Immune Responses to Stress
Stress can be thought of as a constellation of events comprised of a stimulus, “stressor,” that precipitates a reaction in the brain, “stress perception,” that activates fight-or-flight mechanisms, “stress response” (Dhabhar and McEwen 1997). This entry will concentrate on what happens in the immune system in response to stress.
In 1884, the editor of the British Medical Journal noted that at funerals, “the depression of spirits under which the chief mourners labour at these melancholy occasions peculiarly predisposes them to some of the worst effects of the chill.” Despite many such anecdotes suggesting a link between psychological factors and immune function, it is only relatively recently that these associations have received widespread acceptance in the scientific and medical communities. In fact, as recently as 1984, an editorial piece in Nature proclaimed the persistence of a “stout band of near skeptics” who, while acknowledging that “there is probably a link between the central nervous system and the immune system,” still questioned whether “enough is yet known to sustain people’s hopes of explanation” (Maddox 1984). The prodigious development of the field of psychoneuroimmunology (PNI) over recent decades is more thoroughly reviewed elsewhere (Ader 2000; Fleshner and Laudenslager 2004); these articles clearly illustrate that, although many mechanisms still require further delineation, the progress of PNI, in terms of quality, quantity, and impact of the research, has exceeded the expectations of all but its most optimistic forefathers. These endeavors have revealed the complex intertwining of the nervous, endocrine, and immune systems that underpin the effects of stress on immunological health.
What Is Stress?
Walter Cannon first coined the term “stress” in this context in 1929, describing it as an emergency mechanism that mobilizes energy for fight-or-flight responses. Richard Lazarus proposed that the initiation of this stress response, be it an emotional (i.e., anger, anxiety), behavioral (i.e., running from threat), or biological response (i.e., cardiovascular changes, immune alterations), is governed by a person’s perception of their ability to cope with a particular stimulus. Psychological stress occurs, therefore, when a person’s perceived ability to cope with a situation is exceeded by the demands of the perceived stressor (Lazarus and Folkman 1984). One way of broadly categorizing psychological stress is into chronic and acute forms of stress. Chronic stressors are typically major life experiences, such as bereavement or caregiving for an ill family member, that have a negative impact lasting months or even years. In contrast, acute stressors, such as public speaking or examinations, are short lived, lasting minutes to hours, and typically elicit fight-or-flight responses. In PNI research, chronic stressors can be investigated by comparing the health and/or immune function of a group of participants who have been exposed to a particular stressful life event to a nonstressed matched control group. Alternatively, questionnaires can be used to assess the extent of the chronic stress experienced by an individual, either by indicating how many of a checklist of life events they have experienced in a set period of time or through more subjective measures such as perceived stress. Acute stress exposure can be manipulated experimentally; for example, psychological and immunological measures can be timed to coincide with naturalistic and predictable acute stressors, such as examination periods. In addition, there are a variety of validated laboratory procedures, such as the Trier Social Stress Task and the Paced Auditory Serial Addition Task, which can be used to induce acute stress in order to examine its immunological consequences.
Physiological Effects of Stress
Although a multitude of factors are likely to underpin the effects of stress on health, stress-induced alterations in immune function are clearly an important mechanism. Stress triggers a cascade of physiological responses, which provide a plausible pathway linking psychological factors with immune function and subsequent health. The two neuroendocrine pathways that have received most attention in the PNI literature are the hypothalamic-pituitary-adrenal axis (HPA) and the sympathetic-adrenal-medullary (SAM) axis. HPA axis activation is initiated during stress at the paraventricular nucleus of the hypothalamus which secretes corticotropin-releasing hormone (CRH). This causes the pituitary gland to release adrenocorticotropic hormone (ACTH), which in turn elicits the production of immunomodulatory glucocorticoids, such as cortisol, from the adrenal glands.
