At its core, the immune system is a tool to distinguish self from non-self. Viruses, harmful bacteria, and parasites — all of which can be considered “pathogens” — have been a threat to multicellular life for more than 500 million years, when the first multicellular organisms first appeared. Multicellular beings — like humans and animals — make ideal hosts for these microscopic organisms, who want to invade and  take advantage of the resources and nutrients available to them. In order to survive, multicellular beings had to develop sophisticated immune systems to detect and eliminate these threats, which are happening constantly. 

The immune system we rely on today is the product of millions of years of evolutionary refinement. Its primary function is to recognize what belongs in the body and what doesn’t. When it identifies something in the body that’s not you — like a virus or harmful bacteria — it attacks it using an army of soldiers and weapons. How does it determine self vs. non-self? If bacteria have been around for billions of years, why haven’t they evolved mechanisms to completely baffle your immune system’s detection capabilities? The answer to these questions lies in the way that bacteria, viruses, and other pathogens are built. Although these microorganisms can build all kinds of different proteins to make themselves look and behave differently to avoid detection, they still need the very basic proteins in order to function. Think of a car — you can mix parts and colors to produce different cars, but you still need wheels and an engine. Your immune cells have receptors that can identify these very basic parts (called Antigens) that are common in most harmful pathogens. A bacteria’s flagella is a good example: the flagella is a tail-like structure made up of proteins that help the bacteria move around. Other than sperm, human cells don’t have a flagella. Therefore, when your immune cells recognize the proteins that make a flagella, they know to kill the organism. This is just one example of how the immune system identifies what doesn’t belong. 

Ultimately, the immune system’s goal is to maintain homeostasis — internal balance — within the body. The symptoms you experience during a cold, such as fever or inflammation, are not caused by the virus or bad bacteria itself but by your immune system’s attacks on these bad actors that have invaded your body.

An interesting note about the immune system and pregnancy: when sperm enter a woman’s body, they are recognized as “other” and are attacked by immune system cells like macrophages and neutrophils. Of the 200 million sperm that enter, only a few hundred make it into the fallopian tubes and have a chance to fertilize the egg. Most are eliminated along the way due to the woman’s acidic vaginal environment, immune system, or simply getting off course. This helps explain why getting pregnant is hard. 

A similar situation unfolds in the case of organ transplants. The process of installing an organ from one person’s body into another is often very challenging because of the immune system. The immune system labels the new organ, and the cells that make up the organ, as “other” and attacks relentlessly. This is why, unfortunately, many people who receive an organ donation have to spend the rest of their lives taking medication that suppresses the immune system, which leaves them vulnerable to other infections (i.e. bacteria, viruses, cancer). 

To understand the immune system, you first have to understand cells. We have about 40 trillion cells and 40 trillion helpful bacteria in, and on, our body. About 36 trillion of those bacteria live in our gut and help us digest food; the other four trillion are on our skin, in our lungs and mouth, and in our eye fluid. Cells come in all kinds of types and are jam packed with millions of proteins, which are created when amino acids are linked together in specific sequences. The instructions for assembling these proteins are stored in the DNA found in each cell’s nucleus. Your DNA is a super long strand that consists of smaller sections, your genes, and each gene is the instruction for one protein. The process of building a protein happens in two main steps:

1. 1. The DNA is transcribed into a messenger molecule called mRNA
   2. The mRNA then exits the nucleus and travels to a part of the cell called the ribosome, where it’s translated into a chain of amino acids that folds into a functional protein.

Proteins come in all shapes and sizes, and cells can use them to both build almost anything and communicate with other cells. Think of cells as “protein robots” that are guided by sequences of interactions between proteins. These “protein robots” (i.e. cells) are blind, deaf, and stupid, so how do they know where to go and what to do? Well, cells are covered with receptors that proteins and other things outside of the cell can bind to in order to cause the cell to behave in certain ways. Half of a receptor is inside the cell, half of it is outside the cell. When a certain protein binds to the outer half of the receptor, it sends a signal inside and causes a certain behavior from the cell. For example, when a cytokine — a protein released by immune cells to call for backup at an infection site — binds to the receptor of another immune cell, it steers that cell to the scene. This is the way cells communicate and are able to do things that make sense. 

