Immunity 2 - Adaptive Immunity to the Rescue

•	In our last lecture we learned about the innate immune system, the more primitive type of immunity that’s common to all animals, and introduced adaptive immunity, a more advanced level of protection found in higher animals like ourselves…

•	In this lecture we’ll tackle the complexities of adaptive immunity, and discover how the body learns to recall the molecular “face” of every pathogen it has ever had to fight
•	Like every learning process, adaptive immunity has to start with the basics…

•	Defensive cells have to master the art of recognizing tiny bits of protein called epitopes, fragments of foreign invaders
•	Molecules with epitopes in their structure are called antigens

•	Defensive cells in the adaptive immune system have special receptor sites for these antigens, called antigen receptors
•	Antigen receptors are proteins whose shape fits the shape of a particular antigen, just like a lock fits a key

•	There are millions of minute differences between the molecules of different microbes
•	So the adaptive immune system has to make millions of different types of antigen receptors in order to match them all

•	And that gives the immune system the ultimate “magic bullet”, a weapon that can target a particular strain of microbe with deadly accuracy
•	Our adaptive immune system is the most advanced of all - we can potentially detect over 100 million different kinds of epitopes

•	But how is that even possible, given that one gene can only code for one protein, or for one part of a larger protein?
•	100 million different antigen receptors would require 100 million different genes - but human DNA only has about 25,000 genes…

•	It seems like an impossible challenge – but not to anybody who’s ever played with Legos
•	With a relatively small number of unique Lego bricks you can make an infinite diversity of structures…

•	In the adaptive immune system, the lego bricks are the genes of special leukocytes, white blood cells, called lymphocytes
•	There are three basic types of lymphocytes, NKT cells, T cells, and B Cells

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NKT, or natural killer T cells, act just like the NK natural killer cells we talked about in our last lecture, but NKT’s also play a key messenger role, releasing cytokines to stimulate the immune response

•	Lymphocytes are made by special cells in our bone marrow called stem cells
•	You’ve all heard of stem cells, I’m sure, and the controversy surrounding their use in medicine

•	What makes stem cells so incredibly valuable, is that they’re relatively primitive and undifferentiated cells
•	That means that stem cells can develop into many different kinds of cells – whatever you need, they can provide
•	Hence the name – many different cells can stem, or originate, from them

•	Stem cells in bone marrow can make lymphocytes, macrophages, cytotoxic cells, neutrophils, red blood cells, and several other cell types – pretty handy!
•	Each stem cell has a group of several hundred genes that code for different antigen receptor shapes

•	Each new lymphocyte gets a random set of five or six of these receptor genes
•	Just enough genes to make one unique antigen receptor…
•	Remember that the genes aren’t “used up” in the process, any more than a recipe is used up when you use it to make cookies

•	Every gene is available for making the next random set
•	So a few hundred genes, parceled out in random groups of five or six, can easily make over 100 million different antigen receptors!
•	In fact, the theoretical upper limit is about 100 trillion different antigen receptors!!

•	But this clever system has a hidden cost…
•	Among those millions of random variations will be a handful that match the body’s own antigens – what we call “self reactive” epitopes
•	It’s like a roomful of typing monkeys - they might accidentally write a Shakespearean sonnet…

•	Very early on, the immune system has to learn which shapes match self, and which shapes do not - which are us, and which belong to invaders
•	A lot of that vital information is acquired while we’re still embryos

•	And that makes a great deal of sense - embryos are a little “self”-contained universe
•	And in that isolated world, any antigen shape encountered by an immune system cell must be a “good” shape, by default

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If an immune system cell is self-reactive during this critical phase of development, it is ruthlessly destroyed
•	Millions of different lymphocytes survive this initial winnowing, and leave us with a prime assortment of keys that could potentially fit a foreign lock

•	Once created, these new lymphocytes swarm throughout our body
•	Each lymphocyte has several copies of its own unique antigen receptor on its outer surface
•	Now think about a bunch of different microbes, floating around in our blood

