Although the concept of stress has earned a bad reputation, it is important to recognize that the adaptive purpose of a physiological stress response is to promote survival during fight or flight. While long-term stress is generally harmful, short-term stress can be protective as it prepares the organism to deal with challenges. This review discusses the immune effects of biological stress responses that can be induced by psychological, physiological, or physical (including exercise) stressors. We have proposed that short-term stress is one of the nature’s fundamental but under-appreciated survival mechanisms that could be clinically harnessed to enhance immunoprotection. Short-term (i.e., lasting for minutes to hours) stress experienced during immune activation enhances innate/primary and adaptive/secondary immune responses. Mechanisms of immuno-enhancement include changes in dendritic cell, neutrophil, macrophage, and lymphocyte trafficking, maturation, and function as well as local and systemic production of cytokines. In contrast, long-term stress suppresses or dysregulates innate and adaptive immune responses by altering the Type 1–Type 2 cytokine balance, inducing low-grade chronic inflammation, and suppressing numbers, trafficking, and function of immunoprotective cells. Chronic stress may also increase susceptibility to some types of cancer by suppressing Type 1 cytokines and protective T cells and increasing regulatory/suppressor T cell function. Here, we classify immune responses as being protective, pathological, or regulatory, and discuss “good” versus “bad” effects of stress on health. Thus, short-term stress can enhance the acquisition and/or expression of immunoprotective (wound healing, vaccination, anti-infectious agent, anti-tumor) or immuno-pathological (pro-inflammatory, autoimmune) responses. In contrast, chronic stress can suppress protective immune responses and/or exacerbate pathological immune responses. Studies such as the ones discussed here could provide mechanistic targets and conceptual frameworks for pharmacological and/or biobehavioral interventions designed to enhance the effects of “good” stress, minimize the effects of “bad” stress, and maximally promote health and healing.
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McEwen BS. Protective and damaging effects of stress mediators. N Engl J Med. 1998;338:171–9.
Ader R. Psychoneuroimmunology IV. San Diego: Academic Press; 2007.
Dhabhar FS. Enhancing versus suppressive effects of stress on immune function: implications for immunoprotection and immunopathology. Neuroimmunomodulation. 2009;16:300–17.
Dhabhar FS, Malarkey WB, Neri E, McEwen BS. Stress-induced redistribution of immune cells—from barracks to boulevards to battlefields: a tale of three hormones. Psychoneuroendocrinology. 2012;37:1345–68.
Padro CJ, Sanders VM. Neuroendocrine regulation of inflammation. Semin Immunol. 2014. doi:10.1016/j.smim.2014.01.003.
Dhabhar FS. Positive effects of stress. TED@Vancouver. 2012. http://talentsearch.ted.com/video/Firdaus-Dhabhar-The-positive-ef or http://www.youtube.com/watch?v=nsc83N-Q1q4.
Dhabhar FS, Miller AH, McEwen BS, Spencer RL. Effects of stress on immune cell distribution—dynamics and hormonal mechanisms. J Immunol. 1995;154:5511–27.
Dhabhar FS, McEwen BS. Bidirectional effects of stress & glucocorticoid hormones on immune function: possible explanations for paradoxical observations. In: Ader R, Felten DL, Cohen N, editors. Psychoneuroimmunology. 3rd ed. San Diego: Academic Press; 2001. p. 301–38.
Dhabhar FS, McEwen BS. Acute stress enhances while chronic stress suppresses immune function in vivo: a potential role for leukocyte trafficking. Brain Behav Immun. 1997;11:286–306.
Goldstein DS, McEwen B. Allostasis, homeostats, and the nature of stress. Stress. 2002;5:55–8.
McEwen BS. The end of stress as we know it. Washington, DC: Dana Press; 2002.
Sapolsky RM. The influence of social hierarchy on primate health. Science. 2005;308:648–52.
Irwin M, Patterson T, Smith TL, Caldwell C, Brown SA, Gillin CJ, Grant I. Reduction of immune function in life stress and depression. Biol Psychiatry. 1990;27:22–30.
Glaser R, Kiecolt-Glaser JK. Stress-induced immune dysfunction: implications for health. Nat Rev Immunol. 2005;5:243–51.
Chrousos GP, Kino T. Glucocorticoid action networks and complex psychiatric and/or somatic disorders. Stress. 2007;10:213–9.
Dhabhar FS, Viswanathan K. Short-term stress experienced at the time of immunization induces a long-lasting increase in immunological memory. Am J Physiol. 2005;289:R738–44.
Dhabhar FS, McEwen BS. Bidirectional effects of stress on immune function: possible explanations for salubrious as well as harmful effects. In: Ader R, editor. Psychoneuroimmunology IV. San Diego: Elsevier Academic Press; 2007. p. 723–60.
Sephton S, Spiegel D. Circadian disruption in cancer: a neuroendocrine-immune pathway from stress to disease? Brain Behav Immun. 2003;17:321–8.
