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Immune Cell Distribution, Effects of Stress on*
Immune Cell Distribution, Effects of Stress on 449
journal articles (see Further Reading for secondary reference sources). This information provides a useful inventory with which we may compare the responses of the same biological systems to other types of laboratory stressors.
Summary and Conclusion Since the mid-1960s, immobilization has become one of the most frequently employed laboratory models of stress. The protocols for acute and chronic immobilization have been described clearly, and many laboratories have incorporated this procedure into their studies of stress. A rich and varied literature is available on biological responses to immobilization, and these findings have provided important insights into the molecular, genetic, endocrine, and neural adaptations that occur in laboratory rats following acute versus chronic stress.
See Also the Following Articles Adrenal Medulla; Adrenocorticotropic Hormone (ACTH); Animal Models (Nonprimate) for Human Stress; Corticosteroids and Stress; Genetic Factors and Stress; Hypothalamic-Pituitary-Adrenal.
Further Reading Chrousos, G. P., McCarty, R., Pacak, K., et al. (eds.) (1995). Special issue on stress: basic mechanisms and clinical implications. Annals of the New York Academy of Sciences (771).
Kvetnansky, R., McCarty, R. and Axelrod, J. (eds.) (1992). Stress: neuroendocrine and molecular approaches. New York: Gordon and Breach. Kvetnansky, R. and Mikulaj, L. (1970). Adrenal and urinary catecholamines in rats during adaptation to repeated immobilization stress. Endocrinology 87, 738–743. McCarty, R., Aguilera, G., Sabban, E. L. and Kvetnansky, R. (eds.) (1996). Stress: molecular genetic and neurobiological advances. Amsterdam: Harwood Academic. McCarty, R., Aguilera, G., Sabban, E. L. and Kvetnansky, R. (eds.) (2002). Stress: neural, endocrine and molecular studies. London: Taylor and Francis. Pacak, K., Aguilera, G., Sabban, E. L. and Kvetnansky, R. (eds.) (2004). Special issue on stress: current neuroendocrine and genetic approaches. Annals of the New York Academy of Sciences (1018). Sabban, E. L. and Kvetnansky, R. (2001). Stress-triggered activation of gene expression in catecholaminergic systems: dynamics of transcriptional events. Trends in Neurosciences 24, 91–98. Usdin, E., Kvetnansky, R. and Axelrod, J. (eds.) (1984). Stress: the role of catecholamines and other neurotransmitters. New York: Gordon and Breach. Usdin, E., Kvetnansky, R. and Kopin, I. J. (eds.) (1976). Catecholamines and stress. Oxford: Pergamon Press. Usdin, E., Kvetnansky, R. and Kopin, I. J. (eds.) (1980). Catecholamines and stress: recent advances. New York: Elsevier North Holland. Van Loon, G. R., Kvetnansky, R., McCarty, R. and Axelrod, J. (eds.) (1989). Stress: neurochemical and humoral mechanisms. New York: Gordon and Breach. Yehuda, R. and McEwen, B. (eds.) (2004). Special issue on biobehavioral stress response: protective and damaging effects. Annals of the New York Academy of Sciences (1032).
Immune Cell Distribution, Effects of Stress on F S Dhabhar Stanford University School of Medicine, Stanford, CA, USA ã 2007 Elsevier Inc. All rights reserved. This article is a revision of the previous edition article by F S Dhabhar, volume 2, pp 507–514, ã 2000, Elsevier Inc.
Introduction Stress The Immune System Stress-Induced Changes in Blood Leukocytes Hormones Mediating a Stress-Induced Decrease in Blood Leukocytes
A Stress-Induced Decrease in Blood Leukocyte Numbers Represents a Redistribution Rather than a Destruction or Net Loss of Blood Leukocytes Target Organs of a Stress-Induced Redistribution of Blood Leukocytes Stress-Induced Redistribution of Blood Leukocytes Conclusion
Glossary B lymphocytes
The antibody-producing cells of the body, originating in the bone marrow. B lymphocytes are also identified by the surface expression of specific molecules such as CD19.
450 Immune Cell Distribution, Effects of Stress on Fluorescenceactivated cell sorter (FACS)
Immune response
Leukocytes
Lymphocytes Monocytes/ macrophages
Natural killer (NK) cells
Neutrophils
T lymphocytes
An instrument used to rapidly quantify the relative percentages of different cell types in a cell suspension. The identification of different cells is achieved based on the size, granularity, and fluorescence properties of the cell. Fluorescence is derived from fluorescently conjugated antibodies that bind specific markers on the cell surface. A reaction mounted by various components of the immune system, which consists of leukocytes, antibodies, cytokines and chemokines (messenger molecules), prostaglandins (inflammatory mediators), and accessory cells. Cells that constitute the immune system. These include T and B lymphocytes, natural killer (NK) cells, monocytes/macrophages, and granulocytes. Leukocytes that specifically recognize and respond to foreign antigen. Cells that phagocytose foreign particles and self tissues that are injured (monocytes generally flow through the blood and mature into macrophages after they are activated and extravasate into tissues). They produce cytokines, which recruit other leukocytes to the site of an immune response, and they perform an important function known as antigen presentation, which is crucial to the initiation of specific immune responses by lymphocytes. Also known as mononuclear phagocytes. Large granular lymphocytes that lyse virally infected cells and tumors in the absence of specific antigenic stimulation. They are identified by surface molecules such as CD16 and CD56. Cells that perform functions similar to mononuclear phagocytes and that form an important component of an acute inflammatory response; also known as polymorphonuclear leukocytes. Leukocytes that are mediators of cellular immunity. Like all leukocytes, they are formed in the bone marrow but mature in the thymus. Helper T lymphocytes (Ths) orchestrate immune responses by secreting cytokines and recruiting other leukocytes to the site of an immune reaction and activating them at that site; most Th cells express a surface protein called CD4, which is used to identify them. Cytolytic T lymphocytes (CTLs) lyse cells that are infected by intracellular viruses or bacteria; most CTLs express a surface protein called CD8, which is used to identify them.
Introduction Effective immunoprotection requires the rapid recruitment of leukocytes into sites of surgery, wounding, infection, or vaccination. Immune cells or leukocytes circulate continuously on surveillance pathways taking them from the blood, into various organs, and back into the blood. This circulation is essential for the maintenance of an effective immune defense network. The numbers and proportions of leukocytes in the blood provide an important representation of the state of distribution of leukocytes in the body and of the state of activation of the immune system. Numerous studies have shown that stress and stress hormones induce significant changes in absolute numbers and relative proportions of leukocytes in the blood. Dhabhar et al. were the first to propose that a stress-induced decrease in blood leukocyte numbers may represent an adaptive response. These investigators suggested that acute stress-induced changes in blood leukocyte numbers represent a redistribution of leukocytes from the blood to other organs, such as the skin and lining of the gastrointestinal and urinarygenital tracts and their draining lymph nodes. They also suggested that such a leukocyte redistribution may enhance immune function in those compartments to which leukocytes traffic during stress. In agreement with this hypothesis, it has been demonstrated that a stress-induced redistribution of leukocytes from the blood to the skin is accompanied by a significant enhancement of a skin immune response. Here we discuss stress- and stress hormone-induced changes in blood leukocyte distribution and investigate the functional consequences of a stress-induced redistribution of blood leukocytes.
