Stress and Disease Processes

Perspectives in Behavioral Medicine

Neil Schneiderman, Philip Mccabe, Andrew S. Baum, Andrew S. Baum,

• Publisher: Psychology Press
• Year: 2018
• Print ISBN: 9780805811612
• eBook ISBN: 9781317844037
• Topic: Psychology
• Subtopic: History & Theory in Psychology
• Index: Psychology

This volume presents chapters by leading figures researching the various pathways by which stress may interfere with health maintenance and contribute to disease etiology and progression. Their work focuses on direct effects of stress on the immune and endocrine systems, on behavioral factors in diseases such as cancer and diabetes, and with the general role of stress in illness processes.

1 Acute and Chronic Stress and the Immune System

Laura Schneiderman
Andrew Baum
Uniformed Services University of the Health Sciences

The relationship between stress and health has long been one block in the foundation of behavioral medicine research and intervention. The contribution of stress to a wide variety of physical illnesses and to mental health are widely believed to be important, and research has addressed stress as a factor in heart disease, hypertension, stroke, cancer, and many other illnesses. Hormonal changes, hemodynamic responses, and other bodily reactions during stress have been considered to be risk factors for illness. Of some interest is the relationship between stress and immunity and whether the changes that have been observed are meaningful. Yet, we still know relatively little about how stress affects immune function, why such effects occur, and whether these changes have any real clinical significance.

One problem has been the relative dearth of research on human subjects, at least until recently. Most work through the 1970s was concerned with animal populations and, although extremely important in revealing links between behavioral factors and immune response (Ader & Cohen, 1981), it provided an imperfect model of stress and immune function in humans. Related to this is the fact that most work with humans considered subjects who had been victimized or exposed to stressful conditions, be they bereaved, caregivers for seriously ill people, medical students facing examinations, or divorced and/or separated spouses. Relatively little research has addressed acute stress in humans and has examined the effects of experimentally applied stress on normal volunteers. The generalizability of the results of studies of intermediate or long-term stress on immunity to short-term events and the meaning of good or poor correspondence across stress durations remains undetermined. This chapter selectively reviews research on animal and human immunological responses during acute and chronic stress to establish how well they correspond and whether one can consider acute and chronic stress as comparable in this instance.

Distinguishing between chronic and acute stress and gauging the severity and duration of stress effects is a complex task. Depending on an individual's experience when he or she is exposed to a stressor, the duration of the psychological and physiological responses may vary. This variation in response duration may depend on the ability of the organism to adjust to an event as much as on the duration or severity of the stressor (Baum, O'Keeffe, & Davidson, 1990). Acute stress may generate brief responses as the stressor passes or as adjustment to the event occurs. However, some acute events, such as traumatic events, may cause long-term responses that outlast the event itself. Similarly, chronic stressors may foster responses that last for a long time due to chronic exposure to an intractable situation or to failure to adjust, but may also lead to adaptation and cessation of stress responding while the stressor persists (Baum et al., 1990). Thus, acute stressors to which adjustment is difficult may generate long-term responses just as chronic stressors may cause chronic responses, and either may generate only brief responses. In addition, there are psychosocial mediators that affect adjustment to the stressful situation, by buffering the distress associated with the stressor (e.g., having perceived control over the stressor) or by augmenting distress associated with the stressor (e.g., by being lonely or depressed). Because it is likely that the duration of stress responding may affect the ways in which stress affects health, determination of these aspects of stress are important.

The complexity introduced by these concepts eliminates the elegance of simplicity, but increases their descriptive power. Although it may be more difficult to convince skeptics that basic stress-immune system relationships exist and are meaningful if we must qualify answers to these questions, the role of psychosocial mediation of this link provides clues as to preventive or ameliorative responses to stress-induced immunosuppression. Social support, efficacious coping, distress reduction, and other putative mediators of stress are potentially important in this effort.

