Immune: A Journey Into the Mysterious System That Keeps You Alive

by Philipp Dettmer

The hulls of viruses are spiked with special proteins that can connect to a receptor type on their victims’ surface. This means that viruses can’t attach to just any cell—only to the ones that have a receptor they can attach to. In a sense every virus has a lot of puzzle-piece proteins that can only connect to a cell if it happens to have the correct puzzle-piece receptor.

Once a virus gets in contact with the kind of cell it is looking for, it quietly takes it over. How a virus does this varies a lot from species to species, but in general a virus transfers its genetic material into its victim and forces the cell to stop making cell stuff. It is turned into a virus production machine.

If cells were conscious, viruses would be terrifying to them. Imagine spiders that don’t crawl on walls, but passively float around the air, hoping to get into your mouth when you are not careful for a moment, crawling into your brain and forcing your insides to produce hundreds of new baby spiders until all your body is filled with them. And then your skin would burst open and all these new spiders would try to get your family and friends. This is literally what viruses do to cells.

The innate immune system is not nearly as effective against pathogenic viruses as it is against bacteria. So in the case of pathogenic virus infections (or bacteria who hide inside cells), your body desperately needs help from the adaptive immune system to stand a chance of clearing an invasion.

Plasmacytoid Dendritic Cells.*1 These special cells spend their lives moving through your blood or camp out in the lymphatic network, scanning specifically for signs of viruses—panic interferons from civilian cells or just straight up viruses that float around in your fluids. In any case, if they do pick up signs of a viral infection, they activate and turn into chemical power plants that ooze out extreme amounts of interferons, alerting not only civilians to turn on their antiviral modes (shut down protein production, etc.) but also the immune system to activate and get ready for a proper fight.

Your soldier cells realize that they are dealing with a virus infection and that they need help on a larger scale, so they release another set of cytokines: Pyrogens. Pyrogen loosely translated means “the creator of heat,” an extremely fitting name in this case. Simply put, pyrogens are chemicals that cause fever

Fever is a systemic, body wide response that creates an environment that is unpleasant for pathogens and enables your immune cells to fight harder. It also is a strong motivator to lie down and rest, to save energy, and to give your own body and immune system the time they need to heal or to fight the infection.

Pyrogens work in quite a cool way, in the sense that they directly affect your brain and make it do things. You probably have heard about the blood-brain barrier, an ingenious contraption that stops most cells and substances (and pathogens of course) from entering the very delicate tissues of your brain, to keep it safe from damage and disturbance. But there are regions of your brain where this barrier is partially penetrable by pyrogens. If they enter and interact with your brain they trigger a complex chain of events that basically cranks up the temperature by changing the internal thermostat of your body.

Your brain cranks up the heat in two main ways: For one, it may generate more heat by inducing shivering, which is just your muscles contracting really quickly, which generates heat as a byproduct. And by making it harder for this heat to escape by contracting the blood vessels close to the surface of your body, which reduces the heat that can escape through your skin. This is also the reason why you can feel so cold when you have a fever—your skin is actually colder because your body is trying to really heat up your core and create unpleasant temperatures at the battlefield to make pathogens really unhappy.

Every cell of your body that has a nucleus (so not red blood cells) has MHC class I molecules. OK, why is that and how does this work? As we said before, cells are constantly breaking down their proteins so their parts can be recycled and reused. The crucial thing here is that while this recycling happens, your cells pick a random selection of protein pieces and transport them to their membranes to display them on their surfaces. The MHC class I molecule showcases these proteins to the outside world, just like a fancy display window would showcase a selection of the items the inside of a store has to offer. This way, the protein story of what is going on inside the cell can be told to the outside. To make sure the story is always up-to-date, your cells have many thousands of display windows—or many thousands of MHC class I molecules—and each one gets refreshed with a new protein, about once a day.

all of your cells constantly display proteins in their MHC class I molecules, infected cells present their insides to the outside world, even if they don’t “know” that they are infected! The display-window thing is an automated process that always happens in the background as part of the normal life of your cells. If an immune cell wants to check if a cell is infected, it simply can move closer and peer into the little “windows” to get a snapshot of the inside. If it recognizes things in the windows that should not be inside the cell, the infected cell will be killed.