•	Each different kind of microbe will have different epitopes on its surface, little molecular patterns which might be unique to their species or strain
•	Those microbes could potentially be recognized by any of several different kinds of lymphocytes

•	It’s just a matter of bumping into the right one - but there’s a problem…
•	There are so many different kinds of lymphocytes, the body can’t keep more than a few of each type around at any one time
•	Not enough to lead a full-scale attack…

•	So when a microbe invades, and when the invader is recognized, the matching lymphocyte has to make many copies of itself
•	It has to create a cloned army to fight the invasion
•	Where have we heard that before…(cue the Stars Wars music, please…)

•	This phase of the infection is called the primary immune response
•	The primary immune response begins with:
>	Presentation - Matching lymphocyte to invader, and
>	Activation - Making large numbers of the correct type of killer lymphocytes

•	The primary immune response can take two to three days
•	Meanwhile the bacteria are increasing at an exponential rate
•	And we’re starting to feel sick…

•	But while the bacteria are busily chewing away, the immune system is quietly marshalling its forces
•	Finally, the body makes enough matching lymphocytes to attack the invading cells
•	We start to get better…

•	But how can we avoid future attacks from the same microbe?
•	The adaptive immune system makes memory cells matched to that particular microbe

•	These memory cells can live for several years, and if the invader returns, they can build up a new population of cloned soldiers so quickly that we might not even get sick at all
•	We are now said to be immune to that disease
•	This “return engagement” phase is called the secondary immune response

•	Being exposed to a given microbe can also give you immunity against related microbes
•	Cowpox victims, for example, acquire immunity to smallpox, because the epitopes of cowpox and smallpox are very similar

•	Unfortunately, this doesn’t happen nearly as often as we would like
•	Remember that one strategy of microbes is altering their surface proteins – that’s the strategy of the influenza virus
•	Change the shape of the reactive antigen, and the immune system has to start all over again

•	Now that we’ve watched the battle from a distance, let’s get small, and get a closer view…

•	Two of the three types of lymphocytes are especially important – B cells and T cells:
>	B cells, which are made in the bone marrow (hence “B” for bone), and
>	T cells, which are made in bone marrow, but migrate to mature in the thymus gland (hence “T” for thymus) – we’ll talk more about this process in our lecture on autoimmunity

•	Each of these cells has a complementary role to play in the immune response
•	The B cells are the deputies, checking cellular ID’s for known villains and marking them for the T cells
•	The T cells are the posse…

•	B cells make tiny little bits of protein called antibodies, lots and lots of them
•	Each antibody matches a surface epitope of a particular outlaw microbe, and fits on to it, like the ultimate “kick me” sign

•	Antibodies all have the same basic shape
•	There’s a constant region, and two variable regions sticking out at one end – like a letter “Y”
•	The variable regions are different for each different type of antibody

•	The antibody can attach to the microbe’s epitopes by its variable regions, if the key fits the lock
•	The rest of the antibody sticks out like a tiny handle, which passing phagocytes, eating cells, can grab hold of

•	Antibodies help us in several ways…
•	They can directly neutralize some toxins by latching on to them, like the toxins made by the diphtheria and tetanus bacterium
•	And if they happen to fit onto the binding site of a virus or a bacterium, they can keep it from attaching to a cell and infecting it

•	But their most important function is to pin a flag on invading microbes – it’s like sending an all points bulletin to call out the posse, the killer T cells…

•	T cells work just like the more primitive cytotoxic cells we talked about in our last lecture, but they’re much more precise
•	T cells also release a wide array of chemicals like interferon that help marshal the attack

•	T cells might have evolved in response to an ancient change in microbial strategy
•	The very first primitive microbes probably just attacked from the outside
•	But when their hosts coevolved a solid defense, microbes also started attacking from within…

•	And it’s a lot harder to find invaders inside the cell – like finding enemy soldiers hiding inside a building
•	Internal invaders like viruses can’t be spotted by lymphocytes or phagocytes passing by outside

