Abstract
Research over the past three to four decades has clearly established that psychological stress affects clinically relevant immune system outcomes, including inflammatory processes, wound healing, and responses to infectious agents and other immune challenges [e.g., vaccinations, autoimmunity, cancer]. Individuals vary in their ability to cope with stressful life events, and differences in perceptions of stress, mood [e.g., depressive symptoms], and adverse life events can modify the magnitude to which stressors exert a negative influence on immune function. In this chapter, we provide an overview of key findings linking everyday stressors to immune function and health. In addition, the complexity of a plausible mechanism through which chronic stress and elevated inflammation might result in serious health consequences including cardiovascular disease, diabetes, and cancer is delineated. The literature provides support for several promising avenues for interventions to prevent stress-induced immune dysregulation. Research examining stressors in everyday life also has strong implications with respect to understanding the effects of more extreme stressors, such as those encountered during space flight, a complex environmental, physiological, and psychological challenge with multiple adverse consequences for human health.
1 Stress, Immunity, and Health
The central nervous system [CNS], endocrine system, and immune system are complex systems that interact with each other. Stressful life events and the negative emotions they generate can dysregulate the immune response by disturbing the sensitive interplay among these systems [Glaser and Kiecolt-Glaser 2005]. Psychoneuroimmunology [PNI] is a field of investigation concerned with the interactions of psychological factors with the neuroendocrine and immune system and consequences for higher brain function and human behavior [Dantzer 2010].
A stressor can be defined as an event that exceeds an individual’s perceived ability to cope [Lazarus and Folkman 1984] and can result in an allostatic load and overload [see Chap. 4]. Individual differences exist in the extent to which people mount a physiological stress response. Individual differences in stress physiology are, among other things, related to the brain, which plays a critical role in appraising stressors, as well as in modulating immune system reactivity to physical and social threats [Slavich and Irwin 2014]. Additionally, certain characteristics of a situation are associated with greater stress responses, including the intensity, severity, controllability, and predictability of the stressor. Physiological reactivity to stressors are commonly observed even after repeated exposure to the same stressor [Dhabhar 2014].
The autonomic nervous system [ANS] and the hypothalamic-pituitary-adrenal [HPA] axis are two major stress-signaling pathways that contribute to immune dysregulation [Glaser and Kiecolt-Glaser 2005]. Experiencing a stressful situation, as perceived by the brain, activates the HPA axis and the sympathetic-adrenal medullary axis [SAM], which provokes the release of hormones which modulate immune function including adrenocorticotropic hormone [ACTH], cortisol, growth hormone, prolactin, epinephrine, and norepinephrine [Glaser and Kiecolt-Glaser 2005] [see Chap. 7].
Immunity is the natural or acquired resistance of an organism to bacterial or viral invaders, diseases, or infections, while having adequate tolerance to avoid allergy, and autoimmune diseases. Lymphocytes, including T and B cells are the main type of cells of the immune system. T cells orchestrate the immune response via the production of cytokines and stimulate B cells to produce antibodies and signal killer cells to destroy the antigen-displaying cell [Sompayrac 2016]. Helper T cells [Th] can be separated into Th2 cells, which primarily produce IL-2, IFN-γ and TNF, and Th2 cells, which produce IL-4, IL-5, IL-6, IL-10, and IL-13. Typically, type 1 cytokines favor the development of a strong cellular immune response, whereas type 2 cytokines favor a strong humoral immune response [Spellberg and Edwards Jr. 2001]. Chronic stress can suppress or dysregulate innate and adaptive immune responses by altering the type 1/type 2 cytokine balance, thereby inducing low-grade inflammation and suppressing the function of immuno-protective cells [Dhabhar 2014].
A primary focus of the field of psychoneuroimmunology has been to understanding the link between stress and inflammatory responses. Although acute inflammation is an adaptive response to physical injury or infection, exaggerated and/or prolonged inflammatory responses are detrimental to health [Dhabhar 2014]. Chronic inflammation secondary to long-term stress has been causally linked with risk for numerous diseases, including infectious illnesses, cardiovascular disease, diabetes, certain cancers, and autoimmune disease, as well as general frailty and mortality [Glaser and Kiecolt-Glaser 2005; Dhabhar 2014; Padro and Sanders 2014; Webster Marketon and Glaser 2008]. One potential explanation for the mechanism linking chronic stress and inflammation in the onset of a wide range of diseases is that prolonged stressors result in glucocorticoid receptor resistance, which, in turn, causes dysregulated HPA axis function and interferes with the appropriate regulation of inflammation [Cohen et al. 2012].
Animal models have provided compelling evidence that biobehavioral stress mechanisms and their molecular and cellular pathways can cause illness behavior and illness itself. These experimental studies have conclusively demonstrated that exposure to restraint stress triggers exaggerated inflammatory responses [Korte et al. 1992; Ahlers et al. 1980; Bartolomucci et al. 2003]. In addition, pharmacological experiments have amply demonstrated that mice injected with proinflammatory cytokines, including IL-1β or TNF, have decreased motor activity, social withdrawal, reduced food and water intake, increased slow-wave sleep, altered cognition, and increased pain sensitivity [Bluthe et al. 2000; Dantzer 2009]. These experiments highlight how conditions of chronic inflammation can induce sickness and depressive-like behaviors in response to chronic stress [Dantzer et al. 2008].
2 Stress and Wound Healing
Wound healing is a vitally important process during recovery from either injury or surgery. Poor healing is associated with increased risks for wound infections and other complications, patient discomfort, prolonged hospital stays, and delays in one’s return to normal activities [Tevis and Kennedy 2013]. Converging evidence from observational, experimental, and interventional studies implies that stress and other behavioral factors can impede wound healing processes and compromise immunity via multiple physiological pathways [Kiecolt-Glaser et al. 1998; Gouin et al. 2008; Ebrecht et al. 2004; Pinto et al. 2016; Walburn et al. 2009].
Wound healing progresses through several sequential and overlapping phases, including inflammation, proliferation, and regeneration. Cellular immunity plays an important role in the regulation of wound healing through the production of proinflammatory cytokines and chemokines [e.g., platelet derived growth factor [PDG]; transforming growth factor [TGF]; vascular endothelial growth factor [VEGF]; TNF; IFN-γ; IL-1β; IL-8], which mediate many of the complex interactions involved in wound healing. These factors act as chemo-attractants for the migration of phagocytes and other cells to the wound site, starting the proliferative phase which involves the recruitment and replication of cells necessary for tissue regeneration and capillary regrowth [Gethin 2012]. Inflammation is a prerequisite to healing. Proinflammatory cytokines help to protect against infection and prepare injured tissue for repair by enhancing the recruitment and activation of phagocytes. Unfortunately, stress disrupts the production of proinflammatory cytokines that are essential for wound healing and, when dysregulated, impose a considerable delay in wound repair [Gouin and Kiecolt-Glaser 2011].
The clinical relevance of the relationship between stress and impaired wound healing has been demonstrated in several studies. In one experiment, individuals with a “slow healing” speed had higher stress and higher cortisol levels at awakening, implicating a key role of elevated cortisol levels in the process of cutaneous wound healing [Ebrecht et al. 2004]. A meta-analysis [Walburn et al. 2009] corroborated these findings, synthesizing 17 articles that documented how stress is significantly associated with impaired healing and dysregulation of biomarkers crucial to wound healing. In addition to this meta-analysis, a statistically significant and moderately strong inverse correlation of r = −0.42 [95% CI = −0.51 to −0.32; p