Monday, October 10, 2011

Why you’re not dead - surviving in a world of enemies

I hate to break it to you, but I’m afraid you have a potentially life-threatening disease; in fact you have quite a few. Aren’t you fortunate that you have the most sophisticated protection system ever devised fighting to keep you healthy? If I took away your immune system right now you most likely would not live to read my next post. What would kill you would be the everyday bacteria, viruses and fungi that are, quite literally, on everything you touch, eat, drink or breathe, and are trying to use up the precious resource that is your body as your read this now. Luckily for you, I’m not going to take your defences away, but I will try and give you a deeper understanding and appreciation of this incredible system and what we know about how it works.

The innate immune system - stone-age defences

Broadly speaking, the mammalian immune system is split into two branches: innate and adaptive. The innate immune system is what’s left over from earlier stages in our evolution and is basically a way of making ourselves a tough place for pathogens to survive. This is done in a number of ways of varying sophistication. One simple mechanism is inflammation at an area of infection. In inflammation, innate immune cells (a branch of white blood cells known as non-lymphocytic leukocytes) such as macrophages or dendritic cells detect fragments of pathogens that are common for many species, things like components of the bacterial cell wall  or particles of viral DNA. This detection is achieved by receptors present at the surface and in the interior of these cells that have developed alongside pathogens throughout our evolutionary history and so are well-tuned to detect them. The activation of these receptors by pathogenic components causes the cells to release a whole host of pro-inflammatory molecules - one well-known example is histamine, which causes vasodilation and hence inflammation, and is why you will have probably taken anti-histamines if you suffer from allergies.

Other aspects of the innate immune system are somewhat more sophisticated as they either actively destroy pathogens or ‘opsonise’ them, which is a way of flagging them up to the rest of the immune system. The complement system is a good example of both of these as it is a collection of proteins that float around in the blood and bind to specific common pathogenic components on invading bugs. These can then either directly damage the pathogen, as in the case of the well-named ‘membrane attack complex’ or act as signals to other immune cells to destroy the pathogen, such as with the ‘classical’ complement pathway.

The adaptive immune system - the sharpshooter of immunity

That’s all very impressive but a little, let’s say, unevolved for us. Don’t get me wrong, the innate immune system is important and without it you would be in some discomfort from warts, parasites and the like, but you’d most likely still be alive. It’s also very important in the early stages of your life, as in early infancy the other ‘adaptive’ branch of the immune system is still developing. However, when it really comes to sophisticated defence against disease, the adaptive immune system is where the real effects are seen.

The adaptive immune system is, as you might expect, adaptive. While the innate system relies on bits of pathogens that are common to many species, the adaptive immune system is able to pick details on individual pathogens and launch attacks specifically against that bug. This has the advantage of allowing a finely-tuned response to infection that is not only more effective at clearing the pathogen, but also does so without the collateral damage that comes hand in hand with mechanisms such as inflammation. This system is reserved only for higher organisms as it originally began to arise in jawed vertebrates about 450 million years ago, and the mammalian system that we enjoy is pretty much as good as it gets! The fact that we’re not all dead or dying is primarily down to the adaptive immune system, and those unfortunate enough to be born without it usually don’t live to see their first birthday despite modern medical intervention.

So how does this amazing system work? Well, what makes the adaptive immune system adaptive is a group of receptors that are expressed on the surface of the adaptive immune cells (called ‘lymphocytes'). Lymphocytes are, broadly speaking, either T or B cells - in future posts I will go into more detail about how these two cell types cooperate to generate an immune response, but for now just knowing their names is enough. Every B cell in your body expresses a different B cell receptor (BCR) at its surface, and every T cell, surprise, surprise, has its own T cell receptor (TCR). Each BCR or TCR has a different structure and so is able to recognise a different set of components, which are generally referred to as ‘antigens’, and can be anything from proteins to DNA to carbohydrates. These antigens may be from pathogens, they may be from your own body, or they may not exist anywhere in nature because TCRs and BCR are not designed with anything specific in mind, they are generated at random in the hope that they will recognise something useful on the surface of a pathogen.

