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Immune System

Introduction to the Immune System

Immune cells

Do you remember the last time you were sick?  Chances are you remember having had a head cold or the flu, or maybe even a stomach virus.  You might have thought that you were never going to recover, but in a few days, you were feeling yourself again, thanks to your immune system!

Pathogens - What makes you sick?

Bacteria and viruses are usually to blame for bringing on nasty colds, fevers and fatigue, and many serious infections. There are other life forms that can infect you as well, such as parasites and fungi, and also non-living things like chemical toxins. Any microorganism that causes infection is called a pathogen.  Some common pathogens are the Influenza virus that causes the Flu, or the bacterium Streptococcus pneumoniae which causes Pneumonia.

Transmission - How do you get sick?

Pathogens can infect you in many ways. Sometimes kissing, sneezing, coughing, or touching contaminated areas can spread infection. This is how the common cold is mainly spread.  Many bacterial diseases can come from leaving open wounds untreated and eating contaminated food; also blood poisoning or food poisoning can develop.  Yet more chronic diseases can spread through transferring blood or sexual contact, like the HIV virus. There are many ways pathogens spread from person to person, and each pathogen is different, but sometimes all we have to do to get sick is breathe in air-born particles! 

With so many points of entry and so many dangerous microbes out there, it seems that we should be sick all the time.  Luckily, our immune system is working ‘round the clock to fend off infections from outside particles and clean the body of dead or old cells.

What is the immune system?

The immune system is not located in a specific organ. It’s easiest to think of our bodies’ immune system as a complex constellation of different types of cells like B and T cells and tissues like the lymphatic system and the thymus that work together to protect nearly every area of our body.  Each type of cell is prepared to perform certain functions, such as killing damaged or infected cells, carrying messages, making antibodies, or carrying away debris.

You might ask, how does each cell know what job to do?  Are they just born that way?  And how do they differentiate between “good” and “bad” cells, knowing not to attack your own healthy cells? 

Distinguishing self from non-self

In fact, this is the most important function of the immune system: to distinguish what cells and substances belong to your body and are healthy, and which aren't! What belongs to the body is referred to as “self,” and something that doesn’t belong as “non-self.” Think of the wide variety of different tissues and cells that can be found in your body: hair cells, teeth cells, bone cells, blood cells, calcium in your bone, there are even some friendly bacteria that live in our intestine to help us eat! Your immune system has to be very smart to be able to discern such a variety of things!

Understanding how the immune system works could reveal the key to curing many infections and diseases.  But if you are just beginning to explore the many functions of the immune system, the most important idea to keep in mind is that our immune system has “learned to learn;” in other words, through millions of years of evolution, our immune system has acquired the ability to learn and remember information about the billions of different cells and substances it comes into contact with every day. Without the ability to learn and remember, you’d keep getting sick from the same thing over and over!

General Mechanisms

Our bodies, like all organisms, live in a constant balance of trying to get oxygen and food from the environment while trying to protect itself from things that could harm it.  In order to eat and breathe without developing disease, we must defend our bodies against harmful outsiders in food, water and air.  Also to have energy to defend ourselves, we must eat and breathe! 

Why is the immune system needed?

Sometimes, a particle from the outside can enter the body, like a bacteria or virus, and try to harm the cells of your body. Depending on the particular pathogen, it can release toxins that destroy healthy cells (like bacteria) or it can invade particular cells and use the cell’s machinery to replicate itself (like viruses.) Also, some cells in the human body can become damaged or die and become harmful. In these situations, the immune system uses its innate and acquired defenses to rid the body of these unwanted visitors.

The First Line of Defense

Most times, outsiders can be stopped before they can infect cells or replicate.  Your skin alone is a major defense mechanism of the immune system that shields your delicate organs and tissues from infection by posing a physical barrier. Also, hair-like structures called cilia in the mucous membranes of your nose sweep out foreign particles like bacteria, pollen, and dust. (This is why you sneeze!) Tears, mucous, and saliva, along with mucous that lines your lungs, intestines, and urinary and reproductive tracts, all contain enzymes that try to destroy bacteria before they penetrate the body.

The Innate Immune System

If a foreign particle is able to pass past these first defenses, cells will release special chemicals like histamine which heats the blood and causes it to flow faster. Warmer temperatures can kill some bacteria, and the rush of blood will bring white blood cells to the site of infection quicker! 

There are many proteins circulating in the blood that make up the complement system that help alert the rest of the immune cells and can also cripple and even kill some invading particles. They can cause infected cells to burst (lysing) and they also release chemicals called cytokines which signal to macrophages that there are cells that need to be eaten. Complement proteins become activated through a cascading effect or a domino effect, where one protein activates the next in a long chain of proteins.

Special white cells called macrophages are swallowing cells that literally engulf and digest any particle that appears foreign.

