Immune, In a Nutshell

Immune: A journey into the mysterious system that keeps you alive, by Philipp Dettmer, is a cross between a high-school biology textbook and an epic two-part saga. At its core there are two stories, describing a bacterial and a viral infection respectively. Both battles introduce us to our immune system, how it recognizes pathogens, and how it dispatches them.

I enjoyed the book a lot. It’s become my late night lecture for the last week, as my body fought off its own battle against COVID-19. Even fatigued and hazy, the book manages to explain and entertain.^[1]

Through the book I learned many useful and fascinating concepts: how the immune system has weaponized evolution to produce antibodies, how proteins come in matching pairs that are used to recognize pathogens, and how the body prevents the immune system from attacking itself.

While simplified, I felt the book did a good job at explaining the reasons why the immune system works the way it does, instead of leaving the reader with just surface metaphors as many others do.^[2]^[3]

One of the many gorgeous illustrations in the book. It represents the immune system fighting a war on two fronts: a bacterial rush and a viral takeover.

Should you read this book? Possibly!

If you want to learn more about immunology, but you are unsure of whether the book is right for you, I would first watch the relevant Kurzgesagt videos:

The videos have a very similar style and cover the same material as some chapters of the book. If they seem interesting and novel, you will definitely enjoy the book!

You should also read this book if you want to learn good communication. The clever use of metaphors and illustrations, interwoven with technical details, make the topic approachable and memorable. I will be thinking from now on of MHC class II molecules as hot dog buns, and I will be wiser because of it.

The only part of the book I am hesitant to recommend is the fourth one. The messages about the importance of vaccinations, the dangers of smoking, and the cruelty of nature fell a bit flat to me. The digression on why autoimmune diseases are on the rise in first world countries, how allergies might have evolved to fight parasitic worms, and the COVID pandemic felt vague and handwavy.

Overall, I am glad that I dedicated time to actively engage with this book. It has helped me shore up my knowledge on one of my weakest subjects, and I had fun while doing so.

In the remainder of this article I plan to offer a summary of what I learned. I’ll proceed chapter by chapter, writing one paragraph for each^[4]. This sadly means I will leave out most of the interesting metaphors, illustrations and stories, which are probably the most valuable part of the book.

I think this will be most useful to people who have already read the book, as a quick recap to jog their memory.

The book has four parts:

Part I: Meet Your Immune System. This is a brief introduction and overview.
Part II: Catastrophic Damage. This part covers the skin, bacterial infections, the innate immune system, the adaptive immune system, and antibody production.
Part III: Hostile Takeover. This part covers the mucosa, viral infections, how the body detects and disposes of infected cells, and immunity.
Part IV: Rebellion and Civil War. This part covers some loose topics like the immunodeficiency virus, autoimmune diseases, how to boost your immune system, cancer, and the COVID-19 pandemic.

Let’s get started!

Part I: Introduction and overview

The immune system is the group of cells and mechanisms meant to identify and destroy pathogens. It is designed to distinguish the self from the other, and destroy and disable the latter.

Our immune cells, tirelessly working to keep us healthy and happy.

Pathogens include some bacteria, viruses, cancer cells, and other organisms. They are dangerous because they steal your body’s nutrients, defecate dangerous substances and/or hijack your cells in order to reproduce (in the case of viruses). The two main points of entrance into the body for pathogens are through the mucosa covering your inner tracks, and through breaches in your skin.

The most fundamental building block of your body, and of pathogens, are proteins. Some proteins interact together, either binding or transforming. Sequences of these interactions are the main way things get done in your body.

The immune system consists of two major interweaved systems: the innate and the adaptive immune systems. The innate immune system are first responders during an infection, and are designed to generically recognize and disable foreign organisms. The adaptive immune system can in a few days evolve specific countermeasures to respond effectively to any pathogen.

Part II: Bacterial infection

Bacteria are small compared to most of your body’s cells (2 μm compared to 10μm), and reproduce very fast (most species can reproduce every 20 to 30 minutes). Most bacteria are harmless to us, a few are symbiotic with us (commensal bacteria), and even fewer are harmful to us.

