Immune

Summary:

A book about how the human immune system works. It goes over the different cell types and how they work together to fight off diseases of all kinds. The body is an incredibly machine, and even though the immune system is just a part of it, it's mindbogglingly complex.

Main Idea

Your body is made up of cells, which are made up of proteins. Proteins are chains of amino acids, and chemicals, twisted into complicated shapes, that do very specific things in your body, there are many proteins and they all do different things. There are a lot of cells and even more proteins.

The main problem of the immune system is to distinguish "self" from "other". This is a hard task, but the body has clever ways of doing it. One of those is that the surface of your cells is covered in specific glycoproteins, that can show the immune system if a cell belongs to your body or not.

These proteins are presented as tests to many cells in the immune system so that they don't match them and try to attack and destroy those proteins. If immune cells fail those tests, they don't get activated and die. Sometimes this process goes wrong, hence sometimes we get auto-immune diseases.

Everything in the immune system sits behind safety switches because if things go wrong the immune system can easily kill you. The lymphatic system is a major component of the immune system, it's draining fluids from in between cells. When infections happen, it carries immune cells to the correct location. It also carries around debris from infection sites, such as broken cells and fragments of pathogens back to lymph nodes, where strong immune cells (T-cells and B-Cells) are waiting to be activated for fighting off infections.

Protein-based weapons (the complement system), chemokines, cytokines and antibodies work together with different kinds of cells like T-Helper Cells, Memory Cells, Dendritic Cells, B-Cells, Plasma Cells, Neutrophiles and Macrophages to fight off infections together. The body has a multilayered defense.

The Immune System can be grouped into the adaptive- and innate immune systems. Generally, the body fights infections with the complement system (proteins that make holes in bacteria), macrophages (that "eat" pathogens) and neutrophils (that just kill everything at the site of infection) first. All of this buys time for the adaptive immune system to kick in. Here Dendritic Cells take information from the ongoing battle through the lymph system, to find T-Cells and B-Cells matching the antigens (protein bits and pieces) collected from the pathogens. T-Cells and B-Cells for every variant of virus, bacteria or "whatever" proteins can be found in your body, hence it takes time to find the right match. Once that happens though, the adaptive immune response kicks in, producing antibodies that specifically target and kill the specific infection within.

Cells with viruses are extra hard for the immune system to detect. Luckily cells have little "windows" into the cells, that can show immune system cells outside, what is going on, inside, by showcasing proteins the cell has produced on its surface, this way if lots of virus proteins are produced the immune system will find it out and order the cell to destroy itself.

Some pathogens are good at avoiding detection or even using the immune system as a means to an end (HIV or Covid are examples). And in certain areas, like the digestive tract or the lungs, certain measures of the immune system (like swelling up of lymph) are normally blocked, because they would cause other problems.

The immune system is incredibly complex, and it's marvelous that we have one that works as well as it does. And the Immune Book does a wonderful job at showcasing the whole complexity, without being overly long and dense. Though at times I wish it could have gone even deeper into the nitty gritty details of the processes involved.

Detailed Notes

Introduction

Knowing about the Immune System always puts things into perspective.

Part I - Meet Your Immune System

Chapter 1 - What is the Immune System?

The Thing that we call health. The basis for a good and free life where we can do what we desire, not held back by pain and disease.

We still fight to carve out more years, months, days, and hours. Because, overall, it is pretty good to be a human and it is worth it to have this experience a little bit longer.

Chapter Summary:

The immune system distinguishes self from other and makes sure that the stuff designated self can thrive while the stuff designated other is terminated quickly. Doing so is a tightrope walk between too much aggression and too little of it, a "tightrope walk" the immune system usually excels at.

Chapter 2 - What is there to defend?

Staying alive is not a thing you should take for granted.

Chapter Summary:

You are essentially a tube, consisting of lots of very specialized cells, that do incredible things each day and that need an army to defend against vast amounts of pathogens every day. The idea of a human, with human-sized cells, is introduced as a fancy imagination to get a better feel of how crazy everything inside the body is.

Chapter 3 - What are your cells?

Your DNA, a long sequence of instructions that are necessary for a living thing to be a living thing.

In the world of proteins shape determines what they can and can't do. Shape is everything.

I think this idea applies to everything, not just Proteins. The difference between different things is just the shape in which energy is organized.

Your cells are nothing but bags of proteins guided by chemistry.

Chapter Summary:

Cells make up the body, proteins make up cells, and everything is governed by biochemistry, each cell, while complex, follows "simple" rules, but together they form things that they alone couldn't. You. But still, the question remains, how can, essentially somewhat stupid things, defend your body - and do such a good job at it?

Chapter 4 - The Empires and Kingdoms of the Immune System

Chapter Summary:

The Immune System is made up of two distinct parts that play together nicely - the Innate Immune System and the Adaptive Immune System, the first is a generic first line, broad defenses while the other is highly specialized on specific strains of pathogens.

