Stress and the Immune System
Manuck, S.B., Cohen, S., Rabin, B.S., Muldoon, M.F., Bachen, E.A. (1991). Individual differences in cellular immune response to stress. Psychological Science, 2, 111-114.
The purpose of this study was to examine the effects of psychological stress on both circulating lymphocyte populations and the T-mitogenic responses of young adults, in order to better understand individual differences in immunologic reactions to psychological stressors. The study measured CD8 cells (cytotoxic T cells), CD4 cells (helper T cells), CD19 cells (total T cells), heart rate, blood pressure, catecholamines (epinephrine, norepinephrine), and cortisol.
The subjects were 25 male volunteers from a university population, and ranged from 18 years to 30 years old. They were separated into three groups: the control group, the 'high' reactors (those who had greater cardiovascular and catecholamine responses to stressors), and 'low' reactors. Subjects underwent two tests: a modified Stroop color-word interference test and a mental arithmetic. These tests were timed and computer-generated answers were used to distract the subject.
Results clearly showed that among high reactors, cardiovascular and catecholamine measurements were higher than baseline (pre-test) levels. Low reactors showed significant elevations only in heart rate and systolic blood pressure, and overall had lower reactions than the subjects in the high reactor group. Cortisol levels remained unchanged in all groups. High reactors experienced a marked increase in CD8 lymphocytes during stress, while low reactors experienced virtually no change. Both groups had similar drops in numbers of CD4 cells.
Naliboff, B.D., Benton, D., Solomon, G.F., Morley, J.E., Fahey, J.L., Bloom, E.T., Makinodan, T., Gilmore, S.L. (1991) Immunological changes in young and old adults during brief laboratory stress. Psychosomatic Medicine. 53, 121-132.
This study addressed the degree and direction of the immune system's response to stress, as well as the effect of age on this response. Earlier studies had not focused on age as a control, which is surprising considering the natural breakdown in cellular function which comes with the aging process. The study measured levels of natural killer (NK) cells, CD8 cells, CD4 cells, CD3 (total T) cells, B cells (cells from the bone marrow), cardiovascular rates, catecholamines, and subjective stress responses.
Subjects were female, and were divided into two groups; young (21-41 years) and older (65-85 years). Both groups were exposed to a 12 minute mental arithmetic exam. Blood was taken both before, during, and after the exam.
Results showed that young female subjects showed increases in NK cell activity, as well as in numbers of circulating CD8 suppressor/cytotoxic T cells, and natural killer lymphocytes following the exam. Older subjects did not show stress-related increase in NK activity. However, older subjects also experienced increases in CD8 cells and natural killer lymphocytes. No changes were found in CD4 cells, total T cells, or B cells for either group. Cardiovascular, catecholamine, and subjective stress responses were similar for the two age groups.
These results indicate that brief psychological stress are associated with some, but not all, rapid immune cells changes, i.e., release of CD8 cells and NK cells into circulation, and in young subjects, an increase of NK activity. The absence of such activity in older subjects indicated that NK cell mobilization and cell death induced by NK cells may be somewhat affected by stress. The results also suggest an age-related deficit in the up-regulation of NK activity when some environmental stressors are present.
Brosschot, J.F., Benchop, R.J., Bodaert, G.L.R., Olff, M., De Smet, M., Heijnen, C.J., Ballieux, R.E. (1994) Influence of life stress on immunological reactivity to mild psychological stress. Psychosomatic Medicine. 56, 216-224.
This study investigated the effects of self-reported life stress and the locus of control on reactivity of several immune parameters to a brief mild interpersonal stressor. Life stress has been shown to be related to cardiovascular reactivity to acute stress, since life stress can cause thickening and weakening of artery walls, and acute stress can cause clots to form and a heart attack to occur.
Subjects were 86 male teachers aged 24 to 55 years. The study measured changes in numbers of monocytes, T-lymphocytes and subsets, B cells, and NK cells. After a 30 minute rest period, subjects were asked to solve a 3-dimensional puzzle, not knowing that it had no solution. Next they were asked to explain how to solve the puzzle to another subject (who was actually part of the experimental staff), without being able to physically help the other person solve the puzzle. The situation continued for 12 minutes. Blood was taken after the rest period and after the stress period.
