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  • H James

Fluid Intelligence: The Immune System Part 1.

This article was started before the SARS-CoV-2 pandemic started to sweep across the world in January 2020. The dynamics behind the spread of this disease and the question of what was and can be done are subjects for another time. In the face of a fair amount of disinformation and sensationalism one needs to be cautious in accessing information, yet respected journals like The Lancet or British Medical Journal have proven their worth (though are a little technical) or sites such as Undark, the Centre for Evidence Based Medicine (CEBM) in Oxford or John Hopkins Coronavirus Resource Centre site are valuable sources of education.

This blog is just an explanation of the immune system in a way which makes sense to me, and you may find it valuable in this time given that immunity is the basis of our own 'personal' response to the current pandemic - and indeed every disease we encounter.

Germs, Sewers and Vaccines

In the 1800s the explanation, by microbiologist Robert Koch, of the 'germ theory' of disease changed how we viewed disease and set the foundation for modern medicine. The previously held belief that infectious diseases such as fevers, agues, poxes and plagues were caused by 'miasmas' or imbalances in the body's 'humors', was overturned. We now knew that infectious diseases were the result of the spread of micro-organisms like bacteria and viruses.

Of course, for as long as people have been living together in groups we have had basic sanitation measures. There is even a persuasive argument to be made that a lot of the 'rules' contained in religious texts started as public health measures designed to prevent the spread of disease (including the sexually transmitted variety). Still, germ theory finally gave us a mechanism to explain how infectious diseases spread. It also set in motion the development of mass sanitation measures - water systems, sewers and the like - which have been the single most effective health measure in human history. The second most effective measure, the development of vaccinations, also stems from our understanding of microorganisms; as does the third, the mass production of antimicrobials, or antibiotics.

Sanitation and vaccination have vastly improved human life expectancy and reduced infant mortality, or the disability that often results from infections such as mumps and polio. They are not without their controversies: while few would argue against the necessity for mass sanitation in recent decades there has been a backlash against vaccinations, despite overwhelming evidence as to their safety and efficacy. The evolution of antibiotic-resistant strains of bacteria is perhaps more worrying and we're certainly not on top of the problem yet.

However, and thanks partly to these measures, the undeniable trend of disease in the 'developed' world over the past half-century has been towards non-communicable illness: diseases such as heart disease, type 2 diabetes, respiratory conditions and certain cancers. These have various causes though are not, essentially, infectious. Of course, the Covid-19 pandemic has been a sobering reminder of the threat of infection (well, at least for a metropolitan such as myself who easily forgets the toll infections such as HIV and malaria play in the global south or in camps for displaced persons). Nevertheless, in the modern world most disease (and 'dis-ease' such as anxiety) is largely the result of socio-economic and lifestyle factors, not infection.

But does our immune system deal only with infections? In the human body, every 'system' usually does more than one thing (our skeletal system makes blood cells, our skin helps produce calcium, and so on) and the immune system is no exception. What is interesting is the extent to which our immune system - which evolved primarily to deal with invading microorganisms - also plays a role in our mental health. And as well as working as a kind of sixth sense - constantly monitoring the outer and inner world - it plays a crucial role in the healing, maintenance and repair of our bodies. We'll start with one of the primary ways it does this: inflammation.

Inflammation; Our Painful Friend

Inflammation is a 'universal process' in the body, affecting all of its myriad parts and systems. Not only that, but it is also our body's way of telling our brain that something is wrong. 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 'cascade mechanisms' to kick start it into action and feedback loops to slow it down when the job is done. Continually overstimulating this intricate system can lead to systemic inflammation, leading ultimately to chronic disease and more subtle dis-ease. A physical toxin can do this - tobacco smoke for example - but we now appreciate that mental stress can also push the body to a 'pro-inflammatory' state.

Inflammation is an essential component of our immune system, the main way we try to combat any particular pathology. Simply put, it creates the 'conditions' which allow the immune system to work. As any military strategist is aware if the conditions of a conflict zone are not right - poor weather, hostile locals, impenetrable terrain - then any 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 plus pain and loss of function. Basically, the first three result from increased blood flow to the affected area - to increase immune cell traffic - and the last two 'guard' the affected area.

Inflammation isn't always obvious however and, unlike with a bruised shin, we may not even be aware of these signs until it's quite late. You will doubtless have had times when you've felt rotten - irritable, tired, anti-social - for no obvious reason only to come down with a cold a week later. In all likelihood you caught the cold a while back and your body was busy undergoing an 'inflammatory cascade' just beneath the radar of awareness. Indeed, one of the reasons coronavirus was able to spread so widely was the 'lag' between people getting infected and showing symptoms around 10-14 days later (to make matters worse people are at their most infective - i.e. they are 'shedding the virus' - usually just as they are beginning to show symptoms). Hence the value of being able to 'listen to your body'.

Yet, not all inflammation is a response to infection or injury. During the night our body goes into a pro-inflammatory state anyway in order to promote healing. This explains why people with any kind of infection - especially children - tend to have worse fevers during the night. Inflammation also accounts for why people with any kind of injury or arthritis tend to feel stiff in the morning and why, if one has been doing a lot of physical work, waking up in the middle of the night can be so uncomfortable.

To better understand inflammation it is useful to get an idea of how the immune system works as a whole. I often visualize the immune system as a kind of military-intelligence-defense system. This isn't entirely fanciful; its basic aim is to protect the body from invading pathogens and remove 'non-self cellular matter' or, like an engineering corps, to repair damage. This 'immune army' has two major branches: the innate and the adaptive systems.

