Monday, January 2, 2012

Treason in the immune army - betrayed by your own

The previous post in this series can be found here.

So far in my series of posts, I’ve tried to give you an insight into how your immune system is organised into divisions with specific roles: B cells  produce antibodies against pathogens; killer T cells demolish infected cells; and helper T cells act as the battle strategists, determining the tactics that will be used to destroy the invaders. Alongside these high-ranking immune cells are innumerable other footsoldiers that take their orders from T cells and sometimes from the antibodies released by B cells: neutrophils, eosinophils, basophils etc.

In any army there is the odd defector, a rogue agent who changes sides or simply goes it alone, and your immune system is no different. The lowly footsoldiers mentioned above are not capable to acting without orders from higher up and so when a turncoat T or B cell starts to send out treacherous commands that you might be in trouble.  In this post, I’m going to explain the different forms of autoimmunity (when the immune system attacks the body) and allergy (when it attacks innocuous molecules). I will also explain how our understanding of the immune system is starting to allow us to treat these disorders and save or improve countless lives.

Autoimmunity and allergy – T and B cells gone bad

Autoimmune diseases affect roughly one in twenty people in the western world; allergies, far more. Their symptoms are hugely variable and range from mild rashes to fatal anaemia. All are caused by misdirection of the adaptive immune system and are driven by conspiratorial T or B cells. Luckily for you and me, immunologists have been working furiously for the last century or so to unravel the causes behind these disorders and are now starting to produce fairly effective and specific cures. As you might expect, the effect of an autoimmune response depends very heavily upon what is rebelling: antibodies fired out by a B cell, for example, will have a very different outcome to a psychotic killer T cell.

Killer T cells on the rampage – Type IV hypersensitivity

We start, naturally, at type IV. Hypersensitivity (the umbrella term for autoimmunity and allergy) is generally classed into five groups depending on the underlying cause. I’m starting here with type IV because it is the only class that generally only requires one type of cell to go rogue for it to occur: killer T cells.

As you may remember from my last post killer T cells patrol the body in search of cells that are presenting pathogenic antigens on their MHC class I molecules. MHC I only presents intracellular antigens and so any cell presenting pathogenic components with it has, unfortunately, been infected and put to work by the invaders. The killer T cell does its job and destroys the cell to prevent its precious resources from falling into the hands of the enemy.

T cells can produce T cell receptors (TCR – see my first post for more on this) specific to pretty much any conceivable organic molecule that can bind to MHC molecules. So, a hell of a lot produce TCRs that can recognise molecules found in your own body. These T cells have to be weeded out and killed during T cell boot camp in the thymus before they are deployed to the field. This is achieved by showing the young (or, appropriately, ‘naïve’ as immunologists call them) T cells a huge range of molecules found all over the body and if they bind any of them then I’m afraid it’s good night T cell. The thymus is unique in this respect as most tissues only express molecules that they need to function, whereas specific thymic cells called medullary epithelial cells have a special protein called AIRE (stands for ‘autoimmune regulator gene’) that allows them to express molecules from all over the body. People unfortunate enough to be born with a defective AIRE protein develop a condition with the rather impressive full name autoimmune polyendocrinopathy candidiasis ecotdermal dystrophy, but luckily we can just call it APECED. The T cells of APECED sufferers graduate from the thymus boot camp without having had their loyalty checked, and so swarm around the body being very trigger-happy about what they destroy. As a result the poor human in whom this is happening develops a multiorgan autoimmune disorder that is almost always fatal.

AIRE acting on a medullary epithelial cell in the thymus (Nat. Rev. Immunol. Mathis & Benoist 2007)

However, even in people with normal AIRE activity, some rogue T cells still sneak through the net and manage to reach full development without being properly screened. This usually happens when the TCR of the T cell in question is only weakly specific to an autoantigen (i.e. an antigen from your own body) and so the levels of that molecule found in the thymus are not high enough to trigger cell death. Once they are let loose into the body, however, they may come across a tissue with very high levels of the molecule in question and start cranking up their cell-destroying weaponry. Unlike in APECED, this is usually limited to just one or a small number of tissues but can be nonetheless devastating. Many of the most common and most debilitating autoimmune disorders are caused by killer T cells that have snuck through unchecked and wreaked havoc. Type I diabetes results when they target the pancreatic cells required to make insulin; rheumatoid arthritis is the outcome of killer T cells turning against a molecule found in the synovial joint space; and individuals whose killer T cells decide to attack the myelin sheath of neurons develop multiple sclerosis. These disorders are, in short, dreadful.

