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Animal Systems

Animal Systems

The Immune System

Kicking the Bad Guys Out

It's payday. You're standing in line at the bank, minding your own business and finally cashing in on your meager paycheck. Maybe you'll buy a snazzy jacket with glittery buttons. You hear the quiet din of the soothing bank music mixed with conversation. You wonder if it might be faster to just use an ATM.

Something is off. You see three Jesse James wannabes in cowboy hats and spurs, and they're yelling at you to get down on the floor. The bank teller, also wearing a sweet cowboy hat (wait, when are we again?), pulls out a revolver and foils the robbers' plan. The snazzy jacket is saved.

With just a few minor tweaks, this foiled bank heist could be the drama that takes place within our body's immune system. Basically, when an intruder—pathogen is the million dollar word—makes its way into the body, a group of cells recognize the oddball in the ski mask and attacks it. Maybe it's not a six-shooter, but the immune system is killing the pathogens to keep all things internal happy and healthy.

Since the immune system needs to function all over the body (microbes can enter pretty much anywhere), immune organs are located throughout the body. Collectively, they are called lymphoid organs. Every bone consists of bone marrow, and this is the place where all immune cells are born as stem cells. Some stay here to develop, while others travel to distant lands, like the thymus, which is located directly under an animal's breastbone. Each animal also has a spleen and lymph nodes (located in the neck, armpit, abdomen, and groin) where immune cells congregate to combat incoming pathogens. Think of them as military bases where the army can gear up before going into battle.

All of these lymphatic organs are connected with a lymphatic network of vessels. These vessels line up pretty closely with blood vessels, and there's a constant exchange between the two so the immune system can immediately recognize any strange looking invaders that are hitching a ride through the blood vessels.

Mammals have two types of immune systems to keep them going:
  • The innate immune system provides a general defense strategy for combating and keeping out pathogens.
      
  • The adaptive immune system responds more systematically to specific threats that might make it over the wall and into the body.
You can think of the innate system like your general police force, patrolling the area and making sure everything is on the up and up. The latter is more like the S.W.A.T. Team, a highly trained unit deployed when the situation demands it.

Innate Immune System

The first line of defense provides innate immunity. All animals have it, and these are the immediate reactions to a pathogen. If we return to our handy bank metaphor, the revolving doors are the innate immune system, generally trying to keep bad stuff outside, whether it be robbers, cold winds, or irate giraffes.

Pathogens looking to wreak havoc in the body first come across a barrier defense—skin, tears, long white nose hairs—which make it hard for things that shouldn't be in the body to make their way inside. But if these pathogens make it past the formidable barrier opponents, the body's internal innate defensive line jumps into action. The body increases production of white blood cells, or leukocytes, that launch an attack on the invading pathogens. If necessary, an animal will develop a fever to combat the growth of bacteria at this point, too. They may make you feel cruddy, but fevers are your body fighting the good fight. And sometimes they even get you out of school. Fevers are the best.

All leukocytes come from the bone marrow, but the ways they ward off the bad guys differs. Some leukocytes carry out phagocytosis (and are called phagocytes), where they go dinosaur on pathogens, straight up swallowing and devouring them. There are several different types of leukocytes in the innate immune system, but they will generally fit into the following categories:
  • Macrophages: Vertebrates are lucky and have some really effective phagocytes called macrophages that are super hungry for pathogens. Consider them the T-Rex of the lot.
      
  • Granulocytes: These cells have small pockets, or granules, with potent killer-chemicals inside. When a granulocyte swallows a virus or protozoa, nasty chemicals are released from these granules to kill the invader.
      
  • Natural Killer Cells: The name says it all. These cells are hard-core pathogen destroyers, the AK-47s of immunity. These cells are so die-hard they kill virally-infected cells on contact, without the need for digestion or internal granules.


Phagocytosis of anthrax bacteria. A super-zoomed in picture of a leukocyte (yellow sphere) consuming the anthrax bacteria (orange rod).Image from here.