This is the unfortunate reason that after you receive a donated organ, you need to be on strong medication that suppresses your immune system for the rest of your life. To minimize the chance that your immune cells find the foreign MHC class I molecules and kill the cells carrying them. But of course this will leave you much, much more vulnerable to infections.

Killer T Cells are the siblings of Helper T Cells but their job is very different. If the Helper T Cell is the careful planner that makes smart decisions and shines through its ability to organize, the Killer T Cell is a dude with a hammer that bashes heads in while laughing maniacally. “Killer” T Cell is a perfect name considering what it does: It kills, efficiently, fast, and without mercy.

Just like the Helper T Cells need hot dog buns to recognize antigens (MHC class II molecules), Killer T Cells depend on the display windows (MHC class I molecules) to get activated.

Natural Killer Cells are sort of inconspicuous fellows that nonetheless are one of the few cells with an official license to kill your own body cells. In a way you can imagine them as inquisitors of the vast empire of your immune system. Always looking for corruption and able to act as a judge, jury, and executioner.

Natural Killer Cells do not look inside cells. Even if they wanted to, they couldn’t—they have no way to look into the display windows, the MHC class I molecules, and read the story of the inside of the cell. No, instead they do something different: They check if a cell has MHC class I molecules. Nothing more, nothing less. This is solely to protect against one of the best anti–immune system tactics virus and cancer cells have. Generally cells that are either infected or unhealthy do not show MHC class I receptors in order to hide what is going on inside them. Many viruses force infected cells to stop showing them as part of their invasion strategy, and many cancer cells just stop putting up display windows, thus making them invisible to the antiviral immune response that we have shown thus far.

While the rest of the immune system looks for the presence of the unexpected, the presence of something other, Natural Killer Cells look for the absence of the expected, the absence of self. This principle is called “The Missing-Self Hypothesis.”

And while you lie in your bed and feel horrible, it is important to remember that the symptoms you feel are mostly created by your own immune system to clear out the infection. If these countermeasures are used too freely, your immune system can do immense and terrible damage to you, much worse than even the influenza A virus could do. So there is an intense need to downregulate the immune response again, to have it strike with just the exact amount of vigor, and to shut it down as soon as it is not needed. To get back to homeostasis

why don’t we just have good medication against viruses? Why is it that we have so many different antibiotics that protect us from most types of bacteria, from the plague to urinary tract infections to blood poisoning, but nothing really great against the flu, the common cold, or the coronavirus? Well, here we encounter a fundamental problem: viruses are too similar to our own cells. Wait. What? Well, they are not similar in the sense that a virus is similar to a cell, but in the sense that viruses mimic or work with your own parts.

Let us use this moment to explain how antibiotics work. Like Prometheus who stole fire from the gods and gave it to humanity and made it more powerful, scientists stole antibiotics from nature to make it live longer. In the wild, antibiotics are typically natural compounds that microbes use to kill other microbes. Basically the swords and guns of the microworld. The first successful antibiotic, penicillin, is a weapon from the mold Penicillium rubens that works by blocking bacteria’s ability to make cell walls. As a bacterium tries to grow and divide it needs to produce more cell walls and Penicillium has a shape that interrupts this construction process and prevents the bacteria from making more of itself. The reason why you can safely be treated with penicillin is that your cells don’t have cell walls! Your cells are lined with membranes, which is a fundamentally different structure, so the drug doesn’t do anything to your cells.

Think about the nature of a virus. Viruses can be attacked in two places, outside of your cells and inside of cells. If you want to attack them outside of your cells, then you basically have to attack the proteins they use to connect to the receptors of your cell. The huge, monumental problem with that, is that if you do this, you may just have created a drug that will also connect to a lot of parts inside your body. Because to connect to one of your receptors a virus needs to mimic a part of your body. A part that fulfills some sort of vital function. If you develop a drug that attacks a virus that connects to this receptor it is likely that it will target all the parts of your body that are supposed to connect to the receptor. It is the same inside your cells—we can’t make antiviral drugs that target different metabolic processes of a virus, like for example the ribosome. Because this is our ribosome the virus is using. A virus is in a perverse way very similar to us because it uses our own parts to make more of itself.