Saul AN, Oberyszyn TM, Daugherty C, Kusewitt D, Jones S, Jewell S, Malarkey WB, Lehman A, Lemeshow S, Dhabhar FS. Chronic stress and susceptibility to skin cancer. J Natl Cancer Inst. 2005;97:1760–7.
Gunnar M, Quevedo K. The neurobiology of stress and development. Annu Rev Psychol. 2007;58:145–73.
Dhabhar FS, McEwen BS, Spencer RL. Stress response, adrenal steroid receptor levels, and corticosteroid-binding globulin levels—a comparison between Sprague Dawley, Fischer 344, and Lewis rats. Brain Res. 1993;616:89–98.
Sternberg EM, Hill JM, Chrousos GP, Kamilaris T, Listwak SJ, Gold PW, Wilder RL. Inflammatory mediator-induced hypothalamic–pituitary–adrenal axis activation is defective in streptococcal cell wall arthritis-susceptible Lewis rats. Proc Natl Acad Sci USA. 1989;86:2374–8.
Dhabhar FS, McEwen BS, Spencer RL. Adaptation to prolonged or repeated stress—comparison between rat strains showing intrinsic differences in reactivity to acute stress. Neuroendocrinology. 1997;65:360–8.
Dhabhar FS, Miller AH, McEwen BS, Spencer RL. Differential activation of adrenal steroid receptors in neural and immune tissues of Sprague Dawley, Fischer 344, and Lewis rats. J Neuroimmunol. 1995;56:77–90.
Gomez-Serrano M, Tonelli L, Listwak S, Sternberg E, Riley AL. Effects of cross fostering on open-field behavior, acoustic startle, lipopolysaccharide-induced corticosterone release, and body weight in Lewis and Fischer rats. Behav Genet. 2001;31:427–36.
Schwab CL, Fan R, Zheng Q, Myers LP, Hebert P, Pruett SB. Modeling and predicting stress-induced immunosuppression in mice using blood parameters. Toxicol Sci. 2005;83:101–13.
Benschop RJ, Rodriguez-Feuerhahn M, Schedlowski M. Catecholamine-induced leukocytosis: early observations, current research, and future directions. Brain Behav Immun. 1996;10:77–91.
Dhabhar FS. A hassle a day may keep the pathogens away: the fight-or-flight stress response and the augmentation of immune function. Integr Comp Biol. 2009;49:215–36.
Van Gaal LF, Mertens IL, De Block CE. Mechanisms linking obesity with cardiovascular disease. Nature. 2006;444:875–80.
Dantzer R, O’Connor JC, Freund GG, Johnson RW, Kelley KW. From inflammation to sickness and depression: when the immune system subjugates the brain. Nat Rev Neurosci. 2008;9:46–56.
Maes MA. A review on the acute phase response in major depression. Rev Neurosci. 1993;4:407–16.
Simpson E. Special regulatory T-cell review: regulation of immune responses–examining the role of T cells. Immunology. 2008;123:13–6.
Piccirillo CA. Regulatory T cells in health and disease. Cytokine. 2008;43:395–401.
Wing K, Sakaguchi S. Regulatory T cells exert checks and balances on self tolerance and autoimmunity. Nat Immunol. 2010;11:7–13.
Bluestone JA, Tang Q. How do CD4+CD25+ regulatory T cells control autoimmunity? Curr Opin Immunol. 2005;17:638–42.
Finn OJ. Cancer immunology. N Engl J Med. 2008;358:2704–15.
Olson BM, McNeel DG. Monitoring regulatory immune responses in tumor immunotherapy clinical trials. Front Oncol. 2013;3:109.
Whiteside TL. Regulatory T cell subsets in human cancer: are they regulating for or against tumor progression? Cancer Immunol Immunother. 2014;63:67–72.
Dhabhar FS, Miller AH, Stein M, McEwen BS, Spencer RL. Diurnal and stress-induced changes in distribution of peripheral blood leukocyte subpopulations. Brain Behav Immun. 1994;8:66–79.
Dhabhar FS, McEwen BS. Stress-induced enhancement of antigen-specific cell-mediated immunity. J Immunol. 1996;156:2608–15.
Selye H. Stress without distress. New York: Nal Penguin Inc.; 1974.
Schleimer RP, Claman HN, Oronsky A, editors. Anti-inflammatory steroid action: basic and clinical aspects. San Diego: Academic Press Inc.; 1989.
Dopp JM, Miller GE, Myers HF, Fahey JL. Increased natural killer-cell mobilization and cytotoxicity during marital conflict. Brain Behav Immun. 2000;14:10–26.
Segerstrom SC, Miller GE. Psychological stress and the human immune system: a meta-analytic study of 30 years of inquiry. Psychol Bull. 2004;130:601–30.
Vivier E, Malissen B. Innate and adaptive immunity: specificities and signaling hierarchies revisited. Nat Immunol. 2005;6:17–21.
