The Sixth Sense

How many senses do we have? Smell is probably our oldest sense, evolved from back when our ocean bound progenitors developed the capacity to detect chemicals in the water. Then we have sight, hearing, touch and taste. We also have our subtle senses such as nociception - the ability to detect damage - and proprioception, the awareness of the position of our joints, which in turn feeds into our sense of balance. These senses tend to operate beneath conscious awareness and we only really appreciate them when something goes array - when we hurt ourselves or fall over for instance. This is all well and good. After all, we only have so much attention to give to what we're doing day-in day-out. We need to look where we're going rather than paying attention to the position of my ankle. And our bodies seem pretty good at taking care of things by themselves. Indeed, one of the pleasures of learning a new skill - say, ice skating, or driving - is that point at which what was difficult and required a lot of conscious effort magically becomes somehow natural and fluid; unconscious.

Yet, it is not quite as straightforward as just receiving messages from our senses and then acting on them. The classic view of our senses is that we receive the world and then act on it, and then receive some more information on what happened, and then act on it and so on, in an endless cascade of action-reaction. However we are now beginning to appreciate how much we actually predict what we experience. The brain has been called a prediction engine and, odd is at may seem, much of our 'reality' is constructed; that is on a second-by-second basis much of what we see and hear (and most definitely what we think) is a prediction. The main reason for this is probably because it's an efficient way of doing things. Our bodies love efficiency. Predicting our way through our day takes a lot of the heavy lifting out of awareness. Paying attention to everything we see, do, feel and hear in any moment takes a lot of effort (when we try it, it's surprising how quickly we slip back into 'autopilot'). The upshot of all this is that, just as much as our senses 'feed back' to our minds, our mind also 'feeds forwards' to our senses. This becomes especially important when we consider such things as pain and discomfort or fatigue. It is now accepted that these experiences are very much a two-way street. Our state of mind, our mood, can influence our senses, including pain, a great deal. Of course this is not to discount the experience of pain. If I have a headache I don't try and think it away. I take a paracetamol. But a lot can be gained from 'reframing' discomfort as not so much something that is happening to me, as something I am participating in, as I am in effect 'doing'. 

For now, going back to the question of how many senses we have: Arguably we have dozens. I've talked about these subtle senses more elsewhere. However for the sake of simplicity I'm going to lump them together into what we could say is our sixth sense, our immune system (Zen Buddhism regards the mind as a sixth sense, that is our self awareness, though to me I see the mind more as a kind of 'super sense'). At first glance this is not a particularly exciting or even logical idea. Isn't our immune systems just a collection of odd cells, a kind of internal army which fights off colds? And how can it be a 'sense'? I don't really know my immune system and I can't exactly bring my attention to it, except for when it's making me feel rotten with the flu.

 

Yet the deeper we go into it the more we see just how extensive the immune system is, how it essentially effects every part of our body and influences our mood, feeding us 'subconscious' instructions, affecting our behavior and ultimately making the difference between good health and bad, well-being and disease. Shortly we'll go into the 'parts' of the immune system - the innate and the adaptive, the different cells - and mention a little about how it connects to our brain, our mind and behavior. However it's worth starting with the 'universal' way the immune system works, the thing that makes it work, and the main way we 'sense' it. It's highly effective. It's also bloody painful.

 

This is the process - or cascade - of inflammation. Inflammation is very 'in' at the moment. A perusal of any bookstore in California will yield a dozen titles like the 'Inflamed Brain' or the 'Your Gut on Inflammation' and so on. It is enough to carry the whiff of faddism about it, yet the more one looks into it, the more convincing is the argument that inflammation is behind a whole array of dis-ease. Primarily inflammation is the main way we try to combat any particular pathology, it's one of our most ancient defenses, and it is universal - that is, it is the body's 'common mechanism' despite whatever separate organ, tissue or system is affected. Not only that, but is is also our body's way of telling our brain that something is up, and to this end it affects everything from our appetite to our mood, and even how social we feel. It is a finely tuned system, equipped with feedback loops and a repertoire of chemical messengers to kick start it into action, then wind it down when the job is done. However continually overstimulating this intricate system will lead to systemic inflammation, leading ultimately to chronic disease and more subtle dis-ease.

