Stress and health: exploring the links; behavioral immunology is mapping the connection between controlling stress and fighting disease – includes 2 related articles on the immune system

Steven F. Maier

Stress and Health: Exploring the Links

After his daughter died, the middleaged doctor could hardly contain his grief. He was disconsolate and felt during the next year as if he were “giving himself cancer.’ He managed, by denying both her existence and her death, to continue to work for the next few years but had continual infections and a nagging cough.

Three years after her death, anticipating the girl’s birthday, the doctor began again to grieve. At the same time, for a three-month stretch, work was particularly stressful.

On the eve of his daughter’s birthday, the doctor, barely able to breathe, was admitted to the local hospital’s intensive care unit. After a lung biopsy revealed that he had a very rare type of pneumonia, he was given antibiotics and promptly responded. Despite his apparent recovery, his infection had made him suspicious. After researching in his local medical library, the doctor, a bisexual, diagnosed his condition as AIDS, a diagnosis later confirmed by a laboratory workup.

The doctor’s trun story is a new variation on a very old theme. Whether as folklore or as the anecdotes of today’s health professionals, the essence of his story has been repeatedly retold: Disease and even death can follow in the wake of grief, unrequited love, financial losses, humiliation and other emotionally painful events. We’ve all heard, for instance, that stress can cause ulcers and heart attacks. Now evidence is mounting that vulnerability to infectious disease– and even cancer–may be affected by how people react to stress.

But only some individuals seem to be vulnerable, and only under certain circumstances. Today’s research challenge is to find out what accounts for these differences and, if possible, to find ways to keep more people well despite life’s stings and setbacks.

Researchers were once reluctant to associate psychological states with infections diseases because they could not imagine a physiological connection between them. But evidence of such connections has grown in the past decades. And researchers in the emerging field of behavioral immunology are beginning to explain how psychological events can affect physical health.

Infectious diseases provide a particularly good example. Since they are caused by exposure to identifiable pathogens such as viruses and bacteria, their origins seem quite simple and biological, not psychological. But that’s not the whole story. Only a fraction of those infected with a pathogen become ill, and psychological factors may play a major role in determining who does and does not get sick.

A number of investigators have studied how some life stresses (such as job change, the birth of a child or marital difficulties) are related to the development of infectious diseases by asking sick people to list stressful life changes they went through before the disease. Their responses are compared with those of people who do not have the illness. The results have revealed that high levels of stress frequently precede illness.

Other researchers use a more informative technique, measuring life stress in healthy people, then tracking them to see who develops an infectious disease and how stress is related to that illness. For example, in 1979, Stanislav Kasl, Alfred Evans and James Neiderman at the Yale School of Medicine studied the development of infectious monnucleosis in a class of West Point cadets. All entering cadets were screened for immunity and susceptibility to the disease, caused by the Epstein-Barr Virus (EBV). Those whose blood contained the antibody to EBV were considered immune, while those without the antibody were classified as susceptible. The susceptible cadets had their blood tested periodically. The investigators also studied interview data on the cadets’ expectations and family backgrounds, obtained by West Point during routine testing of new cadets.

About one-fifth of the susceptible cadets became infected each year. However, only about one-quarter of the infected cadets developed mono’s clinical symptoms. Several psychological factors were involved: Cadets who had described their fathers essentially as “overachievers’ were more likely to develop symptoms. Moreover, the cadets most likely to become ill most strongly wanted a military career but performed poorly academically, just the ones who ought to be under the greatest stress.

Studies such as these strongly support the idea that psychological factors can influence the development of infectious disease, presumably by altering the immune system, the body’s major defense against pathogens (see “Fighting to Stay Well’ box).

More than 40 years ago, Hans Selye, a pioneer of stress research, noticed an increase in adrenal-gland activity and a decrease in immune-system activity in response to physical stress. Modern immunology has confirmed Selye’s findings. In animal studies, stressors include electric shock, high-intensity sounds, burn injuries and physical restraint. In studies of humans, more complex psychological stressors, such as a number of life changes, exams and academic pressures, sleep deprivation, bereavement and depression, have been associated with lowered immune response. Certainly, in both animals and humans, the link between stressors and impaired immune functioning is quite strong. But why, then, do only some stressed individuals become ill?