Innate Immunity: Self and Non-Self

The innate immune system is the first line of defense. It includes the barriers of the skin, mucous membranes and the gut as well as such tricks as turning up the heat - fever - to kill off invading microorganisms. The innate system has legions of deadly cells to assist in its work. These cells are trained in the thymus gland, which sits behind the sternum, and also to a considerable extent in the gut, and in these training grounds they learn the essential art of distinguishing friend from enemy, to learn the difference between self cells (don't attack) and foreign proteins (attack). It's an unforgiving training camp; immune cells which pass the test and attack foreign pathogens go on to the next stage, but those who 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. Other cells of the innate system include neutrophils, macrophages and dendritic cells (DCs). These are 'phagocytes', so called because they basically eat invading cells. Having eaten the invading cell they are promoted 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. These T cells are 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.

Stress and Immunity

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, IFN-alpha or the aforementioned cytokines, 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 also activates the hypothalamic-pituitary axis (HPA) which is an essential part of our stress response.

The HPA - a kind relay network between the hypothalamus deep in the brain, the pituitary gland just beneath it and the adrenal glands above the kidneys - regulates the release of cortisol which is a powerful anti-inflammatory. Cortisol dampens down the inflammatory effects of the immune system, especially during 'active times' such as after waking up. It also increases metabolism to make more energy available to fight disease, raising blood sugar levels, numbing pain and fighting fatigue. It is a finely tuned system, very effective for short-term stressful events, but when chronically stimulated it is responsible for many features of chronic disease and 'burnout'. Those raised sugar levels reduce our insulin sensitivity putting us at risk of metabolic and diabetic disease, and the fatigue and pain fighting-effects in time lead to numbness and an inability to properly rest or sleep. (The immune-boosting effects of short bursts of exercise or cold showers, as well more pleasant activities such as meditation, yoga and saunas, are likely due in large part to their ability to 'reset' this overstimulated stress response.)

Adaptive Immunity: A Second Brain?

The innate immune system is certainly sophisticated enough, but it more or less does the same thing over and over. The adaptive immune system on the other hand is able to actually accumulate knowledge. When we say that we are immune to something, we are talking about our adaptive system. It consists of cells called lymphocytes, which are created mainly in bone marrow and which spend most of their lives in the lymphatic system or on the walls of blood vessels. 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 has 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 however, usually around 10-14 days, and works roughly by destroying invading 'non-self' organisms. This is done by a class of the T-cell we mentioned earlier, the 'cytotoxic' T'-lymphocyte (CTL). 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 sniff-and-go-catch, shows 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 recruit yet more cells to fight infection. They are pro-inflammatory, leading to those features of inflammation mentioned earlier, including those 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. It is worth noting that T-cells play a crucial role in identifying and eradicating neoplastic (cancer) cells. At any one time there will be, among the trillions of cells in our body, such neoplastic cells, though fortunately these are almost always being picked up and destroyed by our immune system.

Antibody Factories

The TH 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. Once introduced to the B-cell it will go on to produce countless numbers of these antibodies. Antibodies are basically molecular 'tags' that circulate in the blood, each one tailored to the particular type of antigen found on the surface of a bacteria and if encountered it will latch on to that organism (or virus-infected cell). This allows for a quicker and more targeted response - one less dependent on the innate immune system and therefore less inflammatory and less debilitating.

In other words, the adaptive immune system is able to identify and destroy the invading pathogen before it has time to multiply enough to cause disease. Vaccines work in this way - they contain non-active fragments of pathogens which trick the immune system into producing the right antibodies to latch onto and destroy the organism if it does ever get into the body (The Vaccine Knowledge Project has a short animation which explains this well

The Battle Scene

The methods used by the adaptive immune system to combat infection are efficient and ingenious, and they often work together to do battle: invading cells or virally-infected cells may be bound together for instance, all the more easier to target and destroy; 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 produces antibodies against 'self-cells' such as the insulin-producing cells of the pancreas - a problem which leads to type 1 diabetes - or the anti-gliadin antibodies which target the gluten protein and can lead to coeliac disease. A more common issue is sensitivity where certain proteins on food or pollen, or industrial or motor vehicle particles, cause an overreaction - specifically the over-release of cytokines and histamines - normally on a barrier site such as the gut or skin (or airways as with asthma). There is no easy solution to this growing problem, though identifying as accurately as possible the trigger and trying to reduce exposure is the current mainstay of management.

Can We Control Immunity?

To recap then; we have an immune system which can be grouped into the innate and the adaptive. Both systems work together. The innate system includes the barriers of the skin, gut and mucosa and uses inflammation to optimize conditions for getting rid of infection and repairing damage. It also presents bits of invading cells - antigens - to the adaptive system to 'learn from' and mount a more targeted response in future, with the help of millions of antibodies. Both systems use chemical messengers to feedback and regulate each other. As well as affecting us physically the immune system also affects us emotionally and changes our behavior. Often this effect is subtle - we hardly notice it beneath the often relentless pace of our day-to-day activity or our ever-busy minds - but it is there and sometimes will make itself felt in dramatic and unexpected ways, which I'll talk more about in the next part, where we'll also explore questions such as; what conscious control do we have over our immune system; what can we do to strengthen our immune system, and why do I always get a cold when I go on holiday?

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