Skip to main content

Advertisement

Log in

Effects of stress on immune function: the good, the bad, and the beautiful

  • IMMUNOLOGY AT STANFORD UNIVERSITY
  • Published:
Immunologic Research Aims and scope Submit manuscript

Abstract

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.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2

Similar content being viewed by others

References

  1. McEwen BS. Protective and damaging effects of stress mediators. N Engl J Med. 1998;338:171–9.

    Article  CAS  PubMed  Google Scholar 

  2. Ader R. Psychoneuroimmunology IV. San Diego: Academic Press; 2007.

    Google Scholar 

  3. Dhabhar FS. Enhancing versus suppressive effects of stress on immune function: implications for immunoprotection and immunopathology. Neuroimmunomodulation. 2009;16:300–17.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  4. 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.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  5. Padro CJ, Sanders VM. Neuroendocrine regulation of inflammation. Semin Immunol. 2014. doi:10.1016/j.smim.2014.01.003.

  6. 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.

  7. 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.

    CAS  PubMed  Google Scholar 

  8. 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.

    Google Scholar 

  9. 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.

    Article  CAS  PubMed  Google Scholar 

  10. Goldstein DS, McEwen B. Allostasis, homeostats, and the nature of stress. Stress. 2002;5:55–8.

    Article  PubMed  Google Scholar 

  11. McEwen BS. The end of stress as we know it. Washington, DC: Dana Press; 2002.

    Google Scholar 

  12. Sapolsky RM. The influence of social hierarchy on primate health. Science. 2005;308:648–52.

    Article  CAS  PubMed  Google Scholar 

  13. 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.

    Article  CAS  PubMed  Google Scholar 

  14. Glaser R, Kiecolt-Glaser JK. Stress-induced immune dysfunction: implications for health. Nat Rev Immunol. 2005;5:243–51.

    Article  CAS  PubMed  Google Scholar 

  15. Chrousos GP, Kino T. Glucocorticoid action networks and complex psychiatric and/or somatic disorders. Stress. 2007;10:213–9.

    Article  CAS  PubMed  Google Scholar 

  16. 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.

    CAS  Google Scholar 

  17. 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.

    Chapter  Google Scholar 

  18. Sephton S, Spiegel D. Circadian disruption in cancer: a neuroendocrine-immune pathway from stress to disease? Brain Behav Immun. 2003;17:321–8.

    Article  CAS  PubMed  Google Scholar 

  19. 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.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  20. Gunnar M, Quevedo K. The neurobiology of stress and development. Annu Rev Psychol. 2007;58:145–73.

    Article  PubMed  Google Scholar 

  21. 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.

    Article  CAS  PubMed  Google Scholar 

  22. 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.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  23. 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.

    Article  CAS  PubMed  Google Scholar 

  24. 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.

    Article  CAS  PubMed  Google Scholar 

  25. 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.

    Article  CAS  PubMed  Google Scholar 

  26. 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.

    Article  CAS  PubMed  Google Scholar 

  27. Benschop RJ, Rodriguez-Feuerhahn M, Schedlowski M. Catecholamine-induced leukocytosis: early observations, current research, and future directions. Brain Behav Immun. 1996;10:77–91.

    Article  CAS  PubMed  Google Scholar 

  28. 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.

    Article  CAS  PubMed  Google Scholar 

  29. Van Gaal LF, Mertens IL, De Block CE. Mechanisms linking obesity with cardiovascular disease. Nature. 2006;444:875–80.

    Article  PubMed  CAS  Google Scholar 

  30. 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.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  31. Maes MA. A review on the acute phase response in major depression. Rev Neurosci. 1993;4:407–16.

    Article  CAS  PubMed  Google Scholar 

  32. Simpson E. Special regulatory T-cell review: regulation of immune responses–examining the role of T cells. Immunology. 2008;123:13–6.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  33. Piccirillo CA. Regulatory T cells in health and disease. Cytokine. 2008;43:395–401.