Part II - Catastrophic Damage

Chapter 5 - Meet Your Enemies

Chapter Summary:

Pathogens are things that make you sick, Bacteria are everywhere, your body doesn't even defend against some of them but accepts them as part of life and cooperates with those good bacteria. The main challenge for the immune system is the bacteria's ability to rapidly reproduce and thereby consume nutrients and by doing so kill cells of your body.

Chapter 6 - The Desert Kingdom of the Skin

You can imagine your skin less as a w all and more like a conveyor belt of death.

Skin cells may be tough, but the world is tougher.

Chapter Summary:

The skin is made up of dead cells, has a low pH and is relatively dry, but covered in fat and oils, and a natural antibiotic called defensins. It is also inhabited by lots of bacteria, working together with the immune system, allowed to live on the skin, but not get into the body. Those take up space and even communicate with the inside and immune system to tell what is going on on the outside.

Chapter 7 - The Cut

Small actions can have big consequences.

Chapter Summary:

A simple cut is a lot of work for your body, and a lot happens to push back the intruding bacteria, fungi and viruses from the opening in the skin, kill and trap them, and keep them at all costs from going further into the body. But some strains of pathogens are strong enough to resist those defenses and that's when one needs antibiotics or other forms of treatment.

Chapter 8 - The Soldiers of the Innate Immune System: Macrophages and Neutrophils

Life hates nothing as much as wasting resources.

Chapter Summary:

Neutrophils are "crazy" soldiers, killing friend and foe alike, thereby living only for a short period because otherwise the risk of them doing unnecessary harm is too high for the body to tolerate. Macrophages are the other type of immune cell introduced. they eat dead cells and pathogens alike, but also communicate the status of the infection and clean up normal debris from cell apoptosis every day.

Chapter 9 - Inflammation: Playing with Fire

For at least one in two people who died today, chronic inflammation was the underlying cause of the disease that killed them.

Pain is a very effective emotion in the sense that we prefer not feeling it.

Chapter Summary:

Inflammation is a flood of fluids into the affected area, that's what's causing the swelling and heating. Inner parts of cells when outside the cells because of unnatural death cause inflammation. Mast cells can enhance inflammation greatly. They play a role in allergies.

Chapter 10 - Naked, Blind, and Afraid: How Do Cells Know Where to Go?

Most places in your body are pretty dark. If your insides are well lit, something has gone terribly wrong.

For cells, information is a physical thing: Cytokines. [...] very small proteins that are used to convey information.

Chemokines are Cytokines that are guiding or attracting immune cells to a place.

Chemokines are Cytokines that make cells move into certain areas.

Cells follow the chemical gradient of Cytokines to get to places.

Receptors for Cytokines are dense on immune cell surfaces to distinguish between "real" and "fake" information, only when a lot of the receptors get triggered does the cell spring into action.

Cells are protein robots guided by biochemistry.

Proteins cascade information by changing their shapes from the outside to the inside of the cell, thereby changing the inside of the cell can lead to different behavior - i.e. proteins within the cell doing different things based on the surrounding of the cell.

Cells can react to information without being conscious or having the ability to think, guided by the biochemistry of life.

Chapter Summary:

Cells can't see, smell or hear anything. They find their way around by using receptors and chemical gradients. Receptors bind to chemicals on the outside, then change shape. A part of that shape hangs inside the cell, where it can affect the inner workings of the cell and therefore change what it is doing. It's all just molecules bouncing into each other changing their shape and thereby their function. Where chemical gradients get denser, more receptors "fire" (read change their shape), so the cell can move towards or away from that direction. The chemicals that convey this kind of information are called Cytokines. When they make cells move they are a special kind named chemokine.

Chapter 11 - Smelling the Building Blocks of Life

The shape of a protein determines what it can do and how it can interact with other proteins, what structure it can build, and what information it can convey.

Proteins are like puzzle pieces - magnetic puzzle pieces! They snap together and can change shape because of the closeness of other puzzle pieces. Uh, and parts of those protein puzzle pieces are quite flexible, so the whole shape can wiggle around and bend and twist, because of ambient heat!

Innate immune cells have receptors that can recognize the protein puzzle shapes that make up flagella, and enable the immune cells to eliminate them.

Chapter Summary:

Toll-like receptors can detect specific protein structures that pathogens can't get rid of and that human cells don't have. This way these receptors only react to things that don't belong in your body and can therefore help the immune system to do its main task - distinguish self from others!

Chapter 12 - The Invisible Killer Army: The Complement System

Chapter Summary

The Complement System has been around with only a few changes for over 500 million years. A long time, so it must be ** useful.

It's a set of proteins, working together in a complementary fashion to cripple enemies and activate the rest of the immune system. They can also rip holes into intruding pathogens to destroy them. Usually, these proteins are inactive. But when one activates, it can activate others in a coordinated dance.

C3 -> C3a (flooded away, activating rest of immune responses) + C3b (attaching to bacterial cell) -> another complement B attaches to complement P to form C3 convertase on the bacteria cell surface. This protein assembly activates more C3 units and soon the bacteria's surface is full of these proteins. The complement unit is positively charged making it easier for phagocytes to grab pathogens. The assembly can mutate once more, into something called Membrane Attack Complex that creates holes in the bacterial cell membrane, killing it.