Skin cells are constantly being produced below, well, your skin. They are pushed outwards and undergo a process by which they harden (using keratin), release pockets of salts and antibiotics (defensins), interlock with each other, and suicide. Our skin is made of up to 50 layers of dead cells, of which we shed about 40,000 per second. It is a very good defence, and skin infections are rare. But the skin can be breached.

When your skin is breached, bacteria swarm in. Your body cells are damaged and stressed, and release a danger signal. The innate immune system reacts immediately. Macrophages show up and start devouring (phagociting) the bacteria. Neutrophils show up as well, and aggressively hunt down bacteria, with little care for collateral damage. Both signal to the body to produce inflammation. Finally, dendritic cells sample the infection site, to possibly activate the adaptive immune system. All meanwhile platelets clump together and cover the breach.

Macrophages grab pathogens and carry them inside themselves, where they are dissolved in a pocket of acids. They act as a sort of field captain, monitoring the infection and deciding whether to scalate or call off the response. Neutrophils are mindlessly aggressive and live on a strict timer to avoid lasting collateral damage. Aside from phagocyting, they are filled with pockets (granules) of dangerous substances they can release to damage everything in the vicinity; and they can reshape their DNA into a web that catches and disables pathogens, the Neutrophil Extracellular Net (NET).

Inflammation starts when a healthy cell is ripped apart. Mast cells in particular sit beneath the skin and are filled with inflammation induced chemicals, to produce a rapid response. Both phagocytes and neutrophils also release signals that cause inflammation. This means to open nearby blood vessels to flood the infected site with warm fluid, which is filled with substances that maim pathogens and attract immune cells. Inflammation directly causes damage to the body, and chronic inflammation causes more than half of deaths worldwide.

Cells have millions of receptors on their surfaces, and communicate with each other by releasing marker proteins called cytokines. Immune cells can detect the direction from which some special cytokines are more abundant, in order to locate infections.

A neutrophil navigates to an infection following higher cytokyne concentrations.

Cells in the innate immune system are equipped with Toll-like receptors that recognize 1) some common building blocks of pathogens (like flagella) and 2) signs of danger (like free-floating DNA).

The complement system is the name of thirty-odd types of protein that saturate your bodily fluids. One important complement protein is C3. When activated, it breaks into a protein C3a that attracts immune cells, and a protein C3b that attaches itself to a target and starts activating other C3 molecules. The attached C3b proteins have positive charge, which makes it easy for phagocytes and neutrophils to grab onto the target (it opsonizes pathogens). C3b proteins can also recruit other complement proteins to form a Membrane Attack Complex, which rips apart bacteria.

Macrophages, neutrophils, inflammation and the complement systems are the main tools of the innate system. Often they are enough to contain an infection. When not, the adaptive immune system needs to step in, activated by dendritic cells.

Dendritic cells fill the role of scouts for the adaptive immune system. They spend a few hours at the site of infection sampling proteins (in this context called antigens). After a while, if the infection is still raging, they stop sampling and move to the lymphatic system.

The lymphatic system is a system of valves that allows fluids that left your arteries to flow back into veins. It also carries waste and remnants from an infection site. Dendritic cells ride the lymphatic system up for a few days until they reach a lymphatic node.

Days after dendritic cells leave the battlefield, helper T cells and antibody proteins arrive on the scene. Helper T cells signal to macrophages to amp their aggression, while antibodies very efficiently opsonize the pathogens. The battle is quickly over, and the T cells signal to macrophages and neutrophils to stop fighting and suicide.

How can the body make such specialised weapons? Because in a sense, it has already made antibodies for every possible pathogen that could invade you.

T cells are born in the bone marrow, and each of them is born with randomly shaped receptors. Afterwards, they travel to the thymus, where they are specially selected. Those with defects or with receptors that bind to any part of your own body are ordered to suicide. The rest go to the lymphatic system, where they transition from lymph node to lymph node. Because of their sheer number, a healthy human almost certainly has T cells of all types matching any possible pathogen’s antigen. During this process, T cells differentiate into various types, including helper T cells, killer T cells and regulatory T cells.