Stress Although the word stress generally has negative connotations, stress is a familiar aspect of life, being a stimulant for some but a burden for others. Numerous definitions have been proposed for the word stress. Each definition focuses on aspects of an internal or external challenge, disturbance, or stimulus; on the perception of a stimulus by an organism; or on a physiological response of the organism to the stimulus. Physical stressors have been defined as external challenges to homeostasis, and psychological stressors have been defined as the ‘‘anticipation justified or not, that a challenge to homeostasis looms.’’ (Sapolsky, 2005, p. 648). An integrated definition states that stress is a constellation of events, consisting of a stimulus (stressor) that precipitates a reaction in the brain (stress perception), which activates
Immune Cell Distribution, Effects of Stress on 451
physiological fight-or-flight systems in the body (stress response). The physiological stress response results in the release of neurotransmitters and hormones that serve as the brain’s messengers to the rest of the body. This article examines the role played by stress and stress hormones in enhancing different aspects of an immune response. It is often overlooked that a stress response has salubrious adaptive effects in the short run, although stress can be harmful when it lasts a long time. An important distinguishing characteristic of stress is its duration and intensity. Thus, we define acute stress as stress that lasts for a period of a few minutes to a few hours and chronic stress as stress that persists for several hours per day for weeks or months. The intensity of stress may be gauged by the peak levels of stress hormones, neurotransmitters, by other physiological changes such as increases in heart rate and blood pressure, and by the amount of time for which these changes persist during stress and following the cessation of stress.
The Immune System Immune Cells and Organs
The immune system consists of organs (bone marrow, spleen, thymus, and lymph nodes), cells (T cells; B cells; natural killer, NK, cells; monocytes/macrophages; and neutrophils), and messenger molecules (cytokines, chemokines, and prostaglandins). These components of the immune system are spread throughout the body and are in constant communication with one another. The appropriate distribution of immune cells in the body is crucial to the performance of the different functions of the immune system. Functions of the Immune System
The functions of the immune system may be classified into six major categories: 1. Constant surveillance of the body in preparation for potential immunological challenges (such as those described in the other five categories). 2. Detection and elimination of infectious agents such as bacteria, viruses, fungi, and other microorganisms and parasites from the body. 3. Detection and elimination of noninfectious foreign matter from the body. 4. Wound repair and healing. 5. Clearance of debris that may result from noninjurious events such as programmed cell death (apoptosis) in host tissues. 6. Detection and elimination of tumors and neoplastic tissue.
Thus, the immune system may be regarded as the body’s army with soldiers (immune cells) moving from their barracks (bone marrow, lymph nodes, spleen, and thymus) through highways (blood vessels and lymphatic ducts) and patrolling almost all organs within the body, especially those organs (skin, lining of gastrointestinal and urinary-genital tracts, lung, liver, lymph nodes, and spleen) that may serve as potential battle stations should the body’s defenses be breached. In order to perform their functions, immune cells communicate with one another and with the rest of the body through messenger molecules such as cytokines and chemokines. Immune Cell Trafficking
The appropriate distribution of immune cells between different tissues in the body is crucial to the performance of the immune functions. Leukocyte trafficking is the process by which leukocytes circulate between immune and nonimmune organs as they patrol the body and discharge their functions. Leukocyte trafficking is accomplished through interactions between adhesion molecules on leukocytes and endothelial cells that ultimately determine the location of immune cells within the body. The three major families of adhesion molecules are the selectins, the immunoglobulin superfamily, and the integrins. Adhesion molecules mediate three important steps (rolling, anchoring, and extravasation) that are involved in capturing leukocytes from the circulation. For example, a T cell flowing through the bloodstream may be selectively retained within the vasculature of the skin if a particular adhesion molecule is expressed on the T cell and its corresponding ligand is expressed on skin endothelial cells. Thus, hormones, cytokines, and chemokines may influence the location of leukocytes in the body by regulating the conformation or expression of adhesion molecules and/or their ligands on leukocytes and endothelial cells. The Immune Response
It is important to note that, although immune reactions are classified into different categories (e.g., innate, acquired, cell-mediated, or humoral reactions), an immune response is often a combination of different immune reactions. The immune response protects the body from infections, wounds, and tumors. Although mechanisms for self- and counterregulation exist between various immune components, mechanisms also exist by which immune responses may be modulated or influenced by mediators such as hormones and neurotransmitters. Stress, and its consequent release of hormones and neurotransmitters, has
452 Immune Cell Distribution, Effects of Stress on
been shown to influence specific immune parameters such as leukocyte trafficking, NK cell activity, lymphocyte proliferation, antibody production, effector cell function, and cell-mediated immune reactions.
A Stress-Induced Decrease in Blood Leukocyte Numbers Represents a Redistribution Rather than a Destruction or Net Loss of Blood Leukocytes
Stress-Induced Changes in Blood Leukocytes
From the discussion so far, it is clear that stress and glucocorticoid hormones induce a rapid and significant decrease in blood lymphocyte, monocyte, and NK cell numbers. This decrease in blood leukocyte numbers may be interpreted in two possible ways. The decrease in cell numbers could reflect a largescale destruction of circulating leukocytes. Alternatively, it could reflect a redistribution of leukocytes from the blood to other organs in the body. Experiments were conducted to test the hypothesis that acute stress induces a redistribution of leukocytes from the blood to other compartments in the body. The first series of experiments examined the kinetics of recovery of the stress-induced reduction in blood leukocyte numbers. It was hypothesized that if the observed effects of stress represented a redistribution rather than a destruction of leukocytes, we would see a relatively rapid return of leukocyte numbers back to baseline on the cessation of stress. Results showed that all leukocyte subpopulations that showed a decrease in absolute numbers during stress showed a complete recovery, with their numbers reaching prestress baseline levels within 3 h after the cessation of stress. Plasma levels of lactate dehydrogenase (LDH), which is a marker for cell damage, were also monitored in the same experiment. If the stress-induced decrease in leukocyte numbers were the result of a destruction of leukocytes, we would expect to observe an increase in plasma levels of LDH during or following stress. However, no significant changes in plasma LDH were observed, further suggesting that a redistribution rather than a destruction of leukocytes was primarily responsible for the stress-induced decrease in blood leukocyte numbers. It is important to bear in mind that, although glucocorticoids are known to induce leukocyte apoptosis under certain conditions, they have also been shown to induce changes in various immune parameters and in immune cell distribution in the absence of cell death. It has been suggested that some species may be steroid-resistant and that others may be steroidsensitive and that glucocorticoid-induced changes in blood leukocyte numbers represent changes in leukocyte redistribution in steroid-resistant species (humans and guinea pigs) and leukocyte lysis in steroid-sensitive species (mouse and rat). However, it is now accepted that, even in species previously thought to be steroid-sensitive, changes in adrenal
The phenomenon of acute stress-induced changes in blood leukocyte numbers is well known. In fact, decreases in blood leukocyte numbers were used as an indirect measure for increases in plasma corticosterone before methods were available to directly assay the hormone. Stress-induced changes in blood leukocyte numbers have been reported in fish, mice, rats, rabbits, horses, nonhuman primates, and humans. This suggests that the phenomenon of stress-induced leukocyte distribution has a long evolutionary lineage and that perhaps it has functional significance. Many of these studies have shown that stressinduced increases in plasma corticosterone are accompanied by a significant decrease in numbers and percentages of lymphocytes and by an increase in numbers and percentages of neutrophils. FACS analyses have revealed that absolute numbers of peripheral blood T cells, B cells, NK cells, and monocytes all show a rapid and significant decrease (40–70% lower than baseline) during stress. These stress-induced changes in leukocyte numbers are rapidly reversed on the cessation of stress.
