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

by Philipp Dettmer

The immune system is the most complex biological system known to humanity, other than the human brain.

Your immune system also has dedicated universities where cells learn who to fight and how. It possesses something like the largest biological library in the universe, able to identify and remember every possible invader that you may ever encounter in your life.

At its very core, the immune system is a tool to distinguish the other from the self.

While identifying what is self and what is other is the core, it is not technically the goal of your immune system. The goal above all things is maintaining and establishing homeostasis: the equilibrium between all the elements and cells in the body.

Health is really an abstract concept because it describes the absence of something. The absence of suffering and pain, the absence of limitations. If you are healthy, you feel normal, you feel right. Once you witness your health go away, even for a brief time, it is hard to forget how fragile you are and how much you are living on borrowed time.

Or take allergies, which are a very intense reaction of your immune system against things it should not be concerned about. An allergic shock shows strikingly how truly powerful your defense system is and how horribly it can go wrong: it may take a disease days to kill you—your immune system can do so in minutes.

To summarize, distinguishing between self and other is core, homeostasis is the goal, and there are seemingly infinite ways for it to all go wrong.

Your real weak points to infections are your mucous membranes—the surface that lines your windpipe and lungs, eyelids, mouth, and nose, your stomach and intestines, your reproductive tracts and bladder.

Proteins are made from chains of amino acids, which are tiny organic building blocks that come in twenty different varieties. All you need to do is to string them together into a chain, in whatever order you like, and voila, you have a protein. This principle enables life to construct a stunning variety of different things. For example, if you wanted to make a simple protein from a chain of ten amino acids, and you have twenty different amino acid types that you can choose from, this gives you a breathtaking 10,240,000,000,000 different possible proteins.

the instructions on the DNA are converted into proteins in a two-step process: Special proteins read the information on the DNA string and convert it into a special messenger molecule called mRNA—basically the language that our DNA uses to communicate orders.

Cells are filled up by proteins. Proteins are three-dimensional puzzle pieces. Their specific shapes enable them to fit together or interact with other proteins in specific ways. Sequences of these interactions, called pathways, cause cells to do things. This is what we mean when we say that cells are protein robots guided by biochemistry. The complex interactions between dumb and dead proteins create a less dumb and less dead cell, and the complex interactions between slightly dumb cells create the pretty smart immune system.

The Realm of the Innate Immune System contains all the defenses you are born with and that can be employed mere seconds after an invasion occurs. These are the basic defenses that go back to the very first multicellular animals on earth and they are absolutely crucial for your survival.

The Realm of the Adaptive Immune System contains specialized super cells that coordinate and support your first line of defense. It contains factories that produce heavy protein weapons and special cells that hunt and kill infected body cells in the case of viral infections.

In contrast to the Innate Immune System, your Adaptive Immune System is not ready yet when you are born. It needs to be trained and refined over many years. It starts as a blank slate and then gets progressively more powerful, only to get weaker again as you age. A weak Adaptive Immune System is one of the main reasons young and old humans are often much more likely to die from diseases than people in the middle of their lives. Mothers actually lend their newborn babies a bit of their adaptive immunity in their mother’s milk to help them survive and give them some protection!

Your Immune System consists of two major realms: Innate and Adaptive Immunity. Your Innate Immune System is ready to fight after birth, and can identify if an enemy is not self, but other. It does the down-and-dirty hand-to-hand combat, but it also determines what broad category your enemies fall in and how dangerous they are. And finally it has the power to activate your second line of defense: Your Adaptive Immune System, which needs a few years before it is ready to deploy efficiently. It is specific and can draw from an incredibly large library to fight every possible individual enemy that nature can throw at it, with powerful superweapons. But while it is powerful, one of its most important jobs is to make the Innate Immune System even stronger.

Any sort of invader that is able to give your immune system a run for its money is called a Pathogen—which appropriately means “the maker of suffering.”

So the skin is like a desert covered in acid, salt, and defensins and the ground is a graveyard of dead cells that are constantly shed away along with everybody unfortunate enough to sit on it. Learning about all of this, one might think that it is impossible for microbes to live on your skin. But this is far from the truth.

Something mildly annoying on the scale of the human giant is a full-blown emergency on the scale of your cells.