Helper T cells are activated by dendritic cells. After sampling the battlefield, dendritic cells disassemble the antigens they collected and display part of them in Major Histocompatibility Class II (MHC II) molecules. Helper T cells can only bind antigens displayed in MHC II molecules. In the lymph node, the few helper T cells with random receptors that bind to a displayed antigen attach to the dendritic cell. The dendritic cell sends a signal that confirms an infection, and the T cell becomes activated. It rapidly multiplies, and makes two groups. One group travels to the site of infection to activate phagocytes. The other goes on to activate B cells.

B cells are made in the bone marrow, and similarly to T cells, they are born with random receptors. They are selected in a similar way in the bone marrow to prevent autoimmune disease. Their specialty is that they can mass-produce their unique receptors uniquely suited to bind a particular antigen: that’s what antibodies are! B cells are activated in two phases. First, they bind to a free-floating antigen. This causes them to start to multiply and to produce antibodies in moderate quantities. It also causes them to capture, disassemble and display chinks of the antigens in MHCII molecules.

Activated helper T cells can now bind to these antigen displays, which commences the second activation. The activated B cells commence a process of purposeful mutation called somatic hypermutation. They multiply and randomly tweak their receptors. The resulting B cells that are best at binding the free floating antigen keep reproducing, while the others suicide. Once they are good enough at binding the antigen, they transform into plasma cells that start producing copious amounts of the fine tuned antibody.

Helper T cells and B cells work together to fine tune very effective antibodies.

Antibodies can opsonize pathogens, bind several pathogens together to impede their movement, and activate the complement system to better guide it into pathogens. In the case of viruses, it can bind their receptors so they are unable to infect cells.

Part III: Viral disease

The mucosa is the inner layer that covers your digestive, respiratory and reproductive tracts.^[5] Mucosa needs to be permeable to nutrients but hard to pass for pathogens. It is covered in mucus, continuously produced by goblet cells. Mucus acts as a physical barrier that prevents pathogens from reaching your insides, and it’s loaded with salts, antibiotics, antibodies and substances that bind crucial nutrients for pathogens. The mucus is constantly moved by epithelial cells, which moves it out of the nose or towards your rear end. The mucosa is very different in your lungs, in your guts and your reproductive organs; each mucosa is suited to the function of the organ it covers.

For example, the gut mucosa is a strange place, where the mucus is home to commensal bacteria we are symbiotic with. That does not mean those bacteria are not dangerous, and any strays that wander into the body are swiftly disposed of. Microfold cells reach out from beneath the thin layer of epithelial cells to continuously sample your gut biome. The antibodies of the gut mucosa are a special type (IgA) that clumps togethers but does not activate the complement system—avoiding inflammation in the mucosa is crucial to keep you alive.

The lung mucosa is vast, more than 120 square metres in area. Mucus must be used sparingly, to not impede gas exchange. And the immune system needs to avoid inflammation and damage to keep you breathing.^[6] Both factors make the lungs a particularly weak point in your defences; most pathogenic viruses use the respiratory tract as an entry point into your body.

Now we get to talk about our deadliest enemy. Viruses are free-floating bundles of protein, often covered in lipids. They do not react to stimuli in any way. Instead they are passively carried around by random motion, until they bump into their targets. Receptors bind to the protein spikes around the virus, and it is pulled inside the victim cell.^[7] There it releases its genetic material, which reprograms the cell to become a virus factory. After an interval usually between 8 and 72 hours, the cell is filled to the brim with new viruses. Viruses either shed off the infected cell^[8], or the cell is forced to dissolve and release its deadly guests. The explosive growth and the high chances of mutation make viruses quick to adapt and hard to fight.

A colleague coughs nearby, expelling droplets that you unwittingly breathe. Inside the droplets an unwelcome guest is travelling: the influenza A virus. It binds to the receptors of your epithelial cells, and one hour after they are brought inside the cell. Within ten minutes they take over and the cell starts producing new viruses. Unimpeded, each infected cell produces in half a day enough viruses to infect other 22 cells on average, before dying of exhaustion. The viral infection has begun.

