Note: The Immune System: Part I is prerequisite in order to understand this part better. We will refer to some of the terminologies and concepts defined in the previous part.

In the first part, we learned some basic concepts about Immune System, what happens when a rusty nail penetrated your shoe and its tip entered to your big toe. Initially, Macrophages and Nutrophils goes to the battlefield and inflammation happens. In this part, we will dive deeper and try to understand how do cells know where to go, what are other killer armies of immune system and how they operate.

How Do Cells Know Where to Go?

How do cells know which way to go and where they are needed? To make this a bit more challenging, cells are blind, which makes sense if you think about it for a moment. The process of seeing something requires light waves to hit the surface of an object and hit a sensory organ like your eye, where a few hundred million specialized cells transform them into electrical signals that are sent off to your brain for interpretation. This system is not available in a cell. Same goes for the “hearing”, seeing and hearing in the sense humans are used to is not a great option in the microworld. So how cells experience their world? How do they communicate with each other?

Cells smell their way through life. For cells, information is a physical thing: Cytokines. In a nutshell, cytokines are very small proteins that are used to convey information. There are hundreds of diffirent cytokines and they are important in almost every biological process going on inside of you – from your development in your mother’s womb to the degeneration you experience as you get older. They are very important, in a sense cytokines are the language of your immune cells.

Lets say a Macrophage floats around and stumbles over an enemy. The discovery needs to be shared with other immune cells, so it releases cytokines that carry the information “Danger! Enemy around, come help out!”. These cytokines then float away, carried purely by the random motion of particles in your bodily fluids. Somewhere else, another immune cell, maybe Neutrophil, smells these cytokines up and “receives” the information. The more cytokines it picks up, the stronger it reacts to them. But this is not all, the smell of cytokines also functions as a navigation system. The closer to the origin of the source of a smell is, the more cytokines it will pick up. By measuring the concentration of cytokines in the space aroun it, it can precisely locate where the message is coming from and then begin moving in that direction. It is sort of “smelling” where the smell is most intense. Which will lead it to the site of battle.

To do this, your immune cells dont have a single nose, they have millions of them, all over their bodies, covering their membranes en every direction. Why so many? For two reasons: First, by being covered by noses, cells have a 360 degress smell system, they can pretty precisely tell from which direction a cytokine is coming from. The another reason, it is good to have millions of noses to prevent cells from making mistake. Because your immune cells are blind and deaf and stupid, the have no way of asking questions. They dont know if a signal is real or if they interpreting it correctly. For example, a Neutrophil could pick up a cytokine that would be left over from an already won battle. Being wrong would be a waste of resources or could distract Neutrophil. The solution is not to rely on one single nose but on many at the same time. This principle is very important. A signal needs to pass a specific threshold to compel a cell to do something.

We sort of have elegantly skipped over a question: How exactly do cytokines convey information and what does this mean? How does a protein tell a cell what to do? As we discussed before, cells are protein robots guided by biochemistry. The chemistry of life causes sequences of interactions between proteins that are called pathways. The action of pathways causes behaviour. In the case of cytokines, the information protein of the immune system, this happens through pathways that involve special structures called receptors on cell surfaces. They are the noses of your cells.

In a nutshell, receptors are protein recognition machines that stick in the membrane of cells. A part of them is outside the cell and another part is inside the cell. Actually, about half of the surface of your cells is covered by myriads of diffirent receptors for all sorts of functions, from taking in certain nutrients to communicating with other cells or as triggers for a variety of behaviours. In a simplified way, receptors are sort of the sensory organs of cells that let the insides of the cells know what happened on the outside. A sequence of proteins interacting with each other that end up signalling the genes of the cell to be either more or less active.

