Because stress activates both the hypothalamic-pituitary-adrenal-axis (HPA axis) and the sympathetic nervous system (SNS), it is not surprising to find that most acute stressors can modify the immune response. It is well known that plasma catecholamines released from the adrenals in response to stress, in addition to the adrenal glucocorticoids, can cause immuno-suppression. There are numerous experimental studies showing that various types of externally applied acute stressors (for example, electric shocks, social defeat, maternal separation, immersion in cold water) suppress some aspects of immune function. Similarly chronic stressors such as overcrowding, have been shown to suppress aspects of cellular and humoral immunity. Indeed, it is difficult to consider any aspect of cellular and humoral immunity that is not altered by some stressor (Maier, Watkins, and Fleshner, 1994).
It is evident from the results of both the experimental and clinical studies of the effects of stress on the immune system that all stressors do not produce identical changes in the immune and endocrine systems. It has long been known that different stressors produce different degrees of SNS and endocrine activation (Mason, 1971). For example, one stressor might strongly activate the SNS but have relatively little effect on the HPA axis whereas another may have the converse effect. In addition, the time course of these changes will differ for different stressors and for the psychological state of the individual. Moreover coping strategies are important in that the individual can learn to modify the adverse impact of the stressor (Mormede, Dantzer, Michaul, Kelley, and Le Maul, 1988). It must also be emphasizd that the specific immune response involves a complex cascade of events that may extend over several days. As the catecholamines, endorphins, glucocorticoids, etc. play crucial roles in modulating this cascade, the effects of stress will, of necessity, be variable. Thus experimental and clinical situations will arise in which stressors may have an effect, have no effect or even an enhanced effect on immune function (see Croiset, Heijnen, Veldhuis, de Wied, and Ballieus, 1987).
Fleshner and co-workers have shown, for example, that a stressor will interfere with antibody synthesis, determined several weeks following the antigen administration, only if the stressor is applied near the time of the antigen exposure (Fleshner, Bellgrau, Watkins, Laudenslager, and Maier, 1995). Such findings serve as a caution from studies that have determined one aspect of immune function at one time point only from which conclusions are drawn that stress suppresses immune function. Many immune parameters are non specific and assess some intermediate aspect of the immune response (for example, the synthesis of the interleukins or proliferative response of T-cells to mitogens) rather than an effector end point that detects and destroys antigen, recognizes virus infected cells, etc. It must be remembered that the immune system contains a high degree of redundancy and therefore the changes in part of the immune cascade are not by themselves evidence that the final end point of the immune process (for example, the production of a specific antibody) is affected (Cunnick, Lysle, Aronfield, and Rabin, 1991).
There is a large and relatively consistent literature on the effects of stressful life events on predisposition to both physical illness and infections. While the correlations between such life events and illness are not large, generally accounting for only about 10% of the variance (Weisse 1992), the effects are consistent across populations and different types of life events.
Bereavement stress has been the subject of several important studies. There is also evidence that risks to health associated with separation and divorce are greater than with bereavement (Kiecolt-Glaser, Garner, Speicher, Trask, and Glaser, 1987). For example, Kiecolt-Glaser et al. (1987) showed that separated or divorced women had a poorer immune function on five of the six immunological variables studies than matched married women. Somewhat similar findings were reported for separated or divorced men (Kiecolt-Glaser and Glaser, 1988). It should be emphasized that the sample size in these studies was quite small, but such data does serve to emphasize the impact of severe life events on the immunological state and consequence health of normal individuals.
The effect of chronic stress on individuals caring for parients with Alzheimer's disease has also been the subject of several studies. It has been shown, for example, that such individuals show a high risk of depression (Crook and Miller, 1985; Fiore, Becker, and Cooppel, 1983). In addition to the greater physical and emotional distress shown by the carers, there is also evidence of impaired immune function (Kiecolt-Glaser, Dura, Speicher, Trask, and Glaser, 1991). Other studies of those individuals subject to chronic environmental stress (for example, living in the vicinity of Three Mile Island in the USA, the site of a nuclear power plant accident some years ago) showed that the residents had fewer T-suppressor cells, B-lymphocytes, and natural killer cells than a comparable group living in a normal environment (Davidson and Baum, 1986). The conclusions of these studies is that chronic stress in man does not necessarily lead to immunological adaptation.
Clearly, there are marked differences between the stress induced changes in rodents and those reported in man.Thus, in rodents, acute stress appears to be immunosuppressive, whereas chronic stress is associated with adaptive changes or even enhancement of the immune response (Cohen and Crnic, 1982; Monjan and Collector 1977).
Examination stress in University students has been the subject of several studies in the United States. Thus, a decrease in natural killer cell number and function has been reported by several groups of investigators (Glaser, Rice, and Speicher 1986; Kiecolt-Glaser and Glaser (1988), effects that were not attributable to poor nutritional status. In addition, academic stress has been associated with significant changes in antibody titers to latent herpes viruses suggesting changes in cellular immunity. In particular, elevated antibody titers to the Epstein Barr virus (the causal agent for infective mononucleosis), herpes simplex virus type 1 (that causes cold sores), and cytomegalovirus (which causes the monucleosis syndrome) were raised prior to examinations but returned to normal levels following the examination (Glaser, Kiecolt-Glaser, and Stout, 1985). There were additional changes in mitogen stimulated lymphocyte replication associated with academic stress. Thus, the incidence of self-reported infectious illness was also increased in these individuals. The effect of relaxation techniques on these immune parameters was also studied and showed that although the percentage of helper T-cells did not decline so markedly in those subjects that were given relaxation exercises, natural killer cell activity was unaffected by such an intervention. It may be concluded from these studies of the effects of stress and adverse life events that adaptive changes in the immune system are not pronounced in man.
One of the major problems arising from the clinical studies lies in the difficulty in adequately defining stress, because the same event may have different effects on different individuals. Furthermore, most of the components of the immune system normally vary within wide limits, thereby making the small, but important changes difficult to detect. Added to these problems is the difficulty in deciding which parameter accurately reflects the true status of the individuals immune defences.
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