The main hypothesis Ð that prior life stress influences the responses of the immune system to an acute laboratory stressor Ð seemed to be confirmed. Interaction effects between degree of life stress and experimental condition were significant for most of the cell types studied. One explanation for the dominant effect of daily hassles may be that minor everyday stressors have a cumulative impact that is greater than that of isolated major events. Another explanation may be that hassles are less readily coped with than life events, since they are by nature uncontrollable and unexpected. However, this does not account for the main finding of this study, that the number of daily hassles influences the immunological reaction to a subsequent stressor. One possible explanation for this finding is that a high degree of life stress 'sensitizes' the individual to subsequent stress.
Kiecolt-Glaser, J.K., Cacioppo, J.T., Malarkey, W.B., Glaser, R. (1992) Acute psychological stressors and short-term immune changes: What, why, for whom, and to what extent? Psychosomatic Medicine. 54, 680-685.
A series of recent studies have examined the effects of short term stressors on the immune system. This study looked at the results of nine of these studies, in order to get a better picture of the effects of short term stress on the immune system.
An increase in natural killer (NK) cell numbers and a decreased mitogen (a substance that produces mitosis in T cells) response were the most consistant changes noted. Changes in CD8 cells were inconsistant, but seemed to increase in studies with longer and/or more intensive stressors (i.e., those that produced larger heart rate increases). B cells and monocytes produced inconsistant results. No differences in CD3 or CD4 numbers were reported.
The immunological changes observed following short term stressors are similar to those that follow epinephrine injections: increased percentages of NK cells, decreased blastogenic responses to mitogens (phytohemagglutinin [PHA], concanavalin A [Con A], and pokeweed), and decreased percentages of CD4 cells; total T cells and monocytes did not change. These epinephrine-induced changes are thought to reflect lymphocyte migration from lymphoid organs and peripheral blood. This is supported by the fact that splenectomized patients show much smaller changes in response to epinephrine infusion than normal subjects.
The short term changes were relatively short-lived, although more intense stressors such as shock and noise may have somewhat longer-lasting consequences. Overall, it is clear that short-term stressors can produce transient immunological alterations, with some facets of the immune response appearing more susceptible than others.
Futterman, A.D., Kemeny, M.E., Shapiro, D., Fahey, J.L. (1994). Immunological and physiological changes associated with induced positive and negative mood. Psychosomatic Medicine. 56, 499-511.
Although there are many studies of immune changes after exposure to stress, there are not as many studies of the relationship between immune processes and affective (emotional) states. This study examined the effects of positive and negative moods on 14 male actors, in an attempt to better understand how the immune system is affected by emotional state. The study measured CD3, CD4, CD8, CD16 (NK cells), CD56 (NK cells), and CD57 (NK cells) cells. The mood states evoked included "happy," "content,' "satisfied," "pleased," "loving," "friendly," "warm," "depressed," "unhappy," "irritated," "frustrated," "afraid," "anxious," "tense," "calm," "relaxed," "fatigued," "aroused," "alert," "excited," "energetic," "bored," and "unemotional." Were positive mood states associated with increases in certain immune parameters and negative mood states associated with decreases?
The subjects were 14 male actors, trained in 'method' acting, a method in which actors relive personal experiences in order to approximate the emotions of the character. Actors were chosen because they may be more comfortable expressing emotions in front of people than untrained subjects, which has been a problem in the past. The actors were told which mood state they would be experiencing. They then read the appropriate scenario, which was about 100 words long, and were told to create and experience a realistic mood by developing the scene and verbally and behaviorally acting it out while seated. Actors were encouraged to use their own personal memories to intensify the experience. The principal investigator played an 'acquaintance' to whom the actor expressed their feelings and thoughts.
Results showed that NK numbers and activity increased after all mood states, although they returned to baseline levels after 20 minutes. More aroused mood states did not have a greater impact on the immune system; in fact, most immune effects were due to the general expression of affect, rather than the specific quality of a mood state. This indicates that immune changes are not induced by specific kinds of feelings or moods, but are induced simply by the presence of such a mood.
Sgoutas-Emch, S.A., Cacioppo, J.T., Uchino, B.N., Malarkey, W., Pearl, D., Kiecolt- Glaser, J.K., Glaser, R. (1994). The effects of an acute psychological stressor on cardiovascular, endocrine, and cellular immune response: A prospective study of individuals high and low in heart rate reactivity. Psychophysiology. 31, 264- 271.
The purpose of this study was to examine the effects of acute psychological stressors on the cardiovascular, endocrine, and cellular immune systems in two groups of people; those who had high heart rate reactions to stress and those who had low reactions.