This process of TCR and BCR design occurs early on in the life of a T or B cell, when it is developing in either the thymus or bone marrow (hence T and B). The genes responsible for encoding the TCR or BCR are chopped up and stuck back together at random (a process known as VDJ recombination) while little random inserts are sometimes stuck in for fun. If, as is the case for most combinations, the way that the genes have been stuck together does not make a functional protein, then the process is repeated until it does. Once the cell has a TCR or BCR that is able to get to the cell surface in tact, the cell undergoes a series of selection mechanisms that cause any cell whose receptor recognises antigens from your own body (so-called ‘self’ antigens) to kill itself, which is about 99% of them! The 1% or so that get through are sent to adaptive immune centres, such as lymph nodes, where they will wait for an opportunity to protect you against infection.

Next time

In my next featured post I will be talking about how T and B cells work once their TCR or BCR recognises antigen from a pathogen, and how the whole system is interconnected and interwoven to give an effective, rapid and long-lasting response. Later in this series of posts I will present some of the important questions that we have about how this system works and what is being done to answer these questions.

The next post in this series is found here.

(Photo is a scanning electron microscope image of two macrophages - rights belong to Steve Gschmeissner and the Science Photo Library)


  1. Dumb questions:

    1) Why is inflammation good for me if I'm fighting a pathogen? Does it somehow inhibit my pathogen's progress to greater glory?
    2) If I take antihistamines am I in some way helping some pathogens achieve this glory? Or does this not really matter because my adaptive immune system is just too awesome?
    3) Why was the jaw correlated with the development of an adaptive immune system? That seems kind of random. Or is this just a coincidence?
    4) What happens when one of the evil TCR or BCR's that wants to destroy my self antigens misses the selection cut? Does it start to attack stuff inside me?

    Someone should write an allegorical novel, personifying the immune system. It's quite moving that every fort (the good guys) will eventually be over-run by the bad guys, but not before most of them setting up new forts. And I presume different forts exchange weapons during the battle (through kissing and stuff).

    I would buy and read it.

  2. The tragedy for the bad guys will be that as soon as they win, they lose because they need the good guys to exist to have something to, well, "feed off".

    And there will be the treacherous "bad guys" who help the forts digest their food and stuff.

  3. In answer to your questions:

    1. Inflammation is good because it recruits a wide array of immune effector cells and molecules to the infected area. Fluid from the blood, for example, brings circulating molecules such as antibodies or complement into the inflamed area. Moreover, cells in inflamed areas often secrete proteins called chemokines or cytokines in response to pro-inflammatory signalling. Chemokines and cytokines act as a marker to things like B cells, T cells, macrophages etc, and these cells will follow the chemical trail until they're at the source.

    2. Yes and No. Antihistamines are usually taken to combat an IgE response. IgE is a type of antibody released by B cells, usually in mucosal membranes such as the eyes or nostrils. When IgE binds to a target pathogen it is then recognised by mast cells, which in turn release a huge amount of stored histamine and other effector molecules. Generally this is believed to be a response to parasitic infection and it's well known that mast cells and other similar cells (such as basophils) are important in clearing parasitic worms. During common allergy, IgE is produced against innocuous molecules such as components of pollen or animal hair, and so you get a lot of inflammation in exposed tissues like the eyes, lungs, nose etc. That's why antihistamines are effective as they block the histamine receptors on recipient cells. Generally, histamine is not that vital for responses to bacterial or viral pathogens, and since parasitic infections have been controlled by advances in living conditions and food preparation, there is really no downside to taking antihistamines.

    Interestingly, there's quite good evidence that it is our modern-day lack of parasitic infection that has lead to the massive increase in common allergies. It's thought that responses to parasites also serve to initiate the process of 'tolerance' towards common non-pathogenic antigens by upregulating the activity of inhibitory aspects of the immune system, such as regulatory T cells. Some people have even given themselves hookworms and other parasites to try and relieve the symptoms of allergy (one example here: and have had moderate success.

