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Hank tells us about the team of deadly ninja assassins that is tasked with protecting our bodies from all the bad guys that want to kill us - also known as our immune system.

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Table of Contents
1) Innate Immune System 1:45
a) Mucous Membranes 2:54
b) Inflammatory Response 3:44
c) Leukocytes 4:45

2) Open Letter 6:33
a) Natural Killer Cells 6:56
b) Dendritic Cells 7:57

3) Acquired Immune System 8:36
a) Antibodies 9:08
b) Lymphocytes 9:48
c) Cell-Mediated Response 10:17
d) Humoral Response 13:00

References
Campbell Biology, 9th ed.
http://faculty.stcc.edu/AandP/AP/AP2pages/Units18to20/blood/white.htm
http://highered.mcgraw-hill.com/sites/0072495855/student_view0/chapter24/animation__the_immune_response.html

This video uses the following sounds from Freesound.org:
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"straw slurp.wav" by dparke4
"Disgusting Slop.wav" by Ighuaran
"Sonar Ping.wav" by digifishmusic
"Swishes.wav" by Pogotron
"swing.mp3" by morgantj

crash course, crashcourse, biology, immune system, anatomy, physiology, human, health, microscopic, pus, pathogen, bacteria, body, organism, virus, immunity, innate, acquired, animal, vertebrate, germ, skin, mucous membrane, digestive tract, mucus, inflammatory response, mast cells, histamine, allergic, allergy, infection, phagocyte, macrophage, natural killer cell, lymphocytes, white blood cells, antigen, t cell, humoral response Support CrashCourse on Subbable: http://subbable.com/crashcourse

Sex and not dying. That's what Biology is all about. And while the sex part is, I'll grant you, a little bit sexier, not dying is also really fantastic, something that I personally like to do every single day.

I, personally, like to not die in all sorts of ways. Like, I don't jump out of planes, I don't go into active combat zones, I don't do heroin, but I can, however,  spend time wallowing in the filth with my cute bacon-producing friends here and not have to worry about dying. Because, somehow, my body can handle a lot of little devils on my hands, in my hair, in my food, little things that literally want to kill me. There are more potential human killers in this pig pen than there are in all of the world's prisons, but I don't have to worry about it because of the elite team of microscopic assassins that live inside my body. 

My immune system. Ah! That was really close to my hand.

(Intro)

You've heard of some of these little ninjas, others maybe not, but everyone knows the work they do by the trail of dead that they leave behind. Pus, being the most disgusting example. And the work these guys do is pretty hardcore. They not only identify incoming enemies, they eliminate them, and then they keep files on them, in case their kind ever come back. So I don't want to freak you out, but you, and I, are covered in pathogens right now. And you really can't blame them for wanting to get a piece of your action. Your warm, high-energy, nutrient rich, salty, watery action. Your body is a theme park for these guys and although the majority of organisms living inside you actually make your life a little more comfy there are some less helpful viruses and organisms, from here on out referred to as pathogens, that will want to turn your body into a factory for their children. So let's avoid that!

We have two basic ways of doing it. Innate or non-specific immunity that responds to all kinds of pathogens the same way and very quickly whether your body has seen that pathogen before or not. And your acquired, or adaptive immunity, which develops more slowly and requires your body to learn the wily ways of the pathogen before it defeats it.

Every animal has an innate immune system -even sponges- but only vertebrates have the acquired kind. You were born with your innate immune system and from the second that you wiggled away out of the sterile environment of your mom, and into this germ-y, disgusting world, that system has been protecting you.

The thing about the innate immune system is that it doesn't care what it's killing. It doesn't worry about whether it's offing a virus or a bacteria or a fungus, its job is to keep the enemy from getting in, or once it's in, to sneak up behind it and break its neck ninja-style.

The first line of defense in keeping sketchy characters out are the skin and mucous membranes. The skin has so many excellent functions -like keeping your organs in- that it's easy to forget that its primary purpose is to keep things out! It's oily, and kind of acidic, and really not easy to penetrate, and I'm about to rock your world with this, but your digestive tract is also technically the outside of you.

Remember how our bodies are basically just built around a tube right? Well, the inside of that tube is exposed to as much weird grody stuff as the outside of the tube so, your body treats the digestive tract like the front lines of this war which is one of the reasons why your stomach takes no prisoners with the whole stomach acid situation.

In addition to the things like skin we've also got mucous membranes providing another barrier to microbes trying to sneak in. Mucous membranes line all of your internal surfaces that are exposed to the outside like your lungs, and the inside of your nose as well as some other parts of your body like the inside of your mouth, and your eyelids, and your sex organs... Mucous membranes, unsurprisingly produce mucus which is a viscous fluid -you probably heard of it- and it traps microbes and helps sweep them away. This is why illness is so often associated with such awe inspiring amount of goop.