When considering how humans react to life events, we must distinguish between exposure to a potential stressor and actual physical and psychological responses to it. Stress does not simply result from a particular negative event, even a loved one’s death. Rather, it results from a complex interaction between the event and a variety of psychological factors, such as the person’s expectations and experience and the presence or absence of a network of caring people. Such factors may be important in determining whether a negative event will affect immune functioning and disease.

Research with both animals and humans indicates that an individual’s control over an event is particularly important in determining its psychological and physiological effects. Research by psychologist Jay M. Weiss of Duke University School of Medicine has shown, for example, that if animals have control over an unpleasant stimulus, they do not develop ulcers, depressed appetite, sleep disturbances or brain-chemistry changes characteristic of stress responses.

The effects of stressor control on behavior are also striking. Animals that have been in an uncontrollable stressful situation show a variety of disturbances when later confronted with stressors that can be controlled by escape or avoidance. Most importantly, they behave passively and do not learn to avoid the stressors. Such behavioral changes, resulting from exposure to uncontrollable stressors, are part of a syndrome called “learned helplessness’ by psychologist Martin Seligman of the University of Pennsylvania and one of us (Maier) when we collaborated in studying this response.

Learned-helplessness effects occur in humans, too, when they lack control over stressful events. But sometimes, just thinking that control is possible, even if it isn’t, can prevent adverse stress effects. Essentially, people’s beliefs that they can control a stressful event affect how they will react.

In 1972, psychologists David Glass and Jerome Singer gave two groups of people a number of mental tasks to do, while exposing them to loud, unpleasant noises. The first group was not told of any way to stop the noise. People in the second group were told they could turn off the noise by pressing a button, although the experimenter would prefer that they did not. This choice of being able to stop the noise gave the second group a feeling of control. Later both groups were given a second task of proofreading, without any noise disturbance. In this experiment, the group who earlier could not control the noise made more errors than the group who had felt in control.

Clearly, the fact and the belief that stressors can be controlled are important in determining psychological and physiological reactions to stressful situations. But how do these factors affect the immune system and the development of disease?

One clue comes from research done in 1979 that showed that in animals exposed to uncontrollable stressors, implanted tumors grew more rapidly and were less often rejected than in those exposed to stressors they could control.

Tumor growth and rejection are affected by the immune system but also by many nonimmune processes. Thus, we and our colleagues at the University of Colorado at Boulder set out to determine directly whether the ability to control a stressor affects the immune system’s activity. We reasoned that if we could show in animals that a purely psychological factor–being able to control a stressor–altered immune function, we could determine which emotional factors were involved, which immune-system changes occurred and which physiological mechanisms produced them.

We studied this in rats by exposing them to controllable and uncontrollable stressors and comparing their immune-system responses. Rats in the controllable-stressor group were put in a box with a wheel in it. We attached to their tails electrodes that could give a mild, intermittent shock to one tail portion. The apparatus was arranged so that the rats could shut off the shock whenever it occurred by turning the wheel; naturally, they quickly learned the trick.

Rats in the uncontrollable-stressor group were put in an identical set-up, but the shocks were actually controlled by the behavior of the rats in the first group. Nothing the rats in the second group did affected the pattern of shocks. Two other groups were used for comparison: those exposed to the apparatus without shock, and those unstressed at all.

As a measure of immune-system response, we studied how readily the rats’ T-cells (a type of lymphocyte, a key component of the immune system) multiplied when “challenged’ by mitogens. Like antigens, the foreign invaders T-cells normally fight in the body, mitogens stimulate these cells to proliferate extensively.

We found that in response to the mitogens, T-cells from rats that could control the shock multiplied as readily as did those from unstressed rats. However, T-cells from rats exposed to identical but uncontrollable shock only multiplied weakly. Thus, the shocks did interfere with the immune response only in rats that could not control them.

