Note and Disclaimer: This post is just braindump of mine after spending some time reading about human immune system. The topic itself is huge and much more complicated. Tried to keep it as simple as possible, using some analogies. These series of posts are Very much inspired from the book “Immune” by Philipp Dettmer (The book explains it much better than me, mine is just summary and includes some interpretation). In addition, this post assumes that the reader possesses high level information about basic cell biology and genetics, including DNA, proteins and cell structure (if not, please refer to my other posts about them). We will be focusing on human immune system.

What is the Immune System?

TL;DR: Immune system is the defense mechanism of your body to protect you from bacteria or viruses or malfunctioning cells or organisms.

Your immune system is not really inside you, it is you. It is an expression of your biology protecting itself and making your life possible. But your immune system is not a singular thing. It is a complex and interconnected collection of hundreds of bases and recruitment centers all over your body. They are connected by a superhighway, a network of vessels, similarly vast and omnipotent as your cardiovascular system. On top of organs and infrastructure, dozens of billions of immune cells patrol either these superhighways or your bloodstream and are ready to engage your enemies when called. Billions more sit guard in the tissue of your body that borders your outsides waiting for invaders to cross them. On top of your active defenses you have other defense systems made up of quintrillions of protein weapons that you can think of as self-assembling, free floating land mines. Your immune system also has dedicated universities where cells learn who to fight and how, also possess something like the largest biological library in the universe, able to identify and remember every possible invader. (We will talk about this university and library in detail, later)

At its core, the immune system is a tool to distinguish the other from the self. It does not matter if the other means to harm you or not. If the other is not on a very exclusive guest list that grants free passage, it has to be attacked and destroyed because the other might harm you. 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 homeostatis: the equilibrium between all the elements and cells in the body. Something that can’t be overemphasized enough about the immune system is how much it tries to be balanced and how much care it puts into calming itself down and not overreacting. Basically, for the immune system being healthy, the absence of suffering and pain, the absence of limitations and having pleasant life is homeostatis.

To summarize, distinguishing between self and other is core, homeostatis is the goal, and there are seemingly infinite ways for it to all go wrong. What make immune system so fascinating is that all this complex work has to be done by parts that are mindless and, individually, pretty dumb.

What is there to defend?

Your body is perfect safe place with lots of “food” for bacteria, viruses and parasites, that is why they would like to “enter” and live there (Why, reason comes from evalution). The cells of your immune system are tasked to defend all of your body. Especially, the weak points where intruders can enter it, which is mostly the borders, the outside of your body. When you think about outsides, the first thing comes to mind is of source, your skin. Luckily, it is not that hard to defend, since most of it is made out of a hard, thick barrier covered with its own defense system. It feels soft, but it is pretty hard to breach if it is intact. Your real weak points to infections are your mucous membrane–the surface that lines your windpupe and lungs, eyelids, mouth and nose, your stomach and intestines, your reproductive tracts and bladder.

Literally billions of parasites are trying to get inside. Some of them are bigger than the others. Mostly, they want to steal the food and make your body their permenant home to raise generations of their offspring.

Types of immune system

Lets very briefly define two types of your Immune system (we will dive a lot dipper, later in this post): Innate Immune System and Adaptive Immune System

Innate Immune System

Innate Immune system contains all the defenses you are born with, and that can be employed mere seconds after the invasion occurs. One of its most central features is that it is the sort of smart part of your immune system. It has the power to tell/distinguish self from other. And once it detects other it immediately springs into action. However, its weapons are not tailored to identify any specific enemy, but instead they try to be effective accross a wide range of common enemies. It doesn’t have specific weapons against specific types of E.coli bacteria, for example, but against bacteria in general. Think of it like your basic starter kit: it has all fundamentals, not the specialised items you would get with an advanced it.

Without your Innate immune system, you would be overwhelmed and killed by microorganisms within days or weeks. Your innate immune system has to make crucial decisions at danger:

  • How dangerous an invasion?
  • What kind of enemy is attacking?
  • Are more heavy weapons necessary?

These decisions are vital, because they influence what sort of weapons your immune system as a whole will deploy. A bacterial invasion needs a different response than a viral invasion. So while fight is going on, the Innate Immune System gathers data and then it makes the decisions that in many cases will decide your fate. If your innate immune system think an attack is serious enough, it has the power to activate and call second line of defense and join them to the fight.

