Stress-Induced Immune Dysregulation: Implications for Wound Healing, Infectious Disease and Cancer

Abstract

The communication between the central nervous system and the immune system occurs via a complex network of bidirectional signals linking the nervous, endocrine and immune systems. The field of psychoneuroimmunology (PNI) has provided new insights to help understand the pathophysiological processes that are linked to the immune system. Work in this field has established that psychological stress disrupts the functional interaction between the nervous and immune systems. Stress-induced immune dysregulation has been shown to be significant enough to result in health consequences, including reducing the immune response to vaccines, slowing wound healing, reactivating latent herpesviruses, such as Epstein–Barr virus (EBV), and enhancing the risk for more severe infectious disease. Chronic stress/depression can increase the peripheral production of proinflammatory cytokines, such as interleukin (IL)-6. High serum levels of IL-6 have been linked to risks for several conditions, such as cardiovascular disease, type 2 diabetes, mental health complications, and some cancers. This overview will discuss the evidence that psychological stress promotes immune dysfunction that negatively impacts human health.

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Fig. 1

Abbreviations

HPA:

hypothalamic–pituitary–adrenal

SNS:

sympathetic nervous system

GC:

glucocorticoids

EBV:

Epstein–Barr virus

NPC:

nasopharyngeal carcinoma

BL:

Burkitt's lymphoma

References

  1. Altemus M, Rao B, Dhabhar FS, Ding W, Granstein RD (2001) Stress-induced changes in skin barrier function in healthy women. J Invest Dermatol 117(2):309–317

    PubMed  CAS  Article  Google Scholar 

  2. Ansell SM, Li CY, Lloyd RV, Phyliky RL (1999) Epstein–Barr virus infection in Richter's transformation. Am J Hematol 60(2):99–104

    PubMed  CAS  Article  Google Scholar 

  3. Bonneau RH, Sheridan JF, Feng NG, Glaser R (1991) Stress-induced suppression of herpes simplex virus (HSV)-specific cytotoxic T lymphocyte and natural killer cell activity and enhancement of acute pathogenesis following local HSV infection. Brain Behav Immun 5(2):170–192

    PubMed  CAS  Article  Google Scholar 

  4. Bonneau RH, Sheridan JF, Feng N, Glaser R (1993) Stress-induced modulation of the primary cellular immune response to herpes simplex virus infection is mediated by both adrenal-dependent and independent mechanisms. J Neuroimmunol 42(2):167–176

    PubMed  CAS  Article  Google Scholar 

  5. Brousset P (2002) Is the Epstein–Barr virus infection relevant in lymphomagenesis? Hum Pathol 33(2):143–145

    PubMed  Article  Google Scholar 

  6. Burns VE, Drayson M, Ring C, Carroll D (2002) Perceived stress and psychological well-being are associated with antibody status after meningitis C conjugate vaccination. Psychosom Med 64(6):963–970

    PubMed  CAS  Article  Google Scholar 

  7. Cacioppo JT, Kiecolt-Glaser JK, Malarkey WB, Laskowski BF, Rozlog LA, Poehlmann KM, Burleson MH, Glaser R (2002) Autonomic and glucocorticoid associations with the steady-state expression of latent Epstein–Barr virus. Horm Behav 42(1):32–41

    PubMed  CAS  Article  Google Scholar 

  8. Capitanio JP, Mendoza SP, Lerche NW, Mason WA (1998) Social stress results in altered glucocorticoid regulation and shorter survival in simian acquired immune deficiency syndrome. Proc Natl Acad Sci USA 95(8):4714–4719

    PubMed  CAS  Article  Google Scholar 

  9. Cohen S, Tyrrell DA, Smith AP (1991) Psychological stress and susceptibility to the common cold. N Engl J Med 325(9):606–612

    PubMed  CAS  Article  Google Scholar 

  10. Cohen S, Frank E, Doyle WJ, Skoner DP, Rabin BS, Gwaltney JM Jr (1998) Types of stressors that increase susceptibility to the common cold in healthy adults. Health Psychol 17(3):214–223

