Named Series: Twenty Years of Brain, Behavior, and ImmunityUnderstanding the interaction between psychosocial stress and immune-related diseases: A stepwise progression
Introduction
The notion that stressful life experiences and one’s psychological state can influence the onset and progression of disease has existed for centuries, despite a paucity of evidence. Research conducted over the past 20 years in the field of psychoneuroimmunology has carefully examined this premise, leading to a much clearer picture of its strengths and weaknesses. The last 2 decades of research in the field of psychoneuroimmunology have been exciting, beginning with rigorous evidence that stress can affect the immune system, followed by intensive investigation of mediating mechanisms and extrapolation to disease processes. This short review focuses on the effects of psychological stress on immune functions and the etiology and progression of immune-mediated diseases since Brain, Behavior and Immunity (BBI) was first published in 1987. We will mainly concentrate on human work, in particular on the effects of stressors on viral infections, autoimmune diseases, wound healing and cancer. Since we are limited in the number of citations, we will predominantly cite review articles and apologize to all those colleagues who contributed to the findings but whose work could unfortunately not be cited due to page and reference limitations.
In response to stressful circumstances, the neuroendocrine system stimulates a series of adaptive responses involving behavioral, cardiovascular, metabolic, and immunological changes. Pituitary hormones such as prolactin and growth hormone, and neuropeptides like corticotropin-releasing hormone (CRH), adrenocorticotropic hormone (ACTH), neuropeptide Y (NPY) and the opioids can be released during stressor exposure and can affect cellular and humoral immune responses (Malarkey and Mills, 2007, Kelley et al., 2007, Blalock and Smith, 2007; see Fig. 1).
Experimental data in rodents and humans demonstrate that: (1) primary and secondary lymphoid organs are innervated by sympathetic noradrenergic nerve fibers, (2) all lymphoid cells express β-adrenoceptors and some subsets express α-adrenoreceptors, and (3) adrenaline and noradrenaline can alter circulation of leukocyte subpopulations and the functional capacity of immuncompetent cells, including cytokine production and release (Glaser and Kiecolt-Glaser, 2005, Sanders and Kavelaars, 2007).
Increased sympathetic adrenal activity appears to play a major role in immune changes observed after acute psychological stress. Hypothalamic–Pituitary–Adrenal (HPA) axis-activity, resulting in enhanced release of glucocorticoids, together with sympathetic mechanisms are mainly responsible for the inhibition of cellular and humoral immune responses after chronic psychological stress exposure (Glaser and Kiecolt-Glaser, 2005) (Fig. 1).
Glucocorticoids regulate multiple aspects of immune cell functions. For example, they regulate innate immune responses to bacterial and viral infection and can cause a shift in the adaptive immune response from T-helper-1 (Th-1) to T-helper-2 (Th-2) cell activity by inhibiting the production of pro-inflammatory cytokines such as Interleukin 12 (IL-12) and Tumor Necrosis Factor (TNF) or IL-2 and by stimulating the synthesis of the Th-2 cytokines IL-10 or IL-4 (Glaser and Kiecolt-Glaser, 2005).
Sensory peptides, such as Substance P (SP), also interact with the immune system and may play a role in the link between stress and inflammatory processes. The primary role of SP in the periphery is to promote inflammation in order to protect tissue from irritants and pathogens. Many immune cell types express receptors for SP and SP afferents innervate immune organs. Binding of SP to its receptor up-regulates pro-inflammatory cytokines, and influences a variety of other immunological processes that support inflammation. SP also plays a role in moderating stress pathways, such as the HPA-axis (see Rosenkranz, in press).
Glaser et al. (1987) published the first study on stress and immune functions in humans in BBI, demonstrating an inhibition of cellular immune functions and poorer cellular immune control of herpesvirus latency during examination stress in medical students. This first report in BBI confirmed earlier studies of this group and others demonstrating a suppression of humoral and cellular immune responses in individuals exposed to psychological stress. Over the last 20 years, the concept of immunosuppression following prolonged psychological stress has been demonstrated by numerous studies employing different stress models (e.g., examination, caregiving, marital conflict, bereavement) and parameters of the innate and adaptive immune response (e.g., circulation of leukocyte subpopulations, lymphocyte activity, cytokine production; Glaser and Kiecolt-Glaser, 2005).
At approximately the time that BBI was first published, an increasing number of publications reported effects of acute psychological stress on human peripheral immune functions. These studies, using public speech, mental arithmetic or naturalistic stressors such as a parachute jump, demonstrated a transient activation in innate immune responses, such as an increase in natural killer (NK) cell activity and NK cell and granulocyte numbers.
Over the last 2 decades we have learned a remarkable amount about how immune responses change during and after stressful events. However, there is still considerable debate over the normal versus pathological nature of these shifts in immunity. In healthy individuals, the changes in immune response following exposure to an acute psychological stressor are generally evaluated as an evolutionary adaptive process, indicating that immune responses are highly sensitive and quickly responsive to environmental stimuli, such as stressful or threatening circumstances. And the healthy immune system is capable of compensating for prolonged exposure to psychosocial stress-induced immune inhibition. However, experimental data in humans clearly indicate that the risk for illness due to the adverse effects of stress on the immune system can be increased.
Not only from animal experiments but also from human studies, we recognize today, however, that even exposure to acute stressors can have prolonged effects on the immune response to pathogens (Edwards et al., 2006). In addition, numerous studies demonstrate that maladaptive neuroendocrine hyper- or hypoactive responses of the HPA or the sympathetic nervous system (SNS) to stress, including glucocorticoid resistance, can function as risk factors for the initiation and progression of specific diseases, in particular viral infection and chronic, inflammatory autoimmune diseases.
Section snippets
Stress and chronic inflammatory diseases
The etiology of chronic inflammatory diseases such as rheumatoid arthritis (RA) or systemic lupus erythematosus (SLE) has been and remains unclear. Clinical observations suggest that stressful life events are associated with the onset and aggravation of symptoms in these autoimmune disorders. Twenty years ago, however, experimental data investigating the effects of stress on neuroendocrine and immunological responses and disease outcome in patients with RA or SLE were rare. Most of our
Stress and chronic inflammatory diseases
Based on knowledge of the kinetics and potential mechanisms of the way stress affects the immune response in the healthy individual, further research activities demonstrated that leukocytes from individuals with chronic inflammatory diseases such as RA or SLE differ in their response to acute psychological stress or adrenergic and corticoid stimulation in comparison to immuncompetent cells from healthy subjects (Straub et al., 2005). This can be explained by a disturbed neuroendocrine–immune
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