With immune privilege comes immune responsibility
/I am not a neuroscientist. Having poked a few cockroaches with electrodes as an undergraduate, I left the brain behind for the glamorous world of immunology. But immunologists and neuroscientists alike are challenging the long-held belief that the brain is separated from the immune system, and are exploring the idea that good immunological health and good mental health are linked. The immunology community considers some organs “immune privileged” – that is to say that immune cells stay away from certain delicate organs because they tend to do more harm than good. When faced with a foreign particle, white blood cells (leukocytes) trigger an immune response typically involving heat, swelling, redness and pain, all of which together comprise inflammation. This is great for dealing with infection, but causes significant collateral damage to tissues, which may have important functions. For example, our eyes are so sensitive that any amount of inflammation would impair vision. Evolutionarily, vision was so important for survival that our ancestors were more likely to survive if their eyes were left alone by the immune system and so avoided any inflammation-induced damage. But with immune privilege comes immune responsibility; reduced surveillance by leukocytes allows bacteria, viruses and other pathogens easier access to the host so organs must maintain a balance between keeping infection out and preserving tissue function.
In the brain, we used to think that this balance erred on the side of caution – that blood vessels in the brain excluded leukocytes almost completely to prevent inflammation and preserve delicate brain tissue. Indeed, when the brain does experience inflammation, the outcomes are usually bad – diseases such as Parkinson’s and Multiple Sclerosis (MS) are associated with inflammation in the brain. However, it turns out that an immune presence in the brain is not all bad. Clinical trials in the early 2000s aimed to use immunosuppressive drugs to reduce the infiltration of T cells (a type of white blood cell) into the brains of MS patients, thus reducing inflammation and alleviating disease. While symptoms did improve in treated patients, a small number of people died of overwhelming viral replication [1]. The infection was caused by JC virus, a common polyomavirus, which we now know is normally kept in check by T cells continuously patrolling the brain and central nervous system (CNS). So even when inflammation is harmful to the brain, leukocytes still have an important role to play. They are keeping the CNS under active surveillance to suppress infection and keep the brain healthy.
Since the emergence of HIV/AIDS in the 1970s and 80s, we have become aware of many other brain and CNS diseases that rely on robust immunity to stay quiet. Many herpesviruses, for example, live in the CNS and are reactivated following the immunosuppression associated with HIV infection. These viruses are present in the vast majority of people, most of whom will never know they’re infected. It’s only when we lose the protection afforded by patrolling leukocytes that these infections get out of control and cause disease.
So it seems that the brain and CNS are not separated from the immune system altogether. Though migration into these tissues is limited, we rely on sentinel T cells and other leukocytes to keep latent neuronal infections in check. But does it work both ways? Do events in the brain affect the immune system? We all recognise the utility of neural connections with body systems – muscles, gut, skin, eyes. But the immune system? How can cells that move freely and continuously around the body establish connections with the brain? And why would they? There are likely to be many answers to this, but one reason for neural/immune crosstalk is surprisingly intuitive: stress.
Dr Firdaus Dhabhar, Associate Professor at the Stanford Center on Stress and Health, studies the interactions between psychological stress and immune function and has described his work in a recent TED talk. He and others have found that leukocytes respond to short-term psychological stress by changing their migration behaviour. In response to the stress-related hormones epinephrine, norepinephrine and corticosterone, leukocytes leave their usual hangouts (organs like the spleen and lymph nodes) and travel in the blood to sites of potential damage, like the skin. This makes sense when one considers that acute stress can often be followed by injury. The immune system is simply preparing for action. Just as our muscles tense and heart rate increases in case we have to run, immune cells head to the skin in case the source of stress has big teeth and a penchant for human sashimi. Should we survive the attack, we may need to repair the skin and fight infection. In the modern world, this translates to bulk relocation of leukocytes in anticipation of trauma such as surgery. Worrying about surgery the night before going under the knife gives patients a short period of psychological stress, which causes leukocytes to migrate to the skin. This means that they are in the right place to repair damage, so patients whose leukocytes relocate in this way experience a more rapid recovery than those who don’t show any change [2]. Having experienced short-term stress gives immunity a boost and this extends to other immune functions. Mice given a psychological stressor or made to do exercise before vaccination have increased responses to the vaccine [3]. By getting the mediators of vaccine responses (leukocytes) to the site of action before or soon after a shot, we allow these cells increased and/or prolonged contact with the vaccine, thus enhancing the response. This suggests a surprising approach to boosting immunity: a short, sharp shock before a shot may be just the thing to maximise vaccine efficacy.
Just as too much immune activity can harm the brain, excessive triggering of leaukocytes by the brain can harm immunity. In the short-term, once the source of stress is removed, stress hormone levels drop and the immune system returns to normal within a few days. However, long-term stress leads to more lasting changes and can have detrimental effects on immunity. Long-term stress has the combined effect of reducing effective immune responses, while at the same time exposing tissues to inflammation-induced damage. People subject to prolonged periods of stress, including people with depression, PTSD and those caring for family members with dementia, have fewer leukocytes in the blood but increased levels of inflammation-associated factors [4-6]. This seems counter-intuitive since immune cells are a source of inflammation. However, in places like the skin, contact with the outside world leads to constant bombardment with foreign particles. By leaving organs like the lymph nodes, which tightly control exposure to foreign particles, and moving into immunologically noisier tissues, leukocytes become more active but less mobile. These activated cells can still pump inflammatory molecules into the circulation but are no longer able to move around the body, thus making them less likely to find infection when it occurs. Immunologists now think that long-term stress has the paradoxical effect of increasing inflammation while reducing effective immunity because of its tendency to trap crucial immune cells in the periphery.
One path to good immunological health then, is to minimise long-term psychological stress and to sharpen acute stress just before an immune insult. So listen to your mother: relax, eat well and sleep well. And maybe get a friend to terrify you before your next tetanus shot.
References:
[1] Clifford et al. (2010). Natalizumab-associated progressive multifocal leukoencephalopathy in patients with multiple sclerosis: lessons from 28 cases. Lancet Neurol. 9: 438–446.
[2] Rosenberger et al. (2009). Surgical stress-induced immune cell redistribution profiles predict short-term and long-term postsurgical recovery. A prospective study. J Bone Joint Surg Am. 91 (12): 2783-94.
[3] Dhabhar and Viswanathan (2005). Short-term stress experienced at time of immunization induces a long-lasting increase in immunologic memory. Am J Physiol Regul Integr Comp Physiol. 289 (3): R738-44.
[4] Dhabhar et al. (2009). Low serum IL-10 concentrations and loss of regulatory association between IL-6 and IL-10 in adults with major depression. J Psychiatr Res. 43 (11): 962-9.
[5] Rawdin et al. (2012). Dysregulated relationship of inflammation and oxidative stress in major depression. Brain Behav Immun. pii: S0889-1591(12)00497-7.
[6] Aschbacher et al. (2013). Good stress, bad stress and oxidative stress: Insights from anticipatory cortisol reactivity. Psychoneuroendocrinology. pii: S0306-4530(13)00042-5.