 

Inflammation is an essential component of our immune system. Simply put it creates the 'conditions' which allow the immune system to work. As any general is aware, if the conditions of a particular area are not right - bad roads, poor weather, hostile locals, impenetrable terrain - then any military campaign is doomed from the start. Likewise the immune system needs the right conditions to fight off invading pathogens and repair damage. To this end inflammation prepares the ground, leading to the notorious 'five cardinal signs of inflammation': rubor, tumor, calor, dolor and functio laesa; respectively redness, swelling and warmth (increased blood flow to the affected area to let the immune cells in) plus pain and loss of function to 'guard' the affected area. Not all inflammation manifests so obviously however and we may not even be aware of these signs even though, as with a flu for instance, they make us feel rotten. Indeed, during the night our body goes into a pro-inflammatory state to promote healing and, especially if one has been doing a lot of physical work, waking up in the middle of this can be astonishingly uncomfortable!

 

To better understand inflammation it is therefore necessary to get an idea of how the immune system works as a whole. I often visualize the immune system as an integrated military-intelligence-defense system, which isn't entirely fanciful as it's basic aim is to protect the body from invading pathogens (and, like an engineering corps, to repair damage), or to put it in the driest possible terms, to remove 'non-self cellular matter'. To this end it has two major branches: the innate and the adaptive systems.

 

Innate Immunity

 

The innate immune system is the first line of defense. It includes the 'barriers' of the skin, mucosal surfaces and the gut as well as such tricks as turning up the heat - i.e. fever - to kill off invading microorganisms. I often explain to concerned parents that the reason their child is spiking such alarming temperatures is because it is the main way they have - as their other system is still growing - to fight off infection (a ruse I'll admit is usually met with polite smiles more than genuine reassurance).  The innate immune system has whole legions of variously deadly cells to assist in its work. These cells are trained in the thymus gland which sits behind the sternum, and also to a large extent in the gut, and in these training grounds they learn the essential art of distinguishing friend from enemy, self cells (don't attack) to foreign proteins (attack). Ideally those immune cells which attack 'self' are basically told to self-destruct, though not all do, and this is thought to be one of the processes by which auto-immune disease can start.

 

Having been thus trained they specialize into their various work - from the quick and dirty complement factors which basically punch holes in invading organisms to the more sophisticated natural killer (NK) cells which lyse (i.e. destroy) virus-infected cells and then recruit other immune cells to the fight. The way they recruit and signal to other cells is via chemical messengers called cytokines, about which more shortly. Other cells of the innate system are neutrophils, macrophages and dendritic cells (DCs) known as phagocytes because they basically eat invading cells. However, having eaten the invading cell they promote themselves to the title of antigen presenting cells (APCs) and then migrate to the lymph nodes where they present antigens - i.e. bits of the invading cell - to 'naive' T cells. Here the T-cells 'learn about' the antigen and prepare for future encounter. They are part of the second branch of the immune system, the adaptive system, and to continue the metaphor, they are akin to a sort of 'military intelligence'.

 

Before going into the adaptive system in more detail, there is something else worth noting about the innate immune system and this is its capacity to induce behavioral changes in us. Certain complex molecules used by the innate system, such as TNF-alpha or IFN alpha, are behind many of the experiences of being ill, which include not only the experience of fever and pain, but also fatigue, malaise and feeling down. Not only this, but the innate system is also  activates the hypothalamic-pituitary axis (HPA) which is an essential part of our stress response which, when chronically stimulated, is responsible for many features of chronic disease and 'burnout'.

 

Adaptive Immunity

 

The innate immune system we just talked about is fairly rudimentary. It is sophisticated enough, but it more or less does the same thing over and over. The adaptive (and sometimes maladaptive) immune system consists of cell called lymphocytes, which are created mainly in bone marrow and which spend most of their time in the lymphatic system. These lymphocytes include T-cell and B-cells. The 'adaptive' system is different from the innate system in that it is able to learn about foreign pathogens and create memory, and in this sense could be said to have a kind of intelligence. Indeed, it is a telling coincidence that the lymphocytes in our body have the roughly the same mass as our brain. 

 

It takes longer to take action against pathogens, usually around 10-14 days, and works roughly by by destroying invading 'non-self' organisms. This is done by a class of T-cell we mentioned, the 'cytotoxic' T'-lymphocyte (CTL), and as we saw the CTL is triggered into action by one of the antigen-presenting cells which - a little like in the films where they give a hunter dog a scrap of the fugitive's clothes to stiff and go catch - they show a fragment of invading cell for the CTL to go and lyse (of course we are talking about millions of such cells, not just one). The other T-cell which learns is the TH 'helper' cell. These TH cells produce cytokines which both recruit yet more cells and are pro-inflammatory, leading to those features of inflammation mentioned earlier as well as behavioral changes - fatigue, lack of energy and so forth, sometimes called sickness behaviors. There are a few other types of T-cell, such as the T regulator cells that 'down-modulate', that is to say, calm down or switch off the activity of CTL and TH cells so the immune system does not get carried away. 