The cells fighting at the site of infection started a crucial defense process: Inflammation. This means they ordered your blood vessels to open up and let warm fluid stream into the battlefield, like a dam opening up towards a valley. This does a few things: For one, it stimulates and squeezes nerve cells that are deeply unhappy about their situation and send pain signals to the brain, which makes the human aware that something is wrong and an injury occurred.

Mast Cells are large, bloated cells filled with tiny bombs containing extremely potent chemicals that cause rapid and massive local inflammation. (For example, the itching you feel when a mosquito bites you was probably caused by chemicals the Mast Cell released.)

If your cells are dying unnaturally, if you rupture or annoy a Mast Cell below the skin, or if your immune system is fighting enemies, they release chemicals that cause inflammation. A flood of fluids and all sorts of chemicals, which annoy your enemies, attract reinforcements, and make it easier for them to get into the infected tissue, all of which make it easier to defend a battlefield. But inflammation is hard on the body and in many cases presents a real danger to the health of the body.

Cells have millions of noses on their outsides that are called receptors. They communicate by releasing proteins that carry information, called cytokines. When a cell smells cytokines with their receptors (noses), they trigger pathways inside the cell that change their gene expression and therefore the behavior of the cell. So cells can react to information without being conscious or having the ability to think, guided by the biochemistry of life. This enables them to do pretty smart things even though they are technically very stupid. Some cytokines do also function as a navigation system—an immune cell can smell where they are coming from and literally follow their noses to the battlefield.

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.

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. 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:

the complement system does three things: It maims enemies and makes their lives miserable and unfun. It activates immune cells and guides them to invaders so they can kill them. It rips holes into things until they die.

The complement system is a beautiful example of how many mindless things can do smart things together. And how important collaboration is between the different defense layers of your immune system.

Your body is wrapped in an ingenious self-repairing border wall that is incredibly hard to pass and that protects you extremely efficiently. If it is breached, your Innate Immune System reacts immediately. First your black rhinos, Macrophages, huge cells that swallow enemies whole, appear and dish out death. If they sense too many enemies they use cytokines, information proteins to call your chimp-with-machine-gun Neutrophils, the crazy suicide warriors of the immune system. Neutrophils don’t live long and their fighting is harmful to the body because they kill civilian cells. Both of these cells cause inflammation, bringing in fluid and reinforcements to an infection, making a battlefield swell up. One of the reinforcements is complement proteins, an army of millions of tiny proteins that passively support the immune cells in their fight and help mark, attach to, maim, and clear enemies. These powerful teams together are enough for most small wounds and infections you encounter.

The immune system does not so much adapt to new invaders as it already was adapted when you were born. It comes preinstalled with hundreds of millions of different immune cells—a few for every possible threat that you could possibly encounter in this universe. Right now you have at least one cell inside you that is a specific weapon against the Black Death, any variant of the flu, the coronavirus, and the first pathogenic bacteria that will emerge in a city on Mars in one hundred years. You are ready for every possible microorganism in this universe.

An antigen is a piece of an enemy that your immune system can recognize.

For every possible antigen that is possible in the universe, you have the potential to recognize it inside you right now.

The Thymus is an unappealing and boring collection of tissue that looks a little bit like two old, lumpy chicken breasts sewn together in the middle. Despite its ugliness, it is one of your most important immune cell universities

T Cells do a variety of things, from orchestrating other immune cells, to being antivirus superweapons, to killing cancer cells.

Your Thymus basically begins shrinking and withering away when you are a small child. A process that is sped up once you reach puberty. Every year you are alive more and more Thymus cells turn into fat cells or just worthless tissue. The university closes more and more departments and gets worse as you age, until around the ripe age of eighty-five, your T Cell university closes its gates for good. Which is sort of horrible if you like the concept of being alive and healthy. There are other places in the body where T Cells can be educated, but for the most part from this point forward your immune system is more limited than before. Because once your Thymus is gone, you have to get by with the T Cells you have trained up to this point. The absence of the immune cell university is one of the most important reasons why seniors are much weaker and more susceptible to infectious diseases and cancer than younger people.

