Since the dawn of time, organisms have been subject to evolutionary pressure from the environment. The ability to respond to environmental threats or stressors such as predation or natural disaster enhanced survival and therefore reproductive capacity, and physiological responses that supported such responses could be selected for. In mammals, these responses include changes that increase the delivery of oxygen and glucose to the heart and the large skeletal muscles. The result is physiological support for adaptive behaviors such as “fight or flight.” Immune responses to stressful situations may be part of these adaptive responses because, in addition to the risk inherent in the situation (e.g., a predator), fighting and fleeing carries the risk of injury and subsequent entry of infectious agents into the bloodstream or skin. Any wound in the skin is likely to contain pathogens that could multiply and cause infection (Williams & Leaper, 1998). Stress-induced changes in the immune system that could accelerate wound repair and help prevent infections from taking hold would therefore be adaptive and selected along with other physiological changes that increased evolutionary fitness.

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Modern humans rarely encounter many of the stimuli that commonly evoked fight-or-flight responses for their ancestors, such as predation or inclement weather without protection. However, human physiological response continues to reflect the demands of earlier environments. Threats that do not require a physical response (e.g., academic exams) may therefore have physical consequences, including changes in the immune system. Indeed, over the past 30 years, more than 300 studies have been done on stress and immunity in humans, and together they have shown that psychological challenges are capable of modifying various features of the immune response. In this article we attempt to consolidate empirical knowledge about psychological stress and the human immune system through meta-analysis. Both the construct of stress and the human immune system are complex, and both could consume book-length reviews.  Physiologic Alterations in Bodily Systems in Response to Disease Processes.Our review, therefore, focuses on those aspects that are most often represented in the stress and immunity literature and therefore directly relevant to the meta-analysis.

Conceptualizing Stress

Despite nearly a century of research on various aspects of stress, investigators still find it difficult to achieve consensus on a satisfactory definition of this concept. Most of the studies contributing to this review simply define stress as circumstances that most people would find stressful, that is, stressors. We adopted Elliot and Eisdorfer’s (1982) taxonomy to characterize these stressors. This taxonomy has the advantage of distinguishing among stressors on two important dimensions: duration and course (e.g., discrete vs. continuous). The taxonomy includes five categories of stressors. Acute time-limited stressors involve laboratory challenges such as public speaking or mental arithmetic. Brief naturalistic stressors, such as academic examinations, involve a person confronting a real-life short-term challenge. In stressful event sequences, a focal event, such as the loss of a spouse or a major natural disaster, gives rise to a series of related challenges. Although affected individuals usually do not know exactly when these challenges will subside, they have a clear sense that at some point in the future they will. Chronic stressors, unlike the other demands we have described, usually pervade a person’s life, forcing him or her to restructure his or her identity or social roles. Another feature of chronic stressors is their stability—the person either does not know whether or when the challenge will end or can be certain that it will never end. Examples of chronic stressors include suffering a traumatic injury that leads to physical disability, providing care for a spouse with severe dementia, or being a refugee forced out of one’s native country by war. Distant stressors are traumatic experiences that occurred in the distant past yet have the potential to continue modifying immune system function because of their long-lasting cognitive and emotional sequelae (Baum, Cohen, & Hall, 1993).Physiologic Alterations in Bodily Systems in Response to Disease Processes.  Examples of distant stressors include having been sexually assaulted as a child, having witnessed the death of a fellow soldier during combat, and having been a prisoner of war.

In addition to the presence of difficult circumstances, investigators also use life-event interviews and life-event checklists to capture the total number of different stressors encountered over a specified time frame. Depending on the instrument, the focus of these assessments can be either major life events (e.g., getting divorced, going bankrupt) or minor daily hassles (e.g., getting a speeding ticket, having to clean up a mess in the house). With the more sophisticated instruments, judges then code stressor severity according to how the average person in similar biographical circumstances would respond (e.g., S. Cohen et al., 1998; Evans et al., 1995).

A smaller number of studies enrolled large populations of adults who were not experiencing any specific difficulty and examined whether their immune responses varied according to their reports of perceived stress, intrusive thoughts, or both. Other studies have examined stressed populations, in which a larger range of subjective responses may be detected. This work grows out of the view that people’s biological responses to stressful circumstances are heavily dependent on their appraisals of the situation and cognitive and emotional responses to it (Baum et al., 1993; Frankenhauser, 1975; Tomaka, Blascovich, Kibler, & Ernst, 1997).

Overview of the Immune System

As many behavioral scientists are unfamiliar with the details of the immune system, we provide a brief overview. For a more complete treatment, the reader is directed to the sources for the information presented here (Benjamini, Coico, & Sunshine, 2000; Janeway & Travers, 1997; Rabin, 1999). Critical characteristics of various immune components and assays are also listed in Table 1.

