Monday, November 21, 2011

Adaptive by name, adaptive by nature - your immune system the tactical genius!

The previous post in this series can be found here.

In my last post I described how the adaptive branch of the immune system is the real player when it comes to fighting infection. In this post I hope to give you some idea of just how sophisticated a tactical machine this system is.

The battle plan

As any good general knows, not all enemies can be fought in the same way. History is littered with examples of mighty empires who were stopped in their tracks by relatively small opponents who simply fought in a way that they were not used to and couldn’t adapt to. The wars that are being fought inside you right now are no different, and require your battle strategies to be adaptive if they are to keep you alive.

Pathogens come in all shapes and sizes. They can be viruses that highjack your cells’ own replicating machinery to make more of themselves; intracellular bacteria that smuggle themselves into your cells and devour them from the inside; extracellular bacteria that float around in the blood or other fluids and generally make a nuisance of themselves; or they can even be multicellular parasites that can be big enough to see, such as tapeworms or the Plamodia that cause malaria. The fact that they all have different molecular components is not a problem since, as discussed in my last post, your B and T cells all have different antigen recognition receptors, and so you’ve most likely got one somewhere that can recognise whatever’s invading you. However, deploying those B and T cells in the most effective way possible is the tough task that awaits your immune system when a pathogen first invades you. A strategy must be devised and honed to the specific weakness of the enemy – but how is this achieved?

B cells – the artillery not the Field Marshall

B cells circulate in the blood and the lymphatic system and so are exposed to all of the potential antigens that lie therein. As a pathogen floats around the bloodstream it will expose its presence by leaving behind fragments of itself, these can then be recognised by any B cell that has a ‘complementary’ BCR at its surface.  B cells can also recognise antigens that are still attached to the pathogen, such as the coat proteins of viruses or cell wall components of bacteria. Once a B cell recognises a pathogen, it becomes partially activated. Full activation of B cells requires T cell help, as we will talk about later, but at this stage the B cell is taking matters into its own hands and acting immediately! The action that the B cell takes is to turn its BCR into a weapon. Since the BCR can recognise the pathogen, it can be very useful in flagging it up to the rest of the immune system as a foreign and potentially dangerous invader, however while it's still attached to the B cell it isn’t much use for that. So, upon activation, the B cell undergoes rearrangement of the genes that encode the BCR much in the same way that it did when it first developed its own unique receptor. These rearrangements mean that the BCR is no longer bound to the surface of the B cell but instead is launched in large numbers into surrounding blood or lymph with a the same antigen-recognition domain but a new additional section called the Fc region, which is constant to all secreted BCRs. This molecule is probably familiar to you as it is now called an antibody and is the laser-guided missile of the immune system!  

There are five main types of antibody: A, D, E, G and M. They each have different roles but generally speaking they work to either directly interfere with the action of the pathogen (what’s called a ‘neutralising’ antibody) or to flag up the pathogen to other parts of the immune system. Antibodies are recognised by immune cells via their Fc regions, which bind to Fc receptors on the surface of cells such as macrophages. When a macrophage has bound to an antibody, it will engulf it and deliver it to specific compartments within itself to destroy the antibody and anything that it is bound to i.e. the pathogen. Neutralising antibodies are also recognised like this, but have the added advantage of binding to the pathogen in such a way that means it can no longer be infections – a double victory!

At this point I here you crying “but James, that sounds fantastic, why would you say B cells are only the artillery?”. Well, that’s a good question! A problem with this is that B cells can be a little promiscuous in their targets, and if the reins of decision-making were handed to them then they might launch an all-out antibody strike against your own body (I guess they could be very aptly called ‘lose cannons’). This is what happens in some autoimmune disorders, including rheumatoid arthritis and lupus. To prevent this, B cells are only able to become partially activated on their own. What this entails is that they only secrete type M antibodies, which are very large and so don’t diffuse out of the blood easily, thereby limiting their impact if they’re autoreactive; and B cells activated without T cell help do not become ‘clonally expansive’, which is essentially a way of saying that they don’t divide loads, which fully active B cells do.

T cell decisions – the real deal

So, while B cells are vital footsoldiers in the fight against pathogen, they don’t really have much impact in the direction of the war in general. Instead, it is T cells that decide what is the best way to fight the invader. They are able to do this because they know more about what type of pathogen they’re facing than do B cells. This is because the TCRs on T cells don’t recognise antigen directly as it floats around the body. Instead, the TCR recognises antigen that has been presented by the MHC system(stands for Major Histocompatibility Complex, but the name’s not important!). MHC molecules are a bit like the TCR or BCR in that they bind to antigen and sit on the surface of cells. Unlike the BCR or TCR, however, they do not vary from cell to cell but do vary from person to person. Every one of us expresses several hundred different MHC proteins but this is a selection of the several thousand that exist in the entire human population.  Your MHC expression profile will determine what diseases you are more susceptible to or resistant against, and also what autoimmune disorders you are more or less predisposed to – diabetes, for example, has been linked to several variants of the HLA-DQB1 MHC molecule. It is also what is used in paternity tests, in case you were wondering, and is also very useful for tracking the movements of early human populations by looking at the MHCs of their ancestors.