Hormones Mediating a Stress-Induced Decrease in Blood Leukocytes Several studies have examined stress hormoneinduced changes in blood leukocyte numbers. It has been shown in rats that both adrenalectomy (which eliminates the corticosterone and epinephrine stress response) and cyanoketone treatment (which eliminates only the corticosterone stress response) virtually eliminate the stress-induced redistribution of blood leukocytes. Studies have also shown that adrenal steroid and catecholamine hormones mediate the stress-induced changes in blood leukocyte numbers and that glucocorticoid treatment induces changes in leukocyte distribution in mice, guinea pigs, rats, and humans. These studies clearly show that glucocorticoid hormones induce a significant decrease in blood lymphocyte numbers when administered under acute as well as chronic conditions. Similarly studies have delineated the importance of catecholamine hormones in mediating stress-induced changes in blood leukocyte distribution in rodents and humans.
Immune Cell Distribution, Effects of Stress on 453
steroids similar to those described here produce changes in leukocyte distribution rather than an increase in leukocyte destruction.
Target Organs of a Stress-Induced Redistribution of Blood Leukocytes Based on this discussion, the obvious question we might ask is: Where do blood leukocytes go during stress? Numerous studies using stress or stress hormone treatments have investigated this issue. Using gamma imaging to follow the distribution of adoptively transferred radiolabeled leukocytes in whole animals, experiments showed that stress induces a redistribution of leukocytes from the blood to the mesenteric lymph nodes. It has been reported that anesthesia stress, as well as the infusion of adrenocorticotropic hormone (ACTH) and prednisolone in rats results in decreased numbers of labeled lymphocytes in the thoracic duct, whereas the cessation of drug infusion results in the normal circulation of labeled lymphocytes. This suggests that ACTH and prednisolone (which produce hormonal changes similar to those observed during stress) may cause the retention of circulating lymphocytes in different body compartments, thus resulting in a decrease in lymphocyte numbers in the thoracic duct and a concomitant decrease in numbers in the peripheral blood. It has also been reported that a single injection of hydrocortisone, prednisolone, or ACTH results in increased numbers of lymphocytes in the bone marrow of mice, guinea pigs, and rats. Fauci et al. suggested that glucocorticoid-induced decreases in blood leukocyte numbers in humans may also reflect a redistribution of immune cells to other organs in the body. Finally, corticosteroids have been shown to induce the accumulation of lymphocytes in mucosal sites, and the skin has been identified as a target organ to which leukocytes traffic during stress. In vitro catecholamine treatment has also been shown to direct leukocyte traffic to the spleen and lymph nodes. It is important to note that in these studies a return to basal glucocorticoid levels was followed by a return to basal blood lymphocyte numbers, further supporting the hypothesis that the decrease in blood leukocyte numbers is the result of a glucocorticoidinduced redistribution rather than a glucocorticoidinduced destruction of blood leukocytes. In view of this, Dhabhar et al. proposed that a transient stressinduced decrease in blood leukocyte numbers reflects a redistribution or redeployment of leukocytes from the blood to other organs (e.g., lymph nodes, bone marrow, and skin) in the body.
Stress-Induced Redistribution of Blood Leukocytes Molecular Mechanisms
It is likely that the observed changes in leukocyte distribution are mediated by changes in either the expression or affinity of adhesion molecules on leukocytes and/or endothelial cells. It has been suggested that following stress or glucocorticoid-treatment specific leukocyte subpopulations (being transported by blood and lymph through various body compartments) may be selectively retained in those compartments in which they encounter a stress- or glucocorticoidinduced adhesion match. As a result of this selective retention, the proportion of some leukocyte subpopulations would decrease in the blood and increase in the organ in which they are retained (e.g., the skin). Support for this hypothesis comes from studies that show that acute psychological stressors such as public speaking can induce significant changes in leukocyte adhesion molecules. Prednisolone has also been shown to induce the retention of circulating lymphocytes within the bone marrow, spleen, and some lymph nodes, thus resulting in a decrease in lymphocyte numbers in the thoracic duct and a concomitant decrease in numbers in the peripheral blood. Moreover, glucocorticoid hormones also influence the production of cytokines and lipocortins that, in turn, can affect the surface adhesion properties of leukocytes and endothelial cells. Further investigation of the effects of endogenous glucocorticoids (administered in physiological doses, and examined under physiological kinetic conditions) on changes in the expression/activity of cell surface adhesion molecules and on leukocyte-endothelial cell adhesion is necessary. Functional Consequences
It had been proposed that a stress-induced decrease in blood leukocyte numbers may represent an adaptive response, that is, a redistribution of leukocytes from the blood to other organs such as the skin, lining of gastrointestinal and urinary-genital tracts, lung, liver, and lymph nodes that may serve as potential battle stations should the body’s defenses be breached. It has been suggested that such a leukocyte redistribution may enhance the immune function in those compartments to which leukocytes traffic during stress. Thus, an acute stress response may direct the body’s soldiers (leukocytes) to exit their barracks (the spleen and bone marrow), travel the boulevards (blood vessels), and take up position at potential battle stations (the skin, lining of gastrointestinal
454 Immune Cell Distribution, Effects of Stress on
and urinary-genital tracts, lung, liver, and lymph nodes) in preparation for an immune challenge. In addition to sending leukocytes to potential battle stations, stress hormones may also better equip them for battle by enhancing processes such as antigen presentation, phagocytosis, and antibody production. Thus, a hormonal alarm signal released by the brain on detecting a stressor, may prepare the immune system for potential challenges (wounding or infection) that may arise due to the actions of the stress-inducing agent (e.g., a predator or attacker). When interpreting data showing stress-induced changes in functional assays such as lymphocyte proliferation or NK activity, it may be important to bear in mind the effects of stress on the leukocyte composition of the compartment in which an immune parameter is being measured. For example, it has been shown that acute stress induces a redistribution of leukocytes from the blood to the skin and that this redistribution is accompanied by a significant enhancement of a skin cell-mediated immune (CMI) response. In what might at first glance appear to be contradicting results, acute stress has been shown to suppress splenic and peripheral blood responses to T-cell mitogens and splenic IgM production. However, it is important to note that in contrast to the skin, which is enriched in leukocytes during acute stress, the peripheral blood and spleen are relatively depleted of leukocytes during acute stress. This stress-induced decrease in blood and spleen leukocyte numbers may contribute to the acute stressinduced suppression of immune function in these compartments. Moreover, in contrast to acute stress, chronic stress has been shown to suppress skin CMI and a chronic stress-induced suppression of blood leukocyte redistribution is thought to be one of the factors mediating the immunosuppressive effect of chronic stress. Again, in what might appear to be contradicting results, chronic stress has been shown to enhance mitogen-induced proliferation of splenocytes and splenic IgM production. However, the spleen is relatively enriched with T cells during chronic glucocorticoid administration, suggesting that it may also be relatively enriched with T cells during chronic stress, and this increase in spleen leukocyte numbers may contribute to the chronic stress-induced enhancement of immune parameters measured in the spleen. It is also important to bear in mind that the heterogeneity of the stress-induced changes in leukocyte distribution suggests that using equal numbers of leukocytes in a functional assay may not account for stress-induced changes in relative percentages of different leukocyte subpopulations in the cell suspension
being assayed. For example, samples that have been equalized for absolute numbers of total blood leukocytes from control versus stressed animals may still contain different numbers of specific leukocyte subpopulations (e.g., T cells, B cells, or NK cells). Such changes in leukocyte composition may mediate the effects of stress even in functional assays using equalized numbers of leukocytes from different treatment groups. This possibility needs to be taken into account before concluding that a given treatment changes an immune parameter on a per-cell rather than a per-population basis.