The Killer Army: The Complement System

Basically, the complement system is an army of over thirty diffirent proteins(not cells!), that work together in an elegant dance to stop strangers from having a good time inside your body. About fifteen quintrillion complement proteins are saturating every fluid of your body right now. Complement proteins are tiny and they are everywhere. If a cell were the size of a human a complement protein would barely be the size of a fruit fly egg. Since it is even less able to think and make decisions than your cells are, it is guided by absolutely biochemistry. And yet it is able to fulfill a variety of diffirent objectives. In a nutshell, the complement system does three things:

It injuries enemies and makes their lives miserable and unfun
It activates immune cells and guides them to invaders so they can kill them
It rips holes into things until they die.

But how? They do nothing until they get activated. Imagine complement proteins as millions of matches that are stacked very close together. If a single match catches fire, it will ignite the matches around it, these ignite more, and suddenly you have a huge fire. In the world of complement proteins, catching fire means changing their shape. As we said before, the shape of a protein determines what it can and can’t do, what they can interact with, and in what way. In their passive shape complement proteins do nothing. In their active shape, however they can change the shape of other complement proteins and activate them.

Lets look at what this looks like in reality. Think back to the battlefield, the injury from the nail. A huge amount of damage was done and the Macrophages and Neutrophils ordered inflammation, which made the blood vessels relese fluid into the battlefield. This fluid carries millions of complement proteins that quickly saturate the wound. Now the first match needs to catch fire. In reality, this means that a specific and very important complement protein needs to change its shape. It has the name C3.

All you need to know for now, is that C3 is sort of the most important complement part, the first match needs to catch fire to start the cascade. When it does, t breaks into two smaller proteins with different shapes that are now activated. The first match is lit.

One of these C3 parts, called C3b, is like a seeker missile. It has a fraction of a second to find a victim, or it will shut itself off. It if does find a target, say a bacterium, it anchors itself very tightly to the bacterium’s surface and does not let go. By doing so the C3b protein changes its shape again, which gives new powers and abilities. In its new form it is able to grab other complement proteins, change their shape, merge with them. In a few seconds, thousands of complement proteins cover the bacteria

Bu there is more, do you remember the other part of that broke off C3? This one is called C3a. It is a message, and alarm signal, just like cytokines. Thousands of C3a flood aday from the site of battle, screaming for attention. Passive immune cells like Macrophages and Neutrophils begin smelling them, picking them up with special receptors. In this case, complement C3a does exactly the same job as citokynes. So far the complement system has slowed down the invaders (C3b flies covering their skin), and called for help. Now the complement system begins to actively help to kill the enemy.

Cell Intelligence: The Dendritic Cell

These pathogenic soil bacteria in your infected wound nourish themselves with the resources that were meant for civilian cells and begin defecating everywhere, releasing chemicals that hurt or kill cells, and defenders. The complement proteins that came with the first waves of fluids from blood have been largely used up and more and more of the immune cells that fought for hours and days are giving up, and dying of exhaustion.

While the battle has been raging, the intelligence portion of your innate immune system has been quietly doing its job in the background: The Dentritic Cell is on its way. Dentritic cells are large cells with starfish-like arms flopping around everywhere, drinking and vomitting constantly. But it turns out they have two of the most crucial jobs of your immune system:

They identify what kind of enemy is infecting you, if it is a bacterium or a virus or a parasite.
They make the decision to activate the next stage of your defense: Adaptive immune cells, your heavy, specialized weapons that need to come in if your innate immune system is in danger of being overwhelmed.

The Dentritic Cell is always looking for a few very particular tastes – the flavor of bacteria or viruses, the taste of dying civilian cells, or the taste of alarm cytokines from fighting immune cells. When it takes a sip and recognizes any of these flavors, it knows that danger is present and goes into a more active sampling mode. Now the dentritic cell begins swallowing. It only has a limited amount of time to sample. Similar to Macrophages, it begins phagocytosis, grabbing and swallowing whatever garbage or enemies that are floating around the battlefield. But with one majot diffirence: The Dentritic Cell is not trying to digest the enemies, it is breaking them down into pieces but it is doing so to collect samples and to identify them. Not only is the Dentritic Cell able to distinguish if an enemy is, for example, a bacterium it can distinguish between diffirent species of bacteria and knows what sort of defense is needed against them (how?? we will learn more about, later)