Pathways Between Stress and the Immune System

How could stress “get inside the body” to affect the immune response? First, sympathetic fibers descend from the brain into both primary (bone marrow and thymus) and secondary (spleen and lymph nodes) lymphoid tissues (Felten & Felten, 1994). These fibers can release a wide variety of substances that influence immune responses by binding to receptors on white blood cells (Ader, Cohen, & Felten, 1995; Felten & Felten, 1994; Kemeny, Solomon, Morley, & Herbert, 1992; Rabin, 1999). Though all lymphocytes have adrenergic receptors, differential density and sensitivity of adrenergic receptors on lymphocytes may affect responsiveness to stress among cell subsets. For example, natural killer cells have both high-density and high-affinity β₂-adrenergic receptors, B cells have high density but lower affinity, and T cells have the lowest density (Anstead, Hunt, Carlson, & Burki, 1998; Landmann, 1992; Maisel, Fowler, Rearden, Motulsky, & Michel, 1989). Second, the hypothalamic–pituitary–adrenal axis, the sympathetic–adrenal–medullary axis, and the hypothalamic–pituitary–ovarian axis secrete the adrenal hormones epinephrine, norepinephrine, and cortisol; the pituitary hormones prolactin and growth hormone; and the brain peptides melatonin, β-endorphin, and enkephalin. These substances bind to specific receptors on white blood cells and have diverse regulatory effects on their distribution and function (Ader, Felten, & Cohen, 2001). Physiologic Alterations in Bodily Systems in Response to Disease Processes. Third, people’s efforts to manage the demands of stressful experience sometimes lead them to engage in behaviors—such as alcohol use or changes in sleeping patterns—that also could modify immune system processes (Kiecolt-Glaser & Glaser, 1988). Thus, behavior represents a potentially important pathway linking stress with the immune system.

Maier and Watkins (1998) proposed an even closer relationship between stress and immune function: that the immunological changes associated with stress were adapted from the immunological changes in response to infection. Immunological activation in mammals results in a syndrome called sickness behavior, which consists of behavioral changes such as reduction in activity, social interaction, and sexual activity, as well as increased responsiveness to pain, anorexia, and depressed mood. This syndrome is probably adaptive in that it results in energy conservation at a time when such energy is best directed toward fighting infection. Maier and Watkins drew parallels between the behavioral, neuroendo-crine, and thermoregulatory responses to sickness and stress. The common thread between the two is the energy mobilization and redirection that is necessary to fight attackers both within and without.

Models of Stress, the Immune System, and Health

Conceptualizations of the nature of the relationship between stress and the immune system have changed over time. Selye’s (1975) finding of thymic involution led to an initial model in which stress is broadly immunosuppressive. Early human studies supported this model, reporting that chronic forms of stress were accompanied by reduced natural killer cell cytotoxicity, suppressed lymphocyte proliferative responses, and blunted humoral responses to immunization (see S. Cohen, Miller, & Rabin, 2001; Herbert & Cohen, 1993;Kiecolt-Glaser, Glaser, Gravenstein, Malarkey, & Sheridan, 1996, for reviews). Diminished immune responses of this nature were assumed to be responsible for the heightened incidence of infectious and neoplastic diseases found among chronically stressed individuals (Andersen, Kiecolt-Glaser, & Glaser, 1994; S. Cohen & Williamson, 1991).

Although the global immunosuppression model enjoyed long popularity and continues to be influential, the broad decreases in immune function it predicts would not have been evolutionarily adaptive in life-threatening circumstances. Dhabhar and McEwen (1997, 2001) proposed that acute fight-or-flight stressors should instead cause redistribution of immune cells into the compartments in which they can act the most quickly and efficiently against invaders. In a series of experiments with mice, they found that during acute stress, T cells selectively redistributed into the skin, where they contributed to enhancement of the immune response. In contrast, during chronic stress, T cells were shunted away from the skin, and the immune response to skin test challenge was diminished (Dhabhar & McEwen, 1997). On the basis of these findings they proposed a biphasic model in which acute stress enhances, and chronic stress suppresses, the immune response. Physiologic Alterations in Bodily Systems in Response to Disease Processes.

A modification of this model posits that short-term changes in all components of the immune system (natural and specific) are unlikely to occur because they would expend too much energy to be adaptive in life-threatening circumstances. Instead, stress should shift the balance of the immune response toward activating natural processes and diminishing specific processes. The premise underlying this model is that natural immune responses are better suited to managing the potential complications of life-threatening situations than specific immune responses because they can unfold much more rapidly, are subject to fewer inhibitory constraints, and require less energy to be diverted from other bodily systems that support the fight-or-flight response (Dopp, Miller, Myers, & Fahey, 2000; Sapolsky, 1998).