Activation usually begins with an initial exposure of immune cells to intruders, like bacteria, or danger signals, like the insides of dead cells. For example, Macrophages get activated when they notice an enemy and release cytokines that call up Neutrophils and cause inflammation. The Neutrophils themselves release more Cytokines, causing more inflammation and reactivating Macrophages, who continue fighting. Complement proteins stream into the site of infection from the blood, attack pathogens, opsonize them, and help the soldier cells to swallow the enemies. Dendritic Cells sample enemies and make their way to the Lymph Nodes to activate Helper T Cells or Killer T Cells, or both. Helper T Cells stimulate the innate immune soldiers to continue fighting and create more inflammation. Killer T Cells start killing infected civilian cells with support from Natural Killer Cells. Meanwhile, activated B Cells have turned into Plasma Cells and release millions of Antibodies that stream onto the battlefield and disable the pathogens, maiming them and making them much easier to clear up. This is the immune response in a nutshell.

Memory cells are one of the main reasons why young children often die of diseases that their parents shake off easily: There are just not enough living memories in their tiny bodies yet, and so even smaller infections can spread and become a mortal danger. Their parents, with an Adaptive Immune System that is remembering thousands of invasions, can just rely on their living memory. And likewise, as we reach old age, more and more Memory Cells stop working as well as when they were younger or just call it quits, leaving us exposed in the last phase of our lives.

The first group is called Long-Lived Plasma Cells who wander into your bone marrow and as their very creative name suggests, they live pretty long. Instead of vomiting out as many Antibodies as they can, they make themselves comfortable and find a home where they will stay for months and years. From there they constantly produce a moderate amount of Antibodies. So their entire job is to make sure that specific Antibodies against enemies we fought off in the past are always present in your bodily fluids.

But it can’t be overstated how incredibly effective memory cells are. They are so powerful and deadly that you usually will not even notice if you are reinfected by the same pathogen—even if it is a serious and dangerous one. Once your body has memory cells against an invader you are basically immune for decades, if not your whole life.

But there is a vicious part of measles that is not discussed as much as the disease itself: Kids who overcome a measles infection have a higher chance of getting other diseases afterwards because the measles virus kills Memory Cells. If you think that sounds a bit scary, that is the correct reaction—the virus basically deletes your acquired immunity. Let us explore how this works now that we know all the different elements of your immune system.

So in the end, being infected with measles erases the capacity of the immune system to protect you from the diseases that you overcame in the past. Even worse, a measles infection can wipe away the protection that you might have gained from other vaccines, since most vaccines create memory cells. Therefore, in the case of measles, what does not kill you makes you weaker, not stronger. Measles causes irreversible, long-term harm and it maims and kills children.

Today, vaccines provide immunity against a whole plethora of dangerous infections by creating Memory Cells that are ready to meet a specific pathogen in case it ever shows up for real.

So to basically cheat the system humans began producing antivenoms—which are nothing more than purified antibodies against the venom molecules that can be injected into the system of a person that got bitten! The way these antibodies are made is pretty curious—venom is first harvested from a snake and then injected into mammals, like horses or rabbits, in a dose they can handle without dying. The dose is slowly increased over time so they have a chance to develop immunity against it—which means that they produce a large number of specific antibodies against the venom that saturate their blood and make them immune. This blood is then harvested and the antibodies are filtered from all the other animal blood components.

The annoying thing about passive immunization is that it is temporary. If you administer Antibodies to someone, they will stay protected as long as the Antibodies are around. But this protective effect goes away as the Antibodies are either used up or decay through natural processes. So as great as passive immunization is, it is not the best way to create immunity for most people.

mRNA vaccines. The basic principle here is pretty genius, it is basically making our own cells produce antigens that the immune system can then pick up. Remember mRNA, the molecule that tells the protein production facilities in your cells what proteins to make? Basically, you inject someone with mRNA that will make a few of your cells make viral antigens, which the cell then showcases to the immune system. The immune system is pretty alarmed by this and will create defenses against this antigen.