The functions of the skin, cilia, bodily fluids, and swallowing cells are all innate defenses of the immune system. 

The innate defenses respond to outsiders as soon as they appear in the body. Although they are very prompt, they are nonspecific, meaning they aren’t tailored to stop any one particular kind of intruder.  They are like family doctors who give you checkups and prescribe medicine for mild problems.  If they find a serious problem, they will call in the specialists and the surgeons - in this case, the acquired immune system.

The Acquired Immune System

The acquired immune system relies on macrophages, T cells and B cells and other cells working together. These cells concentrate in parts of the body that are more vulnerable to germs, like the very absorbant lining of the intestine.

To survive in our environment, our immune system has developed acquired defenses which depends on special immune cells. These cells are specific, they can distinguish a particular outsider, and are able to learn and remember what particles are harmful. These specialized cells are called T cells and B cells. T cells and B cells remember that foreign particle so that the next time it enters your body, they are prepared to fight it faster.

Together, the innate and acquired defenses of the immune system pose a double threat to pathogens!

Passive Immunity

There is a third kind of immunity: passive immunity. Passive immunity comes from receiving antibodies from another person. This happens between a mother and her child, since they share blood and also during lactation. This protection is immediate and very effective but does not last long.

Major Players and the role of proteins

In these pages we discuss extensively the innate immune system and its swallowing cells (like macrophages and dendritic cells), and the aquired immune system in the form of antibodies and B cells and in the form of Helper and Killer T cells. The less known players in the immune response are all the proteins involved! Proteins act on their own in the body as the complement system, they are involved in the communication between all cells in the immune system, and also play a very important role in identifying each cell or germ.

Identifying Cells and Other Particles: Proteins

Proteins and Identifying Cells - the Antigen

All cells (human, bacterial and everything in between) hold some form of genetic material.  This genetic material is expressed into proteins that become part of the surface of the cell, its membrane. The proteins are called antigens in the context of the immune system.

All livings things are made of cells, from one cell to millions of cells – including us and the organisms we refer to as pathogens. In all organisms, each cell holds genetic material in the form of DNA in their nuclei. Combinations of different molecules called nucleic acids make up who we are—they encode for every aspect of our bodies.  The formation of our organs, bones, muscles and tissues as a fetus, the color of our hair, eyes, and skin, and even our own immune systems—all expressions of our unique DNA.  Even though we each have our own variations of DNA which is most noticeably expressed in physical features, each species has a different set of DNA, except for viruses, which only have RNA (one strand of ribo-nucleic acids instead of two). Likewise, there are millions of different bacteria, viruses, and infectious organisms that exist in the world, and each one has a different genetic makeup. 

DNA holds the information, but how does the body use it? Each cell builds proteins from the different combinations of amino acids encoded in the DNA.  Proteins carry out many functions in each cell, in the body, and they play a major role in the immune system.  At any point in time, each cell in your body is actively producing proteins from its DNA, and these proteins can stay inside the cell, become a part of cell's membrane and even go out of the cell.

Proteins are characterized by having really exquisite 3D shapes that depend on their composition. Since each protein usually has a unique composition, proteins can be distinguished by shape (and by other molecular interactions).

Each cell makes different proteins according to its type (whether it’s a bone or a brain cell, for example) and it also makes different proteins in different circumstances: if it’s healthy, if it’s about to divide, if its dealing with a lack of an essential nutrient, or if it’s unhealthy! For example. if it is infected by a virus, the virus injects its own genetic material into the cell and so the cell makes proteins from the genetic material of the virus! So, the proteins a cell produces are a pretty good indicator of how the cell is doing.

The proteins produced by a body cell in the course of its natural life is called a self antigen - "self" meaning belongs to the self. Proteins produced by an infected cell (or that belong to a germ cell) are nonself antigens - "nonself" meaning that it does not belong in a healthy body and must be destroyed!

Immune cells take advantage of this and developed a couple of ways to "read" (by binding) the antigen – this is the basis of the specificity of the immune cells.Binding occurs by fitting together a special spot on the immune cells (a binding site) with the antigen - if they fit together kind of like a lock and a key, they bind!

T cells will check the antigens of cells they find in the body to see if they are healthy. If they find a self antigen on a cell, they decide that the cell is healthy and leave it be. If they find a nonself antigen, they know it means that the cell is either unhealthy or it may not belong to the body at all, so they start an immune response to kill it. Each T cell can only bind one kind of infected cell - they are specific.

Macrophages like most swallowing cells don't bind to antigens, they bind to non-specific proteins. This means they are good at recognizing some groups of proteins that are shared by a lot of different bacteria (like some of the proteins in their capsule).

B cells can only bind one kind of antigen - they are specific. The specific antigen that it can bind is the match of the unique binding site that each B cell has, the antibody. B cells are usually good at targeting outsider organisms.