 

Helper cells also direct the other cells of the adaptive immune system, the B-cells. These are essentially factories for producing antibodies. Any given foreign organism, once smashed up by the immune system, will yield fragments of proteins that can be used to identify similar cells in the future. Antibodies are basically molecular tags that circulate in the body, each one tailored to a particular type of antigen - say a type of flu-virus or bacteria - and if encountered will latch on to that organism. This allows for a quicker and more targeted response - one less dependent on the innate immune system and therefore less inflammatory and less debilitating. The ways in which the adaptive immune system combats infection is a masterclass in efficiency. Invading or virally infected cells may be bound together, all the more easier to target, they may be made 'slippery' so they cannot attach to anything, they may be made 'tasty' so that phagocytes will chomp them up or they may just simply be lysed - their cell walls broken down and destroyed. 

 

By adulthood we have billions of antibodies in our system. Of course sometimes the system malfunctions and produced antibodies against 'self-cells' such as the insulin producing cells of the pancreas - a problem which leads to type-one diabetes - or more commonly the anti-gliadin antibodies which target the gluten protein and can lead to coeliac disease. However a note of caution should be sounded here, because - in an age of increasing blood tests and immune screens - presence of an antibody does not necessarily mean one is going to mount an immune response against it.

To summarize then, by adulthood we should have a functioning immune system that detects and fights of foreign pathogens such as viruses and bacteria. Without it, we would soon succumb to infectious disease. It consists of the innate immune system which is made up of the barriers of the skin, gut and mucous membranes, induces fever in us, and has a host of cells which detect, capture and destroy foreign organisms. It works in tandem with the adaptive immune system which is able to 'remember' these foreign antigens in order to mount a quicker and more focused (and less inflammatory) response the next time. Once they have done their job and infection has been fought off the system has mechanisms in place to wind it down​. It's worth bearing in mind that this is an overlapping process taking place with multiple infections at any given time - bugs don't form an orderly queue to infect us one at a time*.

* Children are especially prone to getting overlapping infections, resulting in the seemingly endless infections that never seem to go away. They also get roaringly hot, because they are so dependent on their innate - and much more inflammatory - immune system while their adaptive system grows. This is the most likely explanation for why, in rare and unfortunate cases, some children appear to have 'bad reactions' to vaccinations. Of course the vaccination itself will cause an immune response, albeit a much milder one than the real infection were they to get it. Almost certainly though the 'bad' reactions we hear about - the high fevers, the malaise, the behavioral changes - are due to a concurrent and entirely co-incidental infection. While it is natural to assume causality in such cases, studies involving millions of subjects have shown no connection between vaccines and say autism. It is regrettable that certain interests continue to propagate this myth.

Both branches of the immune system use chemical messengers - such as cytokines and interleukins - to communicate each other, to mobilize other immune cells and to cause inflammation. However growing research is showing how our nervous system - our brain and nerves themselves - interplay with the immune system. In other words, the immune system is not just a 'liquid' sense, but an electric one too. We've already seen how inflammation itself causes phenomena which make us 'feel' ill and induces 'sickness behavior': nausea, fatigue, anhedonia, irritability, fragmented sleep, social withdrawal, poor concentration and so forth. And like so many messages from our body, this often continues 'under the radar' - for days we may slope around in low mood for example, or everybody just gets on our nerves for some reason - until it reaches a point when we realize we are unmistakably 'ill'. On the other hand we have our own array of anti-inflammatories (such as interleukin-10) to ameliorate that sickness.  

The central nervous system reacts to environmental stimuli using the same signalling pathways as the immune system.

We traditionally thought the brain was 'shut away' from the immune system at large by the formidable blood-brain-barrier, but now we find that cytokines can cross this to communicate to the brain. The brain also has its own immune cells, its own microglia, macrophages and cytokines. And the brain monitors the immune response 'outside' via nerves. The sympathetic 'fight and flight' nervous system actually has nerves leading to 'lymphoid structures' such as the spleen and bone marrow. It also innervates the adrenal medulla which sit above our kidneys and release catecholemines such as adrenaline. Adrenaline and noradrenaline are activated when we are under stress, and both lead to the release of cytokines such as inteleukin-6 or TNF-alpha which are pro-inflammatory. Understandably, because the body wants to be ready to fight off infection, repair damage and so forth. This is balanced by our parasympathetic nervous system which releases chemicals such as acetylcholine which binds to receptors on immune cells to reduce the inflammatory response.