Adaptive Immune System

The realm of Adaptive Immune system contains specialised 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 infection. Its defining feature is that it is specific. Your adaptive immune system “knows” every possible intruder, has a specific answer for every possible microorganism that exists on this planet right now. We will talk in detail later in this post about this fascinating specific defense and how it works, but for now, just remember that your Adaptive immune system possesses largest library in the known universe, with an entry for every current and future possible enemy.

In contrast to 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 blank slate, and then gets progressively more powerful, only to get weaker 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.

Meet your Enemies

In modern world, when we are thinking of things that make us sick, we are mostly talking about bacteria or viruses. All sort of invader that is able to give your immune system a run for its money is called a Pathogen – which means “the maker of suffering”. So, every microorganism that causes disease is a pathogen, no matter what species, no matter how big or small. And almost everything can become a pathogen under the right circumstances. For example, a regular old bacteria living on your skin might not bother you at all, but can become a pathogen if you are going through chemotherapy and are immunocompromised, making it easy to invade you. So whenever you read pathogen, just remember it means “a thing that makes you sick”.

Your immune system is “aware” that there are very diffirent kinds of pathogens, that all require very diffirent responses to get rid of them. The well-known microorganism that your immune system has to deal with is Bacteria. Bacteria are single-celled protein robots that come in a wide variety of shapes and sizes and are guided by chemistry and their genetic code. Bacteria are masters of survival and can be found basically everywhere where nutrients are found. Bacteria saturate the soil you walk on, the surface of your desk, they float around in the air.

In a pleasant environment, a single bacterium can reproduce once every twenty to thirty minutes by dividing into two bacteria. So after four more ours of dividing, tere would be already 8000 of them. There are a lot of unfriendly, pathogenic bacteria that try to invade your body and make you sick. They cause a wide an scary variety of diseases from diarrhea and all sorts of gut unpleasantries to tuberculosis or really scary things like the black plague, leprosy or syphilis. If they get the chance, they also use any opportunity to infect your flesh when you injury yourself and get your insides in touch with the environment where they exist, just everywhere. Even today with all the magic of modern medicine, the bacterial infections are responsible for a good chunk of deaths each year.

The Skin as a defense layer

The life of your skin cells begins around one millimeter deep. Here, the Skin Industrial Complex is situated. In the basal layer, stem cells do nothing, but calmly multiply. They are cloning themselves, all day and night, producing new cells that begin a journey from the inside to the outside. The skin stem cells constantly make new skin cells, and each new generation pushes the older ones further up. So your skin cells are constantly pushed upward by younger skin cells emerging below them. The closer they get to the surface, the more the need to become ready to be living defenders. And so as your skin cells mature, they develop long spikes and interlock with the other cells around them to form a dense and impassable wall. Next your skin cells begin facturing lamellar bodies, tiny bags that squirt out fat to create a waterproof coat that covers the cells and the little bit of space that is left between them. The coat does three things: It acts as another physical border that is extremely hard to pass; it makes it easier to dispose of dead skin cell later on; and it is filled with natural antibiotics called defensins, which can straight up murder enemies on their own.

As the skin cells are pushed up further towards the surface they begin preparing for the ir final job: Dying. They become flatter and bigger and begin to stick together even tighter until they merge together into inseparable clumps. And then they shed their water and kill themselves. You could say that the purpose of their life is to die in the right place and become neat carcasses. Up to fifty layers of dead cells, fused together on top of each other, form the dead part of your skin that ideally cover your whole body. Depending on your age, it takes your skin between thirty and fifty days to completely turn over. Every single second, you shed around 40,000 dead skin cells.

When it is warm, humans sweat a lot, which both cools us and also transports a lot of salt to the surface. Most of it is reabsorbed but some of it remains, overall making your skin a pretty salty place, which many microbes dont like. As if that’s not enoough, sweat contains even more natural antibiotics that can passively kill microbes.

