Stress and Immunity

Have you ever noticed that during periods of intense stress you are more prone to catch a cold or to come down with the flu? Scientists have long known that psychological stress, whether from a sudden trauma or a routine event of daily life such as a difficult commute, adversely affects our immune responses. How can we explain this? What are the cellular and molecular mechanisms that lead to a compromised immune system during stressful times?

We now know that many of the body’s important systems are closely interconnected. For instance, the immune system has connections to the nervous system and to the metabolic system. Many molecules that are used by the nervous system are also used by immune cells, and molecules in one system can have an important, and different, effect on the other. Now for the first time, interdisciplinary studies of a molecule found in both the nervous system and the immune system have revealed a clear link between stress and immune suppression. 

Stress and Its Consequences

Psychological stress may be defined as any external condition or trauma that disturbs an individual’s psychological and physical well-being. This stress is subjective, as situations that stress one person may not stress another (for instance, I find air travel particularly unpleasant). People’s individual genetic makeup, combined with their life experiences, especially when they are young, results in a wide spectrum of responses to psychological stress. Stress is a worldwide challenge to health. Sometimes it comes from extreme conditions of poverty, starvation, persecution, or war. It can also be the result of caring for a sick family member, the loss of a loved one, troubled relationships, being in an occupation that involves a high level of responsibility or danger (police, airline pilots, air traffic controllers, firefighters), or the heavy workloads and the challenges of balancing professional and family life that are common in the Western world.

The most often noted manifestations of psychological stress are mental and physical fatigue, anxiety, anger, and depression. The second-most-common symptoms are immune disorders, especially an increased susceptibility to viral infections (herpes, flu, colds), bacterial or fungal infections (pneumonia, mycosis, meningitis), and inflammation (stomach ulcers, gastritis). Stress can also trigger allergies, asthma, autoimmune diseases such as juvenile diabetes, and inflammatory bowel disease. A link between chronic stress and the inability of immune cells to mobilize a strong defense against cancer has also been suggested.

Perhaps as a result of the considerable sources of psychological stress in our lives, the wellness industry has emerged, providing relaxation techniques, yoga, therapeutic massage, and psychological counseling. The irony is that for many people, adding stress-relieving activities to their busy schedule often creates additional stress. Moreover, our genes play an important role in how we react to stress, and so any positive response to relaxing activities varies considerably from person to person. The reality is that while relaxation cannot hurt, a sea change is not always possible, and a change of genetic makeup is impossible. Therefore, science must find new solutions to alleviate both the psychological and the immune-system side effects of stress. Here, then, is an opportunity for immunologists and brain researchers to collaborate.

The Many Roles of Neuropeptide Y

A considerable amount of evidence now supports the existence of “crosstalk” between the immune system and the nervous system. The nervous system, including the brain and peripheral nerves, can stimulate or inhibit various parts of the immune system.  Conversely, the immune system can influence functions of the nervous system through the release into the blood of factors such as “messenger” proteins called cytokines, which are produced by white blood cells.

Interestingly, a number of peptides (very small proteins) with neural or neuroendocrine functions also have potent antimicrobial activities.  One possibility is that the nervous system uses these peptides as a defense against infection at nerve terminations throughout the body. New research is also showing that one of these peptides, neuropeptide Y (NPY), appears to have other functions in the immune system.

NPY is a hormone that is secreted under stressful conditions by cells in the brain, and possibly by some immune cells, and is then carried throughout the body in the blood. The NPY hormone uses at least five receptors located on the surface of other cells, such as certain immune cells, to attach to those cells. These receptors are called Y1, Y2, Y4, Y5, and Y6.¹ NPY’s effects are as varied as its receptors. A range of research studies has shown that this hormone is involved in functions ranging from eating behaviors to anxiety, memory, seizures, pain, drug addiction, circadian rhythms, cardiovascular disease, bone mass development, and blood vessel dysfunction. Because so many NPY receptors can be found, and NPY can carry out so many different functions depending on the receptor to which it binds, researchers have had trouble understanding what function is controlled by what receptor.  To study this, scientists have genetically engineered animals, such as mice, that lack one or more of the NPY receptors.  These new animal models have been instrumental in understanding the respective contributions of each NPY receptor in behavior, cardiovascular function, and metabolism, but little research on the immune system had been done until very recently. 