    PubMed  CAS  Article  Google Scholar 

  11. Cohen F, Kemeny ME, Kearney KA, Zegans LS, Neuhaus JM, Conant MA (1999) Persistent stress as a predictor of genital herpes recurrence. Arch Intern Med 159(20):2430–2436

    PubMed  CAS  Article  Google Scholar 

  12. Cole SW, Kemeny ME, Taylor SE, Visscher BR, Fahey JL (1996) Accelerated course of human immunodeficiency virus infection in gay men who conceal their homosexual identity. Psychosom Med 58(3):219–231

    PubMed  CAS  Google Scholar 

  13. De Bosscher K, Vanden Berghe W, Vermeulen L, Plaisance S, Boone E, Haegeman G (2000) Glucocorticoids repress NF-kappaB-driven genes by disturbing the interaction of p65 with the basal transcription machinery, irrespective of coactivator levels in the cell. Proc Natl Acad Sci USA 97(8):3919–3924

    PubMed  Article  Google Scholar 

  14. Dentino AN, Pieper CF, Rao MK, Currie MS, Harris T, Blazer DG, Cohen HJ (1999) Association of interleukin-6 and other biologic variables with depression in older people living in the community. J Am Geriatr Soc 47(1):6–11

    PubMed  CAS  Google Scholar 

  15. Dhabhar FS (2003) Stress, leukocyte trafficking, and the augmentation of skin immune function. Ann NY Acad Sci 992:205–217

    PubMed  CAS  Article  Google Scholar 

  16. Emery CF, Kiecolt-Glaser JK, Glaser R, Malarkey WB, Frid DJ (2005) Exercise accelerates wound healing among healthy older adults: a preliminary investigation. J Gerontol A Biol Sci Med Sci 60(11):1432–1436

    PubMed  Google Scholar 

  17. Esterling BA, Kiecolt-Glaser JK, Glaser R (1996) Psychosocial modulation of cytokine-induced natural killer cell activity in older adults. Psychosom Med 58(3):264–272

    PubMed  CAS  Google Scholar 

  18. Glaser R, Kiecolt-Glaser JK (2005) Stress-induced immune dysfunction: implications for health. Nat Rev Immunol 5(3):243–251

    PubMed  CAS  Article  Google Scholar 

  19. Glaser R, Pearson GR, Jones JF, Hillhouse J, Kennedy S, Mao HY, Kiecolt-Glaser JK (1991) Stress-related activation of Epstein–Barr virus. Brain Behav Immun 5(2):219–232

    PubMed  CAS  Article  Google Scholar 

  20. Glaser R, Kiecolt-Glaser JK, Bonneau RH, Malarkey W, Kennedy S, Hughes J (1992) Stress-induced modulation of the immune response to recombinant hepatitis B vaccine. Psychosom Med 54(1):22–29

    PubMed  CAS  Google Scholar 

  21. Glaser R, Pearson GR, Bonneau RH, Esterling BA, Atkinson C, Kiecolt-Glaser JK (1993) Stress and the memory T-cell response to the Epstein–Barr virus in healthy medical students. Health Psychol 12(6):435–442

    PubMed  CAS  Article  Google Scholar 

  22. Glaser R, Pearl DK, Kiecolt-Glaser JK, Malarkey WB (1994) Plasma cortisol levels and reactivation of latent Epstein–Barr virus in response to examination stress. Psychoneuroendocrinology 19(8):765–772

    PubMed  CAS  Article  Google Scholar 

  23. Glaser R, Kutz LA, MacCallum RC, Malarkey WB (1995) Hormonal modulation of Epstein–Barr virus replication. Neuroendocrinology 62(4):356–361

    PubMed  CAS  Google Scholar 

  24. Glaser R, Friedman SB, Smyth J, Ader R, Bijur P, Brunell P, Cohen N, Krilov LR, Lifrak ST, Stone A, Toffler P (1999a) The differential impact of training stress and final examination stress on herpesvirus latency at the United States Military Academy at West Point. Brain Behav Immun 13(3):240–251