Even with this modification of the biphasic model, neither it nor the global immunosuppression model sufficiently explains findings that link chronic stress with both disease outcomes associated with inadequate immunity (infectious and neoplastic disease) and disease outcomes associated with excessive immune activity (allergic and autoimmune disease). To resolve this paradox, some researchers have chosen to focus on how chronic stress might shift the balance of the immune response. The most well-known of these models hypothesizes that chronic stress elicits simultaneous enhancement and suppression of the immune response by altering patterns of cytokine secretion (Marshall et al., 1998). Th1 cytokines, which activate cellular immunity to provide defense against many kinds of infection and some kinds of neoplastic disease, are suppressed. This suppression has permissive effects on production of Th2 cytokines, which activate humoral immunity and exacerbate allergy and many kinds of autoimmune disease. This shift can occur via the effects of stress hormones such as cortisol (Chiappelli, Manfrini, Franceschi, Cossarizza, & Black, 1994). Th1-to-Th2 shift changes the balance of the immune response without necessarily changing the overall level of activation or function within the system. Because a diminished Th1-mediated cellular immune response could increase vulnerability to infectious and neoplastic disease, and an enhanced Th-2 mediated humoral immune response could increase vulnerability to autoimmune and allergic diseases, this cytokine shift model also is able to reconcile patterns of stress-related immune change with patterns of stress-related disease outcomes (Marshall et al., 1998).

Who Is Vulnerable to Stress-Induced Immune Changes?

If the stress response in the immune system evolved, a healthy organism should not be adversely affected by activation of this response because such an effect would likely have been selected against. Although there is direct evidence that stress-related immunosuppression can increase vulnerability to disease in animals (e.g., Ben Eliyahu, Shakhar, Page, Stefanski, & Shakhar, 2000; Quan et al., 2001; Shavit et al., 1985; Sheridan et al., 1998), there is little or no evidence linking stress-related immune change in healthy humans to disease vulnerability. Even large stress-induced immune changes can have small clinical consequences because of the redundancy of the immune system’s components or because they do not persist for a sufficient duration to enhance disease susceptibility. In short, the immune system is remarkably flexible and capable of substantial change without compromising an otherwise healthy host.

However, the flexibility of the immune system can be compromised by age and disease. As humans age, the immune system becomes senescent (Boucher et al., 1998; Wikby, Johansson, Ferguson, & Olsson, 1994). As a consequence, older adults are less able to respond to vaccines and mount cellular immune responses, which in turn may contribute to early mortality (Ferguson, Wikby, Maxson, Olsson, & Johansson, 1995; Wayne, Rhyne, Garry, & Goodwin, 1990).Physiologic Alterations in Bodily Systems in Response to Disease Processes.  The decreased ability of the immune system to respond to stimulation is one indicator of its loss of flexibility.

Loss of self-regulation is also characteristic of disease states. In autoimmune disease, for example, the immune system treats self-tissue as an invader, attacking it and causing pathology such as multiple sclerosis, rheumatoid arthritis, Crohn’s disease, and lupus. Immune reactions can also be exaggerated and pathological, as in asthma, and suggest loss of self-regulation. Finally, infection with HIV progressively incapacitates T-helper cells, leading to loss of the regulation usually provided by these cells. Although each of these diseases has distinct clinical consequences, the change in the immune system from flexible and balanced to inflexible and unbalanced suggests increased vulnerability to stress-related immune dysregulation; furthermore, dysregulation in the presence of disease may have clinical consequences (e.g., Bower, Kemeny, Taylor, & Fahey, 1998).

The Present Analysis

We performed a meta-analysis of published results linking stress and the immune system. We feel that this area is in particular need of a quantitative review because of the methodological nature of most studies in this area. For practical and economic reasons, many psychoneuroimmunology studies have a relatively small sample size, creating the possibility of Type II error. Furthermore, many studies examine a broad range of immunological parameters, creating the possibility of Type I error. A quantitative review, of which meta-analysis is the best example, can better distinguish reliable effects from those arising from both Type I and Type II error than can a qualitative review. Physiologic Alterations in Bodily Systems in Response to Disease Processes.

We combined studies in such a way as to test the models of stress and immune change reviewed above. First, we examined each stressor type separately, yielding separate effects for stressors of different duration and trajectory. Second, we examined both healthy and medical populations, allowing comparison of the effects of stress on resilient and vulnerable populations; along the same lines, we also examined the effects of age. Finally, we examined all immune parameters separately so that patterns of response (e.g., global immunosuppression vs. cytokine shift) would be clearer.

Method

Results