A No-Brainer Initiative

Like most immunologists, I have focused my interest strictly on the immune system and not on the brain.  It took some rather unusual circumstances to change the way I now look at immune defenses. At the Garvan Institute, my immunology research group works side by side with researchers from different disciplines. For a long time, this structure has been viewed as a handicap, and many scientists have campaigned for a more specialized structure with a critical mass of scientists focused on the same area of research, rather than being spread thin with smaller groups that have little in common. Like members of most institutes, Garvan scientists meeting in a corridor talk about their busy schedules and the pressure to find more research funding and to publish, lamenting that the stress will kill them—until the day they finally asked the relevant question: why will the stress eventually kill them?  That question precipitated my collaboration with Herbert Herzog, Ph.D.

Herzog, who directs the neuroscience program at the Garvan Institute, is an expert in NPY in the nervous system and the biology of stress. He has developed genetically modified mice that lack NPY or one or more of its numerous receptors, but he knows little about the immune system. Because indirect evidence from earlier research suggested that NPY had a role in the immune system, Herzog and I decided to embark on a project that would study the immune system of mice that were deficient in NPY or its Y1 receptor, chosen for its expression pattern in the immune system.  He bred special mice for our research that had a genetic background suitable for immunological studies and gave us a background in NPY biochemistry.

Julie Wheway, a talented Ph.D. student in my lab at the time, started the pilot experiments with NPY and soon came back to my office with data clearly showing immune disorders in mice that had been injected with NPY and in mice lacking the Y1 receptor. Our further research yielded evidence that NPY, working through the Y1 receptor, suppresses the action of key immune cells named T cells. T cells and other adaptive immune cells are part of the body’s defense. They help us fight specific infections and also participate in surveillance for cancerous cells. 

T cells are activated by another set of immune cells that are the body’s first line of defense. These are called innate cells and are mostly macrophages and dendritic cells. These innate immune cells patrol the human body in search of microbes or cancerous cells, which they kill and consume. The dead invaders are placed on the surface of the innate immune cells like small “hunting trophies.” The patrolling cells then report back to the nearby lymph node, where they inform T cells that they have found an infectious problem somewhere, evidence of which is displayed on their cell surface.  Upon receiving this warning, T cells are activated for immediate response, dividing quickly and forming armies of cells ready to go help to clear the infection. T cells also help another type of adaptive immune cell, named B cells, which produce antibodies, small molecules that bind to microbes and help clear them.

Our discovery that immune T cells can be suppressed by NPY was soon followed by another discovery. Wheway and I found that, in contrast to NPY’s suppression of T cells, some NPY is necessary for the patrolling of innate immune cells to be fully functional. However, too much NPY, such as that produced during chronic stress, may create overzealous patrolling of innate immune cells and, consequently, inappropriate inflammation in tissues. So you can imagine how, in the same overstressed person, a doctor might detect inflammation caused by macrophages or dendritic cells that have been overactivated by NPY and, at the same time, find a persistent viral infection that has flourished because T cells have been suppressed by NPY. 

What Was Mother Nature Thinking?

This research shows that NPY and its receptor Y1 have a critical but dual role. Why might Mother Nature have designed this “yin-yang” way of regulating the immune system?

We still don’t fully understand the natural advantages of this dual mechanism, and it will be important to integrate this effect within a general understanding of how other brain factors regulate immune function. But let’s go back in time through human evolution and try to better understand what the main purpose of NPY could have been when the causes of psychological stress were very different than they are now. 