Epithelial cells have receptors in their insides that can detect the presence of certain viral proteins. When one is detected, if the cell is still able to, it releases interferons—a cytokine that signals nearby cells to slow down their protein production process. Since viruses rely on their victims’ protein production to take over, this slows down the infection. Plasmacytoid dendritic cells continuously scan for the presence of viral proteins or interferons, and subsequently release more interferons and cytokines to attract immune cells. Macrophages and dendritic cells release pyrogens. Once these reach the brain, they cause fever by ordering the muscles to shiver and blood cells near your skin to contract. The extra heat energises your immune cells and makes viruses unstable. All of this delays a viral infection, but won’t eradicate it. The Innate Immune System can’t do much to viruses, as they spend most of their life cycle inside cells, where they cannot be phagocytosed by macrophages, attacked by neutrophils, or bound by complement proteins.

To address these issues, almost all cells are equipped with Major Histocompatibility Complex Class I (MHC I) molecules. Those periodically bind to proteins inside the cell and display them outwards. During a viral infection, interferons stimulate cells to produce more MHC I. This helps detect infected cells.^[9]

MHC I are harnessed by killer T cells to eliminate infected cells. Like their cousins the helper T cells, each killer T cell is tuned to a specific antigen. Killer T cells are activated in the lymph nodes as well, when they bind the MHC I displays dendritic cells put together for them. It needs to be activated after by a helper T cell to fully unlock.^[10] Killer T cells engage in a process called serial killing. They scan for infected cells, and forcefully insert in them instructions to commit controlled suicide (apoptosis).^[11] The cell then breaks into small virus-ridden packages which are consumed by macrophages.

But what if the virus hijacks the production of MHC I molecules in the infected cell? To prevent this, the innate immune system counts on natural killer cells. On and off infections, natural killer cells scan for cells that lack MHC I molecules or display other signs of stress, and induce apoptosis in them. During an infection, they also scan for antibodies that have bound viruses about to be shed from an infected cell.^[12]

While natural killer cells help slow down the infection, the innate immune system is still helpless against the invader. But the combination of killer T cells and antibodies is very effective at eradicating viral infections. While killer T cells eliminate infected cells, neutralising antibodies bind the spikes of the virus to prevent them from infecting cells, and other antibodies disable the virus in other ways.

After the battle is won, the immune system needs to shut down before causing too much collateral damage. Macrophages and neutrophils wont release inflammation cytokines when not engaged in battle, and those already emitted are used up quickly and depleted. As Helper T Cells stop detecting signs of pathogens they stop encouraging macrophages to fight for longer. Regulatory T Cells step in, and signal dendritic cells, helper T cells, killer T cells and inflammation to slow down.

Most T cells and B cells suicide after the fight. But a few persist, becoming memory cells ready to react to future invasions. Some B cells become long lived plasma cells that continuously produce antibodies. Others become memory B cells, and sit in your lymph nodes waiting for a future invasion. About a tenth of the T cells remain in the site of infection as tissue-resident T cells, dormant agents ready to react. A few others start patrolling your blood and lymph as effector memory T cells. And a last group joins memory B cells in the lymph nodes as central memory T cells. This system is incredibly effective at addressing future infections of the same pathogen—and is the reason why we experience most illnesses only once.

This natural process is so great that we have learned to harness it further to our advantage. First, there is passive immunity. We distil the antibodies from an animal or a donor and inject them into a patient to help them fight the disease. This is, for example, how we produce antivenoms. Second, and more importantly, there is active immunisation. We inject the patient with a weakened version of the pathogen to induce the production of memory cells. This could be a version of the pathogen artificially evolved to be weak (a live-attenuated vaccine), a dead pathogen (an inactivated vaccine), some parts of the pathogen we produce via eg genetically engineered yeast (a subunit vaccine)^[13], or more recently, injecting proteins that instruct the cells that pick them up to produce some of the pathogen antigens (a mRNA vaccine).