In the SAM axis, activation involves preganglionic sympathetic nervous system (SNS) neurons that descend along the spinal cord from nuclei in the brain stem. The release of the neurotransmitter acetylcholine from these neurons in the adrenal medulla stimulates chromaffin cells to secrete the catecholamine epinephrine. In contrast, postganglionic SNS fibers predominantly secrete the catecholamine norepinephrine upon activation. Therefore, activation of the SAM leads to the release of both epinephrine and norepinephrine. These catecholamines can influence immune cells as all leukocytes express adrenergic surface receptors. In addition, postganglionic nerve fibers directly innervate lymphoid organs including the thymus, spleen, lymph nodes, and bone marrow and therefore come into close proximity with immune cells (Glaser and Kiecolt-Glaser 2005).
It should also be noted that immune cells can also influence the SAM and HPA axis and subsequently impact brain function and psychological responses. Inflammatory cytokines, released during infection, can access the central nervous system through leaky regions in the blood-brain barrier, via specific transport molecules on the brain epithelium, and through the activation of vagal afferent fibers. These cytokines influence neurotransmitter and CRH function and can induce symptoms of “sickness behavior,” including anorexia, anhedonia, and reduced locomotor activity. It has been proposed that these changes in behavior reflect a reallocation of available resources, away from metabolically expensive activities such as foraging, toward behaviors likely to promote recovery from infection (Kelley et al. 2003).
Stress, Immune Function, and Disease
Psychological stress is implicated in the pathogenesis and exacerbation of many diseases and pathologies. For example, there is now evidence that stress can promote tumor growth and progression in a variety of cancers. These effects are likely to be mediated at a number of levels, including changes to local inflammatory signaling supporting initial tumor cell growth and proliferation and stress hormone-induced changes to cancer cell-matrix attachments, cell movement and invasion, angiogenesis, and sensitivity to apoptosis (Armaiz-Pena et al. 2009).
There is also a substantial body of evidence linking psychological factors such as chronic stress, depression, and coping strategies with various markers of HIV progression. Further, behavioral interventions designed to improve psychological functioning have had some success in modifying disease-relevant markers of immune function (Antoni 2003). It has been proposed that these associations between stress and HIV progression are likely mediated predominantly by changes in sympathetic nervous system activity, leading to alterations in cellular vulnerability to infection and innate antiviral responses (Cole 2008).
The PNI models of cancer and HIV are both consistent with the model in which stress is associated with decrements in immune function which leave the host vulnerable to tumor growth or infection. However, there is also evidence that stress exacerbates diseases in which the overactivity, rather than underactivity, of the immune system is implicated. For example, stress has been proposed to be an “aggravating factor” in asthma, where those people with asthma exhibit worsened symptoms during periods of psychological stress (Chen and Miller 2007). These observations are contrary to the intuitive perspective that a stress-induced reduction in immune activity would be beneficial for patients with conditions characterized by excessive inflammation. Instead, research has shown that in asthma, stress accentuates the inflammatory response in the airway induced by allergens and irritants, leading to more severe symptoms (Chen and Miller 2007). Taken together, there is clear evidence that psychological stress impacts the prognosis in a variety of different diseases via neuroendocrine-immune mechanisms.
Stress and Immune Function in Healthy Populations
Psychological stress can also affect the immune function of otherwise healthy individuals. One of the most dramatic demonstrations of this phenomenon was a series of studies conducted by Sheldon Cohen in which he gave 394 healthy participants nasal drops containing live respiratory viruses. Psychological stress, measured by questionnaire, was associated in a dose-response manner with an increased risk of acute infectious respiratory illness. As the extent and timing of the exposure to the pathogen was controlled, these studies provide compelling evidence that stress impacts the individual’s ability to protect themselves against infection. Later studies suggest that this effect is mediated by stress-induced disruption of the regulation of proinflammatory cytokines (Cohen 2005).
However, a key challenge for scientists investigating stress and immune function in healthy people is choosing an appropriate outcome measure in the absence of the disease-specific indicators. The immune system comprises a complex array of different cell types that are required to orchestrate precise and appropriate responses to a wide range of pathogens, all within the context of a variable neuroendocrine milieu. Not only are these cells required to work together in order to produce an effective immune response, what constitutes “effective” may change depending on the nature of the pathogen. For example, different immunological responses are required for intracellular viruses, compared to bacteria or parasites. As such, it is difficult to establish meaningful measures of “effective immune function” in healthy participants. The wide range of psychological and immunological measures employed by researchers to date is demonstrated in an excellent meta-analysis by Segerstrom and Miller, which examines the results of over 300 PNI studies (Segerstrom and Miller 2004).