Conclusion An important function of endocrine mediators released under conditions of acute stress may be to ensure that appropriate leukocytes are present in the right place and at the right time to respond to an immune challenge that might be initiated by the stress-inducing agent (e.g., attack by a predator or invasion by a pathogen). The modulation of immune cell distribution by acute stress may be an adaptive response designed to enhance immune surveillance and increase the capacity of the immune system to respond to challenge in immune compartments (such as the skin, the epithelia of the lung, and the gastrointestinal and urinary-genital tracts) that serve as major defense barriers for the body. Thus, neurotransmitters and hormones released during stress may increase immune surveillance and help enhance immune preparedness for potential (or ongoing) immune challenge.
See Also the Following Articles Immune Response; Immune Function, Stress-Induced Enhancement; Immunity.
Further Reading Benschop, R. J., Rodriguez-Feuerhahn, M. and Schedlowski, M. (1996). Catecholamine-induced leukocytosis: early observations, current research, and future directions. Brain, Behavior, & Immunity 10, 77–91. Cox, J. H. and Ford, W. L. (1982). The migration of lymphocytes across specialized vascular endothelium. IV: Prednisolone acts at several points on the recirculation pathway of lymphocytes. Cellular Immunology 66, 407–422. Dhabhar, F. S. and McEwen, B. S. (1996). Stress-induced enhancement of antigen-specific cell-mediated immunity. Journal of Immunology 156, 2608–2615. Dhabhar, F. S. and McEwen, B. S. (1999). Enhancing versus suppressive effects of stress hormones on skin immune function. Proceedings of the National Academy of Sciences USA 96, 1059–1064.
Immune Function, Stress-Induced Enhancement 455 Dhabhar, F. S. and McEwen, B. S. (2001). Bidirectional effects of stress & glucocorticoid hormones on immune function: possible explanations for paradoxical observations. In: Ader, R., Felten, D. L. & Cohen, N. (eds.) Psychoneuroimmunology (3rd edn., pp. 301–338). San Diego, CA: Academic Press. Dhabhar, F. S., Miller, A. H., McEwen, B. S., et al. (1995). Effects of stress on immune cell distribution – dynamics and hormonal mechanisms. Journal of Immunology 154, 5511–5527. Dhabhar, F. S., Miller, A. H., McEwen, B. S., et al. (1996). Stress-induced changes in blood leukocyte distribution – role of adrenal steroid hormones. Journal of Immunology 157, 1638–1644. Dhabhar, F. S. and Viswanathan, K. (2005). Short-term stress experienced at the time of immunization induces a long-lasting increase in immunological memory. American Journal of Physiology: Regulatory, Integrative & Comparative Physiology 289, R738–R744. Dougherty, R. F. and White, A. (1945). Functional alterations in lymphoid tissue induced by adrenal cortical secretion. American Journal of Anatomy 77, 81–116. Fauci, A. S. (1975). Mechanisms of corticosteroid action on lymphocyte subpopulations. I: Redistribution of
circulating T and B lymphocytes to the bone marrow. Immunology 28, 669–680. Goebel, M. U. and Mills, P. J. (2000). Acute psychological stress and exercise and changes in peripheral leukocyte adhesion molecule expression and density. Psychosomatic Medicine 62, 664–670. Mills, P. J. and Dimsdale, J. E. (1996). The effects of acute psychologic stress on cellular adhesion molecules. Journal of Psychosomatic Research 41, 49–53. Sapolsky, R. M. (2005). The hierarchy on primate health. Science 308, 648–652. Stefanski, V., Solomon, G. F., Kling, A. S., et al. (1996). Impact of social confrontation on rat CD4 T cells bearing different CD45R isoforms. Brain, Behavior & Immunity 10, 364–379. Viswanathan, K. and Dhabhar, F. S. (2005). Stress-induced enhancement of leukocyte trafficking into sites of surgery or immune activation. Proceedings of the National Academy of Sciences USA, 102, 5808–5812. Zalcman, S. and Anisman, H. (1993). Acute and chronic stressor effects on the antibody response to sheep red blood cells. Pharmacology, Biochemistry & Behavior 46, 445–452.
Immune Function See: Immune Response; Immune Function, Stress-Induced Enhancement; Immune Suppression; Immune System, Aging; Immunity; Immune Surveillance – Cancer, Effects of Stress on.
Immune Function, Stress-Induced Enhancement F S Dhabhar Stanford University School of Medicine, Stanford, CA, USA ã 2007 Elsevier Inc. All rights reserved. This article is a revision of the previous edition article by F S Dhabhar, volume 2, pp 515–522, ã 2000, Elsevier Inc.
The Stress Spectrum Hypothesis Conclusion
Glossary Antigen Cytokines
Stress The Immune System General Assumption: Stress Suppresses Immune Function and is Detrimental to Health – Reasons for Modifying This General Assumption Studies Showing Stress-Induced Enhancement of Immune Function Functional Implications
Immune response
Leukocytes
A foreign substance that induces an immune response. Protein hormones that mediate various functions of immune cells. A reaction mounted by various components of the immune system, which consists of leukocytes, antibodies, cytokines and chemokines (messenger molecules), prostaglandins (inflammatory mediators), and accessory cells. Cells that constitute the immune system. These include T and B lymphocytes, natural killer (NK) cells, monocytes/ macrophages, and granulocytes.
journal articles (see Further Reading for secondary reference sources). This information provides a useful inventory with which we may compare the responses of the same biological systems to other types of laboratory stressors.