We wondered whether our results might extend to another immune-system measure: the tumor-killing ability of natural killer (NK) cells, which play a key role in tumor surveillance. In collaboration with psychologists John Liebeskind and Yehuda Shavit of the University of California at Los Angeles, we removed and studied NK cells from rats exposed to controllable, uncontrollable or no stress. NK cells from unstressed rats or those that could control the stressor killed tumor cells normally, while NK cells from rats exposed to an uncontrollable stressor were less able to kill tumor cells.

These studies are the only ones to manipulate directly the effect of controllability of stressors on immune function. But many other situations involving an uncontrollable stressor have been studied. One is the separation of infants from parents, an especially obvious and potentially important example. In 1982, one of us (Laudenslager), working with psychiatrist Martin Reite of the University of Colorado Health Sciences Center, set out to study whether separating an infant from its mother would alter immune functioning. Since human subjects could not be used, the next-best subject was chosen: the monkey. Two weeks after 6-month-old monkeys had been separated from their mothers, the youngsters’immune-system responses were lessened, as indicated by lowered lymphocyte proliferation. Similar separation studies by psychologists Christopher Coe and Seymour Levine at Stanford University in California have shown lowered ability to generate antibodies to specific viral invaders. Thus, stressors do not have to be simple physical events such as noise or shock to suppress immunity. They can be as psychological as an infant’s “grief’ at being separated from its mother.

Are human reactions similar? It appears that they may be. We can infer from various studies that the immune responses of some people may be suppressed when they cannot control severe negative events. The death of a spouse is perhaps the most potent uncontrollable and negative event for many of us. Roger Bartrop of the University of New South Wales and his colleagues in 1977 monitored several aspects of immunity in 26 people soon after their spouses died. Six weeks after the death, immune function was impaired: Lymphocyte proliferation was lowered.

Other studies have shown that some bereaved people may become seriously depressed, and that some depressed people tend to show less immunity to disease. Perhaps bereaved people who feel able to control their negative circumstances are more protected than others from depression and lessened immune responses.

A recent study by psychiatrist Steven Locke and his colleagues at Harvard University Medical School supports this sort of argument. Healthy volunteers were given questionnaires on life stresses within the past month and the past year, as well as a checklist of common psychological complaints. A blood sample was taken and NK-cell activity was assessed. Surprisingly, the occurrence of life stresses, even very severe ones, did not predict NK-cell activity. Many people, despite repeated upheavals, did not show abnormally low levels of NK-cell activity. What was critical, however, was how people reacted emotionally to stressful events. Those who reported many life stresses as well as high levels of anxiety and depression had the lowest NK-cell activity. Those with similarly extensive life stresses but little anxiety and depression showed the highest NK-cell activity, even higher than in people who experienced few life stresses and were low in anxiety and depression.

Locke and his colleagues speculate that people who, despite many negative life events, do not react with anxiety or depression can cope well, a psychological characteristic reflected in their very high NK-cell activity. Conversely, those who react with anxiety and depression seem to have poor coping skills, reflected as well in their lowered NK-cell activity.

Psychologist Sandra Levy has reached similar conclusions in her exploratory study of how personality factors are related to NK-cell activity and the spread of cancer to the lymph nodes in women treated for breast cancer. Women who accepted the disease and adjusted to their condition showed lower NK-cell activity than those who responded with anger and agitation.

Levy argues that acceptance of the cancer and adjustment to the situation may reflect a belief that nothing can be done about the disease, a helpless reaction. In contrast, anger and disturbance may reflect attempts to alter the course of the disease. Thus, beliefs in possible control might have profoundly affected NK-cell activity in these women. When it was high, lymph-node involvement was less likely.

Much of what has been discovered through behavioral immunology still needs to be clarified, verified and more fully explained. Immunology itself is a rapidly developing field, and current understanding of the immune response and ways to measure it is changing daily. We expect the field of behavioral immunology to reveal additional links between behavior and health, yielding more comprehensive approaches to treating illness and new ways to help people maintain good health.

Photo: David vs. Goliath: (left) Small white blood cell (lymphocyte) takes on large cancer cell; (right) lymphocyte wins and cancer cell is destroyed.

COPYRIGHT 1985 Sussex Publishers, Inc.

COPYRIGHT 2004 Gale Group

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