We have divided the chapter into four sections, separately discussing animal and human studies of acute and chronic stress. It is difficult to classify some studies: Duration of stressor exposure varies greatly and distinctions between acute and chronic may become arbitrary at some level. Further, the duration of stress response does not necessarily match that of stressor exposure. These issues have led to extended analyses of chronic stress that are beyond the scope of this chapter (see Baum, 1990). Regardless, studies fall more or less into these categories and provide useful insights into the nature of stress and its health consequences.

Acute Stressors and Immunity

In psychophysiological studies of stress, acute laboratory exposure to stressful conditions is more common than are longer term or naturalistic studies of stress. This is particularly true of human studies where ethical and logistical concerns make the latter more difficult. In studies of stress and immune function, the reverse seems true; relatively few studies of acute stress and immune function in humans have been reported. To some extent this may be due to the time course of immune system changes: If these changes do not occur for several hours after exposure to a stressor, one must keep subjects in the laboratory and prevent potentially contaminating events for a long period of time. If they occur more rapidly, however, these studies can and should be pursued.

Animal Studies

In many animal studies simple physical events such as electric shock or immobilization have been used to generate stress and affect immune function (Gisler, 1974; Harmsen & Turney, 1985; Keller, Weiss, Schleifer, Miller, & Stein, 1983; Laudenslager, et al., 1988; Shavit, Lewis, Terman, Gale, & Liebeskind, 1984). For example, Harmsen and Turney (1985) exposed rats to 3 hours of intermittent shocks of one shock per minute. Neutrophil function was measured and results indicated that stressed rats demonstrated poor accumulation at a zymosan (yeast cell fragment) injection site compared to control rats. Acute physical stressors have also been found to decrease natural killer cell activity (Shavit et al., 1984) and lymphocyte proliferation to mitogen challenge (Keller et al., 1983). It is likely however, that physical stressors are emotionally arousing and that some of the consequences of these stressors are psychologically mediated (Mason, 1975). Being restrained or shocked is an aversive event that may involve psychological reactions as well as sensations associated with physiological changes.

The perception of a stressor as threatening may be necessary for stress responses to occur and therefore adjustment to a stressful event may only result if the stressor is no longer perceived as threatening (Mason, 1975). Kant and her colleagues (1984) have also suggested that response habituation results from behavioral experiences with a particular stressor, and not to biochemical adaptation or habituation of endocrine and neurotransmitter systems after repeated use. When rats were exposed to 15 minutes of restraint, footshock, or forced running for 10 consecutive days it was found that prolactin and pituitary cyclic AMP responses to each stressor gradually diminished and all but disappeared by the Day 10. However, those exposed to a novel stressor on Day 11 showed fully restored responses, whereas those exposed to the same stressor on Day 11 showed little response (Kant et al., 1984). Thus, exposure to a new stressor elicited an augmented hormonal and neurochemical response, whereas there was a diminished biochemical response to the same stressor experienced previously. This suggests that behavioral experiences with a particular stressor may lead to habituation but that this is not due to biochemical adaptation to stressors.

Acute psychosocial stressors have also been examined in animal populations and their relationship to changes in immunity measured. Fleshner, Laudenslager, Simons, and Maier (1988) studied immunological changes associated with brief bouts of territorial invasion. Rats living singly in plexiglass enclosures were divided into two groups: (a) animals who were directly exposed to aggressive rats living in a colony in pairs, and (b) animals who were separated from the colony groups by a barrier. Immediately before the first colony exposure, the intruders in both groups were immunized with keyhole limpet hemocyanin (KLH). The intruders were then exposed to five different colonies, each for 10 minutes. Intruders who directly interacted with aggressive colonies had lower levels of KLH serum IgG antibodies 1 and 2 weeks after immunization than the controls, suggesting that the animals exposed to a stressful situation (i.e., repeated confrontation with aggressive rats) were less able to launch an immune response against the KLH antigen. Apparently this was due to repeated exposure to dominant others, as those rats who reacted to the aggressive encounters by assuming more submissive postures had the lowest levels of antibody to KLH. Submissive posturing was associated with the frequency of being bitten but this variable was not correlated with KLH IgG levels. And, although the duration of the stressor exposure was acute (five, 10-minute exposures) differences in antibodies were still found 2 weeks later.