Adamo SA. Bidirectional connections between the immune and the nervous system in insects. In: Beckage NE, editor. Insect immunology. Amsterdam: Academic Press; 2008. p. 348.
Baines D, Downer RG. Octopamine enhances phagocytosis in cockroach hemocytes: involvement of inositol trisphosphate. Arch Insect Biochem Physiol. 1994;26:249–61.
Sprent J, Tough DF. Lymphocyte life-span and memory. Science. 1994;265:1395–400.
Pickford GE, Srivastava AK, Slicher AM, Pang PKT. The stress response in the abundance of circulating leukocytes in the Killifish, Fundulus heteroclitus. I The cold-shock sequence and the effects of hypophysectomy. J Exp Zool. 1971;177:89–96.
Bilbo SD, Dhabhar FS, Viswanathan K, Saul A, Yellon SM, Nelson RJ. Short day lengths augment stress-induced leukocyte trafficking and stress-induced enhancement of skin immune function. Proc Natl Acad Sci USA. 2002;99:4067–72.
Jensen MM. Changes in leukocyte counts associated with various stressors. J Reticuloendothel Soc. 1969;8:457–65.
Viswanathan K, Dhabhar FS. Stress-induced enhancement of leukocyte trafficking into sites of surgery or immune activation. PNAS USA. 2005;102:5808–13.
Dhabhar FS, Miller AH, McEwen BS, Spencer RL. Stress-induced changes in blood leukocyte distribution—role of adrenal steroid hormones. J Immunol. 1996;157:1638–44.
Rinder CS, Mathew JP, Rinder HM, Tracey JB, Davis E, Smith BR. Lymphocyte and monocyte subset changes during cardiopulmonary bypass: effects of aging and gender [see comments]. J Lab Clin Med. 1997;129:592–602.
Toft P, Svendsen P, Tonnesen E, Rasmussen JW, Christensen NJ. Redistribution of lymphocytes after major surgical stress. Acta Anesthesiol Scand. 1993;37:245–9.
Snow DH, Ricketts SW, Mason DK. Hematological responses to racing and training exercise in Thoroughbred horses, with particular reference to the leukocyte response. Equine Vet J. 1983;15:149–54.
Morrow-Tesch JL, McGlone JJ, Norman RL. Consequences of restraint stress on natural killer cell activity, behavior, and hormone levels in Rhesus Macaques (Macaca mulatta). Psychoneuroendocrinology. 1993;18:383–95.
Herbert TB, Cohen S. Stress and immunity in humans: a meta-analytic review. Psychosom Med. 1993;55:364–79.
Schedlowski M, Jacobs R, Stratman G, Richter S, Hädike A, Tewes U, Wagner TOF, Schmidt RE. Changes of natural killer cells during acute psychological stress. J Clin Immunol. 1993;13:119–26.
Mills PJ, Ziegler MG, Rehman J, Maisel AS. Catecholamines, catecholamine receptors, cell adhesion molecules, and acute stressor-related changes in cellular immunity. Adv Pharmacol. 1998;42:587–90.
Redwine L, Mills PJ, Sada M, Dimsdale J, Patterson T, Grant I. Differential immune cell chemotaxis responses to acute psychological stress in Alzheimer caregivers compared to non-caregiver controls. Psychosom Med. 2004;66:770–5.
Bosch JA, Berntson GG, Cacioppo JT, Dhabhar FS, Marucha PT. Acute stress evokes selective mobilization of T cells that differ in chemokine receptor expression: a potential pathway linking immunologic reactivity to cardiovascular disease. Brain Behav Immun. 2003;17:251–9.
Rosenberger PH, Ickovics JR, Epel E, Nadler E, Jokl P, Fulkerson JP, Tillie JM, Dhabhar FS. Surgery stress induced immune cell redistribution profiles predict short- and long-term postsurgical recovery: a prospective study. J Bone Joint Surg. 2009;91:2783–94.
Hoagland H, Elmadjian F, Pincus G. Stressful psychomotor performance and adrenal cortical function as indicated by the lymphocyte reponse. J Clin Endocrinol. 1946;6:301–11.
Fauci AS, Dale DC. The effect of in vivo hydrocortisone on subpopulations of human lymphocytes. J Clin Invest. 1974;53:240–6.
Fauci AS, Dale DC. The effect of hydrocortisone on the kinetics of normal human lymphocytes. Blood. 1975;46:235–43.
Carlson SL, Fox S, Abell KM. Catecholamine modulation of lymphocyte homing to lymphoid tissues. Brain Behav Immun. 1997;11:307–20.
Benschop RJ, Oostveen FG, Heijnen CJ, Ballieux RE. Beta 2-adrenergic stimulation causes detachment of natural killer cells from cultured endothelium. Eur J Immunol. 1993;23:3242–7.
Redwine L, Snow S, Mills P, Irwin M. Acute psychological stress: effects on chemotaxis and cellular adhesion molecule expression. Psychosom Med. 2003;65:598–603.