    Article  CAS  PubMed  Google Scholar 

  34. Wing K, Sakaguchi S. Regulatory T cells exert checks and balances on self tolerance and autoimmunity. Nat Immunol. 2010;11:7–13.

    Article  CAS  PubMed  Google Scholar 

  35. Bluestone JA, Tang Q. How do CD4+CD25+ regulatory T cells control autoimmunity? Curr Opin Immunol. 2005;17:638–42.

    Article  CAS  PubMed  Google Scholar 

  36. Finn OJ. Cancer immunology. N Engl J Med. 2008;358:2704–15.

    Article  CAS  PubMed  Google Scholar 

  37. Olson BM, McNeel DG. Monitoring regulatory immune responses in tumor immunotherapy clinical trials. Front Oncol. 2013;3:109.

    Article  PubMed Central  PubMed  Google Scholar 

  38. Whiteside TL. Regulatory T cell subsets in human cancer: are they regulating for or against tumor progression? Cancer Immunol Immunother. 2014;63:67–72.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  39. 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.

    Article  CAS  PubMed  Google Scholar 

  40. Dhabhar FS, McEwen BS. Stress-induced enhancement of antigen-specific cell-mediated immunity. J Immunol. 1996;156:2608–15.

    CAS  PubMed  Google Scholar 

  41. Selye H. Stress without distress. New York: Nal Penguin Inc.; 1974.

    Google Scholar 

  42. Schleimer RP, Claman HN, Oronsky A, editors. Anti-inflammatory steroid action: basic and clinical aspects. San Diego: Academic Press Inc.; 1989.

    Google Scholar 

  43. 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.

    Article  CAS  PubMed  Google Scholar 

  44. 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.

    Article  PubMed Central  PubMed  Google Scholar 

  45. Vivier E, Malissen B. Innate and adaptive immunity: specificities and signaling hierarchies revisited. Nat Immunol. 2005;6:17–21.

    Article  CAS  PubMed  Google Scholar 

  46. 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.

    Google Scholar 

  47. Baines D, Downer RG. Octopamine enhances phagocytosis in cockroach hemocytes: involvement of inositol trisphosphate. Arch Insect Biochem Physiol. 1994;26:249–61.

    Article  CAS  PubMed  Google Scholar 

  48. Sprent J, Tough DF. Lymphocyte life-span and memory. Science. 1994;265:1395–400.

    Article  CAS  PubMed  Google Scholar 

  49. 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.

    Article  CAS  PubMed  Google Scholar 

  50. 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.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  51. Jensen MM. Changes in leukocyte counts associated with various stressors. J Reticuloendothel Soc. 1969;8:457–65.

    Google Scholar 

  52. Viswanathan K, Dhabhar FS. Stress-induced enhancement of leukocyte trafficking into sites of surgery or immune activation. PNAS USA. 2005;102:5808–13.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  53. 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.

    CAS  PubMed  Google Scholar 

  54. 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.

    Article  CAS  PubMed  Google Scholar 

  55. Toft P, Svendsen P, Tonnesen E, Rasmussen JW, Christensen NJ. Redistribution of lymphocytes after major surgical stress. Acta Anesthesiol Scand. 1993;37:245–9.

    Article  CAS  Google Scholar 

  56. 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.

    Article  CAS  PubMed  Google Scholar 

  57. 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.

    Article  CAS  PubMed  Google Scholar 

  58. Herbert TB, Cohen S. Stress and immunity in humans: a meta-analytic review. Psychosom Med. 1993;55:364–79.

    Article  CAS  PubMed  Google Scholar 

  59. 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.

    Article  CAS  PubMed  Google Scholar 

  60. 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.

    Article  CAS  PubMed  Google Scholar 

  61. 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.

    Article  PubMed  Google Scholar 

  62. 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.

    Article  CAS  PubMed  Google Scholar 

  63. 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.