Chapter 13 - Cell Intelligence: The Dendritic Cell

Chapter Summary:

Dendritic Cells have starfish-like flopping arms and they sample bodily fluids constantly looking out for unfamiliar proteins and other signs of infection. When they find some, they gather and store it, creating something like protein imagery of what the pathogen looks like. They deliver that information to the adaptive immune system, and they get there via the lymphatic system.

Chapter 14 - Superhighways and Megacities

Your network of lymphatic vessels is miles long and covers your entire body.

One job is to drain excess fluid, that was left behind because of blood, from the tissue. In this fluid - called lymph - there is a lot of detritus as well, dead and living cells, proteins, sometimes bacteria etc. The Lymph system even transports fats around in its lymph as well.

Dendritic cells arrive in lymph nodes with the protein parts from the infection.

Spleen - stores extra blood, recycles old blood cells and holds reserves of platelets and red blood cells as well as so-called Monocytes. Spare part macrophages that can be customized to fit certain situations better.

Lymph nodes filter the lymph detritus. The spleen does the same but for blood instead of lymph.

Tonsils sample proteins and pathogens from the mouth and food to train the immune system, especially in young people.

Chapter Summary:

The Lymph system is quite vast, has small muscles, that squeeze around a fluid called lymph, that carries around all kinds of stuff, mostly water and cell junk, and is filtered, where dendritic cells and the Adaptive immune systems cells can meet.

Chapter 15 - The Arrival of the Superweapons

Chapter Summary:

Adaptive Immune System = T-Helper Cells + Antibodies. Antibodies clump pathogens together and t-helper cells re-activate and invigorate macrophages so they gobble up the opsonized (stuck together and immobilized by antibodies and thereby made "tastier") pathogens. Once the infection is cleared, immune cells undergo apoptosis except for macrophages and some t-helper cells. The lymphatic system carries away excess blood from the inflammation reaction.

Chapter 16 - The Largest Library in the Universe

Right now your Adaptive Immune System has a specific weapon against every possible enemy in the universe.

Chapter Summary:

Bacteria can multiply so fast that during an infection they can adapt to the body's immune responses by pure chance and thereby avoid them. To make that impossible the body needs specific weaponry targeted at exactly the species of bacteria and other pathogens encountered. That's why we have a "weapon" against every thinkable pathogen combination ready at any time.

Chapter 17 - Cooking Tasty Receptor Recipes

A protein piece that is recognized by the immune system is called an antigen.

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

Chapter Summary:

The adaptive immune system shuffles around gene fragments to create unique genetic codes to produce unique protein shapes in great variety. The main question posed for the next chapter - how come this great variety doesn't include proteins that are specifically you? And could therefore harm you?

Chapter 18 - The Murder University of the Thymus

The Thymus is an unappealing and boring collection of tissue that looks a little bit like two, old, lumpy chicken breasts seen together in the middle.

Each T-Cell has one specific type of receptor recognizing one specific type of antigen (protein/protein fragment). Some of them will recognize proteins from the body, ones that do get killed in the thymus. If they don't get killed properly for some reason that is exactly what causes autoimmune diseases. T-Cells also kill themselves if they don't communicate

Thymus gets smaller when we age and loses functionality. That's why old people are so prone to diseases and so weak against them.

Chapter Summary:

Thymus kills every T-Helper cell that binds to self or is otherwise inadequate to function properly as an immune cell. It gets less active as people age. And only 2% of T-Helper cells survive the Thymus intact, but that's still enough to have at least one against every pathogen one would ever encounter.

Chapter 19 - Presenting Information on a Gold Platter: Antigen Presentation

Chapter Summary:

The immune system chooses which defense to use, only at the time of infection, massively multiplying T-Helper cells that are deemed useful when presented with the battlefield information from a dendritic cell.

Dendritic cells cover themselves with antigens from pathogens, presenting them on their surface attached to MHC (Major Histocompatibility Complex) II molecules.

MHC-I is necessary for the activation of T-Helper cells. Only if presented with an antigen attached to an MHC protein, will the T-Helper activate. That is a safety mechanism so it can't accidentally activate from some floating junk.

Dendritic cells die after some time, taking the gathered antigen information with them. So if there is no more infection the adaptive immune system response will also fizzle out.

Humans have different MHC proteins and find sexual attraction in others with different MHC proteins. We can smell the difference because we have receptors that trigger the proteins related to the MHCs. We can smell the immune system of somebody else.

Chapter 20 - Awakening the Adaptive Immune System: T Cells

Chapter Summary:

There are lots of different types of T-Cells, one is the T-Helper cell.

T-Helper Cells multiply in some lymph nodes after being activated, then half of them go to the site of infection, and activate macrophages to go into a "frenzy mode", but only for a short while. If the T-Helper cell doesn't reactivate the macrophage shuts down. The severity of the Innate Immune system response is thus regulated tightly by the Adaptive Immune system.

After the infection is cleared up, some T-Helper cells turn to Memory T Cells. These are what give immunity to disease.

