The Human Immune System – Part 3

What happens when pathogens get past your skin defenses?

Continuing this essay series on the human immune system, this essay explores what happens when pathogens get past your skin defenses.  As Philipp Dettmer writes in his book Immune: A Journey into the Mysterious System That Keeps You Alive, describing what happens when you experience a slight cut:

In most cases, if things go well … [a]ll bacteria are killed and the immune system assists the civilian cells to heal. In the end this turns out to be a tiny wound, the kind you sustain all the time and never think about. But in this story things do not go well. Among the intruders there is a pathogen. A soil bacteria that is actually able to deal with the immune response and to multiply quickly.

When a pathogen gets past your skin defenses, a large variety of cells associated with the immune system come into play:

Similarly to Macrophages, Dendritic Cells have long tentacles to catch invaders and rip them into pieces. But their goal was not to devour them— no, they prepared samples made from the dead intruders, to present their findings to the intelligence centers of the immune system. After a few hours of sampling, the Dendritic Cells get on the move, leaving the battlefield behind to get help from the Adaptive Immune System. It takes the Dendritic Cell about a day to reach its destination and when it finds what, or better, who it is looking for, a beast will rouse from its sleep and all hell will break loose … [When] a Macrophage wants to swallow an enemy, it reaches out to it and grabs it tightly. Once it has a firm grip, it pulls its victim in, folds a part of its membrane into itself, and engulfs the victim, trapping it in a sort of mini prison that is now inside the Macrophage. In a sense, a part of the outside of the Macrophage becomes a sort of tightly closed garbage bag that is pulled inside. The Macrophage is equipped with an abundance of compartments that are filled with the equivalent of stomach acid— substances that dissolve things. These compartments then merge with the tiny prison and pour their deadly contents all over the victim, dissolving it into its components, into amino acids, sugars, and fats that are not only harmless, but even useful. Some become food for the Macrophage itself and others are spat out so other cells can have a meal too.

In an interesting aside regarding tattoos, Dettmer writes:

As a bonus they did not ask for, if you have a tattoo, a lot of it is probably stored in your Macrophages.  Have you ever asked yourself why your body would be OK with having huge amounts of ink below its skin? Because in general, your immune system is not OK with anything that is not itself, or did not get a special permit, hanging around in the body. But somehow, you can push ink with a fast- moving needle into the second layer of your skin and it remains there for many years. While the body is not excited about having ink under its skin, if the person scratching tasteful art into your flesh is doing their job correctly, it is also not particularly harmful. Still, your local immune system is not pleased by the intrusion. And so your skin swells and some of the ink particles are carried away. The majority stays in the tissue though— not because Macrophages do not try to gobble them up. Most of the metallic ink particles are just too large to be swallowed, and so they remain where they are. The ones that are small enough to be eaten, though, are eaten. While Macrophages are really great at breaking down bacteria and other cell garbage, they aren’t actually able to destroy the ink. So they just keep it inside themselves and store it. If you have a tattoo, when you look at it remember that it is partially trapped within your immune system. Unfortunately if a few years later you decide that the Chinese characters that turned out to mean “soup” are not as tasteful anymore and want to get them removed, your immune system also makes it really hard to get rid of a tattoo. The most common process of tattoo removal is a special laser that permeates your skin and heats up the ink particles so much on one side that it is put under tension and breaks apart into smaller pieces. Some float away, others are now eaten by Macrophages. This can make tattoo removal very hard, because even though old ink- filled Macrophages die at some point, young replacements arrive and swallow the remains of their dead predecessors, complete with all the ink inside. Again they can’t destroy it and so they just store and ignore it. This way tattoos stay visible for years. Over time, with each new cycle of replacement some of the ink gets lost and swept away in the process, or a few of the new Macrophages move a tiny bit around. So your tattoo will fade out and becomes less sharp on the edges.

Dettmer then describes the process of inflammation, a process that acts to contain the damage caused by pathogens:

Inflammation is something you probably never have thought about that much, since it’s pretty banal. You hurt yourself and the wound swells and reddens a bit, big deal. Who cares. But actually, inflammation is critically important for your survival and your health, enabling your immune system to address sudden wounds and infections. Inflammation is the red swelling and itching from an insect bite, the sore throat when you have a cold. In a nutshell, its purpose is to restrict an infection to an area and stop it from spreading, but also to help remove damaged and dead tissue and to serve as a sort of expressway for your immune cells and attack proteins directly to the site of infection! The way inflammation helps immune cells to get to the battlefield is very weird and fascinating. What basically happens is that the chemical signals from inflammation trigger a change in your blood vessels close to where the inflammation signals are coming from, and in your immune cells that get activated by these signals. Both parties extend many little special adhesion molecules that work a bit like Velcro. The immune cells that are speeding through the blood now can stick to the cells making up the blood vessels, and slow down close to the site of infection. On top of that, inflammation makes your blood vessels more porous, which makes it easier for your immune cells to squeeze through tiny spaces and move towards the battlefield. In a nutshell, inflammation is a process that makes the cells in blood vessels change their shape, so that plasma, the liquid part from your blood, can flood into a wounded or infected tissue. You can literally imagine this as floodgates opening and a tsunami of water, filled with salts and all sorts of special attack proteins, flooding the spaces between your cells so rapidly that tissue on the scale of a metropolitan area balloons up. Wherever your cells suspect that something fishy is going on they order inflammation as a dramatic first response … The injured toe becomes hot as the blood brings extra body heat. This heat does useful things for you: Most microorganisms do not like it hot— so making the wound hotter slows them down. In contrast, your civilian repair cells like the extra temperature very much as it speeds up their metabolism and enables your wound to heal faster. Then there is pain. Some of the chemicals released by inflammation make your nerve endings more susceptible to pain and through the process of swelling, there is pressure on nerve cells with pain receptors, motivating them to send whiny signals to the brain. Pain is a very effective motivation in the sense that we prefer not feeling it. The first way inflammation gets started is through dying cells. Amazingly, your body evolved a way to recognize if a cell died a natural way or if it died a violent death. The immune system has to assume that cells dying an unnatural death means grave danger, and so death is a signal that causes inflammation … Normally, when a cell has reached the end of its life, it kills itself through apoptosis that we encountered already. Apoptosis is basically a calm suicide that keeps the contents of the cells nice and tidy. But when cells die in unnatural ways, for example by being ripped into pieces by a sharp nail, burned to death by a hot pan, or poisoned by the waste products of a bacterial infection, the insides of your civilian cells spill all over the place. Certain parts of the guts of your cells, like DNA or RNA, are high-alert triggers for your immune system and cause rapid inflammation.