But this is still not all. Another one of the great passive defenses of your skin is that it is covered in a very thin film of acid, appropriately called the acid mantle, which is s mixture of sweat and other substances secreted by glands below your skin. The acid mantle is not so harsh that it would hurt you, it just means that the pH of your skin is slightly low and therefore, slightly acidic that is something a lot of microorganisms dont like. The acid mantle has another great passive effect mostly geared towards bacteria: The inside and outside of your body have diffirent pH levels. So if a bacterium adapts to the acidic environment on your skin and then gets an opportunity to enter bloodstrea, for example, through an open wound, it has a problem: Your blood has a higher pH, so the bacterium suddenly finds itself in an environment that it is not adapted to, with very little time to do so, which is considerable challenge to some species.

A healthy individual’s skin holds up to forty diffirent bacteria species, as diffirent areas of your skin are drastically diffirent environments with their own specific climates and temperatures. Overall, an average square centimeter of your skin is home to around a million bacteria.

The Scenario of “The Cut”

In this part, we will describe the steps that are happening when you cut some part of your body. I will try to describe step by step for simplicity, however, the reality is much more complicated.

Imagine you are hiking to a hill, and suddenly a long ad rusty nail penetrated your shoe and its tip entered to your big toe. Much worse though, the nail was covered with soil and dirt and hundreds of thousands of bacteria that suddenly found themselves beyond the gates of your impenetrable skin border wall. Hundreds of thousands of cells have died, and others are wounded and distressed. These panic signals, the guts of dead cells, and the stench of thousands of bacteria are carried into the surrounding tissue, raising an urgent alarm. Your Innate Immune system reacts immediately. Sentinel cells are the very first show up – they were peacefully patrolling the premises when the impact happened and are quickly making their way right to ground zero. These cells are called Macrophages and they are the largest immune cells your body has to offer. Physically, Macrophages are pretty impressive. If an average cell would be the size of a human, Macrophage would be the size of a black rhino. Their purpose is to devour dead cells and living enemies, coordinate defenses, and help heal wounds. As the Macrophages devour one enemy after another they realize that they can at best slow this invasion down, not stop it. And so they begin to call for help, sending out urgent alarm signals, and start preparing the battlefield for reinforcements that will arrive shortly. In the blood thousands of Neutrophils have heard the cries for help and smelled the signs of death and begun to move. Immediately they begin hunting and devouring bacteria whole but with much less care for their surroundings. Neutrophils are on a tight timer: Once activate they only have hours before they will die of exhaustion and use weapons do not regenerate. So they make the best of the situation and use them freely – not only killing enemies but also causing real damage to the tissue they should be protecting in principle. The small wound is already closed superficially as millions of specialized cells from the blood flooded in the battlefield: Platelets, blood cells that exist mainly to act as an emergency worker that closes wounds.

The cells figthing at the site of infection started a crucial defense process: Inflammation. This means they ordered blood vessels to open up and let warm fluid stream into the battlefield. 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 injury occurred.

Now, let go back to the battlefield, amond the intruders there is a pathogen. A soil bacteria that is actually able to deal with the immune system response and to multiply quickly. Bacteria are living things and able to react to situations. And so they do, setting off defense mechanisms that make them harder to kill. The best the Immune system can o is to keep them in check. So another immune cell now makes a serious decision. It has been acting quietly in the background, monitoring the events. Now, hours after the catastrophe happened and the infection began it is time to shine for them. The Dentritic Cell, the mighty messenger and intelligence officer of the Innate Immune System. They are shaken up by the chaos and panic, they urgently began collecting samples of the battlefield. Similarly to the Macrophages, Dentritic 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, Dentritic Cells get on the move, leaving the battlefield behind to get help from the Adaptive Immune System. It takes the Dentritic 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.

Macrophages and Neutrophils

Now, it is time to learn more about these damage dealers of the Immune System. Together they are special class of cells called phagocytes, it means “Eating Cell”. Macrophage means Great Eater, which is a great fit. Since cells dont have tiny mouths, eating on this level has to mean something else.
When a phagocyte, like a Macrophage, wants to swallow an enemy, it reachs out to it and graps 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 of Macrophage. 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 Macrophage itself, and others are spat out so other cells can have a meal, too. No wasting resources!