You second line of defense is your inflammatory response.
The honchos here are specialized cells in your connective tissue called mast cells that constantly search for suspicious objects, usually unknown proteins, and then release signalling molecules like histamine when they find them.

Histamine makes your blood vessels more permeable, which allows a whole bunch of fluid to flow to the affected area and that is what causes inflammation. But it also brings in a crap ton of white blood cells -infection fighters- to go all Balrog on whatever's trying to make it's way in. This is great if you get a splinter in your toe or a bunch of viruses in your face, but sometimes something gets into you that's not actually dangerous like pollen or dust or like a peanut and your immune system triggers an inflammatory response anyway even though it's not a big deal. 

This is what we call an allergic reaction and you know what those are like with the swelling and the redness and the mucus production and the itching and occasionally a little bit of death. So that is why we take antihistamines to suppress the histamine trigger so our immune system stop freaking out about nothing. Also, that is why you should always tell people when there are peanuts in your cookies!

Most of the immune system activity that happens inside your body's fortress is done by white blood cells, or leukocytes. Leukocytes are awesome for a lot of reasons but one reason is they've got full VIP access to anywhere in the body that they want to go, with the exception of the Central Nervous System -the brain and the spinal cord- which are, for obvious reasons, super high security areas.

Leukocytes can move through the circulatory system and when they get to a place where they're needed, they can basically send a signal to ask the capillary to open a gap between it's cells, and then it oozes through that gap to the site of the infection. This is called - get ready for it- diapedesis from the Greek for "oozing through". Now there are lots of different kinds of leukocytes, like different branches of your own personal microscopic army. The kind specific to the innate immune system are phagocytes, more Greek this time, "phago" meaning eating, they're just any cells that ingest microorganisms through the process of phagocytosis.

Phagocytes are pretty cool. They can literally chase down invading cells, grab them and then completely engulf them. And some like the super abundant neutrophils, move around the blood stream and can quickly get to where the action is. Once a neutrophil kills an invading microbe, they basically just roll over and die. Dead neutrophils collect together into what we lovingly call pus.

Now the biggest and baddest of the phagocytes are the macrophages the "big eaters" which don't generally travel a lot but instead hang out like body guards in your various organs. Not only do they kill outside invaders they can also detect when one of your cells has gone rogue, like a cancer cell and kill those too. And they unlike the neutrophils don't die once they've killed a bacterium, they can eat up to hundred before they die. Big eater!

Of all the grizzly stuff that goes on in the never ending street war that is your immune system, some of the most gruesome stuff is done by a kind of cell call Natural Killer cells. Which reminds me, I think it's time for our very first open letter!

An open letter, to 1973:

Dear 1973, You had a lot going on: the Vietnam war ending, Roe v. Wade, Watergate... It was a tumultuous time. But part of me wishes that you, 1973, had an opportunity to name everything in biology, because you got one chance to name a new type of immune cell, and you named it "the natural killer cell", and I freaking love that.

I look around at today's script, with all of it's dendritic cells, and macrophages, diapededisises and I think what if we let 1973 name all these things? Would we have "Spiky Death Cells" and "Devourers" and "Oozing action" instead? I don't know. Maybe you would have screwed it up, but I don't think we could have done any worse than all this GD Greek we have to deal with all the time!

Thanks for the Endangered Species Act!

Hank.

OK! Natural killer cells: more than just a great name; also the only phagocyte in the innate immune system that destroys other human cells. When your cells are healthy, they have a special protein on their surface called MHC1 (MHC for Major Histocompatibility Complex), but when your cells are infected with a virus, or when they're cancerous, they stop producing that protein.

So the natural killers are always going around checking up on each of your cells, and when it finds one that's not normal, it pulls out its AK-47 and unloads.

Actually, it just binds with it, and it secretes an enzyme that dissolves its membrane... But still. Killing.

Finally, dendritic cells are a type of phagocyte that hangs out on the surface of much of your body that comes in contact with the environment. In you nose, on your skin, in your stomach, in intestines. They eat up pathogens and then, carry information about them back to the spleen or the lymph nodes where it passes intelligence about what is going on on the war front: the acquired immune system. 

I actually studied dendritic cells in my undergraduate thesis and I kind of fell in love with them. They're lethal, but they're also intelligent. Great heroes from any Robert Ludlum novel. To be fair though, macrophages can do this too.

The activity of these cells give us a chance to transfer from innate immune system to the acquired immune system which is going to make things a little more complicated.

The acquired system has to learn as much as it can about every pathogen it interacts with, store that information and then use it to invent defenses against them. It's your super elite, double secret strike force delta. 

You get to work building your acquired immune system immediately after you're born. Harvesting bacteria and other stuff not just good bacteria -that can help your guts out- but also harmful ones that your body learns from, and stores information about. 

That system keeps an eye out for any foreign substance like toxin or virus or bacteria, even parts of those things that could be tell-tale signs of a bad guy. We call those signs antigens, a word that comes from antibody generator. An antigen is anything that causes your immune system to ID a pathogen and then create an antibody against it.