Part IV: Odds and ends

The Human Immunodeficiency Virus (HIV) is a sexually transmitted disease^[14] that targets your immune system. HIV is a retrovirus, which means that it merges with your cells’ DNA^[15]. The disease develops in three phases. In the acute phase, it infects T cells and produces symptoms similar to the common cold. In the chronic phase, some copies of the virus have successfully hidden inside T cells, and reactivate periodically to infect T cells when they interact with each other. The virus periodically causes an infection in the lymph nodes, mutating along the way. The immune system can contain, but not eradicate the virus. Finally, profound immunosuppression begins: HIV finds a very successful mutation that takes over, and the immune system is knocked down. This causes Acquired Immune Deficiency Syndrome (AIDS), which makes you extremely susceptible to pathogens. HIV used to be a death sentence, though nowadays it’s possible to treat it to prevent AIDS.

Allergies are caused by your own B cells reacting against a harmless antigen—in this context called an allergen. At any time during your life, exposure to an allergen might activate your skin or gut B cells. From then on, they continuously produce IgG antibodies that bind to the allergen. These antibodies attach to mast cells. When the mast cell covered in IgGs enters in contact with the allergen in the future, it will violently react. The mast cell releases histamine, which triggers rapid inflammation. And it releases cytokines that attract basophils, which prolong the inflammation. Lastly, the cytokines released by mast cells and basophils might attract eosinophils, which produce chronic inflammation, for example asthma.

Why does the body produce allergies? One hypothesis is that they are a defence mechanism against parasitic worms. Worms have evolved to fight the allergic reaction by secreting substances that downregulate the immune system. In response, the immune system evolved to make allergies more violent.^[16]

T cells and B cells with receptors that match your own body self-antigens are killed in the thymus (for T cells) and in the bone marrow (for B cells). This process often has errors, and produces autoreactive immune cells. Since T cells and B cells need to be activated by dendritic cells, this is most often harmless. But it can happen^[17] that a dendritic cell samples a self-antigen during an infection, and this binds an autoreactive T cell, activating the adaptive immune system against your own body. Some of this activated T cells and the B cells they activate become memory cells—you develop an autoimmune disease. ^[18]^[19]

During the second half of the 20th century we saw a decline in pathogen infections while allergies and autoimmune diseases skyrocketed. Apparently some studies suggest that e.g. kids growing up in a city are more prone to self-immune disease than those raised on farms. Some scientists speculate that this is due to a change in the microbiomes we interact with^[20]. More hand waving ensues.

How can we improve our immune system? The immune system is a finely tuned machine. Make it more aggressive and it will cause autoimmune diseases. Make it weaker and it will be overwhelmed by pathogens. That is why we know of no ways to efficiently boost the immune system. The low hanging fruit is a varied diet, regular exercise, and avoiding smoking.

On top of that, the book claims a connection between mental health and the immune system. Chronic stress seems to disrupt the ability of the body to shut down inflammation, affects the behaviour of helper T cells, prompts the release of cortisol that suppresses the immune system, and increases risk of auto-immune diseases and cancer. In general, the mechanisms are unclear and the section handwavy, so I would not put much weight on this. Plus I am not sure whether “chill out” is good medical advice.

Cancer happens when cells in your body mutate and begin to grow uncontrollably. Cancer can develop in solid organs (tumours)^[21] or in your blood or lymph (leukemia). To become cancer, a cell needs to suffer mutations in the part of its genetic code that controls growth (the oncogenes), in the part that repairs broken genetic code (the tumour suppressor genes), and the part that controls programmed cell death (the apoptosis genes). As the tumour grows large, it causes nearby cells to starve, which attracts the immune system. Macrophages and natural killer cells can kill most of the cancerogenous cells. But if things go wrong, the most discreet cancer cells will survive^[22]. The improved cancer cells expand, and create a partially isolated environment where immune cells cannot easily reach them—a stable tumour is formed. In the worst case, the tumour will begin expanding to other tissue (it becomes metastatic).