•	And internal defenses are much more challenging, because cells would have to sort through their contents molecule by molecule, looking for the invader, or its toxins
•	So internal attacks required a more sophisticated defense
•	That’s where lymphocytes come in…

•	At any given moment there are roughly 900 billion lymphocytes moving through your body
•	Millions of new lymphocytes are formed each day from bone marrow stem cells
•	And millions of lymphocytes die each day in the lymph nodes and spleen

•	Most of the time, these lymphocytes are concentrated in the lymph nodes, a part of the lymphatic system
•	The lymphatic system consists of a network of capillaries, little vessels filled with fluid called lymph, which transports white cells throughout the body

•	The lymphatic system works like an elaborated drainage system, collecting intracellular fluids and delivering them back into the circulatory system
•	The body has cleverly co-opted this drainage system to serve as the framework for the immune system

•	Every time we get a cut or a wound, for example, bacteria and viruses enter the tissues, only to be caught up in the currents of the lymphatic system
•	Some of them eventually get carried past the sentinel cells of the immune system, along with any bits or pieces of invading microbes anywhere in the body

•	The lymphatic system is as complete a circulatory system in its own right as the blood circulatory system
•	The lymph nodes are like a series of forts, or headquarters
•	Swollen lymph nodes are a sure sign that the body is fighting off an infection (“swollen glands”)

•	Now - no battle can start before the generals are informed - and the generals of the immune system are certain T cells that live in the lymph nodes
•	And, as in any battle, good scouts and messengers are vitally important

•	Fortunately, the immune system has some reliable messengers to call upon, both professional and non-professional…
•	These messenger cells, or antigen-presenting cells (APC’s), include macrophages, B cells, and an important type of phagocyte called dendritic cells

•	Dendritic cells and macrophages, incidentally, like many other types of cells, function in both the innate and adaptive immune systems
•	Remember that macrophages and lymphocytes can’t really tell which species of microbe they’re attacking just from their sugar molecule antigens alone

•	A scout could find a piece of a bacteria’s surface sugar molecule, like a horn broken from an enemy helmet – and bring it back to the general’s tent
•	But it wouldn’t tell you who was attacking you – much better to bring back the enemy’s flag

•	And when it comes to flags, the microbial equivalent is an invader’s unique proteins
•	Once a flag is captured, cells run it up their own molecular flagpole, a structure called the MHC
•	The major histocompatability complex, or MHC, is how infected cells tell the immune system cells that they’ve been invaded

•	The MHC is a special receptor site on the outside of every vertebrate cell, that can hold an epitope
•	Infected cells can put a piece of the invader’s protein on their MHC, to flag themselves (and their dangerous contents) for destruction by any passing killer cells

•	Humans have about 1,460 different alleles, or versions, of the genes that code for our MHC
•	Each of us can inherit between 13 and 16 different alleles for MHC

•	Few other genes come in that many different forms, and their endless combination helps to make each of us a truly unique being – only identical twins will have the same MHC combination
•	And that turns out to be both a blessing and a curse…

•	It gives us each a unique cellular identity
•	But it also means we can’t exchange body parts with one another
•	Because the MHC molecules of the cells in the transplanted organs will be just different enough to provoke an immune response

•	The only way we can make transplants work, is to chemically nuke the immune system, which leaves the poor transplant patient wide open to infection

•	Now it’s time to put on your thinking cap…
•	Let’s say you’re a general, with a squad of scouts
•	Their mission is to capture flags that mark an enemy post, tie the flags to their belts, and carry the flags back to headquarters

•	Sounds like a game of “capture the flag”, doesn’t it? - but as my mom would be the first to tell you - it’s always fun until somebody loses an eye…
•	So – here’s the puzzle - how can you keep your scouts from being attacked by your own troops, while they’re carrying the enemy’s flag?