    Article  PubMed Central  PubMed  Google Scholar 

  64. 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.

    Article  CAS  Google Scholar 

  65. Fauci AS, Dale DC. The effect of in vivo hydrocortisone on subpopulations of human lymphocytes. J Clin Invest. 1974;53:240–6.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  66. Fauci AS, Dale DC. The effect of hydrocortisone on the kinetics of normal human lymphocytes. Blood. 1975;46:235–43.

    CAS  PubMed  Google Scholar 

  67. Carlson SL, Fox S, Abell KM. Catecholamine modulation of lymphocyte homing to lymphoid tissues. Brain Behav Immun. 1997;11:307–20.

    Article  CAS  PubMed  Google Scholar 

  68. 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.

    Article  CAS  PubMed  Google Scholar 

  69. 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.

    Article  CAS  PubMed  Google Scholar 

  70. 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.

    Article  CAS  PubMed  Google Scholar 

  71. Dhabhar FS, McEwen BS. Enhancing versus suppressive effects of stress hormones on skin immune function. PNAS USA. 1999;96:1059–64.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  72. 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.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  73. 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.

    Article  CAS  PubMed  Google Scholar 

  74. 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.

    Article  CAS  PubMed  Google Scholar 

  75. 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.

    Google Scholar 

  76. 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.

    Article  CAS  PubMed  Google Scholar 

  77. 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.

    Article  CAS  PubMed  Google Scholar 

  78. 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.

    Article  CAS  PubMed  Google Scholar 

  79. 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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  81. Kripke ML. Ultraviolet radiation and immunology: something new under the sun-presidential address. Cancer Res. 1994;54:6102–5.

    CAS  PubMed  Google Scholar 

  82. Granstein RD, Matsui MS. UV radiation-induced immunosuppression and skin cancer. Cutis. 2004;74:4–9.

    PubMed  Google Scholar 

  83. 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.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  84. Amkraut A, Solomon GF. Stress and murine sarcoma virus (Moloney)-induced tumors. Cancer Res. 1972;32:1428–33.

    CAS  PubMed  Google Scholar 

  85. 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.

    CAS  PubMed  Google Scholar 

  86. Nance DM, Sanders VM. Autonomic innervation and regulation of the immune system (1987–2007). Brain Behav Immun. 2007;21:736–45.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  87. Sanders VM. The beta2-adrenergic receptor on T and B lymphocytes: do we understand it yet? Brain Behav Immun. 2012;26:195–200.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  88. 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.

    Article  CAS  PubMed  Google Scholar 

  89. 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.

    Article  PubMed  Google Scholar 

  90. 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.

    Article  CAS  PubMed  Google Scholar 

  91. 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.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  92. 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.

  93. 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.

  94. Capuron L, Miller AH. Immune system to brain signaling: neuropsychopharmacological implications. Pharmacol Ther. 2011;130:226–38.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  95. 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.

    Article  CAS  PubMed  Google Scholar 

  96. Miller AH, Haroon E, Raison CL, Felger JC. Cytokine targets in the brain: impact on neurotransmitters and neurocircuits. Depress Anxiety. 2013;30:297–306.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  97. 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.

    Article  CAS  PubMed  Google Scholar 

  98. Quan N. Brain’s firewall: blood–brain barrier actively regulates neuroimmune information flow. Brain Behav Immun. 2006;20:447–8.

    Article  PubMed  Google Scholar 

  99. Quan N. In-depth conversation: spectrum and kinetics of neuroimmune afferent pathways. Brain Behav Immun. 2014. doi:10.1016/j.bbi.2014.02.006.

  100. Besedovsky HO, Rey AD. Physiology of psychoneuroimmunology: a personal view. Brain Behav Immun. 2007;21:34–44.

    Article  CAS  PubMed  Google Scholar 

  101. 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.

    Article  CAS  PubMed  Google Scholar 

  102. 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.