The other half of the T-Helper Cells go to a different place than the infection - they go to activate B Cells.

Chapter 21 - Weapon Factories and Sniper Rifles: B Cells and Antibodies

Chapter Summary:

B Cells can recognize antigens and produce fitting antibodies, they go through the same test of self and other in the bone marrow that T-Helper cells go through in the thymus. They need two steps of activation. One by an antigen floating in the lymph from the fight of the Innate Immune System at the site of infection and then another one by an activated T-Helper Cell.

Why not use a dendritic cell for that? Because the MHC protein limits the size of the antigens that could be presented. For the activation of the T-Helper cells, that's alright, but if the body should produce useful antibodies these small antigen protein pieces are not enough, it needs less processed, bigger protein pieces to build truly effective weapons against those. And that's why B cells sample the lymph directly and get their first activation from antigens in the lymph specifically.

Complement System proteins on antigens in the lymph make it 100x more likely to trigger B Cell activation. The first activation means moving the B Cell and cloning, to around 20k and producing less effective antibodies, without second activation they die again within a day.

B Cell also has MHC on its surface and can grind up the first activation "big complicated" antigen into lots of small variants and then present all of those together on the surface on the MHC similar to a dendritic cell. Now if a T-Helper cell comes along and recognizes one of those, the activation happens. That's also why there is a need for the second protein receptor binding for the activation of the T-Helper cell by the extra route of the dendritic cell. So they don't accidentally activate when finding an activated B Cell that was gorging on lymph.

Once both activations happened the B Cell turns into a plasma cell and produces LOTS (2000 per second per cell) of antibodies.

Chapter 22 - The Dance of the T and the B

Chapter Summary:

Activated B cells don't have a perfect antibody to antigen fit, but before they become plasma cells they have to have that perfect fit. If a T-Helper cell interacts with a B Cell, that B Cell can undergo Somatic Hypermutation, which means that it can change its antibody recipe slightly to make a better matching one. It tests those mutations against the antigens swimming around in the lymph again, if it got better - it will get more interactions and then more interactions with T-Helper cells, further refining the antibody that it has until it's perfect. The ones that didn't match better than before the mutations die, the other ones keep mutating and therefore getting better over time.

Chapter 23 - Antibodies

Chapter Summary:

Antibodies are specialized, they are essentially B Cell receptors, targeted to one specific antigen. They grab onto that antigen, bind to it, and then don't unbind again, they "grab" it. On the non-grabbing end, they have a piece of protein that can be "grabbed" by immune cells. This way antibodies greatly help immune cells discover and kill pathogens. They also "opsonize" whatever they grab and can grab more than one pathogen, thereby clumping lots of pathogens into giant bundles that can then be targeted en masse by neutrophils or macrophages. Antibodies also activate the complement system, sort of making it into a guided missile system.

An Aside - The Four Classes Of Antibodies:

IgM

first defenders - many (10) antigen binding sites, first to be reproduced, unrefined, but a fast response, 5 immune cell binding sites, 2 of those for complement system activation

IgG

specialists - not causing more inflammation at end of infection, carried over from mother to child over Plazenta, mostly better at opsonizing than complement system

IgA

bouncer - protecting the mucosa constantly mouth, gut, eyes etc. Doesn't activate the complement system because immune binding ends are merged, important otherwise guts etc. would have constant inflammation reaction because of complement activation, mothers give IgA to babies via breast milk, protecting their guts

IgE

cause allergies - is there to protect from large pathogens - like certain worms for example (scratch out the worm eggs, sneeze them out etc.)

How Do B Cells Know What Sort of Antibody to Make?

T-Helper cells tell them via info from Dendritic cells what is necessary to produce and the B cells can switch based on that

Chapter 24 - The Swamp Kingdom of the Mucosa

Chapter Summary

Mucosa are at the intersection between inside and outside, we have to get in certain things while keeping other things out. That is a tough problem. The whole intersection is lined with mucus - yes you have something similar to snot - in your guts and lungs! Mucus is produced by goblet cells. Mucus is filled with weapons, IgA antibodies, salts and enzymes that attack the cell membranes of pathogens. Mucosa's first layer is made from epithelial cells which have cilia sticking out that constantly move around the mucosa produced by the goblet cells. Finally, different parts of mucosa have different immune system functions, depending on where they are, think gut vs. nose vs. female genitalia

Chapter 25 - The Weird and Special Immune System of Your Gut

Your gut immune system is a peacekeeping force.

Chapter Summary:

Commensal bacteria live in the gut and break down parts of food we can't digest and in return get a pretty comfy place to live. Epithelial cells connect, bonding closely to prevent anything from getting inside, but still, sometimes commensal bacteria do enter all this way through the deadly layer of mucus filled with deadly proteins, defensins and antibodies, and then try to get past the Epithelial cells as well. Behind the epithelium is the Lamina Propria which hosts slightly different versions of B Cells, Dendritic cells and macrophages. All a bit more tuned down and adapted to not cause inflammation too easily.

Chapter 26 - What Is a Virus?