One way in which acute stressors may cause responses that outlast their physical presence is through conditioning, wherein neutral stimuli present during stressor exposure come to elicit responses independent of the stressor. Similar to the conditioned immunosuppression phenomenon (Ader & Cohen, 1981), the idea here is that the neutral stimuli could come to evoke immune responses or change responses when the stressor is no longer present. One study paired electric shock with an unrelated stimulus to determine if it would come to elicit similar immune changes when presented alone (Lysle, Cunnick, Fowler, & Rabin, 1988). Experimental animals were exposed to pairings of shock and either a clicking sound or flashing light. Ten presentations of the shock (5 seconds each) and conditioned stimulus (15 seconds each) were administered on consecutive days. Control animals were exposed to similar pairings of neutral and aversive stimuli but were not exposed to the conditioned stimulus (CS) during the test phase. After a 6-day recovery period the experimental group was given a test session of 10 presentations of the stimulus without shock.

Lymphocyte proliferation to mitogen challenge with concanavalin-A (Con A) and phytohemagglutinin (PHA) was suppressed following exposure to the CS. This suppression of proliferation was reduced during extinction when the conditioned stimulus was repeatedly presented in the absence of footshock. Additionally, pretreatment with repeated exposure to the conditioned stimulus before pairing with shock was found to lessen immune effects when the conditioned stimulus was later presented alone.

Psychosocial Mediators. Psychosocial variables influence the impact of stressors and immunological sequelae of stress. Studies have examined psychological mediators that may buffer the effects of stressors; control or lack of control over stressors appears to be one such factor. Laudenslager (1983) observed lymphocyte proliferation to Con A and PHA following acute exposure to escapable or inescapable shock. Twelve rats were placed in a "wheel-turn" box and shock was given through tail electrodes on an average of one shock per minute for 80 minutes. The shock could be terminated by moving the wheel. Twelve more rats were each yoked with the escapable shock subjects and therefore received comparable amounts of inescapable shock. A home cage control group was also studied. Twenty-four hours later the rats in the two experimental groups were given five 5-second footshocks and blood was collected from all animals. Inescapable shock led to a suppression of lymphocyte proliferation to PHA in comparison to escapable shock and control procedures. The Con A-stimulated cultures revealed somewhat different results; inescapable shock depressed lymphocyte proliferation but escapable shock appeared to increase lymphocyte proliferation.

A similar study examined stressor (shock) controllability and its relationship to proliferation of lymphocytes to mitogen challenge (Mormede, Dantzer, Michaud, Kelly, & LeMoal, 1988). Splenic lymphocytes were examined instead of peripheral blood lymphocytes and in vivo antibody response to sheep red blood cells (SRBC) injected into the rats was measured as a function of stressor controllability. Animals in the controllable stressor group were able to postpone electric shocks by jumping over a barrier. Yoked animals were run at the same time and received the same amount of shock at the same intervals as the controllable stressor animals but were not able to regulate when the shocks would be administered. Control rats were placed in comparable settings but received no shock.

Lymphocyte response to PHA was significantly reduced in animals that had no control over the stressor relative to the controllable stressor or control groups, which were comparable. There were also significant differences in antibody titer levels to SRBC but these findings were seemingly inconsistent; animals in the controllable stressor group had lower antibody titers than did controls or animals in the uncontrollable stressor group. In observing decreases in antibody titer formation to SRBC in the controllable stressor group without changes in proliferation and depression of lymphocyte proliferation to PHA it is important to note that consequences of controllability may vary depending on the type of immune response measured.

Uncontrollable shock may also affect immune-mediated health outcomes such as tumor development. Visintainer, Volpicelli, and Seligman (1982) examined tumor rejection in male rats exposed to inescapable or escapable shock, or not exposed to shock. Tumor cells were injected subcutaneously into the left lower anterior flank of each animal and 24 hours later each was exposed to shock or no-shock conditions. In the two shock conditions 60 random shock trials were delivered to the grid floor and sides of two identical chambers. Pressing a bar in the controllable shock chamber terminated the shock in both boxes, but depressing the bar in the inescapable shock chamber had no effect. Only 37% of the rats exposed to escapable shock, compared to 46% of the rats given no shock and 73% of the inescapable shock animals developed tumors. Thus, rats exposed to inescapable shock were considerably less likely to reject the tumor as rats in the escapable shock condition. Visintainer et al. (1982) suggested that differences in immunocompetence was probably an important factor in fighting against the tumors.