    Article  PubMed  Google Scholar 

  103. 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.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  104. Pace TW, Miller AH. Cytokines and glucocorticoid receptor signaling. Relevance to major depression. Ann N Y Acad Sci. 2009;1179:86–105.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  105. Dantzer R, O’Connor JC, Lawson MA, Kelley KW. Inflammation-associated depression: from serotonin to kynurenine. Psychoneuroendocrinology. 2011;36:426–36.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  106. Kelley KW, Dantzer R. Alcoholism and inflammation: neuroimmunology of behavioral and mood disorders. Brain Behav Immun. 2011;25(Suppl 1):S13–20.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  107. 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.

    Article  PubMed  Google Scholar 

  108. 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.

    Article  CAS  PubMed  Google Scholar 

  109. 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.

    CAS  PubMed  Google Scholar 

  110. 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.

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  111. Solomon GF. Emotions, stress, the central nervous system, and immunity. Ann N Y Acad Sci. 1969;164:335–43.

    Article  CAS  PubMed  Google Scholar 

  112. 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.

  113. Webster Marketon JI, Glaser R. Stress hormones and immune function. Cell Immunol. 2008;252:16–26.

    Article  CAS  PubMed  Google Scholar 

  114. Fagundes CP, Glaser R, Kiecolt-Glaser JK. Stressful early life experiences and immune dysregulation across the lifespan. Brain Behav Immun. 2013;27:8–12.

    Article  CAS  PubMed  Google Scholar 

  115. Sanders VM, Straub RH. Norepinephrine, the beta-adrenergic receptor, and immunity. Brain Behav Immun. 2002;16:290–332.

    Article  CAS  PubMed  Google Scholar 

  116. 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.

    Article  CAS  PubMed  Google Scholar 

  117. Irwin MR. Human psychoneuroimmunology: 20 years of discovery. Brain Behav Immun. 2008;22:129–39.

    Article  CAS  PubMed  Google Scholar 

  118. American Psychological Association Practice Organization. Psychologically Healthy Workplace Program Fact Sheet: By The Numbers; 2010. p. 1–15.

  119. 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.

    Article  CAS  PubMed  Google Scholar 

  120. 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.

    Article  CAS  PubMed  Google Scholar 

  121. 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.

    CAS  PubMed  Google Scholar 

  122. 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.

    Article  CAS  PubMed  Google Scholar 

  123. Fleshner M, Laudenslager ML, Simons L, Maier SF. Reduced serum antibodies associated with social defeat in rats. Physiol Behav. 1989;45:1183–7.

    Article  CAS  PubMed  Google Scholar 

  124. Bartrop R, Lazarus L, Luckhurst E, Kiloh LG, Penny R. Depressed lymphocyte function after bereavement. Lancet. 1977;1:834–6.

    Article  Google Scholar 

  125. 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.

    Article  CAS  PubMed  Google Scholar 

  126. 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.

    Article  CAS  PubMed  Google Scholar 

  127. 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.

    CAS  PubMed  Google Scholar 

  128. Wistar R, Hildemann WH. Effect of stress on skin transplantation immunity in mice. Science. 1960;131:159–60.

    Article  PubMed  Google Scholar 

  129. 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.

    Article  CAS  PubMed  Google Scholar 

  130. 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.

    Article  CAS  PubMed  Google Scholar 

  131. 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.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  132. 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.

    PubMed Central  CAS  Google Scholar 

  133. Blackburn EH, Epel ES. Telomeres and adversity: too toxic to ignore. Nature. 2012;490:169–71.

    Article  CAS  PubMed  Google Scholar 

  134. 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.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  135. 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.

    Article  PubMed  Google Scholar 

  136. Sood AK, Lutgendorf SK. Stress influences on anoikis. Cancer Prev Res (Phila). 2011;4:481–5.

    Article  CAS  Google Scholar 

  137. 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.

