Stress is an intrinsic part of life, and successfully adapting to stimuli that induce stress is necessary for the survival of an organism in its environment that is constantly changing. Although there is not a commonly used definition of stress, the concept of stress is often broken down into the challenge (called the stressor) and the behavioral and physiological responses to this challenge (called the stress response). A stressor is any stimulus that disrupts internal homeostasis, and can involve psychological, physical, or physiological stimuli. Initiation of the response to physiological and physical stressors is often subconscious and completely biological in nature. But, psychological stressors evoke an additional cognitive processing where the stressors must first be encoded as exceeding the organism's ability to cope with the demand. This cognitive processing sets into motion a coordinated behavioral and physiological response that is similar to the response to physiological and physical stressors. Two neuroendocrine pathways are major contributors to the stress response, namely, the hypothalamic-pituitary-adrenal (HPA) axis and the sympathetic nervous system (SNS). Activation of the HPA results in increased circulatory levels of adrenocorticotrophic hormone (ACTH) produced by the pituitary gland as well as mineralcorticoid and glucocorticoid hormones derived from the adrenal cortex. In contrast, SNS activation results in the release of norepinephrine (NE) from sympathetic nerve termini in SNS innervated tissues, including the GI tract and lymphoid tissues. As such, periods of stress are associated with increases in circulating glucocorticoid hormones (primarily cortisol in humans and corticosterone in rodents) as well as increased circulating and tissue levels of NE. These hormones have a variety of effects throughout the body, such as mobilizing energy for the well known "fight-or-flight" response, that are all aimed at helping the body respond to the demands being placed on it.
Research in the field of PNI has amply demonstrated that stressful periods are associated with exacerbations of a variety of different diseases. For example, it has been demonstrated that individuals reporting higher levels of stress in their daily lives are more likely to develop clinical symptoms during experimental respiratory viral infection (Cohen 2005). To determine if these effects are due to stressor-induced immunosuppression, many researchers have studied the immune response to vaccination during stressful situations, and have found that stressors influence antibody and T-cell responses to vaccines. For example, it was demonstrated in medical students that responsiveness to hepatitis B vaccination was significantly reduced during final exams, an effect found to be associated with stress perception and feelings of loneliness (Glaser et al. 1992; Jabaaij et al. 1996). Likewise, the chronic stress associated with caring for a spouse with Alzheimer's disease (AD) resulted in lower antibody responses to influenza vaccination (Kiecolt-Glaser et al. 1996). Determining the mechanisms through which these stressors affect immune reactivity in humans is difficult, but many animal studies demonstrate that stressor-induced hormones are in fact responsible for the stressor-induced exacerbations of infectious diseases. For example, stressor-induced elevations in corticosterone have been found to suppress lymphocyte trafficking and cytokine production during influenza viral infection (Dobbs et al. 1996; Hermann et al. 1995), as well as antigen processing and presentation by dendritic cells infected with recombinant vaccinia virus (Elftman et al. 2007; Truckenmiller et al. 2005, 2006). The anti-inflammatory effects of glucocorticoid hormones are now well known, and it is evident that glucocorticoid hormones suppress inflammatory cytokine production in part through negative regulation of NF-kB activation and function (Sternberg 2006).
The catecholamines can also have immunomodulatory effects through activation of adrenergic receptors. Animal models have demonstrated that adrenergic signaling is responsible for stressor-induced suppression of cytolytic CD8+ T cell responses during influenza viral infection (Dobbs et al. 1993). Likewise, an acute cold/restraint stressor significantly suppressed the CD4+ T cell response to Listeria monocytogenes infection through a b1-adrenergic receptor mediated mechanism (Cao et al. 2003). Ex vivo and in vitro data has revealed that catecholamine stimulation of b-adrenergic receptors at the time of immune challenge, suppresses cytokine production, NK cell activity, and T cell proliferation. In this case, cAMP is thought to be involved in this catecholamine induced immunosuppression (Padgett and Glaser 2003).
Under some circumstances, though, stressors can also enhance certain components of the immune response, particularly the innate immune response. For example, Lyte et al. (1990) demonstrated that exposing mice to a social stressor, called Social Conflict, significantly increased the phagocytic capacity of elicited peritoneal macrophages (Lyte et al. 1990). And, rats exposed to acute shock as a stressor produce higher levels of nitric oxide upon subcutaneous bacterial challenge (Campisi et al. 2002). Because in vitro studies have shown that culturing macrophages with NE increases phagocytosis (Garcia et al. 2003) and the production of nitric oxide (Chi et al. 2003), it is likely that stressor-induced increases in phagocyte activity are NE dependent.
These studies reflect the complex nature of the impact of neuroendocrine hormones on the immune response. The field of microbial endocrinology (Lyte 2004) has added an additional layer of complexity by demonstrating that microbes themselves can be influenced by stressor-induced hormones. Moreover, research by our group and by others have shown that more primitive defense mechanisms, such as microbial barrier defenses at cutaneous and mucosal surfaces, can also be affected by the stress response. These studies are a logical extension of previous findings within the fields of PNI and microbial endocrinology, and will be discussed within the context of stress physiology and infectious disease.
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