Our immune system is made up of two different realms — the Innate Immune System and the Adaptive Immune System. 

The Innate Immune System contains all of the defenses you were born with and can be deployed immediately after an invasion occurs. Its weapons are not tailored to any specific bacteria, virus, or any other pathogen — instead, they try to be effective across a wide range of common invaders. For example, it doesn’t have specific weapons against specific types of bacteria like E.coli; but it does have weapons against bacteria in general. The Innate Immune System is your first line of defense and does most of the actual fighting — in fact, most of the billions of soldiers in your immune system are part of the Inmate Immune System. In addition to fighting bad actors, it has to make crucial decisions after an invasion has occurred: How dangerous is this threat? What kind of enemy is attacking? Are more heavy weapons needed? If your Innate Immune System thinks the threat is big enough, it has the power to activate a second line of defense to join the fight: the soldiers of the Adaptive Immune System.

The Adaptive Immune System contains highly specialized super cells that coordinate and support your first line of defenders in the Innate Immune System. Think of these cells as super soldiers that can come to the rescue if the Innate Immune System is having trouble with a particular bacteria or virus and calls for help. Your Adaptive Immune System knows every possible intruder in the universe and has an answer for every single possible microorganism that exists. It possesses the largest library in the universe, and the library is filled with detailed profiles of every current and future possible enemy. Unlike the Innate Immune System, your Adaptive Immune System is not born with these capabilities; they need to be trained and refined over many years, hence the name “adaptive.” In fact, a weak Adaptive Immune System is part of the reason babies and old people are more likely to die from diseases than people in their middle years.

These two realms are interconnected and play off of each other in a beautifully complex way. The Adaptive Immune System is very powerful in its own right, but its main function is to support the Innate Immune System, which is your first line of defense. If a particular bacterium or virus causes too much trouble for your Innate Immune System at the initial site of the infection, it activates The Adaptive Immune System via Dendritic Cells. 

Most harmful bacteria we encounter aren’t much of a problem. Our immune system recognizes their basic protein parts (Antigens) easily and deals with them without much of an issue every single day. Your real enemies are a small group of elite bacteria and viruses that have found ways to overcome your defenses. These are known as pathogens, a term for any microorganism that can make you sick or cause disease. If something makes you sick — whether it’s a virus, bacterium, fungus, or parasite — it’s considered a pathogen.

Let’s start with bacteria. Bacteria are among the oldest living things on this planet. Emphasis on living; these things are alive, unlike viruses. Like your cells, these are single-celled protein robots that come in a wide variety of shapes and sizes based on their DNA. They have evolved over billions of years and have been very successful on Earth. Bacteria are everywhere! We have 36 trillion in our gut (mostly helpful) and another four trillion on our skin. In one gram of plaque on your teeth, there are more than 7 billion bacteria. 

Bacteria view us as a great place to sustain life and reproduce. Because they are single-cell organisms, they can reproduce extremely quickly, which is what makes them difficult for your immune system to deal with. They can also change their genetics at any time, which can also cause problems for our immune system. We are absolutely covered in bacteria — but, fortunately, most bacteria are harmless to us. In fact, some even work with us to keep harmful bacteria away, and trillions of them live in our gut, where they primarily help us break down and digest food. These are “friendly” bacteria. And make no mistake, we wouldn’t be alive without some of these friendly bacteria. 

If successful, harmful bacteria that invade us can cause a wide variety of diseases and death. They are especially good at entering your body through cuts, where our protective barrier (the skin) has been breached. Antibiotics have certainly helped us fight bacterial diseases, which used to be one of the leading killers of humans. In 1941, 82% of people who incurred bacterial infections of the blood died. Unfathomably, this means a scratch and a tiny bit of dirt might mean the end of your life. Today, in developed countries, less than 1% of these kinds of infections cause death. 

Now let’s discuss Viruses. Unlike bacteria, viruses are dead — there is nothing alive about them. In a nutshell, they are made of a couple lines of genetic code and a few proteins. This is why they must infect living things to stick around. Infecting living things is their No. 1 goal, and if all living things on the planet died, they would die as well because there would be nothing to infect. They can’t reproduce or do anything without first infecting a living thing, like a human cell. Unbelievably, there are actually billions and billions and billions of viruses in the world, but only about 200 of them have the proteins necessary to attach to human cells and infect us. Thank goodness. 