•	That’s the dilemma that every macrophage has to face…
•	Why don’t other macrophages attack these flag-bearing macrophage scouts, as they’re headed toward the lymph nodes to sound the alarm?
•	Because these microscopic scouts are real pro’s…

•	The foreign epitopes they carry, the enemy’s flag, are actually attached to a slightly different kind of flagpole, an MHC complex, called MHC Class-II
•	Antigen presenting cells that use MHC II are called “professional” APC’s

•	Using the MHC II tells other phagocytes that the macrophage is not really an infected cell asking to be destroyed, it’s just a scout carrying a message
•	Macrophages are the most efficient and active professional APC’s
•	They’re constantly cruising for trouble…

•	Macrophages can go anywhere in the body, except for the cornea of the eye
•	Macrophages are always fishing for microbes, whose epitopes will inevitably betray them
•	And when it finds them, it reels them in and devours them

•	When a macrophage eats a microbe, it sticks some of the microbe’s protein, an epitope, to its MHC
•	It then slowly creeps to the nearest lymph node, where it presents the foreign antigen to the T cells

•	It looks for a matching T cell, one that has an antigen receptor that will fit the shape of the foreign antigen
•	If it finds a match, the act of presentation will activate that particular T cell, which will start reproducing in large numbers to repel the invasion

•	But once the T cells have recognized the invader from its flag, how do they know where to send the troops?
•	Different groups of macrophage scouts tends to patrol one particular part of the body
•	T cells can recognize the different groups of scouts, and know right where that group must have run into danger

•	Now let’s put the pieces together…
•	What would happen if a virus entered your body, invaded a cell and started to replicate?
•	The virus rapidly fills the cell with copies of itself, then emerges to spread to other cells
•	The adaptive immune system to the rescue!

•	An APC, usually a passing macrophage or a dendritic cell, encounters the virus, and devours it
•	The APC then puts a protein fragment from the invader on its MHC complex and heads for the nearest lymph node

•	Once it reaches the lymph node, the APC presents a piece of the invader to the T cells
•	Hopefully, it will find a T cell whose randomly shaped receptor site will match the antigen that the APC is presenting
•	Talk about a Cinderella story…this one has thousands of stepsisters waiting to try on that glass slipper…

•	There are two kinds of T cells, helper T cells (TH cells, h for helper) and killer T cells (TC cells, c for cytotoxic)
•	Just to make things more confusing, helper T cells are also called CD4+ cells, and killer T cells are also called CD8+ cells, after two slightly different versions of a surface protein they both share in common

•	Helper T cells are very special – they are the “team leaders” among the T cells
•	Antigen-presenting cells release interleukin-1, which activates the helper T cell

•	Interleukin-1 also stimulates cells in the hypothalamus to raise the body temperature - we get a fever
•	Interleukin-1 is a cytokine – we’ve already mentioned cytokines that function as alarm chemicals in innate immunity

•	More generally, cytokines are molecules that mediate interactions between cells
•	Fever-causing cytokines are called, appropriately enough, pyrogens - pyros means fire
•	Many bacterial toxins also act as pyrogens

•	Fever stimulates macrophages to start rapidly eating bacteria, and causes the liver and spleen to begin iron withholding, which slows down the rate of bacterial growth
•	The helper T cell releases another cytokine called interleukin-2, which triggers the activation of both killer T cells, and B cells

•	The activated killer T cell rapidly clones itself, and goes off to seek the enemy
•	Any microbe or infected cell waving that particular epitope flag is doomed!
•	This part of the primary immune response, the process of presentation and activation, is called the cellular immune response

•	Helper T cells also activate any B cells whose surface markers match the foreign antigen
•	This activated line of B cells begins a clonal baby boom, which splits into two lines - plasma cells and memory cells
•	B cells that become plasma cells start to make antibodies against the antigen

•	And B cells that become memory cells will retain the memory of the attack, in the form of cells with the appropriate receptor site, in case the invader ever returns
•	These memory cells can last for several years

•	B cells that become plasma cells are amazing little antibody factories
•	They only live for a few days, if they aren’t activated, but at their peak, each B cell can crank out an incredible 2,000 antibodies per second!
•	Antibodies for the foreign antigen quickly flood the body