The innate immune system is completely indebted to phagocytes. Not only do they have a fond taste for pathogens, but they also secrete communication chemicals called cytokines. These are chemicals that tell other cells (other phagocytes and cells in the adaptive immune system) that they should get their act together and prepare for an attack.

When cells become virally-infected, they release interferons that alert neighboring innate immune cells of the unwelcome guest. It's like a burglar alarm going off in a sleepy neighborhood. Neighboring cells then prepare themselves for attack (maybe they'll dead bolt their doors or wake up their ill-tempered Rottweiler), and secrete chemicals that prevent the virus from spreading.

All of these cells and chemicals of the innate system have a common purpose: ward off infection. And this system has figured out some of the best ways to do just that.

If pathogens enter the body through the skin (by stepping on a rusty nail, for example), the innate immune system launches an inflammatory response to kill the invading pathogens. Inflammation is simply an attempt at isolating infection or trauma, and preventing it from affecting the rest of the body. Increased blood flow is why the damaged area is red and feels hot. All that extra blood brings with it antimicrobrial proteins that attract more macrophages and bump up the pathogen-killing power even more.



Inflammation. Since it's such an important part of the immune system, there are lots of players that contribute to the inflammatory process.

Another part of the innate immune system lies in tissue repair. Phagocytes are the key players here since they devour dead or damaged cells. Once the accident has been cleaned up and all lanes are functioning again, certain chemicals will stimulate new tissue growth and get things back to normal.

With all the macrophages working overtime and consuming dangerous pathogens, they also secrete toxins that reset body temperature and cause a fever. It's just another step in this world of the innate immune response.

Adaptive Immune System

The innate immune system typically does a great job; we just ran down the wide range of tools that are set loose when the body faces an intruder. Just to be on the safe side, vertebrates have a second line of defense that only gets turned on if the pathogen somehow survived the innate immune system. This adaptive immune system responds to specific pathogens only (a security guard shooting poison-tipped arrows at the bank robbers, if you will).

The immune cells in this specialized immune system get a special name: lymphocytes. These white blood cells are divided between two smaller divisions: the humoral and cell-mediated immune systems.

The humoral immune system is composed of B cells that begin as stem cells in the bone marrow but never leave home to mature. These B cells aren't still sleeping on their parents' couch. These B cells have a job. Each B cell learns to recognize a particular pathogen.

B cells are activated by antigens, which are the biological trademarks of pathogens. These are usually proteins and may be a part of the pathogen's cell wall or flagella. Each type of bacteria or protozoa has at least one distinct antigen, meaning there are thousands of antigens out there in the big wide world. B cells have receptors that are extremely picky when it comes to finding their long-lost antigen, and can distinguish one from another with incredible accuracy. They aren't content to lay waste to just any old pathogen. No sir, each one of these B cells is looking for their long-lost nemesis, which they have been trained to hunt and destroy. For these lymphocytes, it's personal.

When a B cell finds its matching foreign antigen, it does two things: makes antibodies and makes daughter cells. An antibody is a water-soluble form of the B cell receptor, and it can go places where B cells can't. Their purpose is the same (to track down and tag pathogens for demise), but B cell receptors are bound to the cell membrane, while antibodies are free to move around the body.

B cells are restricted to areas below the epithelial layer of the gut, but antibodies can circulate in the stomach's mucus layer. If pathogens sneak into your food, they will see antibodies first before they even encounter any B cells.

B cells love their antibodies; that's why they make lots of them super-fast—on the order of 2,000 antibodies each second for as long as the B cell is activated (usually around 4 days). That's a lot of antibodies: 691,200,000 to be exact.

Antibodies look like a "Y" and antigens can bind to both arms. Like B cell receptors, each antibody is designed to recognize a particular antigen, and their "Y" arms have chemical properties that distinguish between antigens.



Antibody. Antibodies bind with high specificity to their particular antigens.