Viruses are the simplest of all self-replicating sorts of living things.

Chapter Summary:

Viruses are immensely successful but rely on other living cells to reproduce themselves, it is still unclear how they exactly arose. Viruses infect cells, then force their biochemistry to produce more viruses until the cell bursts open. And it spills out the newly produced viruses, which then go on to stumble into new cells by accident eventually. Viruses mutate all the time since they lack the safety replication mechanisms cells have.

Chapter 27 - The Immune System of Your Lungs

Chapter Summary:

Lungs need special defense mechanisms since inflammation would quickly drown you in your liquid. There is no mucus on the alveoli since they need to exchange gases but there are Alveolar macrophages patrolling the surface of the epithelial cells there, cleaning up. There might exist a microbiome in the lungs but finding out more about it is hard since taking samples from the inner workings of the lungs is hard without killing or injuring people while doing so.

Chapter 28 - The Flu - The "Harmless" Virus You Don't Respect Enough

Cells are made from millions of parts moved by thousands of processes going on at the same time, in a complex and wonderful dance that we call life.

Chapter Summary:

Viruses connect with cells using spike proteins. These are highly specific to each cell type, so viruses can usually only infect a specific cell of a specific organism. When they do connect to a cell, that cell, envelops the virus and takes it down into its inners, where the virus takes over the biochemistry of the cell, using hostile viral proteins and RNA or DNA, which interrupt the ways a cell works and turns it into a virus manufacturing machine. Before a cell dies because of exhaustion from the viral infection, it will have produced enough new viral particles to infect a lot more cells, so a huge spike in exponential growth happens. A single infected cell quickly turns into a few million. Though in a typical infection the overall size of infected tissue remains "small" the explosive nature of the growth is what makes those infections so scary to our immune systems. And that's why we have evolved special anti-virus defenses as well.

Chapter 29 - Chemical Warfare: Interferons, Interfere!

In case of a serious vital infection, your innate immune system and the infected civilian cells need to fight for the most valuable thing in the universe: Time.

Cells can detect if they have been infected by having receptors on their insides that are sensitive to viral proteins. When this happens they release a special form of Cytokines known as Interferons. Interferons are a "Get-Ready-For-A-Virus" signal for other cells. One way to slow viral infection is that Interferons tell cells to slow protein production, and thereby also "interfere" with virus protein production. Viruses have evolved counter mechanisms - viral attack proteins which destroy the receptors before they can release the interferons. It's an evolutionary arms race.

Plasmacytoid Dendritic Cells are "Antivirus Alarm Cells" - they detect the Interferons and other signs of viral infection. When they detect something like this, they mass produce more interferons.

A spike of interferons in your blood is usually the earliest sign of a virus infection, long before any real symptom or the virus itself is detectable.

All the unpleasant things you are about to experience are the result of the desperate attempts to halt the brutal invasion of your lungs.

In a viral infection, immune cells release a special form of Cytokines called Pyrogens - the name means molecules that "generate heat", these are what cause fever. Pyrogens directly manipulate your brain into doing things like shivering and constricting blood flow on the body's skin surface. Fever makes it harder for pathogens to live, but is also a very taxing investment of the body because it uses up lots of energy to heat itself. Even cold-blooded animals can have a fever. But behavioral fever, they search out extra hot places when infected.

To effectively fight viral infections the immune system has to fight and kill infected cells. It has to quite kill parts of you!

Chapter Summary:

Interferons -> Plasmacytoid Dendritic Cell -> Immune Response -> Pyrogens -> Fever. It's all about slowing the reproductive cycles of the virus, to buy time for the adaptive immune system to kick in. Slow down the curve of virus particles in the body to have enough time to develop appropriate weapons against this specific type of infection.

Chapter 30 - The Window into the Soul of Cells

Chapter Summary:

Cells show present parts of the proteins they build i.e. antigens on the surface of their cells. They use MHC-I for that. Not MHC-II but MHC-I. MHC-II is only reserved for immune cells and the special "teacher" cells in the thymus or bone marrow. MHC-I receptors on the other hand occur in every cell that has a nucleus.

The immune system can check if the response from those MHC-I presented antigens is normal or not and kill cells where this answer is not normal anymore. Interferons make cells produce more MHC-I giving the outside more information about what kinds of proteins are produced on the inside and increasing the chance of being detected as infected by a virus.

MHC-I is unique to each person. This is the reason why organ transplants are "rejected" by the immune system. The different MHC-I is almost automatically treated as "different" even if the proteins presented are "normal" and "correct" and hence the immune system kicks into action, trying to kill the cells of the transplanted organ.

Chapter 31 - The Murder Specialists - Killer T Cells

"Killer" T Cell is a perfect name considering what it does: It kills, efficiently, fast and without mercy.