22 healthy undergraduate men ranging in age from 18 to 31 participated in this study. Subjects were instructed to prepare a 3 minute speech to defend themselves against a false shoplifting charge. Later, the subjects were asked to complete a 12 minute mental-arithmetic exam during which loud noises were played randomly. Blood was drawn after each test.
The brief stressors increased NK cell activity in the young men, and also increased the level of circulating catecholamines, with norepinephrine being affected to a higher degree than epinephrine. Additionally, a high heart rate reactors showed a significant increase in cortisol compared with low heart rate reactors, and high reactors showed a greater increase in NK activity than the low reactors. These immune responses are thought to reflect a movement or redistribution of immune cells from one part of the body to another rather than any longer-term enhancement in cellular immune function. Similarly, although NK cells numbers and NK cell cytotoxicity increased after brief psychological stress, they decreased during longer lasting stressors. However, the plasma cortisol levels found in high, but not low, heart rate reactors following the stressor indicate that the pituitary adrenocortical system can be activated by acute psychological stressors. Together, these results suggest that the interactions among the autonomic nervous system, endocrine system, and immune system are not only amenable to psychophysiological analysis, but that such analyses may play an important role in discovering underlying mechanisms.
Benschop, R.J., Nieuwenhuis, E.E.S., Tromp, E.A.M., Godaert, G.L.R., Ballieux, R.E., van Doornen, L.J.P. (1994). Effects of beta-adrenergic blockade on immunologic and cardiovascular changes induced by mental stress. Circulation. 89, 762-769.
This study examined whether beta-adrenergic mechanisms mediate the immunologic responses to acute mental stress. Several aspects of the immune system were examined, including lymphocyte subset distribution and functional parameters of cellular immunity. Cardiovascular variables were also monitored to see if the responses were mainly sympathetic in nature and to examine the effectiveness of the beta- blockade.
Subjects were all non-smoking, healthy males, ranging in age from 18 to 32 years old. Subjects ingested a capsule labeled "propranolol 40 mg", which was either 40 mg of propranolol or a lactose placebo. Following that subjects sat and read popular magazines. Then, the subjects took a tone avoidance reaction time task, where they had to hit a certain button when a signal flared up in the corner of the screen. The second test involved memorizing a set of four letters that appeared in various forms later. The subjects were instructed to press a button depending on whether the letters appeared later or not. Tasks were made more demanding if the subjects started to perform better.
The results showed that mental stress induces changs in both cardiovascular and immunologic variables. With the exception of blood pressure, changes in heart rate, PEP, and immunologic variables were abolished under beta-bloackade. This indicates that catecholamies are involved in the rapid physiological changes that are induced by mental tasks and further suggests that the changes in the cardiovascular and immune systems share the same regulatory mechanism.
Brosschot, J.F., Benschop, R.J., Godaert, G.L.R., De Smet, M.B.M., Olff, M., Heijnen, C.J., Ballieux, R.E. (1992). Effects of experimental psychological stress on distribution and funtion of peripheral blood cells. Psychosomatic Medicine. 54, 394-406.
This study investigated the effects of brief psychological stress on the distribution and number of peripheral blood cells, including CD8, CD4, NK, and B cells. Earlier studies have shown a relationship between stress and cell distribution in peripheral blood, since cells tend to migrate from that area to combat the stressor.
Subjects were 86 male teachers aged 24 to 55 years. The study measured changes in numbers of monocytes, T-lymphocytes and subsets, B cells, and NK cells. After a 30 minute rest period, subjects were asked to solve a 3-dimensional puzzle, not knowing that it had no solution. Next they were asked to explain how to solve the puzzle to another subject (who was actually part of the experimental staff), without being able to physically help the other person solve the puzzle. The situation continued for 12 minutes. Blood was taken after the rest period and after the stress period.
It was shown that a short, mild psychological stressor can influence the distribution patterns of lymphocytes and NK cells in peripheral blood. No differences were observed when the effect of the stressor was tested on proliferative responses of T and B lymphocytes. The number of NK cells and CD8 cells appeared to increase after a brief period of stress, while the CD4 ratio decreased. Lymphocyte counts were also increased, probably reflecting the change in NK cell numbers. Although proliferative responses and several subsets of blood lymphocytes did not change for the whole group, it is still conceivable that these and other parameters do change for subgroups, representing differences in personality characteristics and chronic stress experience.