Summary and Conclusion Since the mid-1960s, immobilization has become one of the most frequently employed laboratory models of stress. The protocols for acute and chronic immobilization have been described clearly, and many laboratories have incorporated this procedure into their studies of stress. A rich and varied literature is available on biological responses to immobilization, and these findings have provided important insights into the molecular, genetic, endocrine, and neural adaptations that occur in laboratory rats following acute versus chronic stress.
See Also the Following Articles Adrenal Medulla; Adrenocorticotropic Hormone (ACTH); Animal Models (Nonprimate) for Human Stress; Corticosteroids and Stress; Genetic Factors and Stress; Hypothalamic-Pituitary-Adrenal.
Further Reading Chrousos, G. P., McCarty, R., Pacak, K., et al. (eds.) (1995). Special issue on stress: basic mechanisms and clinical implications. Annals of the New York Academy of Sciences (771).
Kvetnansky, R., McCarty, R. and Axelrod, J. (eds.) (1992). Stress: neuroendocrine and molecular approaches. New York: Gordon and Breach. Kvetnansky, R. and Mikulaj, L. (1970). Adrenal and urinary catecholamines in rats during adaptation to repeated immobilization stress. Endocrinology 87, 738–743. McCarty, R., Aguilera, G., Sabban, E. L. and Kvetnansky, R. (eds.) (1996). Stress: molecular genetic and neurobiological advances. Amsterdam: Harwood Academic. McCarty, R., Aguilera, G., Sabban, E. L. and Kvetnansky, R. (eds.) (2002). Stress: neural, endocrine and molecular studies. London: Taylor and Francis. Pacak, K., Aguilera, G., Sabban, E. L. and Kvetnansky, R. (eds.) (2004). Special issue on stress: current neuroendocrine and genetic approaches. Annals of the New York Academy of Sciences (1018). Sabban, E. L. and Kvetnansky, R. (2001). Stress-triggered activation of gene expression in catecholaminergic systems: dynamics of transcriptional events. Trends in Neurosciences 24, 91–98. Usdin, E., Kvetnansky, R. and Axelrod, J. (eds.) (1984). Stress: the role of catecholamines and other neurotransmitters. New York: Gordon and Breach. Usdin, E., Kvetnansky, R. and Kopin, I. J. (eds.) (1976). Catecholamines and stress. Oxford: Pergamon Press. Usdin, E., Kvetnansky, R. and Kopin, I. J. (eds.) (1980). Catecholamines and stress: recent advances. New York: Elsevier North Holland. Van Loon, G. R., Kvetnansky, R., McCarty, R. and Axelrod, J. (eds.) (1989). Stress: neurochemical and humoral mechanisms. New York: Gordon and Breach. Yehuda, R. and McEwen, B. (eds.) (2004). Special issue on biobehavioral stress response: protective and damaging effects. Annals of the New York Academy of Sciences (1032).
Immune Cell Distribution, Effects of Stress on F S Dhabhar Stanford University School of Medicine, Stanford, CA, USA ã 2007 Elsevier Inc. All rights reserved. This article is a revision of the previous edition article by F S Dhabhar, volume 2, pp 507–514, ã 2000, Elsevier Inc.
Introduction Stress The Immune System Stress-Induced Changes in Blood Leukocytes Hormones Mediating a Stress-Induced Decrease in Blood Leukocytes
A Stress-Induced Decrease in Blood Leukocyte Numbers Represents a Redistribution Rather than a Destruction or Net Loss of Blood Leukocytes Target Organs of a Stress-Induced Redistribution of Blood Leukocytes Stress-Induced Redistribution of Blood Leukocytes Conclusion
Glossary B lymphocytes
The antibody-producing cells of the body, originating in the bone marrow. B lymphocytes are also identified by the surface expression of specific molecules such as CD19.
450 Immune Cell Distribution, Effects of Stress on Fluorescenceactivated cell sorter (FACS)
Immune response
Leukocytes
Lymphocytes Monocytes/ macrophages
Natural killer (NK) cells
Neutrophils
T lymphocytes
An instrument used to rapidly quantify the relative percentages of different cell types in a cell suspension. The identification of different cells is achieved based on the size, granularity, and fluorescence properties of the cell. Fluorescence is derived from fluorescently conjugated antibodies that bind specific markers on the cell surface. A reaction mounted by various components of the immune system, which consists of leukocytes, antibodies, cytokines and chemokines (messenger molecules), prostaglandins (inflammatory mediators), and accessory cells. Cells that constitute the immune system. These include T and B lymphocytes, natural killer (NK) cells, monocytes/macrophages, and granulocytes. Leukocytes that specifically recognize and respond to foreign antigen. Cells that phagocytose foreign particles and self tissues that are injured (monocytes generally flow through the blood and mature into macrophages after they are activated and extravasate into tissues). They produce cytokines, which recruit other leukocytes to the site of an immune response, and they perform an important function known as antigen presentation, which is crucial to the initiation of specific immune responses by lymphocytes. Also known as mononuclear phagocytes. Large granular lymphocytes that lyse virally infected cells and tumors in the absence of specific antigenic stimulation. They are identified by surface molecules such as CD16 and CD56. Cells that perform functions similar to mononuclear phagocytes and that form an important component of an acute inflammatory response; also known as polymorphonuclear leukocytes. Leukocytes that are mediators of cellular immunity. Like all leukocytes, they are formed in the bone marrow but mature in the thymus. Helper T lymphocytes (Ths) orchestrate immune responses by secreting cytokines and recruiting other leukocytes to the site of an immune reaction and activating them at that site; most Th cells express a surface protein called CD4, which is used to identify them. Cytolytic T lymphocytes (CTLs) lyse cells that are infected by intracellular viruses or bacteria; most CTLs express a surface protein called CD8, which is used to identify them.
Introduction Effective immunoprotection requires the rapid recruitment of leukocytes into sites of surgery, wounding, infection, or vaccination. Immune cells or leukocytes circulate continuously on surveillance pathways taking them from the blood, into various organs, and back into the blood. This circulation is essential for the maintenance of an effective immune defense network. The numbers and proportions of leukocytes in the blood provide an important representation of the state of distribution of leukocytes in the body and of the state of activation of the immune system. Numerous studies have shown that stress and stress hormones induce significant changes in absolute numbers and relative proportions of leukocytes in the blood. Dhabhar et al. were the first to propose that a stress-induced decrease in blood leukocyte numbers may represent an adaptive response. These investigators suggested that acute stress-induced changes in blood leukocyte numbers represent a redistribution of leukocytes from the blood to other organs, such as the skin and lining of the gastrointestinal and urinarygenital tracts and their draining lymph nodes. They also suggested that such a leukocyte redistribution may enhance immune function in those compartments to which leukocytes traffic during stress. In agreement with this hypothesis, it has been demonstrated that a stress-induced redistribution of leukocytes from the blood to the skin is accompanied by a significant enhancement of a skin immune response. Here we discuss stress- and stress hormone-induced changes in blood leukocyte distribution and investigate the functional consequences of a stress-induced redistribution of blood leukocytes.