Once Dentritic cell collect enough sample, it leaves the battlefield – its destination is the great gathering place, the intelligence center where millions of potential partners await. Once Dentritic cell is on its way, it has become something like a snapshot of the state of the battlefield. A living information carrier of what was going on at the site of infection when they took their samples. In a nutshell, the Dentritic Cell delivers context to the Adaptive Immune System. One important point to mention, if it continued to sample while it was in transit, this could cause two issues:

the samples it had collected would be diluted by samples from the journey, and the level of danger would not be as obvious from the snapshot.
if the cell sampled outside the battlefield, it could pick up harmless material from your body and accidently cause an autoimmune disease.

In any way, the battlefield snapshot, the living information carrier needs to be delivered to a lymph node. To get there, the Dentritic Cell has to enter the Immune System Highway: The Lymphatic System, which is a great opportunity to get to know your internal plumbing.

The Lymphatic System

Now, lets talk about the megacity and superhighway network of your immune system: The Lymphatic System. Just like your cardiovascular system, it does have a far-reaching network of vessels and its own special fluid. And without it, you would be equally dead as without a heart.

Your network of lymphatic vessels is iles long and covers your entire body. It is a sort of partner system to your blood vessels and blood. The main job of your blood is to carry oxygen to every cell in the body and to do that, some of the blood needs to actually leave your blood vessels and drain into your tissue and organs to deliver the goods directly to your cells. Most of the blood is then reabsorbed by your blood vessels. But some of its liquid part remain in the tissue between your cells and need to be transported back into circulation again. The lymphatic system is responsible for this job. It sort of constantly drains your body and tissues of excess fluid and delivers it back to the blood where it ca circulate again. There is only one direction, as very gradually small lymph vessels merge into bigger ones, which then continue to merge into larger ones. Since the lymphatic system has no real heart, the water flows slowly.

The liquid transported through the lymphatic system is called lymph. When lymphatic system drains the excess liquid between your cells, it picks up all sorts of detritus and garbage: damaged and destroyed body cells, dead or sometimes even alive bacteria or other invaders, and all sort of chemical signals and stuff hanging out. But while the lymph carries many diffirent tings, maybe its most important job is to serve as superhighway for immune system. Every second of your life, billions of them are travelling through it, looking for a job. These jobs are given out in the megacities of your immune system that the lymph must pass through before it can become part of the blood again: Your bean-shaped Lymph Node – the organs of your immune system. You have around 600 of them spread all over your body.

The lymph node megacities are like huge dating platforms where the Adaptive Immune system meets the Innate Immune system for hot dates. Adaptive immune cells go and look for their ideal match. This is where the traveling Dentritic Cell arrives from the battlefield.

The Spleen and the Tonsils

The Spleen is a sort of large lymph node, about a size of peach, but bean shaped. The spleen is the place in your body where 90% of your old blood cells are filtered and recycled when their life comes to an end. On top of that, your spleen stores an emergency reserve of blood, but a cup, which is invaluable if something bad happens and you could use a bit of extra blood in you body. In addition, 25-30% of your red blood cells and 25% of your platelets are stored here for emergency.

But the spleen is not just an emergency blood storage for injuries but also one of the centers of your soldier cells. The main home for another immune cell we did not mention before, even though it did help out during the cut: Monocyte. Monocytes are basically reinforcement cells that can transform into Macrophages and Dentritic Cell. If you suffer an injury and an infection that drains and kills a lot of your Macrophages, they (Monocytes) come in as backup. Once they enter the site of infection, they stop being Monocytes, and transform into fresh Macrophages.
On top of serving as an emergency reservoir and a barracks, the spleen really is just huge lymph node that filters your blood and does all other things lymph nodes do. So, when we discuss the function of lymph nodes in more detail, just remember that your spleen does the same thing, only with your blood.