    Article  CAS  PubMed  Google Scholar 

  138. 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.

    Article  CAS  PubMed  Google Scholar 

  139. 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.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  140. 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.

    Article  PubMed  Google Scholar 

  141. 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.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  142. Levine S, Saltzman A. Nonspecific stress prevents relapses of experimental allergic encephalomyelitis in rats. Brain Behav Immun. 1987;1:336–41.

    Article  CAS  PubMed  Google Scholar 

  143. 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.

    Article  CAS  PubMed  Google Scholar 

  144. Griffin AC, Warren DL, Wolny AC, Whitacre CC. Suppression of experimental autoimmune encephalomyelitis by restraint stress. J Neuroimmunol. 1993;44:103–16.

    Article  CAS  PubMed  Google Scholar 

  145. 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.

    Article  CAS  PubMed  Google Scholar 

  146. Besedovsky HO, del Rey A. The cytokine-HPA axis feed-back circuit. Z Rheumatol. 2000;59(Suppl 2):II26–30.

    Article  Google Scholar 

  147. del Rey A, Besedovsky HO. The cytokine-HPA axis circuit contributes to prevent or moderate autoimmune processes. Z Rheumatol. 2000;59:II31–5.

    Article  Google Scholar 

  148. Straub RH, Kalden JR. Stress of different types increases the proinflammatory load in rheumatoid arthritis. Arthritis Res Ther. 2009;11:114.

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  149. 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.

    Article  PubMed  CAS  Google Scholar 

  150. Sternberg EM. Neuroendocrine regulation of autoimmune/inflammatory disease. J Endocrinol. 2001;169:429–35.

    Article  CAS  PubMed  Google Scholar 

  151. 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.

    CAS  PubMed  Google Scholar 

  152. Straub RH. Evolutionary medicine and chronic inflammatory state—known and new concepts in pathophysiology. J Mol Med (Berl). 2012;90:523–34.

    Article  Google Scholar 

  153. Straub RH. Interaction of the endocrine system with inflammation: a function of energy and volume regulation. Arthritis Res Ther. 2014;16:203.

    Article  PubMed Central  PubMed  Google Scholar 

  154. Hackney AC. Exercise as a stressor to the human neuroendocrine system. Medicina (Kaunas). 2006;42:788–97.

    Google Scholar 

  155. Pedersen BK, Hoffman-Goetz L. Exercise and the immune system: regulation, integration, and adaptation. Physiol Rev. 2000;80:1055–81.

    CAS  PubMed  Google Scholar 

  156. Pedersen BK. Special feature for the Olympics: effects of exercise on the immune system: exercise and cytokines. Immunol Cell Biol. 2000;78:532–5.

    Article  CAS  PubMed  Google Scholar 

  157. 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.

    Article  PubMed  Google Scholar 

  158. Friedenreich CM. The role of physical activity in breast cancer etiology. Semin Oncol. 2010;37:297–302.

    Article  PubMed  Google Scholar 

  159. Friedenreich CM, Neilson HK, Lynch BM. State of the epidemiological evidence on physical activity and cancer prevention. Eur J Cancer. 2010;46:2593–604.

    Article  PubMed  Google Scholar 

  160. Clague J, Bernstein L. Physical activity and cancer. Curr Oncol Rep. 2012;14:550–8.

    Article  PubMed Central  PubMed  Google Scholar 

  161. Gleeson M. Immune function in sport and exercise. J Appl Physiol. 2007;103:693–9.

    Article  CAS  PubMed  Google Scholar 

  162. Walsh NP, Whitham M. Exercising in environmental extremes: a greater threat to immune function? Sports Med. 2006;36:941–76.

    Article  PubMed  Google Scholar 

  163. Woods JA, Vieira VJ, Keylock KT. Exercise, inflammation, and innate immunity. Immunol Allergy Clin North Am. 2009;29:381–93.

