Glaser & Kiecolt-Glaser (2005). Stress-induced immune dysfunction: Implications for health – Article summary

The central nervous system (CNS), endocrine system and the immune system interact with each other. Stressors can dysregulate the immune response by affecting the interplay of these systems. Stressors are often categorized by duration and course (i.e. discrete vs. continuous). Stressors that are perceived as unpredictable or uncontrollable may continue to be associated with increased levels of stress hormones, even after repeated exposure. The ability to return to neuroendocrine baseline in a relatively short time (i.e. unwind) influences the total burden that stressors place on an individual.

Chronic stressors are detrimental to the immune system whereas brief stressors may enhance aspects of immune function. Stressors can increase susceptibility to infectious agents (1), influence the severity of infectious disease (2), diminish the strength immune responses to vaccines (3), reactivate latent herpesviruses (4), lead to slow wound healing (5) and can increase the production of pro-inflammatory cytokines that are associated with a spectrum of age-related diseases (6).

Stressors can activate the sympathetic-adrenal-medullary (SAM) axis as well as the HPA axis. This provokes the release of pituitary and adrenal hormones. Depression boosts cortisol levels and increases in cortisol can provoke immunologic changes. Most immune cells have receptors for one or more hormones associated with the SAM and HPA axes, the so-called stress-hormones.

Immune modulation through the stress hormones might occur directly through binding of the hormone to its cognate receptor at the surface of the cell. It may also occur indirectly by inducing dysregulation of the production of cytokines, which, in turn, affect target cells. Communication between the SNS and the immune system is bidirectional. Stressed individuals are more likely to have health habits that put them at greater risk (e.g. smoking).

Short-term stressors increase natural-killer-cell activity and increase the numbers of some types of leukocyte. This may be beneficial, however, this is still controversial.

Stressors can enhance the risk of developing infectious disease and can prolong infectious illness episodes. The HPA axis and the SNS are the main immunoregulatory pathways that can influence the pathophysiology of a viral infection. The protective capacity of antiviral vaccines depends on their ability to induce humoral and cell-mediated immune responses. However, this is poorer in stressed individuals. There is a poorer antibody response in individuals who are stressed both in regular infection and in viral or antibacterial vaccine. Being stressed leads to a delayed, shorter and weaker immune response.

Distress can also affect susceptibility to infection with respiratory viruses. The stress index is a measure of stress consisting of the number of stressful life events (1), the degree that a participant felt that current demands exceeded one’s abilities to cope (2) and scores from negative emotion word list. Stressors that lasted for one month or more were the best predictors for developing colds. Stress dysregulates the humoral and cellular immune responses to pathogens and increase the risk for developing infectious disease.

The cellular immune response has an important role in controlling the pathophysiology of herpesvirus infection and the expression or replication of latent herpesviruses. One or more herpesviruses can be reactivated when the cellular immune response is impaired and the infections are often more severe. Stress increases the development and severity of HSV infection. In addition to that, it also suppresses components of primary and memory cytotoxic T lymphocyte responses to HSV infection.

Expression of latent infection can be modulated by psychological stressors. Stressors can modulate the steady-state expression of latent HSV, EBV and CMV, downregulating the specific T-cell response to the virus to an extent that is sufficient to result in viral reactivation. Different types of stress could have an impact on the reactivation of latent HSV-1 and EBV.

Experiencing a stressful situation leads to the activation of the HPA and the SAM axis. The production of adrenocorticotropic hormone by the pituitary gland results in the production of glucocorticoid hormones. The SAM axis can be activated by stimulation of the adrenal medulla to produce catecholamines adrenaline and noradrenaline. It can also be activated by hard-wiring through SNS innervation of lymphoid organs.

Leukocytes have receptors for stress hormones that are produced by the pituitary and adrenal glands and can be modulated by the bindings of these hormones to their respective receptors. Noradrenaline produced at nerve endings can also modulate immune cell-function by binding its receptor at the surface of cells within lymphoid organs. The interactions are bidirectional. Cytokines produced by immune cells can modulate the activity of the hypothalamus.

The stages of wound healing are the inflammatory stage (1), the proliferative stage (2) and wound remodelling (3). Immune function has a key role in the early stages of wound healing. Stress disrupts the production of inflammatory cytokines that are important for wound healing. Wound healing is delayed as a result of stress.

Disruption of neuroendocrine homeostasis modulates the early stages of wound healing. Dysregulation of glucocorticoid secretion is one neuroendocrine pathway through which stress alters healing.

The inflammatory cytokine IL-6 is produced by T-cells, B-cells, monocytes and non-lymphoid cell types. It is an inducer of C-reactive protein (CRP). The combination of IL-6 and CRP is important in the process that leads to the development of cardiovascular disease. Negative emotions augment the production of IL-6. Stressors and depression can sensitize the inflammatory response which produces heightened responsiveness to subsequent stressful events. This can lead to an increased risk for age-related diseases and conditions.

Chronic stress might be associated with premature ageing of immune cells. This may accelerate the risk of developing age-related diseases.