Now antibodies aren't cells. They're highly specialized proteins produced by B-cells to recognize and help lay the smack down on intruders. But antibodies can't kill invaders themselves, they're just well, proteins after all.

The best that they can do by themselves is sort of just swarm all over the invader, making it harder for it to move and to excrete toxin or otherwise infiltrate other healthy cells. But more often, antibodies serve as tags, attaching themselves to the scumbags and then releasing chemical signals to nearby phagocytes, alerting them that it's dinner time.

Your acquired immune system also has it's own type of white blood cells -not phagocytes, which goes after everything which looks a little bit sketchy- but lymphocytes which goes after specific things that they already know about. There are two major types of lymphocytes, the T cells which from in you bone marrow and them migrate to mature in the thymus gland right behind your breast bone, and the B cells which originate and mature in the bone marrow. What T and B actually stand for is a long story, but if it helps you to remember, T is mature in the thymus, B is in the bone marrow.

We have two different types of lymphocytes because our bodies have two different types of acquired immunity. The cell-mediated response, which is for when the cells are already infected and the humoral response, for when the infection is just in the humorous (the bodies fluid, not in the cells).

First lets look at the cell mediated response, this process mainly involves T cells and there are quite a number of different types of them. 

Helper T cells have a cute sounding name, but in a lot of ways they call the shots for the whole immune system. While they can't kill pathogens themselves, they activate and direct the cells that can. If 1973 had named them they might have been called admiral T cells or something more awesome!

Helper T cells get their information from other immune cells that are out cracking skulls. Say for instance a macrophage finds a pathogen and destroys it, after the deed has been done, it has the ability to shred up the proteins from an invader and put a bit of that antigen on it's membrane surface. 

This is called antigen-presentation because the cell is presenting antigens! A helper T cell can detects when this happens and it comes over to attach itself to the presented antigen. The two cells talk to each other chemically, the antigen presenting cell produces a chemical called Interleukin 1 which basically tells the helper T cell "uh..boss I uh- I found this guy over here and then I broke his neck and then he stuck his guts all over my cell membrane". The helper T cell gives it a look and then releases a chemical called Interleukin 2 which is like a bullhorn. An alarm that tells all the lymphocytes in the area, "There are problems here! We got a problem over here in Sector 69!".

This alarm activates a couple different things all at once. First, the helper T cells starts making copies, tons of copies of itself. Most of those copies differentiate into effector T cells which travels around secrete signalling protein that stimulate other nearby lymphocytes to take action. Most of the rest of them become memory T cells, they're the ones that keep a record of the intruder and provide us future immunity against it.

And now for the saddest story of the day, what happens when the cell gets infected, so infected that it knows that it's a goner that it in fact is being converted from a healthy useful part of the body to an evil zombie farm, pumping out viruses or bacteria, suddenly co-opted to help destroy everything it loves?

Well, with its last bit of strength it'll start presenting antigens, not asking to be rescued but instead asking for a mercy killing. Cytotoxic T cell has the job of granting that request. Once a cytotoxic T cell gets the message from the helper T cells that there is an infection to deal with it starts patrolling the area for any normal cells presenting antigens. When it finds one, it latches on to it and releases enzymes that create holes in the cell's membrane, and eventually breaks down the whole cell, killing the cell and the pathogen in the process. A human cell, killing another human cell.

And now, for the humoral response. The humoral response is designed to catch pathogens that are floating around your body that haven't actually invaded any of your cells yet. The primary players are B cells which are constantly patrolling your blood stream like cops walking the beat until they get a signal from the helper t cell that something is wrong.

B cells are covered in antibodies that can detect and bind to a specific antigen. A single B cell can be covered in a forest of up to 100, 000 antibodies, say for the virus that causes the common cold. And the B cell next to it will have just as many receptors for a different antigen. for chicken pox or something. When a B cell bumps into a pathogen that it recognizes, it attaches to it and starts cloning it self like crazy. Suddenly there are tons of that B cell with the same receptor, but during the cloning process, the clones differentiate into new versions of the original just like the T cells did.

Most turn into plasma or effector cells which use the antibody as a blueprint to create a crap ton of antibodies for that specific pathogen, like 200 antibodies per second. Once, these antibodies are released, they bind to the pathogens like crazy marking them for death until the phagocyte can come along and do the dirty work.

The rest of the cloned B cells mostly become memory cells which have the same receptor, and stick around providing future immunity from this invader.

And we are now very out of time! But I really love this stuff so I didn't want to gloss over anything. Mucus, natural killer cells, macrophages, killing things, breaking them up and sticking them on their cell membranes, effector cells spewing out antibodies and memory cells making sure that our immune system hold that grudge. All because my favorite thing to do every single day is not die.

If you wanna review anything we discussed in this episode there's a table of contents over there, if you have any questions for us we'll be down the comments or on Facebook or Twitter, and we'll see you next time.