Less dreadful but still debilitating, are a group of allergies collectively known as contact dermatitis. This is the rash and inflammation that you get if you are allergic to touching something, usually a metal like nickel or gold, but also substances such as latex or external antibiotics like neomycin. In these conditions the allergen in question enters the skin and binds to a specific protein found therein, whereby it changes its structure in some way. The new structure of the protein is now recognisable by T cells that were, until now, happily unaware that the protein even existed. They launch an all-out attack on the ‘infected’ area until the allergen is gone, and you have an uncomfortable couple of days or weeks until it is cleared.

B cell autoimmunity – conspiracy, deception, and destruction

B cells, as you no doubt remember, are responsible for firing out the antibody artillery of the immune system. They do this only after authorisation from T cells because, even though B cells undergo a similar process of screening out the self-targeting traitors, they can also change their antibody specificity after they have left their bootcamp: the bone marrow. The antibodies that they launch bind to infected cells and free pathogens and flag them up for destruction by cells such as natural killer cells. B cell hypersensitivities are known as types I-III.

When B cells turn against the body they must do so with the help of helper T cells, for without stimulation from these cells they do not have clearance to fire. So, in any case of B cell autoimmunity there must also be a similarly conspiratorial T cell willing to help. In reality it is in fact more likely that the T cell has recruited the B cell to its cause because T cells are far more strictly screened and regulated that any helper T cell with turncoat ambitions is likely to find a B cell able to assist. However sometimes the T cell may be entirely innocent and simple deception may be afoot. This can happen if the B and T cell recognise different portions of a pathogenic antigen. The T cell recognises an area that is wholly pathogenic and non-human, it has no intention of harming the body and only wants to do its bit for the war effort! The B cell, however, recognises a different portion of the same antigen that is very similar to something human. The well-meaning T cell will then activate the B cell in the hope that it will target the pathogen, but it will in fact turn its weapons on the body’s own tissues and so cause untold collateral damage.

Exactly what damage is caused depends very specifically on what’s being targeted. If the target is a molecule found on the surface of a cell then this is known as type II hypersensitivity. In such cases the cell under fire faces a truly terrifying prospect (for a cell, at least): it will be chemically hacked up by natural killer cells; engulfed by phagocytes; and even attacked by the old-school innate immune system and its deadliest weapon - the membrane attack complex. It will, in brief, be toast. What this means for the human in which this coup d’état is occurring depends entirely on the severity of the attack and the tissues that are being targeting.  In autoimmune haemolytic anaemia, for example, the antigens targeted are found at the surface of red blood cells and so sufferers become severely anaemic. Most sufferers from of this disease are affected all the time, but interestingly a small number are only affected when exposed to cold temperatures, as the antibody is more efficient below 37°C.  Many other tissues can also be affected, including the skin, lungs, and  kidneys.  

Aside from the actual attack raging against the cells from duped footsoldiers, the antibody weapons themselves can do severe damage to cell function. This is sometimes referred to as type V disease and usually happens when the antibodies target some key receptor at the cell surface thereby hindering its normal activity. In myasthenia gravis, for example, the autoantibodies latch onto receptors in neurons for the neurotransmitter acetylcholine and block their activity. This impairs signal transmission over the synapses between neurons and so leads to partial paralysis and severe muscle weakness. Conversely, in Graves’ disease the antibodies stimulate the receptor to thyroid-stimulating hormone, meaning the patient has an overdeveloped thyroid and suffers from a number of symptoms including weight loss, tremors, nausea and even feminisation of male patients.

Not all autoantibodies target cell-bound antigens, however. Those that cause type III autoimmunity bind to antigens in the blood or the fluid between cells. As the antibodies bind to the free antigen they cluster together to form what’s known as an immune complex. This is like immune system napalm, burning everything in the area through the activation of the inflammatory activity of the innate immune system. If this happens in a localised region it can be devastating to the tissues nearby; some types of reactive arthritis are caused by this. Alternatively, the napalm can be spread throughout the whole circulatory system and so cause extensive damage everywhere. This is what happens in lupus, although, as Dr House has taught us, it’s never lupus.

 Allergy – misguided but not evil B cells

Not all immune cells that cause damage to the body are betraying their case. In fact, the hypersensitivity with which most people are familiar is simple allergy. This is also caused by B cells launching incorrect antibody strikes, but in this case the target it not the body but some innocuous molecule such as a specific type of pollen or one the Ara h proteins found in peanuts. The weapon of choice in this situation is the type E antibody that was mentioned in my previous post.