Your Adaptive Immune System doesn’t make any real decisions about who to fight and when it is time to activate—this is the Innate Immune System’s job, and this is where the Dendritic Cell, this big, weird-looking cell with many octopus-like arms that takes samples, comes into play. When an infection happens it covers itself with a selection of the enemy’s antigens and tries to find a Helper T Cell that is able to recognize one of the antigens with its specific receptors. And this is exactly the reason why the Dendritic Cell is so crucially important. Without Dendritic Cells, there would be no second line of defense.

To activate your Adaptive Immune System, a Dendritic Cell needs to kill enemies and rip them into pieces called antigens, which you can imagine as wieners. These antigens are put into special molecules, called MHC class II molecules, that you can imagine like hot dog buns. On the other end, Helper T Cells rearrange gene segments to create a single specific receptor that is able to connect to one specific antigen (a specific wiener). The Dendritic Cell is looking for just the right Helper T Cell that can bind its specific receptor to the antigen. And if a matching T Cell is found the two cells interlock. But then there needs to be a second signal, like a gentle encouraging kiss on the cheek, that tells the T Cell that all is good and the signal from the presented antigen is real. And only then does a Helper T Cell activate.

The genes that are responsible for the MHC molecules are the most diverse genes in the human gene pool, leading to a huge variety of MHC molecules between individuals. Of all the things that are different between humans, why are the MHC molecules so unique to every person? Well, different types of MHC are better or worse at presenting antigens from different enemies, like one type might be especially good at presenting a specific virus antigen while another type could be great at presenting a bacteria antigen. For humans as a species this is enormously beneficial because it makes it really hard for a single pathogen to wipe us out. For example, when the Black Death ravaged Europe in medieval times, there were people whose MHC class II molecules were just naturally really good at presenting the antigens of the bacterium Yersinia pestis, which caused the plague. They had a higher chance of surviving the disease and making sure humans as a species survived. This is so incredibly crucial for our collective survival that evolution may have made it a contributing factor in mate selection. In human words: You find potential partners with MHC molecules that are different from yours more attractive! OK wait, what? How would you even know this? Well, you can literally smell the difference! The shape of your MHC molecules does influence a number of special molecules that are secreted by your body—which we pick up subconsciously, from the body odor of other people—so you communicate w...

Looking at a T Cell, you would not be very impressed. They are average size, and don’t seem special in any way. But they are absolutely indispensable for your survival. People who don’t have enough T Cells, because of a genetic defect, chemotherapy, or a disease like AIDS, have a very high chance of dying from infections and cancers. Sadly, even with the best our modern medicine has to offer, the lives of patients without T Cells often can’t be saved. Because as we will learn in a moment, T Cells are the coordinators of the immune system. They orchestrate others and directly activate your heaviest weapons.

Memory Helper T Cells. Whenever you hear that you are immune to a disease, this is what this means. It means that you have living memory cells that remember a specific enemy. And that enemy might come back, so they stick around and become powerful guardians. Memory Cells are able to recognize a familiar enemy much quicker than the Innate Immune System ever could. In case of another infection, this makes the long trip of the Dendritic Cell to the lymph node unnecessary because these Memory Helper T Cells can immediately activate and call for heavy reinforcements.

What makes B Cells special, and very dangerous for friends and foes, is that they produce the most potent and specialized weapon the immune system has at its disposal: Antibodies.

Virgin B Cells sit in your lymph nodes, where they bathe in lymph and take in all the antigens that are transported through the area from the closest battlefield. Their B Cell Receptors can just grab big chunks of antigens directly from the lymph and this way B Cells can get activated.

an activated T Cell needs to find an activated B Cell and BOTH cells need to be able to recognize the same antigen! OK, wait a second. So are we seriously saying that two cells in your body mix gene fragments randomly, with hundreds of millions to billions of possible outcomes? And then a pathogen shows up and coincidentally both need to be activated independently and then they need to meet each other? And only then, in this absurdly specific and seemingly impossibly unlikely case will your immune response fully be activated? Well yes, although the way this works is a bit mind-bending and the fact that nature came up with it is extremely elegant.