  4. 3. The development of the jaw and the adaptive immune system don't really have anything to do with each other, it just happened in an early jawed vertebrate and so all of its descendants have and adaptive system as well.

    4. Yes - that's exactly what autoimmunity is. The mechanisms by which TCRs and BCRs are screened are extremely thorough during cell development and then continue during the adult life of the cell through so-called 'non-central' mechanisms such as inducing 'anergy' (a kind of limbo-like non-active state) in T and B cells that show some self-reactivity. Despite this some do slip through the net and the effects are extremely varied depending on the target. Type I diabetes, for example, is often caused by a T cell response against markers on the surface of the pancreatic beta cells that make insulin; whereas rheumatoid arthritis is due to aberrant antibody release by B cells targeting synovial membranes in the joints. Some unfortunate people have genetic defects in the primary mechanisms of tolerance and so develop a wide variety of debilitating autoimmune disorders (the condition is catchily known as autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy).

    It's not all bad, though. We might be able to use autoimmunity to help clear us of certain conditions. The primary target with this is cancer, since it is a disease of the self the immune system doesn't target it (although there's some controversy on that, I won't go into it here!). If we can induce immune responses against cancerous cells then the immune system would do all the hard work for us! This is a very tough and ambitious goal, but there are a hell of a lot of people working on many ways to try and achieve it and progress is being made. Tumours have been cleared in mice by sensitisation of T cells against cancer antigens and one day this may be possible in humans too. Even now we use the immune system to help treat cancer, as anyone who has ever been given Herceptin will know. Herceptin (which is actually a trade name, it's officially known as trastuzumab) is an antibody against HER2, a receptor often over-expressed on breast cancer cells. Binding of trastuzumab to HER2 has a number of effects, including recruitment of immune cells to destroy the cancerous tissue via 'antibody-dependent cellular cytotoxicity'.

    Finally, I would definitely read that book! There's also a whole level of intercommunication that I haven't mentioned yet (such as T cell activation of B cells) and decisions made by the system (such as Th1 vs Th2 response to pathogen - details to follow in later posts) that would make the narrative quite anthropomorphic!

  5. This really would make for a good book. From your responses to my questions it seems accurate to guess that the innate immune system, although much older than the adaptive now interacts quite extensively with the adaptive. It seems like things like inflammation now do good mostly because they help the adaptive system do its job rather than having an innate goodness to them.

    Which would all make a good story... the soldiers devoted to the "old ways" have realised they are no good on their won anymore and so devote themselves to helping the followers of the "new way".

    And then autoimmune problems would in fiction-land turn into traitors of the forts, turning against the fort and using their defenses against them.

    This thing practically writes itself.

    The really exciting part of the novel would be when the individual soldiers started to realise that the fort wasn't just a building, but seemed to have its own self-awareness sometimes aiding (taking good medicine), sometimes harming (getting maggot, eww!) the fight.

  6. Bit late for this discussion, but just wanted to add that the stuff that James wrote about using the immune system against cancer - that's kind of what my DPhil is about, tis very interesting (well more interesting than James' DPhil anyway!)

    Also with the book idea - I think it was brought to life quite nicely in that Doctor Who episode with the miniature people inside the big robot body, although I do wish they expanded on it a bit more, but it would have probably deviated from the storyline too much!

    And James - I hope this sounds like me now and not some random American person ... :)

  7. Very true; the Dr Who episode had robotic 'antibodies' floating around inside the giant human that killed anything that didn't have 'privilege' (read up about immune privilege here:

    Yes, Ling's DPhil work is very interesting - perhaps she'd be kind enough to write us a guest post one day (nudge, nudge).