How does a virus infect us? First it gets inside of us. Rather than breaking through the skin, the most common way it gets inside of us is through our lungs as we breathe in air that a virus is hanging out in (think about someone with the flu coughing near you). Once inside, it usually binds to one of the Epithelial Cells that line the protective mucous layer inside our lungs and takes the cell over by transferring its genetic material. This transfer of genetic material turns the cell into a virus-producing machine. At some point, the cell is completely filled up with viruses. The cell then dies and bursts open, releasing hundreds of new viruses that go out and repeat this same process with cells nearby. Before you know it, the virus has become a raging wildfire inside of your body. And this is a defining feature of these things: Nothing multiplies, and mutates (changes), as fast as a virus does. 

Influenza (the flu) and COVID-19 are examples of viruses. The Spanish Flu killed 40 million people in 1918-19. Because viruses like these mutate and multiply so quickly — and because their tactics are different than bacteria — the immune response to a bacterial infection and a viral infection are much different. 

Whether it’s harmful bacteria, a virus, a parasite, or even cancer, these pathogens all have one thing in common: they want to destroy your cells. If they manage to get inside, multiply, and spread, they can hijack or kill enough cells to overtake your body, which manifests as serious illness or even death. The immune system’s mission is to protect your cells — and therefore, protect you — by detecting, attacking, and eliminating anything that poses a threat. In this way, every illness or disease comes down to what’s happening with your cells. 

How does your immune system recognize and begin attacking these pathogens? Every pathogen — whether it’s bacteria or a virus — has something called Antigens, which are basically small pieces of protein on the surface of the pathogen that serve as “tiny ID tags.” Antigens are really, really important for two main reasons: (i.) they are what your immune system uses to identify exactly what the pathogen is, and (ii.) your Adaptive Immune System uses the Antigens to activate and make the correct Antibodies, Helper T Cells, and Killer T Cells that can lock onto and destroy that specific pathogen. Even our own cells have these “tiny ID tags,” and when our immune system weapons accidentally lock onto our Self-Antigens, it usually leads to Autoimmune Diseases. 

For a harmful bacteria or pathogen to become a problem for you, it first has to find a way to break through your skin. Other than your gut, which is made for and ruled by about 36-40 trillion helpful bacteria that your body has welcomed in, the skin is the second most populated place on your body in terms of bacteria. You have about 10 billion bacteria on your skin at all times, some good and some bad. Fortunately for us, our skin is an outstanding protective barrier. Think of it as a dead, salty desert that’s hostile to most microbes, or The Desert Kingdom of the Skin. 

The skin is basically made up of hundreds of layers of skin cells that are constantly being regenerated by our skin stem cells. The skin stem cells lie underneath, or deeper in the epidermis, and crank out new skin cells, which form the very bottom layers of your skin and slowly move up over time. As they are pushed up, these living skin cells get coated in a fatty layer of “passive antibiotics” that protect you from harmful enemies. By the time the skin cells reach the surface layers, they’re dead. All of the skin you see in the mirror is dead skin, made up of up to 50 layers of dead skin cells. As this dead layer of skin is damaged and used during your daily life, it is constantly being shed and replaced by new skin cells that are moving up from below. It takes skin between 30-50 days to completely turn over, and you shed about 40,000 dead skin cells every second! That’s important because when your dead skin flakes away, harmful bacteria crawling on it go with it. When you wipe away some dust, a lot of what you’re wiping up is your own dead skin cells.

The skin also becomes salty when you sweat, which harmful bacteria don’t like. As mentioned earlier, we have 10 billion bacteria crawling on our skin at all times — most of these bacteria are not harmful and actually do us a favor by taking up real estate from harmful bacteria. Finally, another great benefit of the skin is that it’s basically immune to viruses, which can only infect living cells — and the surface of your skin consists only of dead cells. Nothing to infect here!