Stress Although the word stress generally has negative connotations, stress is a familiar aspect of life, being a stimulant for some but a burden for others. Numerous definitions have been proposed for the word stress. Each definition focuses on aspects of an internal or external challenge, disturbance, or stimulus; on the perception of a stimulus by an organism; or on a physiological response of the organism to the stimulus. Physical stressors have been defined as external challenges to homeostasis, and psychological stressors have been defined as the ‘‘anticipation justified or not, that a challenge to homeostasis looms.’’ (Sapolsky, 2005, p. 648). An integrated definition states that stress is a constellation of events, consisting of a stimulus (stressor) that precipitates a reaction in the brain (stress perception), which activates
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physiological fight-or-flight systems in the body (stress response). The physiological stress response results in the release of neurotransmitters and hormones that serve as the brain’s messengers to the rest of the body. This article examines the role played by stress and stress hormones in enhancing different aspects of an immune response. It is often overlooked that a stress response has salubrious adaptive effects in the short run, although stress can be harmful when it lasts a long time. An important distinguishing characteristic of stress is its duration and intensity. Thus, we define acute stress as stress that lasts for a period of a few minutes to a few hours and chronic stress as stress that persists for several hours per day for weeks or months. The intensity of stress may be gauged by the peak levels of stress hormones, neurotransmitters, by other physiological changes such as increases in heart rate and blood pressure, and by the amount of time for which these changes persist during stress and following the cessation of stress.
The Immune System Immune Cells and Organs
The immune system consists of organs (bone marrow, spleen, thymus, and lymph nodes), cells (T cells; B cells; natural killer, NK, cells; monocytes/macrophages; and neutrophils), and messenger molecules (cytokines, chemokines, and prostaglandins). These components of the immune system are spread throughout the body and are in constant communication with one another. The appropriate distribution of immune cells in the body is crucial to the performance of the different functions of the immune system. Functions of the Immune System
The functions of the immune system may be classified into six major categories: 1. Constant surveillance of the body in preparation for potential immunological challenges (such as those described in the other five categories). 2. Detection and elimination of infectious agents such as bacteria, viruses, fungi, and other microorganisms and parasites from the body. 3. Detection and elimination of noninfectious foreign matter from the body. 4. Wound repair and healing. 5. Clearance of debris that may result from noninjurious events such as programmed cell death (apoptosis) in host tissues. 6. Detection and elimination of tumors and neoplastic tissue.
Thus, the immune system may be regarded as the body’s army with soldiers (immune cells) moving from their barracks (bone marrow, lymph nodes, spleen, and thymus) through highways (blood vessels and lymphatic ducts) and patrolling almost all organs within the body, especially those organs (skin, lining of gastrointestinal and urinary-genital tracts, lung, liver, lymph nodes, and spleen) that may serve as potential battle stations should the body’s defenses be breached. In order to perform their functions, immune cells communicate with one another and with the rest of the body through messenger molecules such as cytokines and chemokines. Immune Cell Trafficking
The appropriate distribution of immune cells between different tissues in the body is crucial to the performance of the immune functions. Leukocyte trafficking is the process by which leukocytes circulate between immune and nonimmune organs as they patrol the body and discharge their functions. Leukocyte trafficking is accomplished through interactions between adhesion molecules on leukocytes and endothelial cells that ultimately determine the location of immune cells within the body. The three major families of adhesion molecules are the selectins, the immunoglobulin superfamily, and the integrins. Adhesion molecules mediate three important steps (rolling, anchoring, and extravasation) that are involved in capturing leukocytes from the circulation. For example, a T cell flowing through the bloodstream may be selectively retained within the vasculature of the skin if a particular adhesion molecule is expressed on the T cell and its corresponding ligand is expressed on skin endothelial cells. Thus, hormones, cytokines, and chemokines may influence the location of leukocytes in the body by regulating the conformation or expression of adhesion molecules and/or their ligands on leukocytes and endothelial cells. The Immune Response
It is important to note that, although immune reactions are classified into different categories (e.g., innate, acquired, cell-mediated, or humoral reactions), an immune response is often a combination of different immune reactions. The immune response protects the body from infections, wounds, and tumors. Although mechanisms for self- and counterregulation exist between various immune components, mechanisms also exist by which immune responses may be modulated or influenced by mediators such as hormones and neurotransmitters. Stress, and its consequent release of hormones and neurotransmitters, has
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been shown to influence specific immune parameters such as leukocyte trafficking, NK cell activity, lymphocyte proliferation, antibody production, effector cell function, and cell-mediated immune reactions.
A Stress-Induced Decrease in Blood Leukocyte Numbers Represents a Redistribution Rather than a Destruction or Net Loss of Blood Leukocytes
Stress-Induced Changes in Blood Leukocytes
From the discussion so far, it is clear that stress and glucocorticoid hormones induce a rapid and significant decrease in blood lymphocyte, monocyte, and NK cell numbers. This decrease in blood leukocyte numbers may be interpreted in two possible ways. The decrease in cell numbers could reflect a largescale destruction of circulating leukocytes. Alternatively, it could reflect a redistribution of leukocytes from the blood to other organs in the body. Experiments were conducted to test the hypothesis that acute stress induces a redistribution of leukocytes from the blood to other compartments in the body. The first series of experiments examined the kinetics of recovery of the stress-induced reduction in blood leukocyte numbers. It was hypothesized that if the observed effects of stress represented a redistribution rather than a destruction of leukocytes, we would see a relatively rapid return of leukocyte numbers back to baseline on the cessation of stress. Results showed that all leukocyte subpopulations that showed a decrease in absolute numbers during stress showed a complete recovery, with their numbers reaching prestress baseline levels within 3 h after the cessation of stress. Plasma levels of lactate dehydrogenase (LDH), which is a marker for cell damage, were also monitored in the same experiment. If the stress-induced decrease in leukocyte numbers were the result of a destruction of leukocytes, we would expect to observe an increase in plasma levels of LDH during or following stress. However, no significant changes in plasma LDH were observed, further suggesting that a redistribution rather than a destruction of leukocytes was primarily responsible for the stress-induced decrease in blood leukocyte numbers. It is important to bear in mind that, although glucocorticoids are known to induce leukocyte apoptosis under certain conditions, they have also been shown to induce changes in various immune parameters and in immune cell distribution in the absence of cell death. It has been suggested that some species may be steroid-resistant and that others may be steroidsensitive and that glucocorticoid-induced changes in blood leukocyte numbers represent changes in leukocyte redistribution in steroid-resistant species (humans and guinea pigs) and leukocyte lysis in steroid-sensitive species (mouse and rat). However, it is now accepted that, even in species previously thought to be steroid-sensitive, changes in adrenal
The phenomenon of acute stress-induced changes in blood leukocyte numbers is well known. In fact, decreases in blood leukocyte numbers were used as an indirect measure for increases in plasma corticosterone before methods were available to directly assay the hormone. Stress-induced changes in blood leukocyte numbers have been reported in fish, mice, rats, rabbits, horses, nonhuman primates, and humans. This suggests that the phenomenon of stress-induced leukocyte distribution has a long evolutionary lineage and that perhaps it has functional significance. Many of these studies have shown that stressinduced increases in plasma corticosterone are accompanied by a significant decrease in numbers and percentages of lymphocytes and by an increase in numbers and percentages of neutrophils. FACS analyses have revealed that absolute numbers of peripheral blood T cells, B cells, NK cells, and monocytes all show a rapid and significant decrease (40–70% lower than baseline) during stress. These stress-induced changes in leukocyte numbers are rapidly reversed on the cessation of stress.