The reasons for the anti-vaccine movements mistrusting vaccines are diverse, but in the United States and Europe the belief that the risks of vaccines outweigh their benefits is especially prevalent. That vaccines are an artificial intervention into natural processes and that it is less dangerous to let nature run its course. If you understand the mechanisms of the immune system and how immunity is created, this idea quickly loses all power because vaccines and diseases both do the same thing: They create Memory Cells by triggering an immune reaction. But while pathogens do this by attacking the body and causing a huge amount of stress, which carries the very real risks of various long-term consequences including death, vaccines arrive at the same goal, without all the risks of diseases.

What makes HIV so incredibly dangerous is that it operates on a completely different level in terms of genetic variability. The genetic code of HIV is extremely prone to copying errors—on average, every time the virus makes a copy of itself it makes an error. Which means even in a single cell there are numerous different variants of HIV. This has three possible outcomes: 1. HIV destroys itself because it mutates in a way that disables itself or it becomes less effective. 2. The mutation does not help or harm and nothing changes. 3. The virus becomes better at avoiding the defenses of the immune system.

It took the Adaptive Immune System about a week to make thousands of Killer T Cells and millions of antibodies that are extremely good at hunting HIV down—but already there are numerous new viruses that have new and different antigens! Different enough that the Killer Cells and Antibodies you just made may be useless against them. And now the new and different viruses infect new cells and make millions of copies of themselves, again. For them, the virus your Adaptive Immune System adapted to is already old news and irrelevant. HIV is always a step ahead of the immune system. And so in the chronic phase of an HIV infection your body is still teeming with the virus.

So let us summarize the tactic of HIV real quick before we move on: By infecting Dendritic Cells, the virus gets a taxi into HIV heaven: The lymph nodes, which are filled top to bottom with Helper T Cells. HIV can build reservoirs in these cells and stay hidden indefinitely. When Helper T Cells begin to proliferate massively, they do so at lymph nodes, which is the ideal place for HIV to also make millions of new viruses. So the place that is most central to building protection against viruses is completely taken over and actually becomes a weak point. This is still not the worst part. Think about what HIV really does by specifically attacking T Cells: It destroys and kills the cells that the Adaptive Immune System needs to properly activate B Cells and Killer T Cells. Still your Immune System does not give up. An epic struggle begins that will go on for years. Every day, HIV makes billions of new viruses and your immune system reacts in kind with new antibodies and new Killer T Cells. A push and pull of death and rebirth, a struggle for survival on both sides. This struggle can take up to ten or more years and usually comes with very few noticeable side effects—which in a perverse twist enables an infected person to serve as a reservoir and infect others. And although your immune system is giving its all, the cards are stacked against you. Not only are your Helper T Cells constantly being infected by HIV, Killer T Cells viciously hunt them down too. (That is because, if y...

HIV infections used to be a death sentence, with the disease marching towards an eventual outbreak of AIDS that was soon followed by death. But thanks to an immense and unparalleled effort of the scientific and medical community, for people receiving proper treatment, HIV has turned into a chronic disease that is manageable. Almost all therapies for HIV are targeted at preventing the last stage—to prevent AIDS from ever breaking out, because this is where people die.

immune system is much more dangerous to your survival than any pathogen ever could be. Think of Ebola, even this pretty disgusting and horrible disease needs about six days to kill you. Your immune system has the power to kill you in about fifteen minutes.

The truth is we don’t know yet why some people produce a lot of IgE Antibodies when they come in contact with certain allergens and others don’t. But while we don’t know for sure why some people are more affected than others, we think we know what IgE Antibodies were originally supposed to do: They are the immune system’s superweapons against large parasites that are too big for your phagocytes, your Macrophages, and your Neutrophils to swallow. Especially one of the most horrible parasites: Parasitic worms. A menace humanity has had to deal with for millions of years.

Parasites could provide some answers to the annoying nature of allergies. One of the worst things to do late at night is to google infections by parasitic worms. You can ruin your life even more if you click on image search. Of all the possible pathogens and parasites that can victimize humans, worms are by far the most upsetting ones. Nothing quite compares to a faceless, slimy, stringy thing that drills itself through your insides, pooping, laying eggs, spending its whole life inside you. It’s right out of a horror movie.