•	This part of the primary immune response, in which antibodies appear in the bloodstream, is called the humoral response (remember that blood was one of the four humors)
•	When an antibody encounters a foreign cell or molecule that matches the shape of its variable region, it fastens on to it

•	The “handle” of the attached antibody, its constant region, always has the same shape, so any killer T cells or macrophage that encounters it can easily grab it, and use it to devour whatever it’s attached to!
•	It’s like finding a steak with a fork already stuck in it…

•	Killer T cells and macrophages will destroy any cell with an attached antibody
•	So the cellular response and the humoral response together, make up the primary immune response
•	The primary immune response takes about 48-72 hours - meanwhile we’re getting sicker and sicker…

•	Suddenly we start to feel a little better…
•	Our immune system has saved us once again…

•	If we should encounter the same pathogen again, this time we’ll be ready
•	The memory cells can immediately start to reproduce, and the B cells they spawn will start churning out the proper antibody
•	This is called the secondary immune response

•	Whew! – Now, let’s stand back and look at the big picture:
•	Primary immune response
>	Cellular immune response
–	Presentation - Macrophages bring epitopes to T cells in the lymph nodes, and present them for a match
–	Activation - Matching helper T cells activate killer T cells
>	Humoral immune response
–	Helper T cells activate B cells to make antibodies and memory cells
•	Secondary immune response
>	The invader returns, and the memory cells respond very rapidly

•	Now you can better appreciate some of the clever strategies that microbes have evolved to fight back, such as:
>	Changing the pattern of epitopes on their surface
>	Covering the epitope in order to disguise it
>	Covering itself in the hosts own molecules

•	It takes about two years for the immune system to fully mature
•	Infants get a starter kit of antibodies from their mothers, in utero or in breast milk, a big argument in favor of breast feeding

•	The immune system is least effective in the very old and in the very young
•	The elderly gradually lose the ability to respond to new pathogens

•	Their immune systems often retains the memory of the microbes they’ve met
•	But it can no longer respond as quickly or as successfully

•	As to the very young, they have to run the same endless gauntlet of microbes that we did when we were growing up
•	And, sad to say, the fact that we caught chickenpox when we were little won’t help our children to avoid it

•	Although if we caught it, and survived it, there’s a good chance that they will too
•	It’s the subtle difference between immunity and resistance
•	These terms are often used interchangeably, but they don’t quite mean the same thing

•	Resistance to a disease can come from a structural change in a cell or molecule - for example, a change in the structure of a cell membrane binding site, that keeps a microbe from attaching to it, or a change in the shape of an enzyme that now lets it break down a bacterial toxin

•	These kinds of structural changes are ultimately caused by changes in the way that amino acids are assembled to make a particular protein – changes that are coded for in our genes, and can therefore be inherited – what we might call genetic resistance

•	But immunity, especially adaptive immunity, is something much more personal - immunity is learned resistance, something we acquire only by encountering a new disease
•	We can inherit genetic resistance to a disease, but not learned resistance to that same disease

•	Our bodies remember every microbial encounter in our lifetime
•	But that memory dies with us…
•	If we get chickenpox, we won’t get it again, because our memory cells will leap into action

•	But our children’s immune system has to learn about chickenpox the hard way…
•	It’s like giving your child your old computer – after you’ve erased the hard drive
•	The computer can still learn to do everything it did for you, but it has to learn how to do those things all over again

•	Same goes for the immune system…
•	We pass on the hardware, the cells and tissues of our innate and adaptive immune system, but not the software, the learning process of adaptive immunity…

•	Adaptive immunity doesn’t replace innate immunity - the two systems work together
•	Adaptive immunity acts to focus attention on a specific target, and also helps make innate immunity more effective

•	Our immune system provides us better protection than that of any other animal on earth
•	It has been shaped by millions of years of coevolution with the microbial world
•	And so far, it has withstood the test of time…

•	In our next lecture, however, we’ll see how AIDS has taken aim at the very heart of the human immune system, using its marvelous efficiency to forge a deadly weapon…