Hormones Mediating a Stress-Induced Decrease in Blood Leukocytes Several studies have examined stress hormoneinduced changes in blood leukocyte numbers. It has been shown in rats that both adrenalectomy (which eliminates the corticosterone and epinephrine stress response) and cyanoketone treatment (which eliminates only the corticosterone stress response) virtually eliminate the stress-induced redistribution of blood leukocytes. Studies have also shown that adrenal steroid and catecholamine hormones mediate the stress-induced changes in blood leukocyte numbers and that glucocorticoid treatment induces changes in leukocyte distribution in mice, guinea pigs, rats, and humans. These studies clearly show that glucocorticoid hormones induce a significant decrease in blood lymphocyte numbers when administered under acute as well as chronic conditions. Similarly studies have delineated the importance of catecholamine hormones in mediating stress-induced changes in blood leukocyte distribution in rodents and humans.
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steroids similar to those described here produce changes in leukocyte distribution rather than an increase in leukocyte destruction.
Target Organs of a Stress-Induced Redistribution of Blood Leukocytes Based on this discussion, the obvious question we might ask is: Where do blood leukocytes go during stress? Numerous studies using stress or stress hormone treatments have investigated this issue. Using gamma imaging to follow the distribution of adoptively transferred radiolabeled leukocytes in whole animals, experiments showed that stress induces a redistribution of leukocytes from the blood to the mesenteric lymph nodes. It has been reported that anesthesia stress, as well as the infusion of adrenocorticotropic hormone (ACTH) and prednisolone in rats results in decreased numbers of labeled lymphocytes in the thoracic duct, whereas the cessation of drug infusion results in the normal circulation of labeled lymphocytes. This suggests that ACTH and prednisolone (which produce hormonal changes similar to those observed during stress) may cause the retention of circulating lymphocytes in different body compartments, thus resulting in a decrease in lymphocyte numbers in the thoracic duct and a concomitant decrease in numbers in the peripheral blood. It has also been reported that a single injection of hydrocortisone, prednisolone, or ACTH results in increased numbers of lymphocytes in the bone marrow of mice, guinea pigs, and rats. Fauci et al. suggested that glucocorticoid-induced decreases in blood leukocyte numbers in humans may also reflect a redistribution of immune cells to other organs in the body. Finally, corticosteroids have been shown to induce the accumulation of lymphocytes in mucosal sites, and the skin has been identified as a target organ to which leukocytes traffic during stress. In vitro catecholamine treatment has also been shown to direct leukocyte traffic to the spleen and lymph nodes. It is important to note that in these studies a return to basal glucocorticoid levels was followed by a return to basal blood lymphocyte numbers, further supporting the hypothesis that the decrease in blood leukocyte numbers is the result of a glucocorticoidinduced redistribution rather than a glucocorticoidinduced destruction of blood leukocytes. In view of this, Dhabhar et al. proposed that a transient stressinduced decrease in blood leukocyte numbers reflects a redistribution or redeployment of leukocytes from the blood to other organs (e.g., lymph nodes, bone marrow, and skin) in the body.
Stress-Induced Redistribution of Blood Leukocytes Molecular Mechanisms
It is likely that the observed changes in leukocyte distribution are mediated by changes in either the expression or affinity of adhesion molecules on leukocytes and/or endothelial cells. It has been suggested that following stress or glucocorticoid-treatment specific leukocyte subpopulations (being transported by blood and lymph through various body compartments) may be selectively retained in those compartments in which they encounter a stress- or glucocorticoidinduced adhesion match. As a result of this selective retention, the proportion of some leukocyte subpopulations would decrease in the blood and increase in the organ in which they are retained (e.g., the skin). Support for this hypothesis comes from studies that show that acute psychological stressors such as public speaking can induce significant changes in leukocyte adhesion molecules. Prednisolone has also been shown to induce the retention of circulating lymphocytes within the bone marrow, spleen, and some lymph nodes, thus resulting in a decrease in lymphocyte numbers in the thoracic duct and a concomitant decrease in numbers in the peripheral blood. Moreover, glucocorticoid hormones also influence the production of cytokines and lipocortins that, in turn, can affect the surface adhesion properties of leukocytes and endothelial cells. Further investigation of the effects of endogenous glucocorticoids (administered in physiological doses, and examined under physiological kinetic conditions) on changes in the expression/activity of cell surface adhesion molecules and on leukocyte-endothelial cell adhesion is necessary. Functional Consequences
It had been proposed that a stress-induced decrease in blood leukocyte numbers may represent an adaptive response, that is, a redistribution of leukocytes from the blood to other organs such as the skin, lining of gastrointestinal and urinary-genital tracts, lung, liver, and lymph nodes that may serve as potential battle stations should the body’s defenses be breached. It has been suggested that such a leukocyte redistribution may enhance the immune function in those compartments to which leukocytes traffic during stress. Thus, an acute stress response may direct the body’s soldiers (leukocytes) to exit their barracks (the spleen and bone marrow), travel the boulevards (blood vessels), and take up position at potential battle stations (the skin, lining of gastrointestinal
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and urinary-genital tracts, lung, liver, and lymph nodes) in preparation for an immune challenge. In addition to sending leukocytes to potential battle stations, stress hormones may also better equip them for battle by enhancing processes such as antigen presentation, phagocytosis, and antibody production. Thus, a hormonal alarm signal released by the brain on detecting a stressor, may prepare the immune system for potential challenges (wounding or infection) that may arise due to the actions of the stress-inducing agent (e.g., a predator or attacker). When interpreting data showing stress-induced changes in functional assays such as lymphocyte proliferation or NK activity, it may be important to bear in mind the effects of stress on the leukocyte composition of the compartment in which an immune parameter is being measured. For example, it has been shown that acute stress induces a redistribution of leukocytes from the blood to the skin and that this redistribution is accompanied by a significant enhancement of a skin cell-mediated immune (CMI) response. In what might at first glance appear to be contradicting results, acute stress has been shown to suppress splenic and peripheral blood responses to T-cell mitogens and splenic IgM production. However, it is important to note that in contrast to the skin, which is enriched in leukocytes during acute stress, the peripheral blood and spleen are relatively depleted of leukocytes during acute stress. This stress-induced decrease in blood and spleen leukocyte numbers may contribute to the acute stressinduced suppression of immune function in these compartments. Moreover, in contrast to acute stress, chronic stress has been shown to suppress skin CMI and a chronic stress-induced suppression of blood leukocyte redistribution is thought to be one of the factors mediating the immunosuppressive effect of chronic stress. Again, in what might appear to be contradicting results, chronic stress has been shown to enhance mitogen-induced proliferation of splenocytes and splenic IgM production. However, the spleen is relatively enriched with T cells during chronic glucocorticoid administration, suggesting that it may also be relatively enriched with T cells during chronic stress, and this increase in spleen leukocyte numbers may contribute to the chronic stress-induced enhancement of immune parameters measured in the spleen. It is also important to bear in mind that the heterogeneity of the stress-induced changes in leukocyte distribution suggests that using equal numbers of leukocytes in a functional assay may not account for stress-induced changes in relative percentages of different leukocyte subpopulations in the cell suspension
being assayed. For example, samples that have been equalized for absolute numbers of total blood leukocytes from control versus stressed animals may still contain different numbers of specific leukocyte subpopulations (e.g., T cells, B cells, or NK cells). Such changes in leukocyte composition may mediate the effects of stress even in functional assays using equalized numbers of leukocytes from different treatment groups. This possibility needs to be taken into account before concluding that a given treatment changes an immune parameter on a per-cell rather than a per-population basis.