    You're right, Shaun, the innate and adaptive systems do interact quite extensively, I've oversimplified it a little in the main post. As far as the book goes, you would have your brave dendritic cells patrolling the body as sentinels before reporting their findings to the lymph node HQs as their last dying act, much like Pheidippides at the battle of Marathon! The responding B cells would be the nervous foot soldiers who are always questioning their own abilities and so undergoing somatic hypermutation to improve themselves, whereas the T cells would be the confident officers who give the B cells a slap around the face and send them out while at the same time making all of the key decisions. Natural Killer cells would be the shadowy secret service-like characters that try to weed out turncoats by scrutinising their loyalty to the MHCI complexes. Then, of course, you'd have the old memory B and T cells that have seen it all before but who have perhaps seen too much and have a strange far-away glint in their eye.

    I'd buy it.

  8. The Dr who episode sounds interesting but I was thinking of it slightly differently. I was thinking more of the Narnia of the Biochemistry world.

    That is, the story would live and die on its own. It would never be acknowledged that the whole thing was an allegory of Biochemistry, even though everyone reading it would secretly know.

    Ling's DPhil sounds like a perfect story as well. It would have a really moving moral element to it. The eventual hero of the story, the one that conquers the evil lord cancer will have spent much of the story almost as much maligned as lord cancer himself. Trained as one of the greatest soldiers to fight the foreign hoards, Mr T becomes disillusioned when 99% of his peers are brutally murdered by their own civilisation. As a result he turns against the very society that gave him life and trained him. From this moment he becomes a hunted man, fighting in the corners of society, always only half a step ahead of those hunting him, not sure what side he is on.

    In the background, an evil much worse than the attacking hoards or Mr T starts to take root in society. Seeming benign at first it is ignored by the system. Until, far too late, the system realises that Lord C is now too powerful to stop. Society seems doomed to fail.

    In a pivotal moment, Mr T must reunite with the society that has been hunting him to defeat Lord C... blah, blah, etc.

    If you write a guest post Ling, it has to be in allegory.

  9. Also, the evil Lord C would have a touching backstory about how he used to be a happy, normal citizen but, over time, became the confused about his role in society and violently introverted. I like to think that he'd have a death throe change of heart, much like Darth Vader in Return of the Jedi.

  10. Incredible. How do biochemists ever get any work done?

  11. I know, it's a tough job anthropomorphising immune cells and cancer, but someone's got to do it.

    A correction to your earlier comment Shaun - I work with Miss B cells, not Mr T. And they're not just nervous foot soldiers, they're the battleships of this fictional army, firing missiles (antibodies) specifically targeting their enemies without any direct contact.

    Or something else, I don't know, I'm running out of army/sci-fi analogies.

  12. Antibodies aren't like missiles, their more like anti-vandal paint...

    T cells are where it's at!

  13. * they're (I apologise for the appalling error)

  14. Awesome... I see a Romeo and Juliet style romance developing in allegory land between Miss B and Mr T.

    While the B's and the T's are technically on the same side, clearly they have a strong rivalry regarding who's role is most importance in the war against the hoard.

    Maybe it is Mr T who finally convinces Miss B to turn away from her rebel role and take up the fight against Lord C?

    I fear no potential employer will ever take us seriously again once they've read this thread.

    Oh and for those readers not in the know, in the real world James and Ling are practically engaged.

  15. ...and the children don't forget the misguided confused overly stimulated but unpolarised Miss Th1, Master Th2, Little Th16 and and and THE regulators!

  16. Links to wikipedia or description!

    I want to know more of the story. Who are these people you speak of? What are their hopes, their dreams? What conflicts do they face in life?

    No really, what are these things?

  17. Don't worry, Shaun, T cell polarisation will be covered in later posts!

    Abs, I see Tregs as the shadowy propaganda agents who brainwash rebellious T cells and make them love the party, much like the Ministry of Love in 1984.

  18. Love this post and following comments :-) Cant wait to read the book! Having close connections to the autoimmune issues (thyroid, rheumatoid) I would be interested in more comment on what is happening here