Enhancing versus suppressive effects of stress on immune function: implications for immunoprotection and immunopathology

Abstract

Stress is known to suppress immune function and increase susceptibility to infections and cancer. Paradoxically, stress is also known to exacerbate asthma, and allergic, autoimmune and inflammatory diseases, although such diseases should be ameliorated by immunosuppression. Moreover, the short-term fight-or-flight stress response is one of nature's fundamental defense mechanisms that enables the cardiovascular and musculoskeletal systems to promote survival, and it is unlikely that this response would suppress immune function at a time when it is most required for survival (e.g. in response to wounding and infection by a predator or aggressor). These observations suggest that stress may suppress immune function under some conditions while enhancing it under others. The effects of stress are likely to be beneficial or harmful depending on the type (immunoprotective, immunoregulatory/inhibitory, or immunopathological) of immune response that is affected. Studies have shown that several critical factors influence the direction (enhancing vs. suppressive) of the effects of stress or stress hormones on immune function: (1) Duration (acute vs. chronic) of stress: Acute or short-term stress experienced at the time of immune activation can enhance innate and adaptive immune responses. Chronic or long-term stress can suppress immunity by decreasing immune cell numbers and function and/or increasing active immunosuppressive mechanisms (e.g. regulatory T cells). Chronic stress can also dysregulate immune function by promoting proinflammatory and type-2 cytokine-driven responses. (2) Effects of stress on leukocyte distribution: Compartments that are enriched with immune cells during acute stress show immunoenhancement, while those that are depleted of leukocytes, show immunosuppression. (3) The differential effects of physiologic versus pharmacologic concentrations of glucocorticoids, and the differential effects of endogenous versus synthetic glucocorticoids: Endogenous hormones in physiological concentrations can have immunoenhancing effects. Endogenous hormones at pharmacologic concentrations, and synthetic hormones, are immunosuppressive. (4) The timing of stressor or stress hormone exposure relative to the time of activation and time course of the immune response: Immunoenhancement is observed when acute stress is experienced at early stages of immune activation, while immunosuppression may be observed at late stages of the immune response. We propose that it is important to study and, if possible, to clinically harness the immunoenhancing effects of the acute stress response, that evolution has finely sculpted as a survival mechanism, just as we study its maladaptive ramifications (chronic stress) that evolution has yet to resolve. In view of the ubiquitous nature of stress and its significant effects on immunoprotection as well as immunopathology, it is important to further elucidate the mechanisms mediating stress-immune interactions and to meaningfully translate findings from bench to bedside.

Fig. 1.

The relationship among stress, immune function, and health outcomes. Acute stress experienced during vaccination, wounding, or infection may enhance immunoprotective responses. Acute stress experienced during immune activation in response to self/innocuous antigens or allergens may exacerbate proinflammatory and autoimmune disorders. Chronic stress-in duced increases in proinflammatory or type-2 cytokine-mediated immune responses may also exacerbate inflammatory and autoimmune disease. Chronic stress-induced suppression of immune responses may decrease the efficacy of vaccination and wound healing and decrease resistance to infection and cancer.

Fig. 2.

The stress spectrum model. We have proposed a definition of stress as a constellation of events, consisting of a stimulus (stressor), that precipitates a reaction in the brain (stress perception & processing), that activates physiologic fight-or-flight systems in the body (physiological stress response) [9] . The duration of a physiological stress response is the critical determinant of its effects on immune function and health. The stressor itself may be acute (e.g. narrowly missing being hit by a car) or chronic (e.g. caring for a chronicallyill child, spouse or parent). Stress perception and processing by the brain are critical for determining the duration and magnitude of the physiological stress response stimulated by any given stressor. Acute or chronic stress is generally superimposed on a psychophysiological health maintenance steady state. The extent and efficiency with which an organism returns to its health maintenance steady state after stress depends on resilience, which we define as the capacity of psychological and interacting physiological systems to recover from challenging conditions. Factors such as coping mechanisms, sense of control, optimism, social support, early life experiences, learning, genetics, and sleep are important mediators of psychological resilience . Factors such as neuroendocrine reactivity, genetics, environment, nutrition, and sleep are important mediators of physiological resilience . Psychological resilience mechanisms are especially important in humans because they can limit the duration and magnitude of chronic stress responses. By the same token, psychogenic stressors can be particularly detrimental in human subjects because they may generate stress responses long after stressor exposure or even in the absence of physical stressors or salient threats. The physiological stress response is the ultimate effector arm of the stress spectrum. It may consist of acute or chronic physiological activation (neurotransmitters, hormones, and their molecular, cellular, organ-level and systemic effects) that results in psychophysiological states that have different effects on health. Acute stress generally results in activation of mechanisms that include enhancement of immune function, while chronic stress results in health-aversive conditions that result in dysregulation or suppression of immune function. The molecular mechanisms me diating conversion from positive to negative effects of stress on immune function and health are slowly beginning to emerge, and merit further investigation. Reprinted from Dhabhar and McEwen [17], with permission.