The Inflamed Mind Read online

  It is a similar story for the lungs, the genital and urinary tracts, the surface of the eye: anywhere that the body is directly exposed to the outside world, macrophages will be found in abundance, waiting for the first sign of trouble. But however effective the frontline defences, some bacteria will inevitably break through from time to time. They will manage to avoid being eaten immediately, they will proliferate and they will disperse through the flow of blood and lymph around the body. To provide additional defence of key internal organs macrophages are also stationed in the spleen, the liver, the brain, the kidneys, the muscles, the fatty adipose tissue and the bones. The key thing is that the immune system, at least in the form of macrophages, is everywhere (Fig. 3).

  Communication: the medium is the message

  The next key ingredient of the immune system’s defensive game plan is communication. To function as a single, integrated, adaptive system the individual macrophage cells must be coordinated. It is the difference between hundreds of isolated centurions and a Roman legion. The science of how immune cells communicate with each other has been at the heart of the recent explosive growth in immunology.

  We now know that there are two main ways that macrophages can communicate with the rest of the immune system: by direct contact with one other cell; or by secretion of cytokines, proteins that can move freely through the body and send a signal to many cells. The cell-to-cell contact mechanism is most useful for communicating very specific information about a particular hostile agent. The cytokine secretion mechanism is better suited for broadcasting a more general message about the current status of an infection or the inflammatory response to it.

  Cytokines are secreted from macrophages into the bloodstream, circulate throughout the body like inflammatory hormones, and then bind to specific receptors on the surface of other macrophages, to send them a signal, to make them angrier or more inflamed. For most of its life - and it can live for decades - a macrophage will be sitting quietly on its own, guarding the same small patch of tissue in the gut or the skin, waiting for something to happen. Then suddenly something does happen. The neighbourhood is invaded by a hostile force of rapidly proliferating and potentially overwhelming bacteria. The macrophage needs to warn the rest of the immune system without immediately deserting its position on the front line. It calls for help by pumping out powerful cytokine signals that can diffuse rapidly into the bloodstream, broadcasting a message of alarm, a call to arms, to any other immune cell in the body that can pick up the signal through cytokine receptors on its surface. Macrophages are highly sensitive to the cytokine signals sent by other macrophages when they need help. These inflammatory cytokines arouse quiescent macrophages, which leave their usual niches and move towards the source of the inflammatory signal, to support their comrade.

  For an example of cell-to-cell communication, let’s think back to the stabbed hand, and suppose that the wound is infected, which triggers a local inflammatory response, so the hand becomes red and swollen. Then, a few days later, there will also be some swelling in the armpit on the same side as the inflamed hand. You might have experienced something similar when a bad sore throat (local inflammation of the pharynx) was followed a few days later by swelling in your neck. In common parlance, your “glands are swollen”; in medical parlance, there is enlargement of the lymph nodes. In the case of the stabbed hand it is the axillary nodes in the armpit; in the case of the sore throat it is the cervical nodes in the neck.

  The reason this happens is that lymph nodes or lymph glands provide a focal point or hub for immune cells to get together and exchange information by direct contact. The axillary lymph nodes become swollen after an infection in the hand because many of the macrophages that have successfully engaged with the bacterial enemy then travel away from the frontline to the nearest lymph node (which happens to be in the armpit if you start from the hand or in the neck if you start from the pharynx). These macrophages that are pouring into their neighbourhood lymph nodes are not running away from a fight; they are reporting back to the immune system as a whole. They are communicating vital, detailed intelligence about the nature of the enemy. Each of them is carrying small protein fragments of the bacteria they have eaten and digested, pieces of the non-self invader, also known generally as antigens. Different macrophages carry randomly different fragments, randomly different antigens, and they crowd into lymph nodes each in search of another immune cell - a lymphocyte - that will recognise their piece of the antigenic puzzle and know what to do about it. The macrophages swirl through the lymph nodes, speed-dating, making brief contact with one lymphocyte after another, until they literally bump into one, maybe the one and only, lymphocyte in that node that can read the signal about the enemy they are bringing back to HQ from the front line. If the macrophage is like a centurion then a lymphocyte is more like a general. Or if you prefer to think of the macrophage as a robotic enforcer or robocop then the lymphocyte is more like an intelligence agent or spook.

  Figure 3: The immune system. We can look at the immune system anatomically: where is it? Lymph nodes in the armpits and elsewhere are connected to each other by a branching network of lymphatic vessels, which allows immune cells to circulate freely throughout the body and to enter the bloodstream. Immune cells in the blood are called white blood cells. The spleen stores immune cells and the bone marrow is important for making new immune cells.

  Or we can look at the immune system physiologically: what is it doing? The immune system is helping us to survive, defending the self against ceaseless attack on all fronts. The macrophages are the front-line troops, trained by evolution to attack hostile bacteria on sight, to eat them, and to carry digested fragments of eaten bacteria on their surface as a way of telling the lymphocytes, the generals of the immunoji army, exactly what a piece of the enemy looks like. Macrophages communicate with lymphocytes in lymph nodes, spleen, bone marrow and the other command-and-control centres of the immune system. Lymphocytes can pump antibodies into the circulation to help macrophages defend the self against attack immediately and in the future.

