The Human Immune System – Part 4

How does the immune system tell parts of “you” from parts that “aren’t you”?

Continuing this essay series on the human immune system, this essay explores how the immune system tells parts of “you” from parts that “aren’t you.”  As Philipp Dettmer writes in his book Immune: A Journey into the Mysterious System That Keeps You Alive:

How does a cell “know” what a bacterium smells like? Why do bacteria smell like bacteria at all? How does your immune system recognize friend from foe? … [H]ow does the Innate Immune System know what and who to attack? Who is self and who is other? And more specifically, how do your soldier cells know what a bacterium smells like? As we discussed earlier, one of the biggest advantages microorganisms have over multicellular animals is the rapid pace at which they are able to change and adapt. As multicellular life has been in competition with microorganisms for hundreds of millions of years now— why didn’t bacteria find ways to start hiding their smell? The answer lies in the structures that make living things. All life on earth is made from the same fundamental molecule types that are arranged in different ways: carbohydrates, lipids, proteins, and nucleic acids. These basic molecules interact and fit together to create structures and these structures are the building blocks of life on earth. We discussed the most important building block already quite a bit, proteins. So for simplicity, we will focus on proteins here as they account for the majority of building blocks— this does not mean the others are not important but the principle is mostly the same and it is helpful to zero in on something. As we said before, the shape of a protein determines what it can do and how it can interact with other proteins, what structures it can build, and what information it can convey. Every shape is a little bit like a 3D puzzle piece that, together with other pieces, makes up the overall puzzle. Puzzle pieces are a good way to imagine protein shapes because they make something else clear too: Only certain shapes can connect with other certain shapes. But if they do, they fit together quite nicely and firmly. Since there are billions upon billions of different possible protein shapes, life has a large variety of pieces to choose from when it wants to build a new living thing— say for example, a bacterium. There are a lot of different bacteria you could build from the available protein puzzle pieces of life. Except actually there are limitations to that freedom. For some specific jobs, the protein puzzle pieces of life can’t be altered and still keep their function. It doesn’t matter how much a bacterium mutates or what new sort of clever protein combination it comes up with: There are certain proteins that it can’t stop using if it wants to be a bacterium. Your immune system is using this fact to recognize if something is self or other. So how does this work in reality? A great example is the flagellum. Flagella are micromachines that some species of bacteria and microorganisms use to move. They are long protein propellers attached to the bacteria’s tiny butts that are able to rotate fast and propel the tiny being forward. Not all bacteria have them, but many do. It is a pretty ingenious way to move around in the microworld, especially if you are living in shallow and stale water. Human cells do not use them at all. So if an immune cell recognizes that something has a flagellum, it knows that this something is 100% other and has to be killed. Of course, your cells don’t know anything because they are stupid. But they have receptors! And it so happens that your innate immune cells have receptors that can recognize the protein puzzle shapes that make up flagella, and will enable the immune cells to eliminate them. The proteins that make up the flagellum of a bacterium are the matching puzzle pieces for the receptors on our immune soldiers. When a Macrophage receptor connects to a bacterium protein that fits, two things happen: The Macrophage gets a tight grip on the bacteria and it also triggers a cascade inside the cell that lets it know that it found an enemy and that it should swallow! This basic mechanism is at the core of how your innate immune system knows who is an enemy or not … It’s a very simple mechanism really: Receptors themselves are special puzzle pieces, able to connect to another puzzle piece— which in this case, means the shape of flagella proteins. If the Macrophage is able to connect, it goes into kill mode. This is how your innate immune cells are able to recognize bacteria, even if they never have encountered a specific species ever before. Every bacteria has some proteins that it can’t get rid of [while still being a bacterium]. And your innate immune cells come equipped with a very special group of receptors that are able to recognize all the most common puzzle pieces of our enemies … This principle of cells identifying the puzzle pieces of enemies with sort of sensory receptors on their surfaces is called microbial pattern recognition and it will become even more important later on for the adaptive immune system, which uses the same basic mechanism, but in a much more ingenious way.

In an interesting aside regarding the fertilization of a human egg, Dettmer writes:

[W]hy does the body of a woman not recognize sperm cells as other and kill them right away? Well, it does! This is one of the reasons you need about 200 million sperm cells to fertilize a single egg! Right after sperm is delivered into the vagina, it is confronted with a hostile environment that it has to deal with. The vagina is a pretty acidic and deadly place for visitors, so sperm cells move on as fast as possible to escape it. Most of them gain access to the cervix and uterus within a few minutes. Although here they are greeted by an onslaught of Macrophages and Neutrophils that kill the majority of the friendly visitors that are only trying to do their job. Sperm cells are at least a bit equipped to deal with the hostile immune system (a little like a specialized pathogen if you think about it). They release a number of molecules and substances aimed at suppressing the angry immune cells around them, to buy them a little bit of time. And it may actually be the case that they are able to communicate with the cells that line the uterus, to let them know that they are friendly visitors, which might turn down inflammation. But there is a surprisingly large number of things that are not completely understood yet, in these interactions. In any case, from the millions of sperm cells that entered, only a few hundred enter the fallopian tubes and get a shot at fertilizing the egg.