Early in the human race, starvation was a main source of stress. NPY in our ancestors played a critical role in adapting to scarce food supplies.  Scientists studying the neuroendocrine system have learned that NPY produced in the brain stimulates food intake, lowers energy expenditure, and facilitates the storage of fat.² Research by Herzog showed that part of the function of NPY is also to inhibit the energy-consuming function of bone formation, as bone density is increased in mice lacking the Y2 receptor for NPY.³ 

In addition, raising armies of T cells through cell-division proliferation is highly energy-consuming.  Perhaps NPY Is secretion during stress is meant to increase the activity of patrolling innate immune cells to enable them to deal with infectious invaders for the short term, while inhibiting T cell activation to save energy. In general, it seems that the NPY system has been designed to help mammals living in a primitive environment cope with harsh times—starvation—by allowing fat storage, while reducing the expenditure of energy in various parts of the body, including the immune system. Therefore, NPY might have originally been a fundamental survival mechanism that allowed mankind to survive on lower supplies of body energy.

Starvation remains a reality for most biological systems, including many human populations. However, it seems that the function of NPY and its receptors, originally designed to help us survive harsh times, has been diverted from its original purpose by the novel forms of stress associated with life in today’s world.  Mother Nature could not have predicted factors of modern life such as industrialization, technological progress, hygiene, and food abundance, which, while bringing undeniable benefits, also change the environment in which our bodies function.  Is it possible that stress-induced NPY, once designed to help humans survive in lean times, is working against us and making us sick?

Before we get too depressed about this possibility, let me make a key point.  In our society, where people say that they get stressed about threats from terrorists, nuclear weapons, climate change, overpopulation, pollution, the quality of food, new epidemics such as avian flu, cancer, obesity, and cardiovascular disease, one must relax a minute and consider that the life expectancy of humans has never been higher.  Modern-day stress can indeed make us sick, but modern-day medicine does a good job of keeping us alive longer and longer. Cavemen may have enjoyed clean air, pure water, plenty of exercise, and free-range organic meat, yet few of them survived past 30 years of age. The occasional NPY-induced shutdown of their T cell function to save body energy had serious limitations. 

The Road Ahead

Our discovery of NPY’s critical role in the immune system was both totally unexpected and very powerful. It provides the first clear molecular mechanism to explain in great part how stress suppresses our immune defenses and makes us sick. This understanding is changing the way scientists look at the immune system and suggests powerful new possibilities for treating immune diseases at the interface of the brain and the immune system.

We now know that the brain talks to the immune system, but it is also likely that the immune system talks back to the brain. The challenge is to decode the exact “language” that these two biological systems are using to communicate. No doubt NPY and its receptors will provide additional exciting clues to the brain’s regulation of normal immune functions and also their dysregulation in immune diseases.

A last important point is that we owe our discovery of neuropeptide Y’s versatility to the willingness of researchers in two disciplines to work collaboratively. It should happen much more than it does, but getting scientists from one discipline to work with those in another discipline has not always been easy.  Often they don’t talk the same language, because the cells and molecules that they study are usually different, and they consider the particular biological systems that they study as operating independently from other systems.  But, now, for example, new technologies allow us to identify genes normally found in one system that are also associated with cells in a completely different one.  The key is not for a scientist to attempt to be an expert in two separate fields, such as immunology and brain research, but rather to bring together experts into a scientific framework that fosters interdisciplinary approaches.

Scientists (particularly immunologists) often detach themselves too much from the outside world, concentrating all their energy and attention on a specific field. Yet an inquisitive scientific mind cannot help but question the invariable outbreak of flu, bronchitis, and common colds among stressed colleagues, immediately prior to an important grant submission deadline that will decide whether their research, and possibly their salaries, will be funded or not. The observation that psychological stress often leads to immunosuppression has always been part of our lives; indeed, many studies have clearly and statistically demonstrated this important relationship. Until we design still more interdisciplinary ways of working to lead us to new discoveries, I guess we can still count on getting sick to take us where we need to go.

The observation that changes in our way of life have resulted in a deviation of NPY biology from its original function is not something to be stressed out about but something that we need to understand. As an immunologist, I am gratified that my lab discovered that NPY and its Y1 receptor play a key and previously unappreciated role in the immune system.⁴ I know that this is only the beginning and that other NPY receptors are also important in the immune system. While my plans to continue to decrypt this system may sometimes seem overwhelming (a last stressful thought), important new discoveries are just around the corner. Among the potential advances from this work may be new therapeutic solutions, new biological concepts, and a new look at life with stress-induced NPY.