COVID-19 is a worldwide pandemic^[23] caused by the Severe Acute Respiratory Syndrome Coronavirus 2 (SARS2)^[24]. The coronavirus targets the ACE2 receptor, used among other things to regulate blood pressure, and common among lung cells. SARS2 seems to be able to delay the release of interferons, making it spread fast and cause widespread inflammation. The damage might cause the patient to need mechanical ventilation, which carries a danger of causing a bacterial infection, leading to even more inflammation. Inside the blood, the virus also causes blood clotting, making it difficult to distribute oxygen and possibly causing circulation problems. For older people with weaker interferon responses or people with comorbidities, this can easily be lethal.

I’d like to thank Justis Mills and the LessWrong team for helping me with editing, and Anne Wisseman for feedback. If you have editing suggestions, please leave them in a comment or directly in this google doc!

^
My only complaint is that the characters feel at times very one-dimensional (and unicellular).
^
With perhaps the exception of some chapters in part IV, where I felt the book was more confusing and handwavy.
^
The science seems solid to me, though it’s out of my expertise, so I can’t say with confidence.
^
Alright, almost.
^
It’s useful to think of these tracks as being outside of you. The body still takes care of maintaining these spaces and having straneus objects in your trachea is not a good thing. But in general the immune system is more chill with having bacteria in your mucosa, similar to how it is okay with bacteria living in your skin.
^
Alveolar macrophages patrol the surface of the lungs. Unlike regular macrophages, they downregulate inflammation.
^
This is also the reason why we don’t have effective antivirals. Bacteria have plenty of common building blocks that bear no resemblance to our bodies, so we can design antibiotics that bind and disable these. Viruses make a living out of mimicking body antigens, so that they can bind to cells’ receptors. Any antiviral would also bind the proteins that were actually meant for these receptors, and so wreak havoc in your body.
^
When viruses shed off the cell, they usually cover themselves in part of its membrane. This serves as a disguise that delays the response of the immune system.
^
The shape of MHC I and MHC II are very different between individuals. Their specific shape can make them better or worse at binding specific antigens. This explains part of why genetics is an important risk factor for susceptibility to pathogen and auto-immune diseases. It also explains why organ transplants are quite commonly rejected by the body.
^
Why? I don’t know.
^
What happens if the cell is broken enough to not suicide? Why don’t viruses evolve to target apoptosis?
^
Specifically, the antibodies that bind viruses while they shed off and are detected by natural killer cells are antibodies of a specific class called type IgG.
^
Neither dead pathogens nor parts of them are sufficient to induce a proper immune response, so they are injected together with small concentrations of some toxic chemicals to induce a reaction.
^
Sexually transmitted diseases transmit through microscopic injuries that expose blood.
^
The human genome project found that up to 8% of our genetic code is made of retroviruses.
^
This comes with a lot of handwaving in the book so take it with a grain of salt. Why would weapons designed to fight worms trigger with harmless allergens? The book does not explain.
^
Especially if you are genetically unlucky and your MHC II molecules are good at binding self-antigens.
^
Autoimmune diseases can be life degrading in many ways, like diabetes or arthritis. But they are surprisingly rarely fatal. I have no idea why.
^
While they are not activated by an infection, dendritic cells sample self-antigens that they use to identify and induce apoptosis in autoreactive T cells.
^
The book claims that all common diseases we fight off today evolved in the last 10,000 years. This includes measles, cholera, smallpox, influenza and the common cold. This might be because of the change from hunter-gatherers to farmers; viruses have an easier time spreading and mutating in populated towns.
^
If a tumour stays confined within an organ you are in luck: it is a benign tumour that only needs to be monitored rather than treated. It might need to be surgically extracted if it grows too large, though.
^
Perhaps because they have evolved a way to shut down natural killer cells.
^
In case you forgot.
^
There have been two recent coronavirus pandemics before COVID19. The original SARS broke in China in 2003, and the Middle East Respiratory Syndrome (MERS) first reported in Saudi Arabia in 2012.