Dettmer describes the “complement system” of our immune system:

Basically the complement system is an army of over thirty different proteins (not cells!) that work together in an elegant dance to stop strangers from having a good time inside your body. All in all, about FIFTEEN QUINTILLION complement proteins are saturating every fluid of your body right now. Complement proteins are tiny and they are everywhere. Even a virus looks reasonably large next to them. If a cell were the size of a human, a complement protein would barely be the size of a fruit fly egg. Since it is even less able to think and make decisions than your cells are, it is guided by absolutely nothing but chemistry. And yet it is able to fulfill a variety of different objectives … Complement proteins float around in a sort of passive mode. They do nothing, until they get activated. Imagine complement proteins as millions of matches that are stacked very close together. If a single match catches fire, it will ignite the matches around it, these ignite more, and suddenly you have a huge fire. In the world of complement proteins, catching fire means changing their shape. As we said before, the shape of a protein determines what it can and can’t do, what they can interact with, and in what way. In their passive shape complement proteins do nothing. In their active shape, however, they can change the shape of other complement proteins and activate them. This simple mechanism can cause self- enforcing cascades. One protein activates another. Those two activate four, which activate eight, which activate sixteen. Very soon, you have thousands of active proteins. As we learned briefly when we talked about the cell, proteins move extremely fast. So within seconds complement proteins can go from being totally useless to an active and unavoidable weapon that is spreading explosively. In reality, this means that a specific and very important complement protein needs to change its shape. It has the amazingly useless name “C3.” Within a few seconds of the first complement protein activating, thousands of proteins cover the bacterium all over. For a bacterium, this process can cripple and maim it, making it helpless and slowing it down considerably … [T]he soldier cells are phagocytes, cells that swallow enemies whole. But to swallow an enemy they need to grab it first. Which is not as easy as we made it out to be. Because bacteria prefer not to be grabbed and try to slip away. And even if they didn’t insist on trying to not be killed, there is a sort of physics problem: The membranes of cells and bacteria are negatively charged— and as we learned from playing with magnets, the same charges repel each other. This charge is not so strong that it can’t be overcome by a phagocyte, but it does make it considerably harder for immune cells to grab bacteria. But! Complement has a positive charge. So when complement proteins have anchored themselves to the bacteria, they act as a sort of superglue, or better, little handles, that make it much easier for your immune cells to grab and hold on to their victims. A bacterium covered in complement is easy prey for soldier immune cells and in a way, much tastier! … On the surface of the bacteria the C3 recruitment platform changes its shape again and starts to activate another group of complement proteins. Together they begin the construction of a larger structure: A Membrane Attack Complex, which, I promise, is the only good name within the complement system. Piece by piece, new complement proteins, formed like long spears, anchor themselves deep in the bacteria’s surface, impossible to remove. They stretch and squeeze, until they rip a hole into it, one that can’t be closed again. A literal wound. Fluids rush into the bacterium and its insides spill out. Which makes it die quite quickly. But while bacteria are not happy about complement, the enemy it might be the most useful against are actually viruses. Viruses have a problem, namely that they are tiny floaty things and need to travel from cell to cell. Outside of cells, they are basically hoping to randomly bump against the right cell to infect it by pure chance, which also makes them virtually defenseless as they float around. And here complement is able to intercept and cripple them so they become harmless. Without complement, virus infections would be a lot more deadly. But more on viruses later. Back in our nail-inflicted wound, millions of complement proteins have maimed or killed hundreds of bacteria, making it much easier for your Neutrophils and Macrophages to clean them up. The fewer bacteria the complement proteins find to attach to, the fewer get activated. And so, the complement activity slows down again. When there are no more enemies around, complement just becomes a passive and invisible weapon again. The complement system is a beautiful example of how many mindless things can do smart things together … Dendritic Cells … identify what kind of enemy is infecting you, if it is a bacterium or a virus or a parasite. And they make the decision to activate the next stage of your defense: Your adaptive immune cells, your heavy, specialized weapons that need to come in if your innate immune system is in danger of being overwhelmed.

Dettmer then describes our lymph node highway system:

[T]he living information carrier needs to be delivered to a lymph node. To get there, the Dendritic Cell has to enter the Immune System Superhighway: The Lymphatic System, which is a great opportunity to get to know your internal plumbing! … The Lymphatic System [has] a far-reaching network of vessels and its own special fluid … Your network of lymphatic vessels is miles long and covers your entire body. It is a sort of partner system to your blood vessels and blood. The main job of your blood is to carry resources like oxygen to every cell in the body and to do that, some of the blood needs to actually leave your blood vessels and drain into your tissue and organs to deliver the goods directly to your cells.

In the next essay in this series, we’ll examine how your immune system catalogues a library of antigens, and how T-cells work.