Overall, the skin is an outstanding barrier. In fact, the skin is so effective as a defense perimeter that pathogens usually don’t have much of a shot at getting inside us here, as long as we don’t cut ourselves and open up an opportunity. Instead, most infections that we deal with throughout our lives enter the body elsewhere, like the nose, mouth, eyes, lungs, digestive tract, and reproductive tract. These are the most vulnerable areas on your body because they are where your insides directly interact with the outside world (i.e. breathing in stuff, eating food, etc.). All kinds of stuff that isn’t YOU comes into your body from these areas. As protection, they are lined with what is called Mucosa — or a mucous layer. Think of this as a giant swampland that provides a layer of protection for our insides. It’s the “skin” of our insides. We can call it The Swamp Kingdom of the Mucosa. 

The immune system has to behave differently in these mucous layers than it does when you have a breach of the skin. Why? It can’t afford to launch a full-blown immune response to every little thing that comes into your body from breathing or eating, for example. It has to walk a fine line between being too aggressive and too relaxed. If it attacked every little thing that entered, you would have constant inflammation. Not good. 

We think of mucous as only being in the nose, but all of these vulnerable areas — the mouth, nose, eyes, respiratory tract (lungs), digestive tract (gut), and reproductive tract — are lined with a layer of it. Just like the skin, mucous contains built-in defense systems that make it difficult for harmful bacteria to get deeper inside of us. For one, the stuff is slimy and is very difficult for bacteria to swim through. Second, it’s loaded with salt, enzymes, and special substances that starve bacteria to death by sponging up critical nutrients that they need. Third, it is saturated with special Antibodies that are ready to “mark” harmful bacteria for destruction by other immune cells if needed. 

Depending on the location, mucous behaves a little differently — the mucous layer in your lungs has a very different job than the mucous layer in your gut, and so on. Because it’s fascinating, let’s look at the gut (intestines) as an example. When you eat something, your saliva starts to break it down. After the food is swallowed, it heads to the ocean of acid in your stomach, which breaks the food down and is also where many bacteria on the food die due to being submerged in literal acid. After the stomach, the journey continues to the intestines, where 90% of the nutrients you need to survive are absorbed. Here in the gut is where we find about 36 trillion bacteria that are essential to our survival — they help us digest the food further and produce vitamins that we can’t produce ourselves. 

Because of all that bacteria (some good, some bad) that sit directly above the mucous layer of your gut, the immune system of the gut acts semi-independently of the immune system guarding the rest of your body. The mucous layer of the gut is always being breached by some of those bacteria, and your immune system has to constantly determine friend or foe. It does this by having immune cells like Macrophages, B Cells, Dendritic Cells, and Antibodies that behave a little differently than they do in other areas of the body. I won’t get into the details. But together, these cells and Antibodies kill a lot of bacteria in the gut that try to cross the mucous layer — in fact, around 30% of your poop consists of dead (or still alive) bacteria. Also, the last thing you want is a big immune response that leads to inflammation in the gut. Inflammation means more fluid in the gut, which is what causes diarrhea. 

Another interesting area to look at is the lungs, where a mucous layer lines the respiratory tract and protects you from all kinds of things. The lungs are where you are most vulnerable to infection from a virus, although bacteria can get in here as well. That’s because you inhale a couple thousand gallons of air through your lungs every day, and there are all kinds of virus, bacteria, fungi, and other stuff hanging out in the air around you. Think about when someone with a cold coughs near you — the stuff in that cloud of air moves quickly and some of it can get into your lungs. Overall, some of the most dangerous pathogenic viruses use the lungs as their main entry point. 

Say you cut your knee sliding during an adult softball game. What happens when your skin is opened up and harmful bacteria on you and in the surrounding environment are able to walk right in? To help understand what happens during a bacterial infection, it’s helpful to look at the body as a huge continent with trillions of civilians (cells). A war breaks out, and the cells of the Innate Immune System are the first soldiers sent to fight the enemy. Below is a very simple look at how your Innate Immune System works while fighting a bacterial infection. The immune system’s process for fighting a virus is different and will be covered in a separate takeaway. 