Chapter Summary:

Dendritic cells do cross-presentation they put antigens from their collection of the infected site not only in their MHC-II receptors but also into their MHC-I receptors. These MHC-I receptor-bound antigens can then, together with a second receptor binding to the Killer T Cell at the same time, activate it. The same security mechanism as with Helper T Cells but on a different MHC protein. Also similar to B Cells - Killer T Cells then need another activation from an activated Helper T Cell, before they become active. Cloning a lot, and killing lots of civilian cells that happen to present virus infection antigens through their MHC-I receptor windows. Ok, technically the Killer T Cells don't kill the infected cell, but just tell them to undergo apoptosis. This way the virus filled inside of the cell doesn't spill but gets packaged into little cell wall bags that are picked up by macrophages. This process of checking and ordering apoptosis is called "serial killing". Problem - viruses often force the cells to stop producing MHC-I proteins so this strategy might be hindered a lot, depending on the virus.

Chapter 32 - Natural Killers

Natural Killer Cells are Creepy Fellows.

Natural Killer Cells patrol the body and check for cells without MHC-I proteins. If one doesn't - it gets killed. That's why other people's organs get killed by the immune system! Now if a virus forced a cell not to present MHC-I on its surface - then it would still get found my those Natural Killer cells, looking for exactly that! Natural Killer cells are only stopped from ordering a cell to kill itself if they encounter the MHC-I they try to bind to. They are "default on".

Natural Killer cells are a bit like nervous agents walking through a city, randomly approaching civilians. Instead of saying hi, they put a gun against your head and wait a few seconds. If you don't show them your passport quickly enough, they pull a plastic bag over your head and give you the gun making yourself shoot you in the face.

Natural Killer cells can also sense stress in cells by other receptor pathways and order apoptosis where they find unusual signs of stress (which usually means cancer or infection)

Chapter Summary:

Natural Killer Cells order apoptosis when they find cells that lack MHC-I or show signs of stress. This way they help the immune system to kill cells that try to hide what proteins they are producing by stopping to show it, through MHC receptors.

Chapter 33 - How a Viral Infection Is Eradicated

An Aside - Why Don't We Have Better Medication Against Viruses?

Viruses are too similar to our cells.

Antibiotics are essentially proteins or other chemicals designed to specifically target and destroy or otherwise disable or inhibit the proteins or chemistry of bacteria in their reproductive cycles. Since the shapes of proteins from bacteria are often different enough from the proteins used in humans the antibiotics don't have any effect. But targeting viruses this way would mean interrupting the workings of normal human cells as well because viruses hijack already present cells. Therefore the biochemistry of an infected cell is much closer to a healthy cell than that of a bacteria is to either of them.

A virus is in a perverse way very similar to us because it uses our parts to make more of itself.

Chapter 34 - Shutting the Immunes System Down

No part of your immune system is made to work forever without stimulation and so if the chain of activation stops, step-by-step, the immune response winds down.

Chapter Summary:

Things for an immune response need active stimulation to keep going, when that stimulation ends, the immune response winds to a halt on its own. However, there exists another type of T Cell called Regulatory T Cell (5% of all) that actively turns down other immune response cells. They reduce inflammation, slow down the proliferation of T Helper and Killer cells and turn down macrophage and neutrophile activity as well as making dendritic cells less likely to activate new T cells. They end immune reactions. Regulatory T Cells make sure that the gut stays calm. But there is also a lot not understood about them yet and a lot more complexity that the book doesn't cover.

Chapter 35 - Immune - How Your Immune System Remembers an Enemy Forever

Immune means exempt. The thing that remembers pathogens encountered already for you is - of course - alive itself. It's a cell called a Memory Cell. We have roughly 100 Billion of them!

Plasma Cells turn into Memory Cells and there are of course different types of memory cells. One is the "Long-Lived Plasma Cell" which goes to the bone marrow after the infection is over and stays there for a long time, producing some antibodies for the rest of their time. These will be always present in our blood, mucus etc.

A single drop of your blood contains about 13.000.000.000.000 Antibodies.

There are also Memory B Cells that just sit down in the lymph and chill, waiting for the sign of another antigen they match, if they find one, they immediately start multiplying and immediately become plasma cells producing antibodies without T Helper Cell activation! this forms a shortcut to the Adaptive Immune System activation which means it kicks into gear much earlier and therefore before the infection had much time to spread and therefore no symptoms will be caused by re-infections.

T Cells can also turn into different types of memory cells. Tissue Resident Memory T Cells stay locally and will wake up the immune system again if they detect signs of another infection as well as Effector Memory T Cells that look for the antigens from their infection in the lymph. There are also Central Memory T Cells, that when finding the same antigen again, produce Effector Memory T Cells en masse to help against a new infection of the same pathogen.

An Aside - What Doesn't Kill You Doesn't Make You Stronger: Measles and Memory Cells

Being infected with measles erases the capacity of the immune system to protect you from the diseases that you overcame in the past.

Why? Because measles infects immune cells, especially memory cells.

Chapter Summary:

The Human Body has a living memory of diseases encountered in the past in the form of Memory Cells, special cells formed from T Helper or B Cells that can produce a specific adaptive immune response to the same pathogen almost immediately after reinfection, killing it with specific antibodies and a strong immune response almost immediately, thereby making us immune to diseases we encountered in the past.