  Once the macrophage has found the right lymphocyte to report to, the couple will stay locked together for several days, in a briefing conference about the detailed content of the antigenic message, before the lymphocyte decides to take action, often to escalate or diversify the immune response initially triggered by the macrophages (Fig. 3).

  Direct contact between immune cells is crucial for communication in detail about the antigen - the nature of the enemy. It is also time consuming (it takes days for the lymph nodes to swell after infection), hit and miss (most contacts between cells do not lead to communication), and it requires special venues. Cells meet each other mainly in lymph nodes, which are clustered in the armpits, the groin, the neck and all along the midline of the thoracic and abdominal cavities. Cells meet each other in patches of lymphoid tissue like the tonsils and the adenoids, which are located throughout the gut. And cells meet each other in the spleen, the bone marrow and the thymus gland. These are sometimes called the organs of the immune system (Fig. 3). We can think of them all as command-and-control centres, places where immune cells congregate to talk to each other face to face about the current state of threat on the front line and how to respond to it.

  Rapid rebuttal and learning

  The immune system has an innate capacity to detect and respond with extreme prejudice to whatever it recognises as non-self and therefore potentially dangerous. This rapid rebuttal function depends especially on the front-line army of macrophages, which has been trained by evolution to respond very fast and very forcefully to the first signs of infection. Speed of response is important because bacteria and viruses - the enemy - can reproduce so fast. A single germ of C tetani can become two in about 20 minutes and that number will keep doubling every 20 minutes. By the scary logic of exponential growth, one bacterium can become millions of bacteria within a few hours. The immune system needs to win the battle quickly - or at least put a dent in the enemy - b
efore the balance of forces tips decisively in favour of the invaders.

  So each macrophage on the front line needs to be able to make a snap decision: self or non-self, friend or foe? It needs to make that decision autonomously, without any timeconsuming consultation with other cells. But how can it be expected to respond so quickly and decisively to an unpredictable and perhaps unprecedented threat? There are millions of different types of bacteria and viruses out there in the hostile world and no single macrophage can have met them all before. But all macrophages have inherited the wisdom of their ancestors. Each of them is innately prepared to recognise at first sight an enemy it has never seen before.

  The biological war between humans and germs has been raging continuously since Homo sapiens first evolved as a distinct species more than 150,000 years ago. The war between mammals and bacteria, or between multi-cellular organisms and single-cell invaders, has been ongoing for aeons. And throughout the entire stretch of biological history, the first commandment of evolution has been obeyed: only the fittest shalt survive. The ancestors that survived to breed and pass on their genes to subsequent generations will often have survived infection. Genetic mutations that conferred even the slightest advantage to resist infection will have been naturally selected. So that by a long and winding road of random genetic mutation and ruthless natural selection, your macrophages have been trained to detect and respond to threats that you personally may never before have encountered, in your lifetime of decades, but that your ancestors will have encountered and survived in an evolutionary lineage dating back to the dawn of biological time.

  For example, you may never have visited Africa in your life. Then one year you go there on holiday and your immune system, especially the immune system in your gut, is suddenly exposed to swarms of exotic, unfamiliar bacteria. Since this biological threat is massive and very foreign to you, it could be lethal. But over evolutionary time, your immune system has learnt something very useful about bacteria. You might say that your macrophages have been robotically preprogrammed by natural selection. They have been pre-loaded with sophisticated software for on-sight detection and killing of many different bacteria.

  The macrophage knows that most of the bacteria that infect the gut, whether in Africa or in America, have something in common. They have a similar biochemical constitution. They have a tough outer wall, to protect them from gut digestion, which is composed of a molecule called lipopolysaccharide, or LPS for short. Crucially, LPS is not a molecule that we make in our bodies, or that our mammalian ancestors made. It is only made by bacteria. Therefore it is a very reliable and convenient guide to the molecular difference between friend and foe. If a cell has LPS molecules on its outer surface then the macrophage doesn’t need to know anything else about it - that molecular barcode or pattern alone is enough to signify that it is not one of our own cells, it must be an enemy cell and it must be destroyed. I know this because I have read about it in immunology textbooks. The macrophages in your gut “know this” by natural selection.

  The enemy identification and elimination process happens very fast: it is an algorithmic response to automatic pattern recognition - shoot on sight. Every macrophage in your body has been highly trained by evolution, equipped with LPS barcode readers and other devices, to enable an innate immune response. That deep ancestral knowledge - expressed in the genetics and molecular machinery of the macrophage - is what protects us, makes us less naïve than we might have thought, when we travel for the first time to Africa.

  The immune system is not only born with knowledge about the enemy it is also smart enough to acquire new knowledge or to learn about the enemy in its lifetime. The most familiar example of immune learning is probably vaccination. Suppose that before going to Africa on holiday, because I know that there is an increased risk of tetanus in tropical countries, I decide to get a tetanus vaccination. This means that I volunteer to be injected with a weakened form of the germ that could kill me if I encountered it for the first time in the wild. What happens next from an immunological perspective?