• Cytokines — The damage caused by whatever caused your skin to open up kills many of your civilians right away. When your immune cells come across other dead cells or harmful bacteria, they raise the alarm by releasing Cytokines, which are small proteins that convey information to other cells. The cytokines carry the message: “Danger! Enemies are around! Come help!” Immune cells like macrophages and neutrophils “smell” the cytokines and follow their trace to the battlefield. The more cytokines that are released by your immune cells, the bigger the threat. In rare circumstances, your immune cells will release tons of cytokines when the battle is over or when there’s no threat at all. Because cytokines signal the need for an immune response, your cells go crazy attacking things for no reason, eventually causing inflammation and tissue damage. This process is common in autoimmune diseases, where your immune system mistakes you for the enemy. 
• Macrophages — Your Innate Immune System responds to the Cytokines immediately by sending Macrophages, the largest immune system cells in the body, to the scene. These cells are huge, much bigger than the average cell — if the normal cell is a human, a Macrophage is a rhino. Macrophages, known as Great Eaters, eat dead cells and living bad bacteria, clear debris from the battlefield, and start the repair process. They swallow as many enemies as they can, but they can’t eliminate the threat by themselves. They release more cytokines and call for backup. 
• Neutrophils — Neutrophil cells travel from the blood to the scene to assist. The most abundant immune cell in your blood, they immediately begin hunting and eating bacteria, but they’re much less careful about it because they die fairly quickly. They are the “crazy suicidal Spartan warriors” of the immune system. They eat, throw acid, and kill themselves to create deadly traps. Their goal is to go as hard as they can, and they’re not too concerned about damaging helpful allies. Many of them explode when they’re done, and the chemicals they release are harmful to bad bacteria. Our own healthy civilian cells are sort of afraid of Neutrophils because they are so aggressive. Every day, even without an infection, 100 billion of these warrior cells voluntarily die and are immediately replaced with new ones. The puss that oozes from your cut is the dead bodies of millions of Neutrophils that fought to the death for you, mixed in with dead civilian cells and bacteria. 
• Platelets — While all of this is going on, the wound on your skin has developed a bit of a crust. This is your platelets closing it off. Platelets are blood cells that lump together and form a sticky substance that clogs the wound. Their goal is to stop blood loss and prevent more intruders from entering. This enables fresh skin cells to slowly start closing the hole.
• Inflammation — Macrophages and Neutrophils fighting at the scene, as well as cells that have been killed in battle, send signals that cause inflammation, which is a crucial defense process and causes the area around your cut or injury to swell up. Inflammation occurs when your blood vessels open up and let warm fluid stream into the battlefield. Imagine this as floodgates opening up, where blood carrying all sorts of helpful immune cell reinforcements comes rushing in very quickly to defend the injured or infected area. When this happens, the extra fluid causes you to experience some swelling in the area. Inflammation is the universal response of your immune system to any sort of breach or damage. No matter if you burn yourself, cut yourself, or get a bruise. No matter if bacteria or viruses infect your nose, lungs, or gut. Damage or danger — perceived or real — causes inflammation. Inflammation is the red swelling and itching from an insect bite, the sore throat when you have a cold. Interestingly, chronic inflammation is terrible for you; in fact, it’s an underlying cause of about 50% of deaths today. Inflammation is also a big reason for many COVID and pneumonia deaths; when the virus infects people’s lungs, it causes a rush of fluid to the area, and the swelling makes it hard to breathe and get enough oxygen. But in the context of a typical immune response, inflammation is very helpful in three main ways: 
  • It restricts an infection to an area and stops it from spreading
  • It helps remove damaged and dead tissue
  • It serves as an expressway to get your immune cells and attack proteins directly to the site of infection
• Complement Proteins — This rush of fluid to the scene caused by inflammation carries a silent killer into the battle zone: Complement Proteins from The Complement System. These proteins are super tiny and float passively in your blood until an infection occurs and one of them is activated. When one of them is activated at the scene of an infection, it causes a chain reaction that leads to the activation of others around it. Soon, an army of millions of these proteins are activated and become a weapon for your immune system. What do they do? Three things: (i.) They “mark” bacteria by coating their surface, making it easier for your Macrophages and Neutrophils to locate, grab, and eat them; (ii.) they call for backup by sending chemical signals to recruit more immune cells to the area; (iii.) they literally “rip holes” in the bacteria, causing them to “bleed out.” Complement Proteins play a big role in creating a very fast Innate Immune System response. Where there’s inflammation, there’s Complement Proteins.