But how exactly do these “signals” and “triggers” work to “communicate” things to cells in the immune system?  As Dettmer writes:

At this point we have totally been ignoring another pretty important detail: How do cells know which way is which and where to go and where they are needed? When we imagine cells as people and remember that they’re patrolling the equivalent area of the European continent, one of the first questions you might have is, how could they possibly go the right way? Wouldn’t they get lost constantly? Also, to make this a bit more challenging, cells are blind, which makes sense if you think about it for a moment. OK, “seeing” and “hearing” in the sense humans are used to is not a great option in the microworld. So how do cells experience their world? How do they sense it and how do they communicate with each other? Well, in a way, cells smell their way through life. For cells, information is a physical thing: Cytokines. In a nutshell, cytokines are very small proteins that are used to convey information. There are hundreds of different cytokines and they are important in almost every biological process going on inside of you— from your development in your mother’s womb to the degeneration you experience as you get older. But the field where they are the most relevant and important is your immune system. They play a crucial role in the development of diseases and how your cells are able to respond. In a sense cytokines are the language of your immune cells.  Let’s say a Macrophage floats around and stumbles over an enemy. The discovery needs to be shared with other immune cell buddies, so it releases cytokines that carry the information “Danger! Enemy around! Come help out!” These cytokines then float away, carried purely by the random motion of particles in your bodily fluids. Somewhere else, another immune cell, maybe a Neutrophil, smells these cytokines up and “receives” the information. The more cytokines it picks up, the stronger it reacts to them … [T]he smell of cytokines also functions as a navigation system. The closer to the origin of the source of a smell a cell is, the more cytokines it will pick up. By measuring the concentration of cytokines in the space around it, it can precisely locate where the message is coming from and then begin moving in that direction. It is sort of “smelling” where the smell is the most intense. Which will lead it to the site of battle. To do this, your immune cells don’t have a single nose, they have millions of them, all over their bodies, covering their membranes in every direction. Why so many? For two reasons: First, by being covered by noses, cells have a 360 ° smell system. They can pretty precisely tell from which direction a cytokine is coming from. These noses are so sensitive that for some cells, as little a concentration difference as 1% in the cytokine signals around a cell is enough to tell it where to go. (Which is a fancy way of saying that there might just be 1% more molecules on one side of the cell.) This information is used to orient the cell in space and then make it move towards its target, always following the path where the most cytokines are coming from. A cell takes a step and then a whiff. And then it takes another step and takes another whiff. Until it gets to where it is needed … The more successful the soldiers at the battlefield are and the fewer enemies are alive, the fewer cytokines the immune cells will release. Over time, fewer and fewer reinforcements will be summoned to the battlefield. And on the battlefield the fighting cells will die over time through suicide. If things go correctly, the immune system shuts itself off … How exactly do cytokines convey information and what does this mean? How does a protein tell a cell what to do? As we discussed before, cells are protein robots guided by biochemistry. The chemistry of life causes sequences of interactions between proteins that are called pathways. The activation of pathways causes behavior. In the case of cytokines, the information protein of the immune system, this happens through pathways that involve special structures called receptors on cell surfaces. They are the noses of your cells … In a nutshell, receptors are protein recognition machines that stick in the membranes of cells. A part of them is outside the cell and another part is inside the cell. Actually, about half of the surface of your cells is covered by myriads of different receptors for all sorts of functions, from taking in certain nutrients to communicating with other cells or as triggers for a variety of behaviors. In a simplified way, receptors are sort of the sensory organs of cells that let the insides of the cells know what happens on the outside. So if a receptor recognizes a cytokine, it triggers a pathway inside the cell … In a nutshell, proteins interact with proteins a few times, until eventually, they change the behavior of a cell … The actual biochemistry of the immune system is a nightmare all on its own so we will skip the details here.

Dettmer adds this aside regarding cytokines:

Why do you lose your appetite when you are sick? Well, you can blame the onslaught of cytokines that your immune system releases for that. The cytokines signal your brain that a serious defense is happening at that very moment that the body needs to conserve energy for. Because as you may imagine, mobilizing millions or billions of cells for a fight is a pretty resource-heavy operation. Digesting food actually requires a lot of energy too, so shutting these processes down is freeing up your system to focus on the defense. It also reduces the availability of certain nutrients in your blood that your invaders would love to get their tiny pathogenic hands on. This does not mean that you should actively try to starve out a disease. Not digesting is a short-term strategy not a long-term solution.

In the next essay in this series, we’ll explore how the immune system tells parts of “you” from parts that “aren’t you.”