Chapter 36 - Vaccines and Artificial Immunization

Chapter Summary:

Variolation - take some infected skin or pus from somebody ill, grind it and stick it in your nose and have a 1-2% to contract the real full-blown thing or a 98% chance of having a very mild form of it, but becoming immune from the real thing... Early but quite mad attempts of "vaccination" so to speak.

There are multiple ways for vaccinating and it's quite hard to provoke an immune response without contracting the disease itself because the immune system makes so damn sure to not activate without good reason to do so!

Passive Immunization - Free Fish

Antibodies can also attack toxins, since toxins are mostly proteins themselves, there can be antibodies against specific toxins. Antivenoms are those antibodies in concentrated form. Similarly one could take antibodies from other people or animals that contracted the disease and use those as medicine. However, the protection is time limited since the antibodies decay over time. In that sense it is like giving somebody a fish, they will use it up and become hungry again.

Active Immunization - Learning How to Fish

Life attenuated vaccines - the real thingy but weakened.

Inactivated Vaccines - kill the thingy beforehand. Those don't provoke the immune system anymore so they are mixed with substances that do.

Subunit Vaccines - just use a part of the thingy - a specific antigen.

mRNA vaccines - inject mRNA so that the body itself creates the antigens but in a limited fashion.

Part 4 - Rebellion and Civil War

Chapter 37 - When Your Immune System Is Too Weak: HIV and AIDS

HIV attacks Helper T Cells. It is a retrovirus - which means that it merges genetic code with yours. So HIV stays inside your DNA as long as you're alive. it's not the first virus to end up there, around 8% of the total genome is thought to be that kind of retrovirus.

Chapter Summary

HIV does not spread like an ordinary virus only, first, it infects a dendritic cell, which carries it to a lymph node, where it infects its main target - T Helper cells, then it sneakily hides in the infected immune cells and only if those have direct contact to another cell, to activate it for example, will the virus be transmitted further. This way it stays hidden and under the radar, but keeps spreading through the immune system slowly but surely. HIV is also good at scrambling (mutating) its antigen surface as well so even if your immune system produces antibodies against it, those will quickly become ineffective since new strains of the virus arise. Over time it kills more and more Helper T cells until there is so little left, that the adaptive immune system collapses and the HIV count explodes. That's the last stage - also known as AIDS. For Acquired Immune Deficiency Syndrome.

Another testament to the fact that humans could solve all of their major problems if they were better at prioritizing.

Chapter 38 - When the Immune System Is Too Aggressive: Allergies

Your immune system has the power to kill you in about fifteen minutes.

*Due to something called anaphylactic shock.

You now have to live with the information that people can just suddenly become allergic to things they ate all their lives with no warning.

Chapter Summary:

Mast cells carry histamines, small molecules that trigger instant and massive inflammation when spilled. IgE antibodies can trigger mast cells. For some reason, sometimes B cells start producing IgE antibodies for foods or pollen or what not, but harmless things, that attach to mast cells and make them trigger antigens of the appropriate type much more easily and therefore en masse locally - leading to the typical symptoms of allergies.

Histamine release also causes more mucus to be created and contracts the smooth muscle of the lungs, making it hard to breathe out normally.

While histamine in the mast cells has to be refilled, Basophils take over and keep the allergic reaction up. Eosinophils get activated by the Cytokines released during the allergic reaction and keep it up semi-chronically. All of these systems are there for one reason probably - to get parasitic worms out of your system!

Chapter 39 - Parasites and How Your Immune System Might Miss Them

Chapter Summary:

Worms were and still are a problem for humans worldwide, without good sanitation and hygiene you kind of inevitably get parasitic worms. The immune system tried finding ways to deal with those - but killing a worm (which is giant compared to immune cells) is no easy task, hence all the ideas and cells from the previous chapter and the strong immune answer they make. However - worms have also adapted to it, down-regulating the immune system of the hosts, so one theory is that our immune system is stronger than it has to be because it expects there to be parasitic worms getting it down. This leads to the sheer scale of allergic reactions we see nowadays when it is triggered in an environment without worms.

Chapter 40 - Autoimmune Disease

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

Chapter Summary:

Self Recognizing T Helper and B cells were accidentally created and survived the Thymus and they get activated, also accidentally, when an infection occurs where some antigen is similar to the self-antigens these T Helper and B cells are primed to. Then they spring into action and start killing healthy normal body cells as if they were "other" as if they were a disease. If these become memory cells the autoimmune disease becomes chronic, especially with long-lived plasma cells - this is very very bad. Treatment is immunosuppressants.

Molecular Mimicry - sometimes certain pathogens purposefully copy antigens from body cells to hide and make it harder for the immune system to find and kill them.

An Aside - Energy

Dendritic Cells collect samples all the time, when they collect things while everything is alright, they try to find T Cells that connect with self-antigens so that those can be deactivated.

Chapter 41 - The Hygiene Hypothesis and Old Friends

Nature is cruel and without any form of care for you. The notion that "natural is better" is something only people who are not living in nature can say and who have forgotten why our ancestors worked so hard to escape it.