Interestingly, the main things Macrophages eat are actually parts of you. Most cells of your body are on a limited life timers to avoid becoming faulty and turning into something bad, like cancer, for example. So every second of your life, around one million of your cells die by controlled cell suicide, called apoptosis. When cells decide their time has come, they release aspecial signal letting everybody else know that they are done. Then they destroy themselves via apoptosis, which means that they split up into bunch of small, neat packages of cell garbage. Macrophages, attracted by the signals, pick upthe shreds of the former cells and recycle the parts.

Macrophages live up to several months. In your brain, they make up around 15% of all cells and are extra calm, so they dont accidentally damage irreplacable nerve cells that you need for important things like thinking or breathing.

The Neutrophil is a bit of a simpler fellow. It exists to fight and to die for the collective. It is the crazy spartan warrior of the immune system. Neutrophils are on tight timer, live a few days when they are not needed before they commit controlled suicide. And so every single day 100 billion Neutrophils give up their lives voluntarily and die. And every single day 100 billon more are born, ready to fight for you if necessary.

They can throw acid at enemies and kill themselves to create deadly traps. Neutrophils are densely packed with granules, which are basically tiny packages filled with a deadly load. You can imagine these granules as little knives and scissors that are made to cut open and criple intruders. So, if a Neutrophil encounters a bunch of bacteria in one place it will just shower them with granules that rip their outside apart. The problem with this approach is that it is not super specific, and it hits whoever is unlucky enough to be in the way. This often means your own healthy civilian cells :(. But even more crazy thing Neutrophils do in battle is to create deadly nets of DNA, sacrificing themselves in the process. They create Neutrophil Extracellular Trap, or NET for short. If Neutrophils get the impression that drastic measures are called for, they begin this crazy kind of suicide. First their nucleus begins to dissolve, freeing up their DNA. As it fills up the cell, countless of proteins and enzymes attach to it. Then Neutrophil literally spits out its entire DNA around itself like a giant net. Not only can this net trap enemies in place and hurt them, it also creates a physical barrier that makes it harder for bacteria or viruses to escape or move deeper in the body. Usually the brave Neutrophil dies doing this.

Macrophages and Neutrophils have another important job that they share with other parts of the immune system, and that we will discuss in the next section. It is super crucial for your defenses: They cause inflammation, a process so important to your defense and your health.

Inflammation

Inflammation is the universal response of your imune system to any sort of breach or damage or insult. No matter if bacteria or viruses infect your nose, lungs, or gut. No matter if a young tumor kills a few civilian cells by stealing their nutrients or you have an allergic reaction to food, inflammation is the response.

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. Inflammation is a process that makes the cells in blood vessels change their shape, so that plasma, the liquid part of your blood, can flood into a wounded or infected tissue.

You can tell if you have inflammation through five markers: Redness, heat, swelling, pain, and loss of function. In the scenario, we described before, the injured toe becomes hot as the blood brings extra body heat. This heat does useful things to you: Most microorganisms do not like it hot – so making wound hotter slows them down and makes their lives stressful. 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.

But wait, what exactly is causing inflammation? The first way inflammation starts is through dying cells. Amazingly, your body evolved a way to recognize if a cell dies 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 do death is a signal that causes inflammation. Normally, as we mentioned before, apoptosis is basically a calm suicide that keeps the contents of the cell nice and tidy. But when cells dies in unnatural ways, for example, by being ripped into pieces by a sharp nail, burned to death by a hot pan, the insides of your cells spill all over the place. Certain parts of the guts of your cells, like DNA or RNA, are high alert triggering for your immune system and cause rapid inflammation.

Let introduce a very special cell that you might learn to hate later or when we learn more about it–if you ever had a severe allergic reaction where your body did swell up, this cell had most likely hand in it: The Mast Cell. 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 fell when a mosquito bites you was probably caused by chemicals the Mast cell released.

The next best way to cause inflammation is more of an active decision: Macrophages and Neutrophils order inflammation when they are engaged in a battle. This way, as long as fighting is going on, they release chemicals that keep the battlefield flooded and ready to take in fresh reinforcements. But this is also one of the reasons why having any kind of battle going on for a long time is bad.

To summarize, if your cells are dying unnaturally, if you 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 sort of chemicals, which annoy 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.

In this post, we went through basic concepts of immune system, and how this system reacts to “the cut” scenario. In the next part, we will dive a bit deeper and try to understand how do cells go to the battlefield, and some more advanced superpowers of immune system.