Non Self Antigen

We just discussed antigens in the context of body cells - self antigen indicating a healthy body cell and and a nonself antigen indicating an unhealthy cell. Well, how about something that never belonged to the body - like a bacteria?

In any immune response, immune cells can bind to a body cell, whole bacteria, whole infected cells, viruses or just parts of bacteria or infected cells, and it’s easy to become confused about what to call all these different targets that can exist in the body.  Always though, this interaction involves the recognition of a protein or group of proteins that an immune cell thinks might mean trouble. We call these antigens. For example, the proteins of the tail of a bacterium, on the membrane of a virus-infected cell, and sometimes even of our own healthy cells can be antigens.

When our immune system targets our own healthy cells, the proteins on their membrane are called self antigens. (“Self” refers to belonging to the body.) Whenever the antigen belongs to a germ or an infected cell it is called a nonself antigen.

Antigen Presenting Cells (APCs) and Professional APCs

Almost all cells in the body present antigens - and they present the antigens in a special protein complex called the Major Histocompatability Complex (MHC). This may sound complicated but MHC is simply a group of proteins that captures proteins within the cell and brings them to the cell membrane. So, (almost) all cells of the body are Antigen Presenting Cells. This makes the immune cells' job easier: they are very good at grabbing onto the MHC and then can take a look at the antigen.

But whenever a germ comes into the body with its own antigens, the immune cells have a harder time grabbing onto them to look at their antigens. So here come in the Professional APC's! Some special white cells, like macrophages and dendritic cells are called professional APC's. The reason they are “professional” is because their main function is to digest germs and display their antigens. They possess a special kind of MHC (MHC class II) where they display the germ antigen that allows the T cells can bind to. This way T cells can check out the germ's antigens on the macrophage!

The MHC (I and II) is very important in T cell immune response, without it, T cells couldn't get to each cell's antigens!

Discover the role of MHC >>

Macrophages

The macrophage is a vital type of white blood cell. A macrophage is a kind of swallowing cell, which means it functions by literally swallowing up other particles or smaller cells.

Macrophages engulf and digest debris (like dead cells) and foreign particles through the process of phagocytosis, so macrophages act like scavengers. They are constantly roaming around, searching for and destroying dead cells and foreign particles that don’t belong in the body. Because they cannot identify specific targets, macrophages are considered part of the innate immune response. Macrophages also directly aid the specific immune response.

Macrophages
Some macrophages concentrate near the lining of the intestine, which is a natural point of entry to many outsiders due to its absorbant nature.

Origin
Macrophages come from specific white blood cells called monocytes. Monocytes are born from stem cells in the bone marrow and circulate throughout the blood stream. Once a monocyte leaves the blood, it matures into a wandering macrophage or a fixed macrophage. Wandering macrophages travel throughout both blood and lymph streams to perform their job; fixed macrophages strategically concentrate in specific areas that are more vulnerable to intruders like the lungs or the intestine. Macrophages can then be found in many areas in the body, like different tissues, lungs, skin, and also organs of the immune system like the spleen, lymph nodes, and bone marrow. 

Innate Immune System Function
By themselves, macrophages excel at getting rid of bacteria, fungus, and different types of parasites (like worms), but they also help fight off tumors.

Macrophages are programmed to look for and eat any foreign particles that live in the fibrous environment (extra cellular matrix) between cells, as well as eat the debris of damaged or dead cells. Special receptors sites on the cell membrane enable the macrophage to receive chemical signals sent out by bacteria, attracting them to points of infection.

Macrophages distinguish between body cells and outsiders by recognizing the specific structure of proteins that coat healthy body cells. This is one way in which the innate immune system is able to differentiate between self and nonselfs, so that macrophages don’t attack healthy cells!

Acquired Immune System - Function

Xray
Macrophages can activate the acquired immune system!

One of the most important functions of the macrophages is that they can activate the acquired immune system! After a macrophage has eaten and digested a particle, it displays some of the broken down germ proteins (antigens) on its cell surface. These antigens act as identification signals for Helper T cells. Helper T cells can “read” these signals and tell what kind of particle the macrophage has eaten! If the T cell determines the macrophage has eaten something harmful (a pathogen), it can trigger a powerful reaction towards the specific pathogen.

Phagocytosis
Phagocytosis (“phago”=eat, “cyte”=cell) is a fundamental biological process, where organisms, cells and/or particles are literally “eaten” or engulfed and digested.

When a macrophage encounters an outsider, it extends its cell membrane around the particle, drawing the particle into itself. It then forms a vesicle called a phagosome. Lysosomes inside of the macrophage release enzymes that break apart the captured particle inside of the phagosome.

Macrophages are not the only types of cells that function through phagocytosis. There are other important swallowing cells that make up the immune system, such as cells called granulocytes, neutrophils and dendritic cells. Macrophages are the biggest and most effective of the phagocytes.