    Article  PubMed  Google Scholar 

  164. Phillips AC, Burns VE, Lord JM. Stress and exercise: getting the balance right for aging immunity. Exerc Sport Sci Rev. 2007;35:35–9.

    Article  PubMed  Google Scholar 

  165. Woods JA, Lowder TW, Keylock KT. Can exercise training improve immune function in the aged? Ann N Y Acad Sci. 2002;959:117–27.

    Article  CAS  PubMed  Google Scholar 

  166. 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.

    Article  PubMed  Google Scholar 

  167. Dhabhar FS. Psychological stress and immunoprotection versus immunopathology in the skin. Clin Dermatol. 2013;31:18–30.

    Article  PubMed  Google Scholar 

  168. 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.

    Article  PubMed  Google Scholar 

  169. 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.

    Article  PubMed  Google Scholar 

  170. Edwards KM, Burns VE, Carroll D, Drayson M, Ring C. The acute stress-induced immunoenhancement hypothesis. Exerc Sport Sci Rev. 2007;35:150–5.

    Article  PubMed  Google Scholar 

  171. 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.

    Article  CAS  PubMed  Google Scholar 

  172. Griffiths CE, Dearman RJ, Cumberbatch M, Kimber I. Cytokines and Langerhans cell mobilisation in mouse and man. Cytokine. 2005;32:67–70.

    Article  CAS  PubMed  Google Scholar 

  173. 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.

    Article  PubMed  Google Scholar 

  174. Arndt J, Smith N, Tausk F. Stress and atopic dermatitis. Curr Allergy Asthma Rep. 2008;8:312–7.

    Article  CAS  PubMed  Google Scholar 

  175. Black PH, Garbutt LD. Stress, inflammation and cardiovascular disease. J Psychosom Res. 2002;52:1–23.

    Article  PubMed  Google Scholar 

  176. 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.

    Article  PubMed  Google Scholar 

  177. Hildebrand HC, Epstein J, Larjava H. The influence of psychological stress on periodontal disease. J West Soc Periodontol Periodontal Abstr. 2000;48:69–77.

    CAS  PubMed  Google Scholar 

  178. Wright RJ, Rodriguez M, Cohen S. Review of psychosocial stress and asthma: an integrated biopsychosocial approach. Thorax. 1998;53:1066–74.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  179. Chen E, Miller GE. Stress and inflammation in exacerbations of asthma. Brain Behav Immun. 2007;21:993–9.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  180. 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.

    Article  PubMed  Google Scholar 

  181. Fortune DG, Richards HL, Griffiths CE. Psychologic factors in psoriasis: consequences, mechanisms, and interventions. Dermatol Clin. 2005;23:681–94.

    Article  CAS  PubMed  Google Scholar 

  182. 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.

    Article  PubMed  Google Scholar 

  183. 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.

    Article  PubMed  Google Scholar 

  184. 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.

    Article  PubMed  Google Scholar 

  185. Danese A, McEwen BS. Adverse childhood experiences, allostasis, allostatic load, and age-related disease. Physiol Behav. 2012;106:29–39.

    Article  CAS  PubMed  Google Scholar 

  186. Dhabhar FS. Harnessing stress on the path to peace. TEDx Hayward. 2013. https://www.youtube.com/watch?v=u2QFJbE1EBs.

  187. Amkraut AA, Solomon CF, Kraemer HC. Stress, early experience and adjuvant-induced arthritis in the rat. Psychosom Med. 1971;33:203–14.

    Article  CAS  PubMed  Google Scholar 

  188. 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.

    PubMed  Google Scholar 

  189. 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.

    Article  CAS  PubMed  Google Scholar 

  190. Cohen S, Tyrrell DAJ, Smith AP. Psychological stress and susceptibility to the common cold. N Engl J Med. 1991;325:606–12.

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgments

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.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Firdaus S. Dhabhar.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

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

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12026-014-8517-0

Keywords

Navigation