Side Note: About 30% of people happen to have a second spleen that is tiny but will grow and take over the job if the first one is removed.

The The Tonsils are known to people only as wierd lumpy thing in the back of their throats that sometimes have to be surgically removed in children. The tonsils are something like a center of immune system intelligentsia in your mouth. A lot of diffirent immune cells that we will get to know, work here to keep you healthy. To get samples to them, your tonsils have deep valley where tiny pieces of food can get stuck. Microfold cells, very curious cells that grab all sorts of stuff from your mouth and pull it deep into the tissue, where they show it to the rest of the immune system to check out. In a nutshell, what you really need to know about tonsils is that they are immune bases that actively sample what comes into your body.

Superweapons

Lets again go back to the battlefield. The battlefield is a chaos of dead civilian and soldier cells, toxins and feces of bacteria, alarm signals, and spent complement proteins. Millions of immmune cells have fought the their demise. All in all, the Innate Immune System will probably win this battle eventually. But it might take weeks and victory is far from certain as there is still the possibility that the immune system will lose and that the invaders will make their way deeper into the your body, causing more descruction. During the war, Macrophages are so tired of figthing and they want to give up and embrace the sweet kiss of death, it is about to do so, but then it notices something. Thousands of new cells arrive at the battlefield and spread out quickly. But these are not soldiers. These are Helper T Cells. Specialist cells from Adaptive Immune System were forged just for this particular battle and they exist only to fight this specific soil bacterium. One of these T cells moves directly towards the tired Macrophage and whispers something, using special cytokines to convey its message. Suddenly a jolt of energy shoots through the Macrophage’s bloated body. In a heartbeat, its spirit comes backs, and it feels fresh again. The Macrophage knows what it needs to do: Kill bacteria, right now! All over the battlefield this begins to happen as Helper T Cells whisper magic words to tired soldiers, motivating them to get back to fight.

But this is not all, another tiny army – this time directly made by the Adaptive Immune System – has joined the fight. Counting in millions, it floods the battlefield, dashing against the enemies. The specialist forces of Antibodies have arrived! Although they are made from proteins just like complement, antibodies are very diffirent. In this case, antibody’s purpose is to maim and disarm this exact kind of bacteria that is present right now at the site of infection. Now, the battle is won. Now the cytokine whisper of the T cells slowly subsides and the Macrophages start to feel tired. The soldiers around it, mostly Neurtophils that fought bravely start killing themselves. The remains of the dead Neutrophils are cleaned up by fresh Macrophages that will take their place as the new guardians of the tissue.

On the human scale, a few days after your unfortunate encounter with the rusty nail, you wake up and notice that your toe is much better. The swelling has gone away, the wound has grown over and nothing left, business is as usual.

Receptors

All living things on earch are made fromm the basic parts, but mostly proteins. Proteins can have countless diffirent shapes, which you can imagine as 3D puzzle pieces. To recognize a bacteria and to grab it, your immune cells need to connect to the protein puzzle pieces of bacteria.

Your Innate Immune System is able to recognize some of the common protein puzzle pieces our enemies use with those special receptors called Toll-Like Receptors. But this somewhat limits the range of the Innate Immune System, as it is only able to recognize the structures that can connect to the Toll-Like Receptors. Nothing more, nothing less. In the language of immunology, a protein piece that is recognized by the immune system is called an antigen. There are hundreds of millions of possible antigens that your Innate immune system does NOT recognize and through the magic of evalution there will always be new ones created in the future. Just to remember: An Antigen is a piece of an enemy that your immune system can recognize.

However, your Adaptive Immune System can generate cells that can recognize all possible antigens possible. Every possible antigen an enemy could make. But what is stopping adaptive immune system from developing receptors that are able to recognize self, the parts of your own body? It seems like the cells that Adaptive Immune System creates need some education. In the next part, we will go though this education system.