Phagocytosis was one of the earliest form of metabolism, meaning that it was initially used simply for getting food for energy. You can still see some organisms using phagocytosis for eating and digestion, like the amoeba from the Protista kingdom. The amoeba is a single-celled organism that can swallow other cells, then break down the cell and use it for energy—the same way that macrophages swallow and break down bacteria and harmful pathogens. This ancient swallowing ability has been retained by some cells in modern organisms, like the macrophages, for protection!

So, phagocytosis has evolved from a simple form of metabolism to being also a major part of our immune system, helping to keep us healthy!

T Cells

Xray
T cells are like the police chiefs of white blood cells.

T cells are white blood cells called lymphocytes.

There are many different types of T cells that all perform different functions, but among the most important are Helper T cells and Killer T cells. Both of these types of cells bind cells in the body and can identify whether the cell is healthy and belongs to the body or whether it's not healthy or doesn't belong. In the latter two cases, the T cell will start an immune reaction to destroy the unhealthy cell or germ. T cells can identify which particular illness they are dealing with (they are specific) and can share this information with other immune cells, so they are like the "police chiefs" of white blood cells.

Helper T cells

In diseases like AIDS (Acquired Immune Deficiency Syndrome) the HIV virus attacks the Helper T cells, affecting Killer T cells and the production of antibodies by B cells. This is one reason why the AIDS virus is so devastating. It shuts down the highly specialized acquired defenses and leaves the body open to infection.

Helper T cells are the mediators of the immune system, they carry information and decide when to give the green light to other immune cells to carry out an immune response.

Helper T cells can only bind to swallowing cells like the macrophage and the B cell. The macrophage has a special binding site that helps the Helper T cell grab on (learn more about MHC II ).

Acquired Immune Response

T cells never work alone, they always work in cooperation with other immune cells, which allows our immune system a level of deliberation or control in how it reacts.

Activation of Helper T cells

The first step in an immune reaction that involves T cells is the activation of helper T cells.

  1. When a macrophage engulfs and digests a particle, it displays some of the broken down proteins (antigens) on its cell surface.
  2. Helper T cells can grab on to the macrophage by a special binding site - the MHC class III complex.
  3. Then, the T cell can attempt to “read” the antigen on the macrophage and tell what kind of particle the macrophage has eaten!
  4. If the Helper T cell thinks it is a self antigen it will drift away.
  5. If the Helper T cell recognizes the antigen as belonging to something harmful and becomes activated.
  6. The activated Helper T cell also activates the macrophage to continue to break down that specific antigen. The macrophage goes into overdrive, replicating and carrying out an aggressive attack on the unwanted microbe. 
  7. Once activated, the Helper T cell starts to divide and produce special proteins to signal other immune cells. The activated Helper T cell will in turn activate other T cells to attack the specific antigen (see below >>). It also can go on to activate B cells and create an antibody-mediated response.
  8. Some of the newly replicated T cells will not engage in the immediate response but will remain in the body as memory T cells, maintaining their specific receptor in the body, and remembering that harmful particle.

Killer T cells

As we’ve said, once a Helper T cell is activated, it goes on to activate other cells. One of these cells is the Killer T cell. These cells are also called Cytotoxic T cells.  Unlike the macrophages that swallow their prey, Cytotoxic T cells kill the infected cell by injecting it with special enzymes that destroy its nucleus and/or its structure.  In scientific terms, this is called apoptosis. Cytotoxic T cells are very good at attacking cells that have been infected with viruses or bacteria, and also cancerous cells.  Normal body cells have special binding sites for Killer T cells (the MHC I). They cannot attack bacteria that live outside of the cell—that function is left for the macrophages and other phagocytes.

Killer T cell action

  1. Cells in the body are subject to infection. When this happens, the infected cell will display bits of the foreign particle on its cell membrane - nonself antigens.
  2. A Cytotoxic T cell can recognize and bind to the antigen.
  3. Whenever T cells react with infected cells, they release special groups of proteins and peptides called cytokines. Cytokines are like messengers; they signal other T cells and macrophages to rush to the infected area. 
  4. If a macrophage-activate Helper T cell comes by, it sends chemical signals that activate the Killer T cell.
  5. The activated killer T cell kills the infected cell.
  6. Afterwards, macrophages help eat up the residue of the dead cell.
  7. Both activated Helper and Killer T cells go on to replicate themselves and continue to attack that specific intruder.
  8. Some Killer T cells will also remain in the body after the reaction as memory cells, to retain information about the virus or bacteria it encountered, so next time the same particle enters the body they will recongnize it and set off an immune response.

Replication, activation and signaling are all part of a specific immune response!

T Cell Specificity

T cells are specific. T cells recognize individual harmful particles which allows them to mount powerful neutralizing immune responses.

What does it mean that T cells are specific?