Another component of the stress response within our brain is the hypothalamic-pituitary-adrenal - or HPA - axis which eventually leads to the release of the 'stress hormone' and natural steroid cortisol. Cortisol inhibits our immune response by binding to receptors on immune cells and thus reducing our inflammatory response.

As with most processes in the mind-body this is a balance of stimulation and inhibition. A threat is sensed - infection, damage, toxins - and the inflammatory drive kicks in, then a counter signal is sent to wind the process down. But as you've probably already guessed, this process can be knocked out of form by chronic overstimulation. For instance chronic stress leads to elevated cortisol levels. As we've seen, in the short term cortisol reduces the immune reaction. However if the body is awash with cortisol for any length of time the immune cells simply stop 'listening' to it by down-regulating the receptors on their cell membranes. The result is an immune system which no longer responds to our own natural anti-inflammatory steroids, and tips over intoa pro inflammatory state.

Chronic 'fight or flight', emotional as well as physical stress (which I hope by now you can appreciate are essentially the same process), will eventually lead to a dysregulated immune system. It this light, it can hardly be surprising that ongoing 'mental' or 'social' anxiety is associated with a host of pro-inflammatory conditions. By the same token being in a 'pro-inflammatory' state will lead to an immune system which is overly reactive, leading to more inflammation, leading to an ongoing sickness 'experience'. This can lead to a great deal of strife and not just physically. Explaining to somebody that their physical condition is intimately tied to their mental and emotional processes is likely to lead to a stinging rebuke. The stigma of 'psycho-somatic' illness usually hangs over such discussions. And being 'explained' what is happening to you rarely puts one in a receptive state of mind! As a result we tend to tiptoe around such conversations.  Both parties feel unacknowledged and frustrated. A classic communication breakdown.

Breaking out of this cycle can be a real challenge. What hardly helps is the sheer complexity of the processes described above. The above explanation of how the immune systems works is really just the tip of an iceberg. In the face of such complexity we often fall back on simplifications and stories - 'my immune system is faulty', 'it's all in their mind' etc. - and one of the most enduring of these is that we have a mind, and then we have a body. We have an emotional, social, thinking life on one hand, then on the other we have a body, an immune system, a gut, muscles. Surely one way out of the impasse above is firstly to acknowledge that we 'don't really know' what is going on. What we are doing is making guesses, some better than others. How can we really know what the problem, or solution, to any one dis-ease is? At any given moment everything we are basing our knowhow on is changing; a dynamic, subtle, intelligent system. Likewise both 'patient' and 'doctor' alike need to own up to the reality that every physical experience is in the mind - where else is it happening? - and that every mental experience happens as part of a body. Every experience we have is, by its very nature, 'psycho-somatic'.

'Whatever Works'   

Perhaps the most compassionate approach is that time honored maxim of trying out whatever works and, conversely, letting go of those things that don't work. It could be trying out something new or long forgotten - say a physical activity, a type of food, more sleep - to see if it works, or letting go of something, some attachment, a lifestyle, even a story we tell about ourselves, which is not working.

Returning finally to the immune system. If anything I would like to see the immune system regarded more as a 'sense'. After all, it connects directly to the outside world and tells us what is going on. It responds to what we eat, how much sleep we are getting, whether what we are putting into our bodies is good for us. It lets us know how much stress we are putting on ourselves. It feeds back to us and we feed forward to it. ​Take care of it, and it'll take care of you.

This inflammation is an essential part of the healing process but it also leads to a lot of the 'sickness behaviors' we experience when unwell: tiredness, pain, irritability, low mood and so on. Furthermore, if not regulated well or if chronically overstimulated, inflammation can begin causing damage to the body. Even aging itself is associated with increased inflammatory activity, as the adaptive immune system becomes less effective and the body relies more on the innate system.

 

 

CTL and TH cells patrol the blood vessels and the lymphatic system of the body, always on the prowl for potential invaders. One of the benefits of physical activity such as exercise, massage or yoga, is that it helps the flow of the lymphatic system which, unlike blood, does not otherwise have a pump of its own. 

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About The Writer

HC James is from London and worked as a teacher before switching careers to medicine. He currently works as a doctor in a south London Emergency Department and in his spare time visits family in California.   

 

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