This entry will focus on two in vivo measures of immune function, wound healing and antibody response to vaccination, in which an immunological “challenge” is administered and the subsequent immune response is assessed. These approaches assess the functionality of an orchestrated immune response, generated within the neuroendocrine milieu, and yield clinically relevant outcome measures. For example, the wound-healing process involves a complex series of processes, including inflammation, cellular migration and replication, and connective tissue deposition and remodeling; each stage is regulated by the cellular immune system. Wound healing can be assessed using naturalistic wounds, such as those experienced by patients with venous disease or by examining incisions administered during surgery. A more controlled method that also allows greater investigation of the mechanisms underpinning any stress effects involves administering an experimental wound and assessing the rate of healing over time. A recent systematic review and meta-analysis found that higher levels of psychological stress were consistently associated with impaired wound healing across a variety of different wound types (Walburn et al. 2009).
Antibody response to vaccination is another in vivo measure of immune function that has clear clinical implications. The controlled dose of an inactivated antigen induces a complex immune cascade that culminates in the production of specific antibodies; the extent of this response can be used as a measure of the functional status of the humoral immune system (Burns and Gallagher 2010). There is now considerable evidence that chronic psychological stress is associated with a poorer antibody response to many different vaccinations (Cohen et al. 2001). However, more recent research has demonstrated that acute stress can, in contrast, augment the immune response to vaccination (Edwards et al. 2007), potentially due to the rapid mobilization of immune cells during acute stress (Segerstrom and Miller 2004).
Models of PNI
Although early PNI research focused on the immunosuppressive effects of stress, more recently, it has become apparent that the precise implications for the immune system are dependent on the nature of the stressor. For example, the recent meta-analysis revealed that although chronic stressors were consistently associated with suppression of immune function, acute stressors often upregulated some parameters of immunity. Further, as chronic stress has been shown to affect diseases characterized by both reduced and excessive immune function, it is apparent that it may be the balance of immunological parameters that is critical (Segerstrom and Miller 2004). As an added layer of complexity, there is also evidence that the effects of stress on immunity are not consistent across individuals, even when the stressor is identical; differences in personality traits and cognitive and affective responses may also account for some variation in stress-induced immune changes (Kemeny 2009).
In terms of the implications of such changes, it is likely that stress-induced immune alterations are part of an adaptive response to threat that serves to enhance immunoprotection. This model postulates that situations of acute stress are likely, from an evolutionary perspective, to be associated with an increased risk of wounding or infection and, therefore, upregulation of immune function in such circumstances would be beneficial. If, however, this upregulation is directed against harmless allergens or self-antigens, or indeed it is dysregulated through chronic activation, it is likely to contribute to immunopathology (Dhabhar 2002). An alternative, ecological model of human PNI has recently been proposed, which instead suggests that even chronic stress-induced immunosuppression is part of a coordinated effort to efficiently conserve resources, rather than a sign of dysregulation (Segerstrom 2010). This ecological perspective emphasizes “phenotypic plasticity,” in which the value of a trait, such as robust immune activity, varies according to the environmental circumstances. Thus, immunosuppression during times of chronic stress may simply reflect a change in organism priorities toward the pursuit or protection of resources; the cost of reduced immunoprotection may, in these circumstances, be offset by the longer term health benefits of having these resources.
An array of compelling evidence now indicates that stress is associated with changes in immune function in both healthy and patient populations. Plausible physiological pathways through which psychological factors can influence cells of the immune system have been identified and explored, although there is much still to determine. It is now important to more fully elucidate the clinical implications of these changes and to translate these findings into effective biopsychosocial interventions.
References and Further Reading
- Lazarus, R. S., & Folkman, S. (1984). Stress, appraisal, and coping. New York: Springer.Google Scholar