MHCs come in two types: I and II. MHC class I molecules are expressed on all cells in your body with the exception of red blood cells. Their job is to bind to antigens of pathogens that have already infected that cell. If a T cell recognises antigen presented by a type I MHC molecule then the decision is made for it – kill the cell immediately! Any cell that has been infected must be destroyed as soon as possible to prevent the pathogen from spreading. The T cells that do this are, aptly, named ‘killer’ T cells and kill the cells by sending it orders to heroically commit suicide. Most cells will obey orders and duly sacrifice themselves for the good of the whole, but this is done very much with a gun to the head as if they do not follow instructions (mainly because the pathogen has been working to prevent it) then the killer T cell does it for them and unleashes all manner of cytotoxic (i.e. cell-killing) molecules at it, thereby killing the cell and whatever is inside.

Type II MHCs are not expressed on every cell, but instead are only found on ‘antigen-presentingcells’, including macrophages, dendritic cells, and B cells, whose job it is to scour the body in search of pathogen antigen. When they locate some, it is loaded onto MHC II molecules and the cell migrates to the lymph nodes, where T cells are waiting. The T cells that recognise MHC II-presented antigen are called ‘helper’ T cells and it is these cells that are the real strategists behind the battle.

Attack – cellular or humoral?

The first rule of war is ‘know thy enemy’ and that is exactly what helper T cells try to do. When they recognise antigen via the MHC II pathway, they use a complex combination of factors, including the type of cell that is presenting, the size of the antigen, the strength of the interaction between the TCR and the MCH-antigen complex, and others to chose what is appropriately named their ‘fate’. This fate will ultimately determine the direction of the war and, ultimately, the likelihood of victory.

Helper T cell fates generally are either TH1 or TH2, though there are others. If a cell decides to become TH1, it immediately starts to divide and secrete factors that encourage a ‘cellular’ response. A cellular response is used to target intracellular invaders, such as viruses or intracellular bacteria, and works by stimulating the activity of killer T cells and macrophages to start hunting down and destroying infected cells. Since artillery is useless against a sheltered enemy, the B cells are not deployed - concentrating fire on the infected cells and not wasting resources on ineffective antibodies ensures an efficient and effective response to intracellular invaders.

If, however, the enemy is extracellular, such as with a Staphylococcus or Streptococcus infection, then trying to hunt down infected cells would be a waste of precious time. Instead, your tactical helper T cells decide that the best plan of attack is ‘humoral’ – i.e. antibody-based. This is the TH2 response, and your helper T cells will start secreting B-cell activating factors to get the antibodies launching. Importantly, however, only those B cells with BCR (and hence antibody) to the pathogen must be activated in order to avoid autoimmunity. To ensure this, a B cell cannot be fully activated unless it proves its loyalty! This is done by the MHC II system, since when the BCR of a B cell binds to its antigen, both the BCR and the antigen are engulfed by the cell and degraded. Fragments of the antigen are then loaded onto MHC II molecules and presented at the surface. If a T cell then recognizes the antigen-MHC complex through its TCR then it knows the B cell must be capable of attacking foreign antigen and hence can be activated.

A T cell activating a complementary B cell - Nature Reviews Immunology 296-105 (February 2002) 

The factors secreted by the T cell onto the B cell not only activate it but also authorise it to start producing antibody that is not class M. Typically class G is the most commonly used, but some infections require a more tailored weapon. Parasitic infection, for example, can’t really be cleared using antibodies alone because the invaders are just too damn big! Instead the B cells are instructed to release their antibodies in the E form, which binds to cells called mast cells. When the E antibody on the mast cell binds to its antigen, it causes the mast cell to release huge amounts of powerful chemical signals that cause smooth muscle contraction, vasodilation and even intestinal tract changes to cause diarrhoea – since these responses are on a scale that can clear the parasite.  You’re probably very familiar with this response if you have allergies as this is what’s being misdirected against non-pathogenic antigens, such as pollen or animal fur.

