Stress, Immunity, and Health: Research Findings and Implications
The interest in the study of relationship between emotional states and disease has a long history. In the second century A.D, Galen popularized the concept of emotions causing illness which he termed “passions or perturbations of the soul”. He made a distinction between diseases caused by organic reasons and emotional reasons. However, it is only recently, this field has received increased attention from researchers. A relatively new branch of interdisciplinary science called “psychoneuroimmunology” looks into the interactions among psychological states, neurological system and immune functions. The term psychoneuroimmunology was coined by Robert Ader, who accidentally found that immune system could be classically conditioned. In an experiment of classical conditioning of rats, Ader and Cohen (1975) fed rats with saccharin while injecting a drug that caused stomach upset. As a result, mice learned to avoid the saccharin. An additional side effect of the drug was that it suppressed immune system. When the experiment was repeated without the injection of drug to reverse the aversion, they found high proportion of the rats died when receiving saccharin alone. This led them to hypothesize that, by classical conditioning saccharin alone suppressed the immune system enough to kill the rats. This experiment indicated that signals from nervous system can affect immune system. A growing body of research has found that negative psychological states such as stressful experiences and depression may influence health and disease by altering immune system (Glaser et al. 1987; Kiecolt-Glaser & Glaser 1994). Evidences indicate that stress suppresses immune functions and consequently impairs resistance to infectious diseases (Glaser & Kiecolt-Glaser, 2005) and lends support to the idea that stress related immune changes mediates the relationship between stressors and various diseases.
Human Immune System
Relationship between stress and immune function is very complex and many mechanisms are yet to be discovered. However, some major pathways are well established. It has been found that stress affects immune system through the mediation of brain and endocrine system (Ader, Felten, & Cohen, 1990). After the perception of a stressor by the brain, hypothalamus releases corticotrophin releasing hormone (CRH). In turn, CRH stimulates the pituitary gland to secrete adrenocorticotropic hormone (ACTH), which in turn stimulates the adrenal cortex to secrete glucocorticoids. In humans, the primary glucocorticoid is cortisol. The hypothalamus also increases the activity of sympathetic nervous system, which in turn stimulates adrenal medulla to secrete hormones called epinephrine and norepinephrine. These stress hormones may make us more resistant to stressors but are generally found to impair immune systems (Boneau et al. 1993). For example, cortisol has been found to inhibit the production as well as activity of white blood cells. Cortisol also suppresses white blood cells to produce chemical messenger, so that different varieties of immune cells become unable to communicate with each other. Cortisol can also signal many immune cells to shut and stop working (Talbott & Kreamer, 2007).
It also merits mention that behavioral component could be an important pathway linking stress and immune response. It is possible that coping with stressful experience may lead individuals to engage in activities such as alcohol use, which ultimately influence immune processes (Kiecolt-Glaser & Glaser, 1988). High alcohol intake has detrimental effect on immunity (Diaz et al., 2002). Stress and immune function may also be mediated by exercise. Individuals reporting high stress are less likely to exercise than low stress (Stetson, Rahn, Dubbert, Wilner, & Mercury, 1997) and exercise may have protective effect on immunity (Venjatraman & Fernandes, 1997). Further, stress may promote sleep difficulties (Rosch, 1996) which in turn may lower various immune cells and their activities (such as suppressor T cells, natural killer cells) (Savard et al., 1999; Irwin et al., 1994; Savard, Laroche, Simard, Ivers, & Morin, 2003).
Stress and Immunity: Theoretical Models
Various models have been propounded to explain the relationship between stress and immune system. One of the first proponents to study the relationship between stress and disease was Hans Selye. Selye (1975) suggested that stress globally suppresses the immune system and provided first model relating stress and immune response. He described three stages of general adaptation syndrome in response to stress. Stages include alarm, resistance and exhaustion phases. “Alarm stage” is the first stage where body prepares for fight-or-flight in response to a threat. If the stressful situation persists, second stage of “resistance” comes into play. In the stage of resistance, body channelizes all its resources by secreting further hormones and blood sugar to sustain energy to fight. Third stage called “exhaustion” phase kick off when the stressor remains for a long time. In this stage, body has run out of its reserve energy and immunity. At this juncture, due to heavy depletion of body resources, one may fall ill or die. Many early studies have supported this model by reporting association of chronic stress with decrease in natural killer cell, suppression of lymphocyte responses (Herbert & Cohen, 1993). Although this global immunosuppressant model continues to be influential, newer models have emerged recently. Dhabhar and McEwen (1997, 2001) proposed a biphasic model which takes account of type of stress (acute or chronic) and their affect on immune response. This model states that acute stress enhances while chronic stress suppresses the immune response. Acute stress helps in the redistribution of immune cells in the body and as a result increases the efficiency to fight against invaders. However, chronic stress depletes resources and weakens immune responses. This conclusion was derived from a series of experiments conducted on rats by Dhabhar and McEwen (1997). They found that acute stress caused T cells to redistribute into skin, where they improved immune response. On the contrary, chronic stress caused T cells to move away from the skin, thereby decreasing immune response.