Conclusion An important function of endocrine mediators released under conditions of acute stress may be to ensure that appropriate leukocytes are present in the right place and at the right time to respond to an immune challenge that might be initiated by the stress-inducing agent (e.g., attack by a predator or invasion by a pathogen). The modulation of immune cell distribution by acute stress may be an adaptive response designed to enhance immune surveillance and increase the capacity of the immune system to respond to challenge in immune compartments (such as the skin, the epithelia of the lung, and the gastrointestinal and urinary-genital tracts) that serve as major defense barriers for the body. Thus, neurotransmitters and hormones released during stress may increase immune surveillance and help enhance immune preparedness for potential (or ongoing) immune challenge.
See Also the Following Articles Immune Response; Immune Function, Stress-Induced Enhancement; Immunity.
Further Reading Benschop, R. J., Rodriguez-Feuerhahn, M. and Schedlowski, M. (1996). Catecholamine-induced leukocytosis: early observations, current research, and future directions. Brain, Behavior, & Immunity 10, 77–91. Cox, J. H. and Ford, W. L. (1982). The migration of lymphocytes across specialized vascular endothelium. IV: Prednisolone acts at several points on the recirculation pathway of lymphocytes. Cellular Immunology 66, 407–422. Dhabhar, F. S. and McEwen, B. S. (1996). Stress-induced enhancement of antigen-specific cell-mediated immunity. Journal of Immunology 156, 2608–2615. Dhabhar, F. S. and McEwen, B. S. (1999). Enhancing versus suppressive effects of stress hormones on skin immune function. Proceedings of the National Academy of Sciences USA 96, 1059–1064.
Immune Function, Stress-Induced Enhancement 455 Dhabhar, F. S. and McEwen, B. S. (2001). Bidirectional effects of stress & glucocorticoid hormones on immune function: possible explanations for paradoxical observations. In: Ader, R., Felten, D. L. & Cohen, N. (eds.) Psychoneuroimmunology (3rd edn., pp. 301–338). San Diego, CA: Academic Press. Dhabhar, F. S., Miller, A. H., McEwen, B. S., et al. (1995). Effects of stress on immune cell distribution – dynamics and hormonal mechanisms. Journal of Immunology 154, 5511–5527. Dhabhar, F. S., Miller, A. H., McEwen, B. S., et al. (1996). Stress-induced changes in blood leukocyte distribution – role of adrenal steroid hormones. Journal of Immunology 157, 1638–1644. Dhabhar, F. S. and Viswanathan, K. (2005). Short-term stress experienced at the time of immunization induces a long-lasting increase in immunological memory. American Journal of Physiology: Regulatory, Integrative & Comparative Physiology 289, R738–R744. Dougherty, R. F. and White, A. (1945). Functional alterations in lymphoid tissue induced by adrenal cortical secretion. American Journal of Anatomy 77, 81–116. Fauci, A. S. (1975). Mechanisms of corticosteroid action on lymphocyte subpopulations. I: Redistribution of
circulating T and B lymphocytes to the bone marrow. Immunology 28, 669–680. Goebel, M. U. and Mills, P. J. (2000). Acute psychological stress and exercise and changes in peripheral leukocyte adhesion molecule expression and density. Psychosomatic Medicine 62, 664–670. Mills, P. J. and Dimsdale, J. E. (1996). The effects of acute psychologic stress on cellular adhesion molecules. Journal of Psychosomatic Research 41, 49–53. Sapolsky, R. M. (2005). The hierarchy on primate health. Science 308, 648–652. Stefanski, V., Solomon, G. F., Kling, A. S., et al. (1996). Impact of social confrontation on rat CD4 T cells bearing different CD45R isoforms. Brain, Behavior & Immunity 10, 364–379. Viswanathan, K. and Dhabhar, F. S. (2005). Stress-induced enhancement of leukocyte trafficking into sites of surgery or immune activation. Proceedings of the National Academy of Sciences USA, 102, 5808–5812. Zalcman, S. and Anisman, H. (1993). Acute and chronic stressor effects on the antibody response to sheep red blood cells. Pharmacology, Biochemistry & Behavior 46, 445–452.
Immune Function See: Immune Response; Immune Function, Stress-Induced Enhancement; Immune Suppression; Immune System, Aging; Immunity; Immune Surveillance – Cancer, Effects of Stress on.
Immune Function, Stress-Induced Enhancement F S Dhabhar Stanford University School of Medicine, Stanford, CA, USA ã 2007 Elsevier Inc. All rights reserved. This article is a revision of the previous edition article by F S Dhabhar, volume 2, pp 515–522, ã 2000, Elsevier Inc.
The Stress Spectrum Hypothesis Conclusion
Glossary Antigen Cytokines
Stress The Immune System General Assumption: Stress Suppresses Immune Function and is Detrimental to Health – Reasons for Modifying This General Assumption Studies Showing Stress-Induced Enhancement of Immune Function Functional Implications
Immune response
Leukocytes
A foreign substance that induces an immune response. Protein hormones that mediate various functions of immune cells. A reaction mounted by various components of the immune system, which consists of leukocytes, antibodies, cytokines and chemokines (messenger molecules), prostaglandins (inflammatory mediators), and accessory cells. Cells that constitute the immune system. These include T and B lymphocytes, natural killer (NK) cells, monocytes/ macrophages, and granulocytes.