Just like the B cell receptor, antibodies recognize a particular antigen in the body fluids, bind to it (they fit together like a lock and key), and tag it for demise. The antibody may bind to the pathogen cell surface, disrupting the bacteria's ability to infect other cells.

For macrophages, antibodies add the sprinkles and chocolate syrup to their sundae, making the pathogens even more appetizing. Pathogen phagocytosis increases when an antibody is attached, and all that bad stuff becomes supper. Other times, an antibody may disrupt an essential bacterial cell process, like cell division, forcing the alien pathogen to self-destruct. Whether it's by making it a meal or sabotaging it from within, the immune system tries its best to clear out nasty invaders.



Clonal Selection of B cells. When B cells bind to their particular antigen, they replicate and make cloned memory cells and cloned plasma cells that release antibodies.

In addition to making antibodies, B cells also produce exact replica daughter cells when they are activated. Some of the clones will become plasma effector cells that recognize the same antigens and produce the same antibodies. It's a true "attack of the clones," since these replicas attack the current infection.

Other daughter cells carry grudges and are called memory cells. These cells stick around for a long time, remembering a particular infection. If there's another exposure to the same antigen sometime down the road, they trigger a larger and more rapid immune response, called a secondary response. In other words, they learn the tricks of the pathogen's trade the first time around, so the immune system can really bring the heat if the repeat pathogen has the guts to show its face again. This whole B cell cloning thing really ramps up the arsenal of antigen-recognizing man-power.
B cell. A zoomed-in picture of an actual effector plasma B cell.

It's tough work being an antigen receptor: long and unexpected hours, minimal pay. To make matters worse, there are loads of different antigen receptors (on the order of 10 with 18 zeros), and each receptor may be specific for just a few antigens. Since they really have to pay attention, there's no sleeping on this job. Sometimes the receptors screw up, and recognize an antigen they weren't supposed to. When the two pair up but aren't exactly right for each other, the body might attack the wrong proteins. On the upside, scientists have found ways to take advantage of antibody "mistakes" and use the idea behind this cross-reactivity for immunizations and vaccinations.

The other type of adaptive immune system in vertebrates is the cell-mediated immune response. Here, the body uses T cells to mount an attack on invading pathogens. Like B cells, T cells originate in the bone marrow as stem cells, but unlike their closely related alphabet-loving lymphocyte cousins, they travel to the thymus to mature—hence the "T" in T cells.

These cells are highly specialized to fight off those sneaky pathogens that have made their way into host cells. They are so passionate about killing strange-looking invaders that they sometimes even end up attacking things we want to put into the body like a brand new kidney. A foreign presence is a foreign presence as far as they're concerned.

T cells work a bit differently than B cells, and only recognize antigens once the pathogen has already penetrated a cell. Once inside, intracellular proteins break the pathogen down into small parts. A group of proteins called the major histocompatibility complex (MHC) pushes these broken down pathogen parts (including the antigen) to the cell surface. When they express the antigen fragment and MHC, these cells are called antigen presenting cells. It's genius, we know.

T cell receptors not only recognize certain snippets of antigen fragments poking through the cell membrane, but they also care about the specific class of MHC at the cell surface. It's an easy game of Hide-and-Seek for the T cells—attack the cells waving a red flag. End of game.

There are 3 different types of T cells, and each differs in the ways it regulates the adaptive immune response:
  • Helper T cells
  • Cytotoxic T cells
  • Suppressor T cells.

Antigen Presenting Cell.T cells recognize the antigen fragment and MHC complex on infected cells.

The role of helper T cells is self-explanatory: they help other T and B cells do their jobs more effectively. When they recognize their special MHC (and antigen fragment), they become active and get to work by dividing and activating other B and T cells. After dividing, most Helper T cell clones mature into effector cells and release cytokines. Imagine the soldier on the front line blowing into his bugle when he sees the enemy coming over the horizon.