Parasitic worms that have adapted to humans are able to modify and recalibrate almost every facet of their host’s immune system. They employ a wide range of immunosuppressive mechanisms. Or put simply: Worms release a plethora of chemicals to downregulate and modulate your immune system to make it weaker.

In evolutionary terms, humans in developed countries in the last few hundred years or so suddenly lost their parasitic wormy guests. The advent of soap and hygiene and the clear separation of poop and drinking water destroyed the life cycles of most of the worms that were living within us. The remaining worms were exiled by drugs and modern medicine. Which left our immune system suddenly without the enemy that had kept it down a notch for millions of years. And so it might be that our immune system still operates under the assumption that worms are making it weaker and that it needs to be more aggressive as a counterbalance. If this general idea is true it might explain a lot of diseases caused by too-aggressive immune systems in people without worms, mostly allergies and inflammatory disease. And not only that—the lack of worms leaves a whole bunch of our cells without the enemy they were made to fight on a regular basis. So the idea makes sense that without wormy stimulation, these weapons just found new targets.

In a nutshell, in autoimmunity, your T and B Cells are able to recognize proteins that are used by your own cells. Self-antigens. The antigens of self. You

What needs to go wrong for your immune system to get so horribly confused? Well, there are a few stages, a few conditions that need to be met: First of all, your MHC molecules actually need to be physically able to bind to your own self-antigen efficiently. This is mostly genetic, and as everything that is etched into our genetic code, bad luck. You can’t choose your parents and you can’t choose your genetic makeup. (At least not yet.) In an earlier chapter we talked about the fact that MHC molecules vary a lot between different individuals and come in a few hundred slightly different shapes. Not all of these shapes are great, just by a whim of nature, some types are pretty good at presenting self-antigen. There is a hereditary risk for autoimmunity that varies between all of us—so while everybody can get autoimmune diseases, chances are higher for some, those with genes that make specific MHC molecule types. But just a genetic predisposition is not enough.

for most autoimmune diseases, these seem to be the steps that cause them: Step one: There are individuals who have a genetic predisposition. (Which is not a required step but it greatly enhances your chances.) Step two: They make B or T Cells that are able to recognize a self-antigen. Step three: An infection provokes the Innate Immune System into activating these faulty B or T Cells.

But some pathogens will also try to mimic the shapes of their host, which makes a lot of sense, since this is a mechanism we can observe plenty in the animal kingdom: Camouflage is hugely beneficial if you have to survive in a world of roaming hunters. And so from butterflies that try to look like leaves to white partridges that blend in to snow and crocodiles that disappear in muddy water, a wide range of animals try to be as hard to spot as possible. For a pathogenic virus or a bacteria your tissue is a jungle full of angry predators that are looking for them, so mimicking the environment to become harder to spot is an effective strategy.

No matter how many civilian cells your immune system kills, your body will make more—and so chronic inflammation, chronic immune system activation, is the consequence. Your misguided immune cells think they are perpetually surrounded by enemies and act like it.

To alleviate pain and inflammation, generally autoimmune diseases are treated with a variety of medication that suppresses the immune system, particularly inflammation, which as you may imagine, is not great either. It may alleviate the symptoms of autoimmunity by making the immune system weaker and less likely to attack the body but it also leaves the patient more vulnerable to infections.

So, as constant background noise when you are not sick or injured, your Innate Immune System uses its free time to low-key fight autoimmune diseases. The level of overlapping systems and how all the different principles of activation and regulation work together to protect you in every possible way is just so, so fascinating. The concert of your immune system uses every available instrument to keep you safe.

Today a considerable percentage of babies are born via cesarean section. This is not ideal because in regular births the tiny human comes in close and intense contact with the vaginal and often fecal microbiome of their mother. So your birth is actually an important step in the microbial priming of your body and immune system. The microbiome of small children varies significantly depending on how they were born.

Adding another puzzle piece in early life is the fact that fewer mothers are breastfeeding than in the past. Mothers’ breast skin and milk contain a vast and diverse array of substances that nurture the very young microbiome and a number of diverse bacteria. Evolution made sure that newborns get plenty of face time with the old and proven microbiome. Both C-sections and the lack of breastfeeding are correlated with a higher rate of immune disorders like allergies.