mechanisms like this one can start cascades that spread very quickly. Imagine the complement proteins as being like millions of matches very close together. Ones one catches fire, it ignites the ones around it. They ignite more and suddenly you have a big fire.
To show the actual mechanisms of The Complement System is a tad complicated and overwhelming. So, I'll simplify here. Now, let's imagine you cut yourself and a bunch of bacteria enter the wound and make it into the surrounding tissue. Our complement attack beings 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 too active. How this happens is complex, but let's just it can happen randomly through other complement proteins that bind to enemies or through antibodies. All you really need to know is that C3 breaks into two smaller proteins, C3a and C3b, that are now activated. One of these parts, the C3b proteins, is like a seeker missile specialised bacteria, fungi, and viruses. It has a fraction of a second to find a victim or it will be neutralised by water molecules. If C3b does find a target, it anchors itself very tightly to its surface and doesn't let go. By doing so, the protein changes its shape again. In its new shape, it's now able to grab other proteins and start a small cascade, changing its shape multiple times, adding other complement proteins to itself. Finally, it transforms itself into a recruiting platform known as C3 Convertase.
This platform is an expert at activating more C3 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. Imagine being covered by thousands of flies. But, these's more. Do you remember the other part of C3- the C3a protein ? C3a is like a distress beacon. Thousands of them flood away from the site of battle screaming for attention. passive immune cells notice the C3a proteins, and awaken from their slumber to follow the protein tracks to the site of infection. The more alarm proteins they encounter, the more aggressive they get. This way, complement guides reinforcements exactly to the place where they're needed the most. So far, the complement has slowed down the invaders and called for help. Now, it's beginning to actively help to kill the enemy.
The first immune cells to arrive at the battlefield are Phagocytes. Which means, cells that swallow you whole, trap you in a tiny prison, and then kill you with acid. But, to swallow an enemy, they need to grab it first. Which is not easy because bacteria prefer not to be grabbed and are sort-of slippery. But now, the complement that has anchored itself to the bacteria acts as a sort-of glue that makes it easy for the immune cells to catch their victims. But it gets even better. Imagine being covered in flies again. Now, imagine them turning into wasps. Another cascade is about to begin. On the surface of a 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.
Piece-by-piece, new proteins shaped like long spears anchor themselves deep into the bacteria's membranes, until they rip a hole into them that can't be closed again. Fluids rush into the bacteria and their insides spill out. They bleed to death. The remaining bacteria are maimed and distracted by the complement, and quickly taken care of by the arriving immune cells. The invasion has been nipped in the bud before it had the opportunity to became dangerous. You probably didn't even notice it. But while bacteria are not happy about complement, the enemies it might be the most useful against are actually viruses. Viruses have one problem: they need to travel from cell to cell. Outside of cells, they're basically hoping to randomly bump against a cell to infect by pure chance. Here, they're completely defenseless. And here, complement is able to intercept and cripple them, so they became harmless and guide the immune system to devour them. Without complement, virus infections would be a lot more deadly.
But wait, if we have such an effective weapon, why do we ever get sick ?
The problem is that in a war, both sides adapt. For example, when the vaccinia virus infects a cell, It forces it to produce a protein that shuts complement activation down. This way, the virus creates safe zones around the cells it infects. When it kills them, and tries to infect more, it has a higher chance of being successful.
The human complement system plays an important role in the defense against invading pathogens, inflammation and homeostasis. Invading microbes, such as bacteria, directly activate the complement system resulting in the formation of chemoattractants and in effective labeling of the bacteria for phagocytosis. In addition, formation of the membrane attack complex is responsible for direct killing of Gram-negative bacteria. In turn, bacteria have evolved several ways to evade complement activation on their surface in order to be able to colonize and invade the human host. One important mechanism of bacterial escape is attraction of complement regulatory proteins to the microbial surface. These molecules are present in the human body for tight regulation of the complement system to prevent damage to host self-surfaces. Therefore, recruitment of complement regulatory proteins to the bacterial surface results in decreased complement activation on the microbial surface which favors bacterial survival. This review will discuss recent advances in understanding the binding of complement regulatory proteins to the bacterial surface at the molecular level. This includes, new insights that have become available concerning specific conserved motives on complement regulatory proteins that are favorable for microbial binding.
So the complement system, while being extremely important, is only one player in the complex and beautiful organization that is our immune system. A beautiful example of how many mindless things can do smart things together.
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