Type E antibody (known as IgE) is used when the battleground is the tissue near the exposed parts of your body, such as your eyes, nose, gut etc. This is because it is generally used to attack the parasites that infiltrate these areas. IgE is supplied by B cells for the armament of specialised cells known as granulocytes , including mast cells and basophils. The granulocyte troops bind to the IgE and use it to locate pathogens and release all sorts of pro-inflammatory weapons and chemical signals to recruit back-up.

If the IgE is misdirected, however, then the battlefield can stretch over huge, exposed areas of the body and rage with a fury that would not normally be achieved. If you are lucky (as most people thankfully are) this only manifests as inflammation around your eyes, nasal tissues and perhaps parts of the skin – leading to uncomfortable but not dangerous runny noses, sneezing and rashes. In some individuals, however, the response can be far more serious; granulocytes under orders from misguided B cells fire out round after round of inflammatory weapons in areas such as the gut, respiratory tract and blood. This can lead to severe abdominal pain, blockage of the airways, or even heart spasms leading to heart attack or cardiac arrest. This condition is often fatal if untreated and is probably known to you: it is called anaphylaxis – an appropriate name when you think about it in the sense of a misguided immune system as it means the opposite of protection (φύλαξις, phylaxis) in Greek.

The immunologists strike back – crushing the rebel scum

Fortunately, our understanding of the organisation of the immune army and the tactics that it uses are allowing us to come up with new treatments to help relieve or remove the effects of the turncoat immune cells.  In cases when we know that T cells are to blame, it may be possible to block the activation of the specific cells involved by activating T cell-specific inhibitory molecules or inhibiting molecules that they need to launch their attack. This has already shown some promise in the treatment of mouse lupus by blocking the stimulatory molecule CD28 using a modified version of its natural partner CTLA-4. We can also use the weapons of the immune system to our own ends by targeting specific molecules using antibodies. An antibody against the inflammatory molecule TNF-a is routinely used in the treatment of rheumatoid arthritis and Chron’s disease, and omalizumab has shown some promise in blocking IgE in allergic reactions.

Better yet, however, is to rehabilitate the rogue cells so that they come back to the side of good or at least take their own lives out of shame! Our best hope for this is to recruit the help of a unique type of T cell known as the regulatory T cell (Treg). Tregs are the military police of the immune system. They patrol around the body searching for T or B cells that recognise antigens the Treg knows are non-pathogenic. When they find them they suppress their activity in a number of ways and or induce them to sacrifice themselves through cell suicide. 

Some of the ways in which regulatory T cells may regulate other T cells (Nat. Rev. Immnol Vignali et al. 2008)

A lot of research has focussed on getting Tregs to target specific antigens and so inhibit whichever cells are responsible for disease. This can be done by introducing the antigen at low levels in the presence of retinoic acid, which is a potent stimulatory of Tregs. Alternatively, it may one day be possible to extract Tregs from a patient and retrain them in the lab to recognise the antigen of interest. These cells, replanted into the body, would then unleash a new wave of law enforcement over the rebellious cells. It’s shown promise in mice so who knows how far we could take it! Unlike pathogenic disease, it is certainly conceivable that most autoimmune and allergic disorders may have been wiped out by the time that my future grandchildren are adults; a fantastic example of how frontline research at the laboratory level can translate into incredible improvements in human lives.

Next time

In my next post I will explain what weapons are available to the enemy and are used to counter our defences or evade detection. I’ll say why I think a vaccine to HIV is likely not soon forthcoming, and why there’s unlikely to be a cure for the common cold! 

The next post in this series can be found here.

(Image at top is the 1893 Battle of Williamsburg by Kurz and Allison, it took place during the American Civil War)


  1. Wow. Reading about what happens in these cells inside our bodies is as interesting as reading about a universe which is growing faster and faster...


    1. I will read all the other pages ..

    2. That's a wonderful idea, Anonymous. Have fun!

  2. Still clearing my backlog of posts at this blog I sheepishly hadn't read yet. I agree with John, fascinating stuff.

    Every time I read one of your immunology posts, James, I think about the allegorical novel. I really am starting to think it is a bad idea to discuss it here, because people will one day steal it and all our glory will be lost, but, anyway... If one of the civilisations was an allegorical person who suffered from Paroxysmal cold hemoglobinuria, then every "Winter" it would start to function badly as a society, specifically because whatever the allegorical equivalent of red blood cells are keep getting attacked.

    "...a fantastic example of how frontline research at the laboratory level can translate into incredible improvements in human lives."

    Show off.