Victory or defeat

The strategic decisions made by your immune system really are vital in fighting an effective campaign against your pathogenic invaders. Once the order has gone out to chose TH1 or TH2 then there is little way back – both fates strongly inhibit the other and so it really is all your eggs in one basket. You better hope that the correct decision has been made because if not it could spell disaster. Leprosy is caused by a class of intracellular bacteria called mycobacteria. As such, the best defence is a TH1 campaign of infected cell destruction. Leprosy patients who show a strong TH1 response have only a mild form, called tuberculoid leprosy, which is well-contained. Those patients whose immune strategists have chosen a TH2 route are not so lucky. Whilst their B cells are firing out round after round of ineffective antibodies, the mycobacteria are busy consuming and expanding – leading to a very nasty case of lepromatous leprosy and ultimately the loss of the war.

The never-ending war

So, assuming the correct decisions were made, the battle is won, your invaders have been destroyed and you are clear once again. Despite this, the war is not over – the exact same pathogens are still out there, waiting to reinfect. Luckily, some of your activated B and T cells have been singled out for a unique task – memory. These cells become extremely long-lived and float around in your body potentially for years, keeping with them the knowledge (in the form of their specific BCR or TCR) of what has come before and how to fight it if it ever comes back. Without this you would have to re-arm for every reinfection – a much slower and less efficient process – but instead these veterans of the first conflict live on to help you in future if ever required.

Next time

In my next post I will be looking at what happens when the battle doesn’t go exactly to plan: when the enemy is clever and comes up with ways to resist or hide from attack; or when your own troops turn on you and attack your own tissues during autoimmune disease.

The next post in this series can be found here.


  1. I love how you've turned this into a novelistic drama with characters, a game plan, and heroic self-sacrifice. Must admit that the T cells seem a bit bossy and controlling. They might be the real deal, but so far my sympathies are with the B cell footsoldiers running around in the trenches.

  2. Well the T cells are also out there doing the fighting. In many ways they're more exposed than the B cells since the B cells float around spitting out antibodies whereas the T cells have to get up close and personal with infected cells!

    T cells also have other important decisions that I haven't mentioned in this post - they have to decide which antigens should be passed as non-pathogenic, and to keep any self-targetting responses in check. Read my next post to find out more...

  3. Bio-blogging is an irresistible magnet for spammers named 'Flu'..

  4. For anyone reading this in the future, Michelle's comment above made sense before we deleted a spam comment from Flu. I deleted the comment entirely when I realised that even Flu's name was a link to his/her site. I feel kind of proud. Our first spammer.


    This post makes me wish the novel discussed here really did exist. Maybe one of us or our readers needs to write it?

    There is so much depth to each of the characters and their roles.

    So, I was thinking, all these great fantasy stories require an interloper, introduced into the great fantasy realm. This way they can be our eyes and ears. They can ask the questions we want to ask and they look upon the world with the amazement that we would too (in Narnia this is obvious, in the The Lord of the Rings the Hobbits play the role, Harry Potter plays the role himself at the start of his story (by the end of HP such a character isn't necessary as we know the wizardry world well enough by then - there are no muggle readers left)).

    I was thinking, that in the allegorical story of the human immune system, this role could be played by some medicine. It would be great. The medicine would arrive, completely oblivious to its role, but possessing of special powers, none of the rest of the kingdom has. slowly it would learn that precisely these powers were somehow necessary to defeat the enemy trying to destroy the kingdom. The medicine wouldn't have much time to realise its power and unleash its hidden potential before the enemy won. Conflict, drama, excitement follows.

    The characters would be able to engage in moments of profound reflection... "Why did the medicine arrive, with precisely the right skills, at precisely the right time, to help us defeat our enemies? Who sent it? Where did it come from? Is there more to existence than just the war against the hordes?"

    Slowly as the story progresses, the characters would begin to wonder whether they were a part of something bigger than themselves. As would the reader about themselves (Sophie's World, style).

  5. The medicine would have all the classical aspects of a messiah/saviour in one of these stories.

    This isn't just going to be a novel, it's going to be an epic franchise. I can't wait until the movie comes out!

  6. I think a vaccine would be a good candidate for our courageous narrator. So many modern vaccines have to manipulate many branches of the immune system, including directing T cell fate - our narrator would have to work with the army he's been sent to warn in order to train the troops up for battle. Also, most vaccines are now done in combination, so there would be a series of characters, each bringing their own unique expertise that would prepare the body for the oncoming war.

    1. I don't know whether I ever wrote this down anywhere, but I'm pretty sure I said it to you in person if I didn't. Nevertheless, having the vaccine as the protagonist would add awesome moral dimensions to the story because the vaccine would resemble the enemy. There could be a whole initial rejection, eventual acceptance story relating to the vaccine.

      The only hope the story's civilisation has is the mysterious outsider who they've shunned for years because of how much he resembled the bad guys.

      This story really does write itself.

  7. James, don't feel any pressure or anything, but we're relying on your narrative skills to take this blog into the stratosphere. It's obvious that you're going to be the one attracting all the spammers, perhaps one day even a hacker.