Stress and Immunity: Empirical Evidences
Several studies have reported associations between stress and immune functions. Impairments in the immune system such as fewer immune cells and increased susceptibility to common cold have been reported among healthy individuals during the periods of stress (Herbert & Cohen, 1993; Cohen et al., 1998). Reduction in the numbers and functions of the natural killer cells (NK) were reported for students undergoing examination stress (Kiecolt-Glaser et al. 1984; Glaser et al. 1986). Poorer immune functions among divorced or separated men and women as compared to their married counterparts were reported (Kiecolt-Glaser et al. 1987, 1988). Similarly, fewer T-cells, B-cells, and NK cells were reported among individuals experiencing posttraumatic stress disorder than unaffected individuals (Davidson & Baum 1986). Research also reported lower percentage of T cells among the female caregivers of handicapped relatives (Pariante et al. 1997) and caregivers of Alzheimer’s patients (Kiecolt-Glaser et al., 1987; Kiecolt-Glaser, 1999). Apart from that, evidences of association between perceived stress and immune functions are also available. An inverse correlation between natural killer cell activity and psychological distress and anxiety (Locke et al., 1984; Cohen et al., 2002) were reported. Similarly, higher perception of stress was found to be associated with poorer response to vaccines (Miller et al., 2004; Jabaaij et al., 1993). The experience of high depression and anxiety symptoms prior to surgery was associated with lower numbers of lymphocytes, B cells, and T helper cells in a sample of women (Tjemsland et al., 1997). Women scoring high on trait anxiety showed decrease in the NK cell activity during chemotherapy treatment as compared to women scoring lower on trait anxiety (Fredrikson, Furst, Lekander, & Blomgren, 1993).
Herbert and Cohen (1993) conducted a meta-analysis of 38 studies relating stressor and immune functions. They included three types of stressors-(a) acute laboratory stressors (such as speaking before audience), (b) short-term naturalistic stressors (such as examinations), and (c) long term naturalistic stressors (such as unemployment, bereavement). They reported that stress is associated with higher numbers of circulating white blood cells and lower numbers of circulating B cells, T cells, helper and suppressor/cytotoxic T cells, and large granular lymphocytes. They also reported significant association of stress with decrease in the percentage of T cells, helper T cells, and suppressor/cytotoxic T cells. Further, they reported that immune function change was greater for objective events as compared to self reported stress. Stressor duration had distinctive outcomes on immune functions. Acute laboratory stressors were associated with the increase in the number of circulating suppressor/cytotoxic T cells, but long-term naturalistic stressors decreased their numbers. In terms of natural killer (NK) cell function, both short and long term naturalistic stressors decreased NK functions whereas a laboratory study showed increase in NK functions in response to acute stressor. This inconsistent result could be a function of the short term enhancement of immune function due to the acute secretion of the stress hormones (Herbert & Cohen, 1993).
Segerstrom and Miller (2004) also conducted an extensive meta-analysis on 293 independent studies reported from 1960 to 2001 (N=18,941). Analysis of the results confirmed that stress alters immune functions. The most distinctive finding was that the short term stress may enhance immune function as an adaptive response, but chronic stress suppresses immune response as a result of too much depletion of body resources. Further, older and sick people are more vulnerable to stress related immune change. Authors also assessed how different types of immune response correlated with different types of stress. Some stressor categories and their immune responses are as follows-
Acute time limited stressor: This category included experimental manipulations of stressful life experiences such as public speaking and mental arithmetic. These types of stressors enhanced natural immunity (provides defense against non-specific different kinds of foreign invaders in a relatively short span of time) as reflected by increase in the number of natural killer cells in peripheral blood. However, some aspects of specific immunity (attacks specific invaders and characterized by less speed) were suppressed.
Stressful event sequences: This category included a focal event such as natural disaster or loss of spouse. This category of stressors was not strongly associated with immune changes when taken as a whole. However, upon the consideration of the category of stressors some evidence emerged. After the loss of a spouse, decline in natural immune responses was observed. A non significant increase in natural and specific immune responses following exposure to natural disaster and no immune alterations with breast biopsy was observed.
Chronic stressors: This category included long term stressors without any clear end point such as living with a handicap, dementia care giving, and unemployment. Chronic stressors have negative effects on almost all functional measures of the immune system (both natural and specific immunity) irrespective of demographic variables such as gender and age.
Conclusion and Implications
Majority of the research on stress and immunity revealed a negative impact of stress on immune responses. This review indicates that both objective as well as perceived stress may negatively influence immune functions. The nature of stressor (acute or chronic) may have significant impact on the immune functioning. Brief acute stressors appear to enhance some parameters of immunity whereas chronic stress consistently showed detrimental effect on almost all parameters of immune functions. Research also elucidate that there is a possibility of behavioral pathways through which stress affects immune functions. Stressful experiences may lead individuals to engage in certain behaviors such as high alcohol intake, reduction in sleep and exercise which may have detrimental effect on immune functions. Pathways through which stress influences immune functions are complex and yet not fully understood. However, research show that stress and immune functions are mediated by the hypothalamic-pituitary-adrenal (HPA) axis and the autonomic (sympathetic and parasympathetic) nervous system.
The detrimental effect of stress on immune function has far reaching implications. One important corollary that can be derived is that the interventions aiming at stress reduction may have immune enhancing effect. Some research evidences are emerging in this direction too. Alexander et al. (1989) reported dramatic reduction in mortality rate by the use of meditation techniques. They found 0% mortality among elderly nursing home patient who practiced meditation daily over a period of 3 years while 40% mortality in control group. In another series of studies, Fawzy and colleagues (1990a, 1990b, 1993) found significantly higher immune cell activity for a group of people who underwent 6-week intensive group psychotherapy (focused on coping strategies for stress management). They reported that this higher immune activity persisted even 6 months after the intervention. Witek-Janusek et al. (2008) reported that therapeutic interventions such as mindfulness based stress reduction prevents decline in NK cell activity and increases cytokines (IL-10 and IL-4) among newly diagnosed breast cancer patients. Similarly, McCain et al. (2008) reported that 10 week cognitive-behavioral relaxation training (such as tai chi, spiritual growth groups) enhanced lymphocyte proliferative responses in a group of HIV patients. However, at present, research on the effectiveness of psychotherapeutic interventions on immune functions is sparse and difficult to make generalizations due to the varieties of immune measures and intervention techniques used. Future research in this direction may provide useful insights for theory as well as therapeutic interventions.
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