Step 1: A battle needs to occur and dead enemies, which are big chunks of antigens (turkey drumsticks), need to float through the lymph node. Here, a B Cell, with a specific receptor needs to connect to the antigen. If the dead enemy is covered in complement, activation will be much easier. This will activate the B Cell, which makes a lot of copies of itself and produces low-grade antibodies, but the B Cells will die after around a day if nothing more happens. Step 2: In the meantime, a Dendritic Cell needs to pick up enemies at the battlefield and turn them into antigens (wieners) which are put in the MHC class II molecules (hot dog buns) and travel to the T Cell dating area in the lymph node. Here it needs to find a Helper T Cell that is able to recognize the antigen with its unique T Cell receptor (eat the wiener from the bun). If this happens the Helper T Cell is activated and makes a lot of copies of itself. Step 3: The B Cell breaks the big chunk of antigen (turkey drumstick) down into dozens or hundreds of small antigens (wiener sized) and begins presenting them in MHC class II molecules (hot dog buns). Step 4: An activated B Cell that is presenting hundreds of different antigens (wiener-sized sausage pieces) needs to meet a T Cell that can recognize one of these antigens with its specific T Cell receptor, which is the second signal for the B Cell. Only if this exact sequence of events occurs does a B Cell get activated for real. Are you impressed yet with your biol...

In the end only the best possible B Cells survive and go on to make many new clones of themselves! These are the B Cells that eventually turn into Plasma Cells, that fine-tuned their receptors and are able to make the best possible weapons against the enemy. This is the reason Antibodies are so deadly effective, why they hit an enemy between the eyes like a sniper. They were not just randomly chosen, they were molded and improved and fine-tuned until they were perfect. This is the reason that even if you know nothing about the immune system, you have probably heard the term “Antibody” a bunch of times from medical professionals. They are your superweapons, the main reason you can survive serious infections.

Antibodies are among the best and most specialized weapons your immune system has at its disposal. Produced by B Cells, Antibodies themselves are not particularly deadly. They are actually nothing more than mindless protein bundles that can stick to antigens. But this they do with extreme efficiency.

Here another safety layer of your immune system comes in. The cute butts of Antibodies that are for friends are in a sort of “hidden mode” when Antibodies just float around, so immune cells can’t just pick them up from fluids. As soon as an Antibody has grabbed a victim with its tiny pincers, its butt changes its shape and is now able to bind to immune cells. This is pretty important since your body is teeming with antibodies at any time, and it would cause all sorts of chaos if your immune cells would bind to the antibody-butts just randomly.

IgA have their little butts merged together, which means that IgA can’t activate the complement system at all. This is no accident: An activated complement system means inflammation. And since IgA Antibodies are constantly produced in your gut, if they could activate complement this would mean that your gut would be constantly inflamed. Which would cause disease and diarrhea and make you very unhappy.

B Cells are not locked into making a certain class of Antibody—they always start with IgM but can switch the Antibody type if the Helper T Cell asks and encourages them to! Having a nasty cold or a gut infection and need a lot of antibodies in your snot or stool? Make IgA! Having a parasitic worm in your intestines? Make IgE! A lot of bacteria have infected a wound? Make IgG flavor one! There are a lot of virus-infected cells? Please, more IgG flavor three! (Once an Antibody class has been switched there is no going back though.)

Your intestinal immune system really does not want to cause inflammation if not absolutely necessary, because inflammation means a lot of extra fluid in the intestines, which you experience as diarrhea. Diarrhea doesn’t just mean watery poop, but also damage to the very sensitive and thin layer of the cells that take up the nutrients from your food. And diarrhea can rapidly dehydrate a patient to dangerous levels.

The Dendritic Cells of your gut behave in a special way too. Many of them sit directly below the layer of epithelial cells and squeeze their long arms between them, reaching right into the mucus of the gut. This way they can constantly sample the bacteria that are cheeky enough to not stay in their lane but venture too deep. At this point lies a huge mystery of immunology that promises another Nobel Prize for the person or team who solve it one day: How do Dendritic Cells know if the bacteria they sample in the gut are dangerous pathogens or just harmless commensal bacteria? Well, right now we don’t know but we know that when Dendritic Cells sample commensals, they order the local immune system to chill out and not be too annoyed by their antigens.

Viruses are so basic that they have no way to actively do anything. They are literally particles floating around in the environment and have to rely on passively stumbling into victims by pure random chance.