  In the first few hours or days after the vaccination, there will probably be some pain and swelling at the injection site. These classical signs of inflammation indicate an innate immune response by local macrophages to the deliberate injection of potently antigenic, provocatively non-self bacteria. But that is a side effect of the vaccination, not its primary purpose. The point of a vaccination is to stimulate the lymphocytes of the immune system to produce antibodies, proteins that are designed specifically to recognise the antigen and to bind to it. And since these antibodies have been selected for mass production because they specifically recognise the tetanus antigen, and since antibody production tends to keep going for several years once it has started, my immune system will now be doubly prepared for the next time it meets C tetani. In addition to the innate immune defences that trigger the shoot-on-sight response of macrophages, inherited from my evolutionary ancestors, I have now acquired an additional line of defence. My immune system has learnt and remembered something about the world in my own lifetime: it has adapted. My lymphocytes have learnt from my vaccination that C tetani is out there, it is a real threat, and they need to remain on guard against it by constantly producing antibodies.

  Auto-immunity: the flip side

  So far I have made the immune system sound like a formidable defensive force, an utterly reliable ally, that manages its ubiquitous location by clear lines of communication between millions of component cells, and that can coordinate sophisticated programmes of rapid rebuttal and adaptive learning to help us survive in a world full of micro-organisms that are out to get us. That is all true but it is not the whole truth. There is also a dark side to the immune system.

  I have used war as a metaphor for inflammation and I might have encouraged you to think that the immune system always wins its inflammatory wars like modern, high-tech armies are sometimes supposed to win military wars: by clean, surgical strikes against targets identified by advanced intelligence. But, in fact, inflammatory wars, like military wars, inevitably cause massive collateral damage to innocent bystanders; and the weapons of the immune system, like guns and missiles, can be pointed in the wrong direction to cause casualties by friendly fire.

  Macrophages are following a tight programme to seek and destroy biological aliens that can be identified on sight by molecular barcodes like LPS. When they engulf the invading bacteria, they spew large quantities of digestive enzymes and bacterial fragments into the surrounding tissue. This macrophage exhaust is toxic to innocent bystanders - like bone or muscle or nerve cells - that happen to be in the vicinity of a bacterial infection but are not protagonists in the immune response to it. As more macrophages are recruited to the site of infection by cytokine signalling, the adverse effects of inflammation on local populations of cells become greater. Intense macrophage warfare is effectively analogous to scorched-earth or carpet-bombing tactics in human warfare. There can be massive collateral damage to non-participants in both kinds of conflict. Macrophages might be able to prevent the infection in the wounded hand from spreading throughout the whole body with lethal effect. But if the infection cannot be completely eliminated, merely contained, and the macrophage army becomes entrenched in its positions for months or years, then the normal, healthy tissues of the wounded hand will be permanently degraded. Muscle, skin and bone will be destroyed, at best replaced by tough, fibrous scars. The macrophage defence could cost the wounded man use of his hand for the sake of saving his life.

  Whereas macrophages collaterally damage swathes of innocent bystander cells indiscriminately, the friendly fire of the lymphocytes is more focused on the distinction between self and non-self. The immune system is extremely good at making this distinction correctly. But it doesn’t always get it right. Sometimes the antigens picked up by macrophages and ferried to lymphocytes are not bits of bacterial proteins but bits of our proteins, molecular fragments of our own tissues. Sometimes the lymphocytes mistakenly presented wit
h these self proteins, as if they were possible enemy barcodes, may then mistakenly direct a hostile immune response against their own self. Instead of producing antibodies against bacteria and other truly non-self antigens, the lymphocytes can start churning out antibodies against self proteins, so-called auto-antibodies.

  The disease-causing effects of auto-antibodies can be as dramatic as the disease-curing or disease-preventing effects of antibodies directed against bacteria and viruses. “Good” antibodies against C tetani can protect me from a fatal tetanus infection; but “bad” auto-antibodies against my own body can cause equally life-threatening diseases. Sometimes the cells in the pancreas that produce insulin come under friendly fire from the immune system. They are hit by auto-antibodies and destroyed, leaving all the other cells in the pancreas completely unscathed. There is no visible scarring but there has been potentially fatal self-harm. Without cells to produce insulin, the body loses control over the levels of glucose in the blood, and many other aspects of its normal metabolism, and the patient becomes diabetic. In the old days, before insulin replacement treatment was invented for diabetes, many patients passed quickly into a coma and died as a result of this discrete but devastating attack on the self by its own immune system.

  • • •

  But you may be beginning to wonder what any of this has to do with depression. I have talked a lot about infection and trauma; but said nothing about moods or states of mind. How is all this beautifully detailed knowledge about white blood cells, lymph nodes, macrophages and cytokines related to mental health?

  Chapter 3

  HIDING IN PLAIN SIGHT