In most cases, this is where the battle ends. All bacteria are killed. Your cut and infection heal up. All is well. But we’ll assume a certain species of harmful bacteria is somehow finding a way to reproduce and evade your Innate Immune System soldiers. Your Macrophages and Neutrophils keep fighting, but the inflammation continues to rise and huge numbers of civilian cells are dying. What happens now? This is when the Adaptive Immune System gets involved. Below is a very high-level look at how this system responds (more detailed information about how some of this unfolds is in the next takeaway): 

• Dendritic Cells — When a certain species of harmful bacteria is able to evade your immune system and reproduce quickly in your body, Dendritic Cells have to make a decision about whether or not to call for help and activate the very powerful Adaptive Immune System. Dendritic Cells belong to the Innate Immune System, and they are crucial. As the initial battle at the scene of an infection is taking place, they lurk in the background and assess the situation. They go around and take “samples” of dead enemies. This process involves crunching a bacterium into a pile of Antigens, which are basically the proteins it’s made up of.
• MHC Class II Molecules — Once the bacterium is reduced to a pile of antigens, Dendritic Cells load the antigens onto a molecule that lives inside them called MHC Class II. These molecules look like an empty hot dog bun, and the antigen is loaded onto them like a wiener. Once loaded with wieners (antigens), the MHC Class II molecules move to the surface of the Dendritic Cell so they can “present” the bacteria’s antigens to Helper T Cells of the Adaptive Immune System.
• The Lymphatic System — But first, the Dendritic Cells have to get to the Helper T Cells using the Lymphatic System. For cells, the human body is an enormous continent. The Lymphatic System provides a way for your immune cells to traverse this huge continent. This system is primarily responsible for draining excess fluid called Lymph from your muscles and tissues and delivering it back to the blood so it can recirculate. This process prevents you from swelling up like a balloon over time as the battle is waging. It transports lymph using a network of superhighways (vessels) that your immune cells can also use to travel through the body, and it’s the system the Dendritic Cells use in this case to transport their antigen samples to the Helper T Cells. 
• Lymph Nodes — Located throughout your body are about 600 “megacities” called Lymph Nodes. Lymph must pass through these megacities before it can rejoin blood circulation. The lymph nodes are also where immune cells from the Innate Immune System, like Dendritic Cells, meet up with immune cells from the Adaptive Immune System, like Helper T Cells. In this scenario, the Dendritic Cells take their MHC Class II antigen hot dogs to the nearest lymph node stations to find Helper T Cells that have receptors that match the bacterium’s antigens. The exact receptor for the particular antigen that the Dendritic Cells are presenting is not always found right away. Instead, Helper T Cells will literally rearrange their genes to manufacture a receptor that matches the exact antigen of the harmful bacteria.
• T Cells and Antibodies — Once Helper T Cells with the right receptor for the specific antigen wieners it is carrying, more of them are created. Additional weapons built specially to hunt and kill the particular bacterium — like Antibodies and Killer T Cells — are also created. Once created in the lymph nodes, Helper T Cells race over to the battlefield and use special cytokine signals to motivate extremely tired Macrophages. It’s as if they give these soldiers a second wind; a jolt of energy that inspires them to get back to ferociously killing bacteria. Not long after, millions of Antibodies and Killer T Cells arrive on the scene. Antibodies are super soldiers created by B Cells that act as assassins specifically designed to eliminate the exact species of bacteria or virus in your system. They do this primarily by “marking” the enemy for destruction by other immune cells. What was once a brutal battle for days now turns into a one-sided slaughter, as your Adaptive Immune System comes to the rescue. 
• Healing — If all goes well, this is where the battle ends. The last bacterium is eaten, Neutrophils and Helper T Cells begin to kill themselves now that victory has been won, Macrophages clean up the debris by eating dead cells before also killing themselves, excess fluid is carried away through the Lymphatic System, inflammation subsides, and young civilian cells take the place of the fallen. Healing is happening. From a human perspective, you notice that the swelling is gone and the wound, injury, or cold feels better. 
• Immune: Memory Cells — A critical final piece to this sequence is Memory Cells, which are created after the war has been won. When you hear that you’re immune to a disease, it means you have living Memory T Cells and Memory B Cells roaming around your body that “remember” a specific enemy’s antigens and can easily eliminate the threat if it ever returns later in your life. This is why you normally will not suffer the same sickness or disease twice.