T cells can recognize whether a cell or particle belongs to the body and whether the cell is healthy or unhealthy. T cells can also recognize whether a macrophage has eaten something (like a bacteria) that might pose a threat to the health of the organism or whether it is not harmful. T cells make this decision by identifying the proteins (antigens) that each cell displays on their surface. T cells are specific because they are able to recognize the specific antigen, and mount an immune response that targets only that antigen.

The Importance of Specificity

The relevance of the specific T cells is that they only attack cells that present nonself antigens, as opposed to killing healthy cells. It also allows the immune cells to "share" this information with other cells and propagate a specific immune reaction:

  1. 1 - Once activated, the T cell replicates to multiply the number of cells that have the correct binding site.
  2. 2 - The activated Killer T cell will go on to only kill the precise type of cell in question.
  3. 3 - Helper T cell will go on and activate more T cells that share the same binding site to propagate the reaction.
  4. 4 - Both kinds of T cells will create some cloned copies that will remain in the body, keeping some immune cells with that antigen-binding site at the ready in case the germ ever appears again.

How Specificity Works for T cells

We talk a lot about specificity, but you might be wondering how it all works. The mechanisms behind the specific immune response involve:

  • STEP 1 - T Cells must bind to the target cell: the MHC
  • STEP 2 – The T cells must distinguish healthy from unhealthy cells: distinguishing self from non-self antigen

Binding or attachment between proteins is the basis for specificity

The binding referred to in this section happens when two cells (or more) have proteins on their surface that fit each other kind of like a lock and a key, so that the two cells attach briefly to each other. We refer to the proteins on both cells as “binding sites” or “receptor sites.”

T cells have special spots on their membrane where the binding occurs: the T cell receptor site (TCR). The TCR actually contains two sites: one that binds particular spots on a cell’s surface, the Major Histocompatability Complex (step 1 - The MHC), and a second receptor site that binds with the antigen displayed (step 2 - distinguishing self from nonself antigen ). Each T cell has many TCR binding sites. But each T cell only has one kind of antigen receptors, so it can only “fit” only one particular antigen, like a lock and key. This makes them specific, allowing T cells to know which particular pathogens like bacteria and viruses is in your body.

The interaction between molecules involved is very complex and depends on their three-dimensional structure and their electrical charge. Protein-mediated binding happens all throughout the body in many different ways and is vital to most biological processes.

STEP 1 - How T Cells Bind to the Target Cell: The MHC Protein Complex

T cells come into contact with threats in two situations:

1 - When a Killer T cell binds to a cell that belong to the body to see if it's healthy and,

2 - When Helper and Killer T cells binds a swallowing cell like a macrophage, to tell if there is an outsider germ in the body.

In both cases, they must first bind to the cell in question.

1 - Binding to Cells that Belong to the Body - The Role of MHC I

To make the immune cells’ job easier, (almost) all cells of the human body have a special group of proteins called the Major Histocompatability Complex class I – the MHC I.

Cells display proteins (antigens) on their membrane with MHC I. The MHC I captures proteins inside the cell and presents them to the outside. For this reason, body cells are called antigen-presenting cells (APCs).

Killer T cells have a special binding site that matches the MHC class I. This allows them to easily “dock” or bind to (almost) any cell of the body by the MHC class I complex.

2 – Binding to a Foreign Particle or Cell - The Role of MHC II

What about cells and particles that don’t belong to the body and don’t have MHCs to present their antigens? This is where swallowing cells like macrophages, professional antigen-presenting cells, come in and help the T cells!

Let’s use bacteria as an example.  Once a bacterium enters the body, it will most likely be gobbled up by a phagocytic white blood cell, like a macrophage.
 
The bacteria that the macrophage eats contains its own specific DNA, and this DNA is different from the DNA of any other type of bacteria. The macrophage eats the bacteria and breaks it down (digests it), coating it in proteins. These proteins are the Major Histocompatability Complex II (MHC II)! The macrophage takes the MHC II-covered bits of bacteria and displays them on its own cell membrane.  In fact it is the MHC II proteins’ job to take the germ proteins to the membrane of the cell.

Helper T cells have special binding sites that bind the MHC II, so they can access the antigen.

Macrophages and T cells are very complex cells with many binding sites on their surfaces. Think of when the macrophage digested the bacteria and displayed bits of it on its cell surface surrounded by the special MHC protein. The macrophage doesn’t just display one bit; it displays many molecules all over its surface. That way it can attract as many T cells—both Helper and Killer—as possible.

Helper T cells and Killer T cells bind different MHCs

Helper T cells and Killer T cells don’t recognize the same MHC protein complexes. Helper T cells recognize MHC I, while Killer T cells recognize MHC II.
Regular APC's (normal body cells) only display MHC I, and so can bind with Killer T cells, but not Helper T cells. The professional APC's actually display antigens in both MHC I and II, so they can bind with Killer T cells and with Helper T cells. 