Mills PJ, Meck JV, Waters WW, D’Aunno D, Ziegler MG. Peripheral leukocyte subpopulations and catecholamine levels in astronauts as a function of mission duration. Psychosom Med. 2001;63:886–90.
Dhabhar FS, McEwen BS. Enhancing versus suppressive effects of stress hormones on skin immune function. PNAS USA. 1999;96:1059–64.
Dhabhar FS, Satoskar AR, Bluethmann H, David JR, McEwen BS. Stress-induced enhancement of skin immune function: a role for IFNg. PNAS USA. 2000;97:2846–51.
Blecha F, Barry RA, Kelley KW. Stress-induced alterations in delayed-type hypersensitivity to SRBC and contact sensitivity to DNFB in mice. Proc Soc Exp Biol Med. 1982;169:239–46.
Wood PG, Karol MH, Kusnecov AW, Rabin BS. Enhancement of antigen-specific humoral and cell-mediated immunity by electric footshock stress in rats. Brain Behav Immun. 1993;7:121–34.
Coe CL, Lubach G, Ershler WB. Immunological consequences of maternal separation in infant primates. In: Lewis M, Worobey J, editors. Infant stress and coping. New York, NY: Jossey-Bass Inc.; 1989. p. 64–91.
Saint-Mezard P, Chavagnac C, Bosset S, Ionescu M, Peyron E, Kaiserlian D, Nicolas JF, Berard F. Psychological stress exerts an adjuvant effect on skin dendritic cell functions in vivo. J Immunol. 2003;171(8):4073–80.
Viswanathan K, Daugherty C, Dhabhar FS. Stress as an endogenous adjuvant: augmentation of the immunization phase of cell-mediated immunity. Int Immunol. 2005;17:1059–69.
Flint MS, Miller DB, Tinkle SS. Restraint-induced modulation of allergic and irritant contact dermatitis in male and female B6.129 mice. Brain Behav Immun. 2000;14:256–69.
Flint MS, Valosen JM, Johnson EA, Miller DB, Tinkle SS. Restraint stress applied prior to chemical sensitization modulates the development of allergic contact dermatitis differently than restraint prior to challenge. J Neuroimmunol. 2001;113:72–80.
Bilbo SD, Hotchkiss AK, Chiavegatto S, Nelson RJ. Blunted stress responses in delayed type hypersensitivity in mice lacking the neuronal isoform of nitric oxide synthase. J Neuroimmunol. 2003;140:41–8.
Kripke ML. Ultraviolet radiation and immunology: something new under the sun-presidential address. Cancer Res. 1994;54:6102–5.
Granstein RD, Matsui MS. UV radiation-induced immunosuppression and skin cancer. Cutis. 2004;74:4–9.
Dhabhar FS, Saul AN, Daugherty C, Holmes TH, Bouley DM, Oberyszyn TM. Short-term stress enhances cellular immunity and increases early resistance to squamous cell carcinoma. Brain Behav Immun. 2010;24:127–37.
Amkraut A, Solomon GF. Stress and murine sarcoma virus (Moloney)-induced tumors. Cancer Res. 1972;32:1428–33.
Solomon GF, Merigan TC, Levine S. Variation in adrenal cortical hormones within physiologic ranges, stress and interferon production in mice. Riv Patol Nerv Ment. 1966;87:74–9.
Nance DM, Sanders VM. Autonomic innervation and regulation of the immune system (1987–2007). Brain Behav Immun. 2007;21:736–45.
Sanders VM. The beta2-adrenergic receptor on T and B lymphocytes: do we understand it yet? Brain Behav Immun. 2012;26:195–200.
Altemus M, Rao B, Dhabhar FS, Ding W, Granstein R. Stress-induced changes in skin barrier function in healthy women. J Invest Dermatol. 2001;117:309–17.
Pace TW, Mletzko TC, Alagbe O, Musselman DL, Nemeroff CB, Miller AH, Heim CM. Increased stress-induced inflammatory responses in male patients with major depression and increased early life stress. Am J Psychiatry. 2006;163:1630–3.
Steptoe A, Hamer M, Chida Y. The effects of acute psychological stress on circulating inflammatory factors in humans: a review and meta-analysis. Brain Behav Immun. 2007;21:901–12.
Aschbacher K, Epel E, Wolkowitz OM, Prather AA, Puterman E, Dhabhar FS. Maintenance of a positive outlook during acute stress protects against pro-inflammatory reactivity and future depressive symptoms. Brain Behav Immun. 2012;26:346–52.
Puterman E, Epel ES, O’Donovan A, Prather AA, Aschbacher K, Dhabhar FS. Anger is associated with increased IL-6 stress reactivity in women, but only among those low in social support. Int J Behav Med. 2013. doi:10.1007/s12529-013-9368-0.
Prather AA, Puterman E, Epel ES, Dhabhar FS. Poor sleep quality potentiates stress-induced cytokine reactivity in postmenopausal women with high visceral abdominal adiposity. Brain Behav Immun. 2013;35:155–62.