Kreitler, S., Aronson, M., Berliner, S., Kreitler, H., Weissler, K., Arber, N. (1995). Life events and personal problems: Their physiological and emotional effects. Personality and Individual Differences. 18, 101-116.
The purpose of this study was to show that life events (LEs) are not related per se to stress, but rather that personal problems (PPs) that are stress related and should be used in stress-related studies. There were four main hypotheses: Only those LEs or changes that are evaluated negatively have adverse effects. It is not the LE per se but the meaning attributed to it which accounts for its adverse effects. The relationship of LEs to health is moderated by personality variables, i.e., sensation seeking, self complexity, hardiness, and religiosity may decrease the stress caused by LEs, whereas external locus of control and low self-esteem may increase the stress. The relationship of LEs to health is moderated by situational factors, for example, social problems exacerbate the effect whereas social support and material support may reduce the stressfulness of LEs.
One major conclusion of the study was that LEs and PPs are distinct constructs. The results showed clearly that PPs are associated with stress indices and LEs are not. A higher number of PPs was related to higher erythorocyte sedimentation rate, neuroticism, stress susceptibility, tension-anxiety, depression-dejection, anger- hostility, fatigue-interia, confusion-bewilderment, and curiosity-interest as well as lower vigor-activity, excitation, joy-happiness, and contentment-satisfaction. This list includes indices from the domains of physiology, personality and emotions. The findings suggest that it would be good to directly asses the major stress agent by asking the subject to list the types or domains of one's PPs. The advantages of this measure are its simplicity, brevity, its proven applicability to individuals of different ages and genders, its discretion, and the evidence that it is related to stress.
Zakowski, S., Hall, M.H., Baum, A. (1992). Stress, stress management, and the immune system. Applied and Preventive Psychology. 1, 1-13.
The importance of the immune system cannot be overstated. Its organs and cells provide the major defense against foreign organisms, pathogens, inert material, and other potential dangers. The skin stops what is virtually an onslaught of microbes and molecules in the air and water around us, and the rest of the immune system is a major factor in combatting diseases. A number of stressful situations and events have been associated with changes in human immunity. These include bereavement and depression, marital discord, examination stress, and chronic stress.
Studies have found that bereaved spouses exhibited weaker responses to mitogen challange than did nonbereaved spouses. Studies linking depression with bereavement have found that bereaved women had significantly lower NK cell activity. More depressed subjects exhibited lower lymphocyte responsiveness to in vitro stimulation by mitogens and by allogeneic lymphocytes.
A study of women who had been separated or divorced for up to 1 year indicated that this was associated with lower levels of a number of indices of immune function. The divorced/separated group had lower lymphocyte responses to mitogens, lower percentages of NK cells, and higher antibody titers to Epstein-Barr virus (EBV). Women who expressed greatest attachment in the marriage exhibited more marked effects than did women with less positive memories or experiences. Similar findings were reported for men.
Decreases in NK cell activity, increased antibody titers to latent viruses such as EBV, decreased in vitro production of interferon-gamma, and decreased interleukin-2 receptor gene expression have been associated with examination stress. A study in 1987 noted a suppression in lymphocyte proliferation in medical students one week after the National Board exams, and similar changes were found in a highly stressed group of psychiatry trainees two weeks before finals. When behaviors such as sleep, diet, and drug use were controlled, it was concluded that many different aspects of the immune system were affected by stress and that the entire system could be involved.
A study of residents of the Three Mile Island (TMI) area more than six years after the accident showed that stress persisted in a number of people and that, as a group, they exhibited a higher level of catecholamines and blood pressure when compared with controls. In addition, subjects living near TMI had higher antibody titers to two latent viruses, suggesting that the disaster has had a long term effect on immune function.
Can stress-related immune system changes be prevented or minimized? Most of the immune 'enhancement' studies focus on somatic and cognitive stress reduction techniques, including relaxation (the relaxation reponse, biofeedback-assisted relaxation, or progressive muscle relaxation), aerobic exercise, self-efficacy training, and multicomponent package approaches using cognitive-behavioral stress management techniques. At the most basic level, such methods are intended to reduce, block, or eliminate stress and the corresponding decrease in immune function. Most studies have concluded that these methods do work, but only if they are regularly practiced for long periods of time. Once a method is no longer being used, immune function returns to pre- intervention levels. Because of this, relaxation may be particularly useful for acute, time-limited, and infrequent stressors.
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