What kind of MHC complex the T cell binds helps determine its fate as a Killer or Helper T cell. This decision occurs during the maturation of the T cell >>

MHC allows the T cells to bind strongly to the target cell and give them time to identify the antigen itself and recruit other cells.

How do the T cells identify the antigen?

STEP 2 – Distinguishing Specific Pathogens: The Self Antigen and the Nonself Antigen.

Once the T cells is bound to a body cell or an APC, how does it know whether the antigen presented is self (signal of a healthy cell) or non self (signal of an unhealthy cell)?

Both the Killer and Helper T cell must attemp to recognize the antigen presented.

Each T cell only has one kind of antigen-binding site, which means it can only bind one kind of antigen - so the antigen-binding site makes the T cell specific. There are millions of structural variations that naturally occur for each bacteria and virus, and so the immune system responds with creating T cells with millions of corresponding antigen-binding sites.

When the T cell has bound to the MHC of its target cell, it attempts to match the shape of its antigen-binding to the antigen presented.

The antigen-binding site of the T cell is selected during the maturation of the T cells to not bind to self antigens, so if the target cell is presenting a self antigen, the T cell will disengage and move on.

If binding site and the antigen match, like a lock and key, it indicates a nonself antigen! The site and antigen form a very strong bond and the T cell is activated!

Both antigen specific and MHC binding are necessary for the T cell to become activated.

The Importance of Specificity

The relevance of the specific T cells is that they only attack cells that present nonself antigens, as opposed to killing healthy cells. It also allows the immune cells to "share" this information with other cells and propagate a specific immune reaction:

  1. Once activated, the T cell replicates to multiply the number of cells that have the correct binding site.
  2. The activated Killer T cell will go on to only kill the precise type of cell in question.
  3. Helper T cell will go on and activate more T cells that share the same binding site to propagate the reaction.
  4. Both kinds of T cells will create some cloned copies that will remain in the body, keeping some immune cells with that antigen-binding site at the ready in case the germ ever appears again.

Origin and Maturation: how T cells become Helpers or Killers

T cells go through a complicated maturation process that allows them to distinguish cells that belong to the body and are healthy from those that aren't healthy or don't belong to the body at all! The maturation process also determines whether they become Helper or Killer T cells.

Origin

T cells come from stem cells in the bone morrow and are sent to the thymus to mature.  The “T” in T cells is named after the thymus. The thymus is an organ behind your breastplate which helps the naïve T cells learn to develop into a specific T cell. The most important lesson the T cell learns is how to distinguish between healthy self and nonself. Basically they learn to only attack intruder organisms, infected cells, and not healthy cells! Only T cells that mature into specific cells are allowed to leave the thymus. This is one of the main reasons why our very potent immune system doesn’t attack our own bodies. 

What makes a T cell?

T cells identify cells by the proteins that the cells produce and have on their membranes - the antigen (read about antigens and identifying cells). Healthy body cells produce self antigens, and unhealthy body cells or germs produce nonself antigens. Most body cells have a special group of proteins - the Major Histocompatability Complex whose job is to display these proteins. The MHC is a common group of proteins the T cells can grab onto to observe the antigen.

So, our T cells need to:

  1. T cells need to bind strongly to the MHC complex of the cells to have time to identify the antigen presented.
  2. T cells must bind strongly with a nonself antigen to start an immune reaction
  3. Or, T cells must not bind strongly to a self antigen, so the T cell will moves on.

So T cells must be able to bind strongly to the MHC complex and strongly to an unknown nonself antigen.

The T cell receptor site (TCR) actually contains two sites: one that binds with the MHC complex (to bind cells ), and a second receptor site that binds with the antigen displayed (to recognize antigens ). Each T cell has many TCR binding sites.

The maturation of the T cells assures that these abilities are developed before releasing them to the body.

Positive selection - Learning Tolerance
When T cells arrive in the thymus they have two kinds of MHC-receptors, CD4 and CD8. In the thymus they are exposed to a wide variety of peptides (MHC I and II among others) that are like what they will find in the fluids of the body or part of cells. The T cells must be able to bind one kind of protein available to be able to recognize cells that belongs to the body. If a T cell's CD4 receptors binds a protein, its CD8 receptors degenerate and the T cell goes on to be a Helper T cell. If its CD8 receptor binds a protein, then the T cell stops making CD4 receptors and the T cell goes on to be a cytotoxic T cell.

If the immature T cell doesn’t bind to any protein then it means that it cannot recognize self proteins, and is triggered to die. Only T cells that bind strongly to any kind of MHC receptor site receive the survival signal (ones that don’t undergo apoptosis).

It is said then the immune cells become tolerant of self proteins.