Capuron L, Miller AH. Immune system to brain signaling: neuropsychopharmacological implications. Pharmacol Ther. 2011;130:226–38.
Maes M. Depression is an inflammatory disease, but cell-mediated immune activation is the key component of depression. Prog Neuropsychopharmacol Biol Psychiatry. 2011;35:664–75.
Miller AH, Haroon E, Raison CL, Felger JC. Cytokine targets in the brain: impact on neurotransmitters and neurocircuits. Depress Anxiety. 2013;30:297–306.
Andreasson A, Arborelius L, Erlanson-Albertsson C, Lekander M. A putative role for cytokines in the impaired appetite in depression. Brain Behav Immun. 2007;21:147–52.
Quan N. Brain’s firewall: blood–brain barrier actively regulates neuroimmune information flow. Brain Behav Immun. 2006;20:447–8.
Quan N. In-depth conversation: spectrum and kinetics of neuroimmune afferent pathways. Brain Behav Immun. 2014. doi:10.1016/j.bbi.2014.02.006.
Besedovsky HO, Rey AD. Physiology of psychoneuroimmunology: a personal view. Brain Behav Immun. 2007;21:34–44.
Schedlowski M, Engler H, Grigoleit JS. Endotoxin-induced experimental systemic inflammation in humans: a model to disentangle immune-to-brain communication. Brain Behav Immun. 2014;35:1–8.
Dhabhar FS, Burke HM, Epel ES, Mellon SH, Rosser R, Reus VI, Wolkowitz OM. Low serum IL-10 concentrations and loss of regulatory association between IL-6 and IL-10 in adults with major depression. J Psychiatr Res. 2009;43:962–9.
Pace TW, Hu F, Miller AH. Cytokine-effects on glucocorticoid receptor function: relevance to glucocorticoid resistance and the pathophysiology and treatment of major depression. Brain Behav Immun. 2007;21:9–19.
Pace TW, Miller AH. Cytokines and glucocorticoid receptor signaling. Relevance to major depression. Ann N Y Acad Sci. 2009;1179:86–105.
Dantzer R, O’Connor JC, Lawson MA, Kelley KW. Inflammation-associated depression: from serotonin to kynurenine. Psychoneuroendocrinology. 2011;36:426–36.
Kelley KW, Dantzer R. Alcoholism and inflammation: neuroimmunology of behavioral and mood disorders. Brain Behav Immun. 2011;25(Suppl 1):S13–20.
Altemus M, Cloitre M, Dhabhar FS. Cellular immune response in adult women with PTSD related to childhood abuse. Am J Psychiatry. 2003;160:1705–7.
Pace TW, Heim CM. A short review on the psychoneuroimmunology of posttraumatic stress disorder: from risk factors to medical comorbidities. Brain Behav Immun. 2011;25:6–13.
Wieck A, Grassi-Oliveira R, Hartmann do Prado C, Teixeira AL, Bauer ME. Neuroimmunoendocrine interactions in post-traumatic stress disorder: focus on long-term implications of childhood maltreatment. Neuroimmunomodulation. 2014;21:145–51.
Fredericks CA, Drabant EM, Edge MD, Tillie JM, Hallmayer J, Ramel W, Kuo JR, Mackey S, Gross JJ, Dhabhar FS. Healthy young women with serotonin transporter SS polymorphism show a pro-inflammatory bias under resting and stress conditions. Brain Behav Immun. 2009;24:350–7.
Solomon GF. Emotions, stress, the central nervous system, and immunity. Ann N Y Acad Sci. 1969;164:335–43.
Vitlic A, Lord JM, Phillips AC. Stress, ageing and their influence on functional, cellular and molecular aspects of the immune system. Age (Dordr). 2014. doi:10.1007/s11357-014-9631-6.
Webster Marketon JI, Glaser R. Stress hormones and immune function. Cell Immunol. 2008;252:16–26.
Fagundes CP, Glaser R, Kiecolt-Glaser JK. Stressful early life experiences and immune dysregulation across the lifespan. Brain Behav Immun. 2013;27:8–12.
Sanders VM, Straub RH. Norepinephrine, the beta-adrenergic receptor, and immunity. Brain Behav Immun. 2002;16:290–332.
Straub RH, Bijlsma JW, Masi A, Cutolo M. Role of neuroendocrine and neuroimmune mechanisms in chronic inflammatory rheumatic diseases—the 10-year update. Semin Arthritis Rheum. 2013;43:392–404.
Irwin MR. Human psychoneuroimmunology: 20 years of discovery. Brain Behav Immun. 2008;22:129–39.
American Psychological Association Practice Organization. Psychologically Healthy Workplace Program Fact Sheet: By The Numbers; 2010. p. 1–15.
Smith A, Vollmer-Conna U, Bennett B, Wakefield D, Hickie I, Lloyd A. The relationship between distress and the development of a primary immune response to a novel antigen. Brain Behav Immun. 2004;18:65–75.