Stressor predictability is related to control: Predictability may not increase instrumental control but appears to facilitate adaptation by permitting preparation and anticipating responses. It also appears to be related to immune system changes (Mormede et al., 1988). A predictable signaled shock condition featured a tone that was introduced 10 seconds before inescapable shock was delivered through a floor grid. In the unsignaled shock condition the tone was distributed randomly throughout the session. Lymphocyte response to Con A was 34% lower in the unsignaled shock than in the signaled shock condition. The same trend was found for lymphocyte responses to pokeweed mitogen (PWM) and PHA, although results were not significant. These results suggest that psychological interventions involving prediction or control may lessen the influence of a stressor on immune function.

The influence of predictability was significant only when cells were challenged with Con A, whereas controllability affected response to PHA. Mormede et al. (1988) suggested that these differences in response to the mitogens may reflect a variation in the sensitivity of the response to the mitogens depending on the conditions implemented during the sessions. This could indicate a differential involvement of immune cells including T lymphocyte subsets, such as helper T cells versus suppressor/cytotoxic T cells.

Conclusions. Animal models are useful in examining stress and immune activity as many of the variabl...

Table of contents

• Cover
• Half Title
• Title
• Copyright
• Contents
• PREFACE
• LIST OF CONTRIBUTORS
• 1 ACUTE AND CHRONIC STRESS AND THE IMMUNE SYSTEM
• 2 STRESS AND IMMUNITY
• 3 SELECTED METHODOLOGICAL CONCEPTS: MEDIATION AND MODERATION, INDIVIDUAL DIFFERENCES, AGGREGATION STRATEGIES, AND VARIABILITY OF REPLICATES
• 4 CORTICOTROPIN-RELEASING FACTOR AND CATECHOLAMINES: A STUDY ON THEIR ROLE IN STRESS-INDUCED IMMUNOMODULATION
• 5 BEHAVIORAL RESPONSES TO CYCLOPHOSPHAMIDE IN ANIMALS WITH AUTOIMMUNE DISEASE
• 6 DEPRESSION AND IMMUNITY: CENTRAL CORTICOTROPIN-RELEASING FACTOR ACTIVATES THE AUTONOMIC NERVOUS SYSTEM AND REDUCES NATURAL KILLER CELL ACTIVITY
• 7 CHRONIC FATIGUE SYNDROME AND PSYCHONEUROIMMUNOLOGY
• 8 PSYCHONEUROIMMUNOLOGY AND STRESS RESPONSES IN HIV-1 SEROPOSITIVE AND AT-RISK SERONEGATIVE GAY MEN
• 9 CLINICAL SIGNIFICANCE OF PSYCHONEUROIMMUNOLOGY: PREDICTION OF CANCER OUTCOMES
• 10 INTERACTIVE MODELS OF REACTIVITY: THE RELATIONSHIP BETWEEN HOSTILITY AND POTENTIALLY PATHOGENIC PHYSIOLOGICAL RESPONSES TO SOCIAL STRESSORS
• 11 INSULIN SENSITIVITY AND BLOOD PRESSURE
• 12 INSULIN RESISTANCE AS A DETERMINANT OF CARDIOVASCULAR REACTIVITY
• 13 GLYCEMIC RESPONSIVITY TO ADRENERGIC STIMULATION AND GENETIC PREDISPOSITION TO TYPE II DIABETES
• 14 PSYCHOSOCIAL ASPECTS OF CHILDHOOD DIABETES: A MULTIVARIATE FRAMEWORK
• 15 COMPLIANCE AND CONTROL IN INSULIN-DEPENDENT DIABETES: DOES BEHAVIOR REALLY MAKE A DIFFERENCE?
• AUTHOR INDEX
• SUBJECT INDEX