Negative Selection - Blocking Self-Antigen Recognition
In the thymus, the T cells are also exposed to many different types of self antigen peptides - examples of the different healthy proteins they will find in the body. If the T cells bind too strongly to self proteins they must also be destroyed immediately. Their extra-strong affinity can mean that they are more likely to mount an attack against the cells that belong to the body (autoimmunity).

So, T cells are matured to bind either MHC I (becoming Killer T cells) or MHC II (becoming Cytotoxic T cells) and to not bind self antigens presented in these MHCs.

The antigen-binding site of each T cell is specific. It will only bind one kind of nonself antigen. This means the body produces millions of varieties of T cell antigen-binding sites, to create antigen-binding sites that will match and bind strongly whatever nonself antigen we may encounter!

Tolerance

Our immune cells learn to be tolerant to what belongs to the body. When this mechanism goes wrong, and the immune system starts an attack on itself, it is called an auto-immune disease. Our bodies can also acquire tolerance, when the body learns to tolerate external substances or cells, like in the case of a pregnant mother whose immune system must tolerate her growing baby.

B Cells and Antibodies

B cells are a type of white blood cell. They are similar to swallowing cells like macrophages but they are specific, meaning they can only attack one kind of intruder. B cells create antibodies during an immune response. 

Origin

Like T cells, B cells are lymphatic cells that are born from stem cells in the bone marrow.

Lymph nodes
The bone marrow can be found in the center of the bone, like the top of the arm bone above. The bone marrow is richly fed with capillaries and is very active producing new cells all throughout your life!

But unlike T cells, B cells stay in the bone marrow until they are mature.  Once mature, they travel through the body, moving in and out of the lymph and blood streams and collecting in the lymph nodes.

The most important aspect of a B cell is its receptor site - called an antibody.  Each B cell is born with a specific site on their membrane that can bind to only one kind of harmful particle. This receptor allows the B cell to recognize and identify one kind infectious foreign particle by binding to the specific protein makeup of the particle’s surface. But antibodies do a lot more, read on!

Antibody-mediated Immune Response

Xray
B cells become plasma cells to produce antibodies.

When a B cell finds a particle in the body that matches its unique receptor site, it attaches by its receptor site and digest it through a process similar to phagocytosis. It then displays the digested viral or bacterial pieces on its surface, attracting a Helper T cell. If the Helper T cell also has a specific binding site that matches the digested bits on the Bcell, then it knows that the digested particle is harmful! If it hadn’t already been alerted (and activated) by a macrophage of the same threat, it now becomes activated.

The activate Helper T cell, in turn, activates the B cell, and this interaction causes the B cell to divide.  After a few days, the young B cells will mature and differentiate into plasma cells and memory B cells.  Plasma cells use their machinery to produce antibodies.

How Antibodies Work

Antibodies are “Y” –shaped protein structures made by T cells. They are made to specifically bind one kind of infecting virus or bacteria, like a lock and key (antibodies are specific, see below). Each type of virus or bacteria requires a different set of antibodies—antibodies made against the Influenza virus don’t have any effect on, let's say, the Mononucleosis virus, although their symptoms are very similar!

Antibodies can travel through the blood and lymph to the site of infection and attach themselves to the designated foreign particle.  This renders the foreign particle immobile, so they can’t infect more cells or reproduce.  Antibodies also make the foreign particle more attractive to macrophages and other phagocytes, who quickly come and eat the immobile particles. Antibodies can also travel to the intestines or our external mucous membranes to stop their pathogen before more of it enters the body!

Memory and a Swift Second Response!
The other set of cells produced during B cell division—memory B cells—continues to exist in the body long after the infection has been cleared.  This way, they retain the antibody that recognizes the specific harmful outsider. In other words, they have the bacteria or virus on file! The next time it enters the body, the memory B cells will have all of the information needed to initiate a quick antibody response and stop a chronic infection before it occurs.  These B cells can stay circulating around your body for years and maybe forever!

Memory B cells are the reason we can have vaccines and, unfortunately, allergies!

Specificity - How do B cells recognize viruses or bacteria? 

Xray
Each B cell only makes antibodies for one kind of germ- they are specific.

Each piece of virus or bacteria that circulates around the body during infection also has its own genetic makeup.  This genetic makeup is expressed in the proteins that are displayed either on its surface or on the surface of an infected body cell.  These proteins are called antigens.

The whole goal of the B cell is to recognize the specific structure of these proteins, and manufacture antibodies that will “fit” their shape. Antibodies then are specific binding sites, because they only bind one kind of antigen. It’s like creating thousands of one type of key—per second—that will unlock one door. It is estimated that there are 10 million different variations in protein structure that viruses and bacteria can express, so the body competes by producing 10 million B cells that each have a uniquely-shaped receptor!  Our B cells represent one way that our immune system has adapted over time, enabling it to acquire and remember information about viruses, bacteria, and other harmful pathogens that threaten our well-being.