Sephton SE, Dhabhar FS, Keuroghlian AS, Giese-Davis J, McEwen BS, Ionan AC, Spiegel D. Depression, cortisol, and suppressed cell-mediated immunity in metastatic breast cancer. Brain Behav Immun. 2009;23:1148–55.
Kelley KW, Greenfield RE, Evermann JF, Parish SM, Perryman LE. Delayed-type hypersensitivity, contact sensitivity, and PHA skin-test responses of heat- and cold-stressed calves. Am J Vet Res. 1982;43:775–9.
Edwards EA, Dean LM. Effects of crowding of mice on humoral antibody formation and protection to lethal antigenic challenge. Psychosom Med. 1977;39:19–24.
Fleshner M, Laudenslager ML, Simons L, Maier SF. Reduced serum antibodies associated with social defeat in rats. Physiol Behav. 1989;45:1183–7.
Bartrop R, Lazarus L, Luckhurst E, Kiloh LG, Penny R. Depressed lymphocyte function after bereavement. Lancet. 1977;1:834–6.
Kiecolt-Glaser JK, Garner W, Speicher C, Penn GM, Holliday J, Glaser R. Psychosocial modifiers of immunocompetence in medical students. Psychosom Med. 1984;46:7–14.
Cheng GJ, Morrow-Tesch JL, Beller DI, Levy EM, Black PH. Immunosuppression in mice induced by cold water stress. Brain Behav Immun. 1990;4:278–91.
Regnier JA, Kelley KW. Heat- and cold-stress suppresses in vivo and in vitro cellular immune response of chickens. Am J Vet Res. 1981;42:294–9.
Wistar R, Hildemann WH. Effect of stress on skin transplantation immunity in mice. Science. 1960;131:159–60.
Bonneau RH, Sheridan JF, Feng N, Glaser R. Stress-induced effects on cell-mediated innate and adaptive memory components of the murine immune response to herpes simplex virus infection. Brain Behav Immun. 1991;5:274–95.
Brown DH, Zwilling BS. Activation of the hypothalamic–pituitary–adrenal axis differentially affects the anti-mycobacterial activity of macrophages from BCG-resistant and susceptible mice. J Neuroimmunol. 1994;53:181–7.
Epel E, Blackburn EH, Lin J, Dhabhar FS, Adler NE, Morrow JD, Cawthon RM. Accelerated telomere shortening in response to life stress. PNAS. 2004;101:17312–5.
Epel ES, Merkin SS, Cawthon R, Blackburn EH, Adler NE, Pletcher MJ, Seeman TE. The rate of leukocyte telomere shortening predicts mortality from cardiovascular disease in elderly men. Aging. 2009;1:81–8.
Blackburn EH, Epel ES. Telomeres and adversity: too toxic to ignore. Nature. 2012;490:169–71.
Antoni MH, Lutgendorf SK, Cole SW, Dhabhar FS, Sephton SE, McDonald PG, Stefanek M, Sood AK. The influence of bio-behavioral factors on tumour biology: pathways and mechanisms. Nat Rev Cancer. 2006;6:240–8.
Chida Y, Hamer M, Wardle J, Steptoe A. Do stress-related psychosocial factors contribute to cancer incidence and survival? Nat Clin Pract Oncol. 2008;5:466–75.
Sood AK, Lutgendorf SK. Stress influences on anoikis. Cancer Prev Res (Phila). 2011;4:481–5.
Ben-Eliyahu S, Yirmiya R, Liebeskind JC, Taylor AN, Gale RP. Stress increases metastatic spread of a mammary tumor in rats: evidence for mediation by the immune system. Brain Behav Immun. 1991;5:193–205.
Thaker PH, Han LY, Kamat AA, Arevalo JM, Takahashi R, Lu C, Jennings NB, Armaiz-Pena G, Bankson JA, Ravoori M, Merritt WM, Lin YG, Mangala LS, Kim TJ, Coleman RL, Landen CN, Li Y, Felix E, Sanguino AM, Newman RA, Lloyd M, Gershenson DM, Kundra V, Lopez-Berestein G, Lutgendorf SK, Cole SW, Sood AK. Chronic stress promotes tumor growth and angiogenesis in a mouse model of ovarian carcinoma. Nat Med. 2006;12:939–44.
Levi B, Benish M, Goldfarb Y, Sorski L, Melamed R, Rosenne E, Ben-Eliyahu S. Continuous stress disrupts immunostimulatory effects of IL-12. Brain Behav Immun. 2011;25:727–35.
Goldfarb Y, Sorski L, Benish M, Levi B, Melamed R, Ben-Eliyahu S. Improving postoperative immune status and resistance to cancer metastasis: a combined perioperative approach of immunostimulation and prevention of excessive surgical stress responses. Ann Surg. 2011;253:798–810.