Hygiene is incredibly important to protect us from all of these diseases.

Communities of commensal microorganisms are as essential to your survival and health as any of your organs.

Wash your hands at least every time you use the restroom, clean your apartment but don't try to sterilize it, and clean the tools you use to prepare food properly. But let your kids play in the forest.

Chapter Summary:

Allergies are more likely in urban societies because the microbiome one encounters on a day-to-day basis is much less varied than that of a farm or a forest and therefore the priming of the immune system in childhood doesn't go along normally. Adding to that the fact that many people are not born normally but via a cesarean section, without the messy contact with both vaginal fluid and often fecal matter from the mother, goes a long way to explain, why autoimmune disease and allergies are much more common in developed countries.

Chapter 42 - How to Boost Your Immune System

Boosting the Immune System is a horrible idea that is used by people trying to make you buy useless stuff.

If you want to "boost" your immune system do that it is healthy, start by taking better care of yourself by living a healthy lifestyle, and the complex concert of your immune system, with all its billions of different parts, will run properly for a longer time.

Chapter Summary:

Things "boosting" the immune system is something sold by quacks everywhere, but the scientific truth is, boosting the immune system is not a thing - it has to be well balanced if anything. If you boost it, it becomes too active, and you get inflammation everywhere and die from that, so a "boosted" immune system is not something you would want. Still, people make good money selling wonder cures to the uneducated. The only thing one can do for the immune system is a sort of tautology and that is to eat healthily and live an overall healthy lifestyle, with a good amount of movement, enough sleep and not too much stress.

Chapter 43 - Stress and the Immune System

Reacting very strongly to stressors in an evolutionary context is something beneficial. Even if the stressor turns out to be nonexistent in the end. Rather safe than sorry. Stress back then usually meant wounds as well and therefore stress puts the immune system on high alert.

Psychological stress and actual and immediate physical consequences for the immune system, many of them not helpful.

Chapter Summary:

Stress over a long time affects the immune system in bad ways. One hormone it releases is cortisol, which actively suppresses the immune system. And stress over longer times is a modern thing, back in the day, the lion either ate you or it didn't. Either way, the stress was over soon.

Chapter 44 - Cancer and The Immune System

Cancer is when cells in a certain part of your body begin to grow and multiply uncontrollably.

You can imagine Tumore like cells starting a new small village that eventually grows into a metropolitan area.

1 in 4 people gets cancer during their lifetime.

Cells accumulate damage to their DNA over time. Cancer is when that damage leads to uncontrolled cell growth and multiplication. A minimum of three mutations is needed for cancer:

1. In oncogenes - switching on rapid growth.
2. In tumor suppressor genes - which normally handle DNA surveillance and repair, never repair the DNA damage that leads to abnormal growth
3. In apoptosis genes - stop doing apoptosis as well. Don't stop anymore when things are going wrong.

Cancer cells are more like egoistic individuals, putting their fate over that of the body. The immune system kills cancer cells all the time.

Immunoediting:

1. The Elimination Phase

The Immune system notices cancer because cancerous cells show signs of stress and so are killed by Natural Killer cells and gobbled up by macrophages.

2. Equilibrium

Some cancer cells are better at evading the immune system. Those are selected by natural selection. They survive and spread even more. One way they could mutate is to inhibit killer cells by showing the correct proteins on their surface.

3. Escape

The new cancer cells that were molded and formed by the countermeasures of your immune system are the ones that will eventually cause all the trouble. In a perverse way they become immune to the immune system.

An Aside - Smoking and the Immune System

Nicotine suppresses the immune system. Especially in the lungs. Alveolar macrophages get turned down and release their enzymes that start breaking down lung tissue. This is what causes scar tissue in long-term smokers. It also suppresses Natural Killer Cells. Which are then not as good at defending against cancer. The main reason why the cancer numbers for lung cancer are so high among smokers.

Chapter Summary:

Cancer are cells gone rogue, via at least three mutations that allow them to grow, not die and not repair DNA anymore. They are killed by the immune system early on because they show signs of being wrong, but some survive because of luck and random mutations which made them better at evading the immune system. Those go on to grow indefinitely and eventually kill you without medical Intervention.

Chapter 45 - The Coronavirus Pandemic

Corona targets the ACE2 receptor. ACE2 regulates Blood pressure and we have these receptors all over the place. So the coronavirus can infect much more than just the lungs and throat and nose.

Corona stops or delays interferon production. Hence immune system response is less deadly to the virus, but inflammation still happens at a normal rate. The virus can go on its exponential growth rate pretty much undisturbed, provoking huge widespread inflammation but without the interferons messing with its replication. A lot of epithelial lining dies, opening up the alveoli for further infection by other pathogens - bacteria etc. The immune response is so strong at this point in the lungs that chemicals used by immune cells rip holes in the lung tissue, scarring the lungs for a long time.

Chapter Summary:

Corona Virus sucks because of the immune response it triggers but also suppresses enough not to be killed which leads to a stronger immune response and so on, in a downward spiral.

A Final Word

You are incredibly lucky to be alive and to have a body that you can call your.