Organs of the Immune System: Significance of the Lymphatic and Circulatory Systems

Many organs are involved in the immune response like the lymphatic system, bone marrow, the spleen, and the thymus. 

Bone marrow, the spongy tissue inside of the bone, is the birthing ground for white blood cells. All T cells, B cells, macrophages and others are first created in the bone marrow.  B cells mature in the bone marrow, but T cells travel to the thymus to grow. 

Just like blood travels through veins and arteries, the cells of the immune system have their own transportation system where they perform many functions.  This is called the lymphatic system. 

Lymph nodes
The lymphatic system highlighted in green spans the whole body. Nodules, circled above, are lymph nodes where immune cells concentrate and communicate with each other.

The lymphatic system is a network of vessels, lymph nodes, and organs extending throughout the body. The lymph vessels enable a quick mode of transportation for white blood cells and easy connection to lymph nodes and the blood stream. White blood cells like macrophages and T cells concentrate in the lymph nodes, where they can quickly disable any bacteria or virus passing through. Here, B cells divide and multiply, sending a flood of antibodies through the lymph vessels and blood. 

Unlike the circulatory system, the lymphatic system lacks a muscle (or organ) that facilitates its movement.  The heart pumps blood throughout the body, but the lymphatic system depends upon the contraction of skeletal muscles for movement. This causes the lymphatic system to move much slower than the circulatory system.

A bad infection will render a lot of activity in the lymph nodes, causing swelling. This is noticeable in some viral infections like Mononucleosis, where the lymph nodes in the neck are swollen and tender.

Stem cells are very important.  Right now, scientists are researching how to use these stem cells to help cure diseases like Diabetes. Read on to Autoimmune Diseases and Diabetes to learn more about stem cells and regenerative medicine (soon)!

Memory in the Immune System

During an immune response, B and T cells create memory cells. These are clones of the specific B and T cells that remain in the body, holding information about each threat the body has been exposed to! This gives our immune system memory. The immune system is thus able to mount a quicker and more powerful response if it encounters the same threat again.

Our immune system's capacity for memory allows us to develop immunities. When our immune system knows what a germ looks like, it can stop any new infections before we get sick again. That means we are immune to that particular germ.

Our immune system's capacity for memory allows us also to gain immunity through vaccines (see below), but it can also get us in trouble with autoimmune disorders or with allergies.

Vaccines

Vaccines and allergies depend on our B cells and their antibodies, check them out >>

Of the thousands of bacteria and viruses in the world, of course there are some which your body has never seen before. That’s why we get vaccines. When you go to the doctor to get a vaccine, you are actually being injected with a form of whatever virus or bacteria you are trying to prevent! Scientists today have engineered vaccines that are very safe. Some vaccines don’t even use the whole virus or bacteria, but merely a part of it.  Your B cells pick up the vaccine and begin making antibodies and memory cells against it.  The next time your body encounters that virus or bacteria, your B cells will be ready to produce the right antibodies against it. 

Ever wonder why it takes days, sometimes weeks to get over a cold? Remember that you produce millions of different B cells. With so many different cells to produce, it’s impossible to make a lot of each. Your body only has so much energy and space. Whenever an infectious outsider is introduced, the right B cell has to be weeded out. Not only that, that B cell has to divide and produce antibodies.  With the common cold, the body needs a few days to get its B cells in full operation.  But with more chronic diseases, like Tuberculosis or Hepatitis, the body benefits from the introduction of a vaccine.  That way it will already have many of the necessary B cells and antibodies needed to prevent infection.

Allergies

Allergies are the result of a wrong immune response! Allergies develop when the body encounters a substance like pollen from flowers that it wrongfully decides is harmful – it is an allergen. The immune response it starts involves B cells and their antibodies.

When a B cell binds this harmless particle by its specific antibody, it transforms into a plasma cell and a memory B cell. The plasma cell produces many antibodies and sets off an immune response that involves other cells, proteins and chemicals. You can see this in some of the symptoms people get: runny noses, sneezing, these are all your body’s natural ways of trying to get rid of something harmful!

Unfortunately the big strength of our immune system, its memory, works against us here. The memory B cells produced in this immune response remain in your body, ready to respond again, quicker and more forcefully next time the body comes across the same harmless substance!

Additional Resources

Lymphatic System and Immunity

The Lymphatic System
Associated with the University of Illinois.

Microbioloy and Immulogy On-Line
This web site is good reference with animated tutorials for high school and above. Associated with the University of South Carolina.

The Immune System in More Detail
This web site is a great reference for middle school and above with cartoons and games. Associated with NobelPrize.Org.

Specific Immunity Animation
This web site contains a great step-by-step animation of some of the more complicated interactions in cell- and antibody-mediated immune response. Associated with North Harris College, Houston TX.

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