Dhabhar FS, Saul AN, Holmes TH, Daugherty C, Neri E, Tillie JM, Kusewitt DF, Oberyszyn TM. High anxiety is associated with higher chronic stress burden, lower protective immunity, and increased cancer progression. PLoS One. 2012. doi:10.31371/journal.pone.0033069.
Levine S, Saltzman A. Nonspecific stress prevents relapses of experimental allergic encephalomyelitis in rats. Brain Behav Immun. 1987;1:336–41.
Rogers MP, Trentham DE, McCune WJ, Ginsberg BI, Rennke HG, Reich P, David JR. Effect of psychological stress on the induction of arthritis in rats. Arthritis Rheum. 1980;23:1337–42.
Griffin AC, Warren DL, Wolny AC, Whitacre CC. Suppression of experimental autoimmune encephalomyelitis by restraint stress. J Neuroimmunol. 1993;44:103–16.
Stefanski V, Hemschemeier SK, Schunke K, Hahnel A, Wolff C, Straub RH. Differential effect of severe and moderate social stress on blood immune and endocrine measures and susceptibility to collagen type II arthritis in male rats. Brain Behav Immun. 2013;29:156–65.
Besedovsky HO, del Rey A. The cytokine-HPA axis feed-back circuit. Z Rheumatol. 2000;59(Suppl 2):II26–30.
del Rey A, Besedovsky HO. The cytokine-HPA axis circuit contributes to prevent or moderate autoimmune processes. Z Rheumatol. 2000;59:II31–5.
Straub RH, Kalden JR. Stress of different types increases the proinflammatory load in rheumatoid arthritis. Arthritis Res Ther. 2009;11:114.
Del Rey A, Wolff C, Wildmann J, Randolf A, Straub RH, Besedovsky HO. When immune–neuro–endocrine interactions are disrupted: experimentally induced arthritis as an example. Neuroimmunomodulation. 2010;17:165–8.
Sternberg EM. Neuroendocrine regulation of autoimmune/inflammatory disease. J Endocrinol. 2001;169:429–35.
Wiegers GJ, Labeur MS, Stec IE, Klinkert WE, Holsboe F, Reul JM. Glucocorticoids accelerate anti-T cell receptor-induced T cell growth. J Immunol. 1995;155:1893–902.
Straub RH. Evolutionary medicine and chronic inflammatory state—known and new concepts in pathophysiology. J Mol Med (Berl). 2012;90:523–34.
Straub RH. Interaction of the endocrine system with inflammation: a function of energy and volume regulation. Arthritis Res Ther. 2014;16:203.
Hackney AC. Exercise as a stressor to the human neuroendocrine system. Medicina (Kaunas). 2006;42:788–97.
Pedersen BK, Hoffman-Goetz L. Exercise and the immune system: regulation, integration, and adaptation. Physiol Rev. 2000;80:1055–81.
Pedersen BK. Special feature for the Olympics: effects of exercise on the immune system: exercise and cytokines. Immunol Cell Biol. 2000;78:532–5.
Winzer BM, Whiteman DC, Reeves MM, Paratz JD. Physical activity and cancer prevention: a systematic review of clinical trials. Cancer Causes Control. 2011;22:811–26.
Friedenreich CM. The role of physical activity in breast cancer etiology. Semin Oncol. 2010;37:297–302.
Friedenreich CM, Neilson HK, Lynch BM. State of the epidemiological evidence on physical activity and cancer prevention. Eur J Cancer. 2010;46:2593–604.
Clague J, Bernstein L. Physical activity and cancer. Curr Oncol Rep. 2012;14:550–8.
Gleeson M. Immune function in sport and exercise. J Appl Physiol. 2007;103:693–9.
Walsh NP, Whitham M. Exercising in environmental extremes: a greater threat to immune function? Sports Med. 2006;36:941–76.
Woods JA, Vieira VJ, Keylock KT. Exercise, inflammation, and innate immunity. Immunol Allergy Clin North Am. 2009;29:381–93.
Phillips AC, Burns VE, Lord JM. Stress and exercise: getting the balance right for aging immunity. Exerc Sport Sci Rev. 2007;35:35–9.
Woods JA, Lowder TW, Keylock KT. Can exercise training improve immune function in the aged? Ann N Y Acad Sci. 2002;959:117–27.
Fondell E, Lagerros YT, Sundberg CJ, Lekander M, Balter O, Rothman KJ, Balter K. Physical activity, stress, and self-reported upper respiratory tract infection. Med Sci Sports Exerc. 2011;43:272–9.
Dhabhar FS. Psychological stress and immunoprotection versus immunopathology in the skin. Clin Dermatol. 2013;31:18–30.
Edwards KM, Burns VE, Reynolds T, Carroll D, Drayson M, Ring C. Acute stress exposure prior to influenza vaccination enhances antibody response in women. Brain Behav Immun. 2006;20:159–68.
Edwards KM, Burns VE, Adkins AE, Carroll D, Drayson M, Ring C. Meningococcal A vaccination response is enhanced by acute stress in men. Psychosom Med. 2008;70:147–51.