Cytokines provide communication to B and T cells as well as phagocytes, and aid in their activation. There are hundreds of different cytokines, and while each has multiple functions, many of them accomplish the same task. Some encourage immune cell growth, but others destroy infected cells, or enhance the innate immune system's inflammatory response.

Other helper T cell clones develop into memory cells. These are similar to the memory B cells, and "remember" a pathogen exposure to mount a quicker response the next time around.

Cytotoxic T cells kill invading pathogens directly; they are the effectors of the cell-mediated immune response. They become active when they bind to an antigen presenting cell (with the appropriate MHC) and when Helper T cells release cytokines. Cytotoxic T cells release potent cell-destroying chemicals that can cause an infected cell to rupture, forcing those nasty invaders to fend for themselves and fight off circulating antibodies. It's not a fair match, and luckily our bodies usually reign victorious.

But, too much immune system is a bad thing. Too many active white blood cells cause unnecessary inflammation, which can progress to disease. Yep, too much fighting disease can cause even more disease; you can see why it's so important to keep everything in check.

The suppressor T cells are the ones who keep the system in check, and actually dampen the immune response by suppressing lymphocyte activation when things have gotten out of hand. It's also important to turn off the immune response when the body becomes healthy and all aliens have been annihilated. All of the robbers are sitting with their hands above their heads, and the job is done.

Scientists aren't quite sure how these suppressor lymphocytes work. It's possible they suppress the immune response by recognizing a particular antigen, and preventing other immune cells from attacking it. But they could also regulate how rapidly B and T cells replicate. Add it to your list of great scientific mysteries, along with Sasquatch and the Loch Ness Monster.

Immunity

Once activated, both B and T cells create antigen memory cells that help ward off future infections. Not only will memory cells mount a more rapid and robust secondary immune response, but they will also provide active immunity to the pathogen. Faster and stronger—what's not to like about that?

Active immunity arises when an animal's own immune system protects the body from a pathogen. The memory cells produced by B and T cells provide active immunity against a particular exposure since they protect the body from harm. If your body naturally produces memory cells for immunity, it's called natural immunity.

Although vaccinations are outside factors added to the body, they are another form of active immunity. They stimulate the production of memory cells. Vaccines are simply small amounts of killed or modified pathogens that trick our body into thinking there's an infection. That means the immune system will attack this harmless pathogen and create antibodies and memory cells against it. Since the memory cells were made in response to an artificial infection (an injection like in the flu shot), this is a type of artificial immunity. The long term antibodies and memory cells protect us from the measles or this year's flu strain.

You can imagine a vaccine being like the cardboard cutout of a criminal stealing an old lady's purse. A police officer in training works on his accuracy by targeting this harmless version of the threat, so that if the real thing ever shows up, he's ready to leap into action and save the day.

Another type of immunity, passive immunity, comes from an outside source and doesn't require the body's memory B and T cells. Imagine you are camping in the woods with your best buds, and a rattlesnake bites your leg. If your friends get you to the emergency room fast enough, a doctor will likely administer antivenom. These are actual antibodies that attack the snakebite toxins and provide passive immunity to the snake venom. Your body doesn't have to do anything.

If you can get your hands on it quickly, there's another perk to antivenom. Your buddy doesn't have to suck the poison out of the wound with his mouth, and he might still be your friend when all is said and done.

Brain Snack

Next time you are out at a fancy restaurant, check the menu for sweetbreads. No, it won't be on the dessert menu next to the vanilla bean cheesecake and chocolate Oreo sundae supreme. Rather, turn back to the entrees where pork loin and grilled tilapia are listed. Sweetbread is actually a more delectable way to describe a calf or lamb's thymus gland. Yes, the thymus gland is where T cells mature.

It's quite the delicacy, with a nice meaty sweetness. They can be poached, deep fried, or roasted.

A raw thymus looks downright disgusting, but the final product might get your mouth salivating. Next time your mom asks you what you want for dinner, why not try a delicacy? Surprise her with this recipe and wow her with your daring taste buds.

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