Edwards KM, Burns VE, Carroll D, Drayson M, Ring C. The acute stress-induced immunoenhancement hypothesis. Exerc Sport Sci Rev. 2007;35:150–5.
Kleyn CE, Schneider L, Saraceno R, Mantovani C, Richards HL, Fortune DG, Cumberbatch M, Dearman RJ, Terenghi G, Kimber I, Griffiths CE. The effects of acute social stress on epidermal Langerhans’ cell frequency and expression of cutaneous neuropeptides. J Invest Dermatol. 2008;128:1273–9.
Griffiths CE, Dearman RJ, Cumberbatch M, Kimber I. Cytokines and Langerhans cell mobilisation in mouse and man. Cytokine. 2005;32:67–70.
Chida Y, Hamer M, Steptoe A. A bidirectional relationship between psychosocial factors and atopic disorders: a systematic review and meta-analysis. Psychosom Med. 2008;70:102–16.
Arndt J, Smith N, Tausk F. Stress and atopic dermatitis. Curr Allergy Asthma Rep. 2008;8:312–7.
Black PH, Garbutt LD. Stress, inflammation and cardiovascular disease. J Psychosom Res. 2002;52:1–23.
Belkic KL, Landsbergis PA, Schnall PL, Baker D. Is job strain a major source of cardiovascular disease risk? Scand J Work Environ Health. 2004;30:85–128.
Hildebrand HC, Epstein J, Larjava H. The influence of psychological stress on periodontal disease. J West Soc Periodontol Periodontal Abstr. 2000;48:69–77.
Wright RJ, Rodriguez M, Cohen S. Review of psychosocial stress and asthma: an integrated biopsychosocial approach. Thorax. 1998;53:1066–74.
Chen E, Miller GE. Stress and inflammation in exacerbations of asthma. Brain Behav Immun. 2007;21:993–9.
Al’Abadie MS, Kent GG, Gawkrodger DJ. The relationship between stress and the onset and exacerbation of psoriasis and other skin conditions. Br J Dermatol. 1994;130:199–203.
Fortune DG, Richards HL, Griffiths CE. Psychologic factors in psoriasis: consequences, mechanisms, and interventions. Dermatol Clin. 2005;23:681–94.
Straub RH, Dhabhar FS, Bijlsma JW, Cutolo M. How psychological stress via hormones and nerve fibers may exacerbate rheumatoid arthritis. Arthritis Rheum. 2005;52:16–26.
Artemiadis AK, Anagnostouli MC, Alexopoulos EC. Stress as a risk factor for multiple sclerosis onset or relapse: a systematic review. Neuroepidemiology. 2011;36:109–20.
Juster RP, McEwen BS, Lupien SJ. Allostatic load biomarkers of chronic stress and impact on health and cognition. Neurosci Biobehav Rev. 2010;35:2–16.
Danese A, McEwen BS. Adverse childhood experiences, allostasis, allostatic load, and age-related disease. Physiol Behav. 2012;106:29–39.
Dhabhar FS. Harnessing stress on the path to peace. TEDx Hayward. 2013. https://www.youtube.com/watch?v=u2QFJbE1EBs.
Amkraut AA, Solomon CF, Kraemer HC. Stress, early experience and adjuvant-induced arthritis in the rat. Psychosom Med. 1971;33:203–14.
Ackerman KD, Heyman R, Rabin BS, Anderson BP, Houck PR, Frank E, Baum A. Stressful life events precede exacerbations of multiple sclerosis. Psychosom Med. 2002;64:916–20.
Garg A, Chren MM, Sands LP, Matsui MS, Marenus KD, Feingold KR, Elias PM. Psychological stress perturbs epidermal permeability barrier homeostasis: implications for the pathogenesis of stress-associated skin disorders. Arch Dermatol. 2001;137:53–9.
Cohen S, Tyrrell DAJ, Smith AP. Psychological stress and susceptibility to the common cold. N Engl J Med. 1991;325:606–12.
I thank current and previous members of my laboratory, particularly, Dr. Kavitha Viswanathan, Dr. Alison Saul, Christine Daugherty, Jean Tillie, and Nicole Taylor, whose work and publications are among those discussed in this manuscript. I also thank my mentors, colleagues, and collaborators for their significant contributions. I am grateful for all the studies that we have done together and the fun that we have had doing them. I am deeply grateful to the following institutions that have been critical for enabling us to conduct our research: The NIH (AI48995, AR46299, CA107498), startup funds from the Carl and Elizabeth Naumann Fund, The Office of Naval Research, The Dana Foundation, and The John D. and Catherine T. MacArthur Foundation.
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Dhabhar, F.S. Effects of stress on immune function: the good, the bad, and the beautiful. Immunol Res 58, 193–210 (2014). https://doi.org/10.1007/s12026-014-8517-0
- Psychological/physical/physiological stress
- Immune cell trafficking
- Stress-reduction interventions