    PubMed  CAS  Article  Google Scholar 

  25. Glaser R, Kiecolt-Glaser JK, Marucha PT, MacCallum RC, Laskowski BF, Malarkey WB (1999b) Stress-related changes in proinflammatory cytokine production in wounds. Arch Gen Psychiatry 56(5):450–456

    PubMed  CAS  Article  Google Scholar 

  26. Glaser R, Sheridan J, Malarkey WB, MacCallum RC, Kiecolt-Glaser JK (2000) Chronic stress modulates the immune response to a pneumococcal pneumonia vaccine. Psychosom Med 62(6):804–807

    PubMed  CAS  Google Scholar 

  27. Glaser R, MacCallum RC, Laskowski BF, Malarkey WB, Sheridan JF, Kiecolt-Glaser JK (2001) Evidence for a shift in the Th-1 to Th-2 cytokine response associated with chronic stress and aging. J Gerontol A Biol Sci Med Sci 56(8):M477–M482

    PubMed  CAS  Google Scholar 

  28. Glaser R, Robles TF, Sheridan J, Malarkey WB, Kiecolt-Glaser JK (2003) Mild depressive symptoms are associated with amplified and prolonged inflammatory responses after influenza virus vaccination in older adults. Arch Gen Psychiatry 60(10):1009–1014

    PubMed  CAS  Article  Google Scholar 

  29. Glaser R, Padgett DA, Litsky ML, Baiocchi RA, Yang EV, Chen M, Yeh PE, Klimas NG, Marshall GD, Whiteside T, Herberman R, Kiecolt-Glaser J, Williams MV (2005) Stress-associated changes in the steady-state expression of latent Epstein–Barr virus: implications for chronic fatigue syndrome and cancer. Brain Behav Immun 19(2):91–103

    PubMed  CAS  Article  Google Scholar 

  30. Glaser R, Litsky ML, Padgett DA, Baiocchi RA, Yang EV, Chen M, Yeh PE, Green-Church KB, Caligiuri MA, Williams MV (2006) EBV-encoded dUTPase induces immune dysregulation: implications for the pathophysiology of EBV-associated disease. Virology 346(1):205–218

    PubMed  CAS  Article  Google Scholar 

  31. Harris TB, Ferrucci L, Tracy RP, Corti MC, Wacholder S, Ettinger WH Jr, Heimovitz H, Cohen HJ, Wallace R (1999) Associations of elevated interleukin-6 and C-reactive protein levels with mortality in the elderly. Am J Med 106(5):506–512

    PubMed  CAS  Article  Google Scholar 

  32. Hofmann TG, Schmitz ML (2002) The promoter context determines mutual repression or synergism between NF-kappaB and the glucocorticoid receptor. Biol Chem 383(12):1947–1951

    PubMed  CAS  Article  Google Scholar 

  33. Hofmann TG, Hehner SP, Bacher S, Droge W, Schmitz ML (1998) Various glucocorticoids differ in their ability to induce gene expression, apoptosis and to repress NF-kappaB-dependent transcription. FEBS Lett 441(3):441–446

    PubMed  CAS  Article  Google Scholar 

  34. Hubner G, Brauchle M, Smola H, Madlener M, Fassler R, Werner S (1996) Differential regulation of pro-inflammatory cytokines during wound healing in normal and glucocorticoid-treated mice. Cytokine 8(7):548–556

    PubMed  CAS  Article  Google Scholar 

  35. Jabaaij L, van Hattum J, Vingerhoets JJ, Oostveen FG, Duivenvoorden HJ, Ballieux RE (1996) Modulation of immune response to rDNA hepatitis B vaccination by psychological stress. J Psychosom Res 41(2):129–137

    PubMed  CAS  Article  Google Scholar 

  36. Kiecolt-Glaser JK, Glaser R (2002) Depression and immune function: central pathways to morbidity and mortality. J Psychosom Res 53(4):873–876

    PubMed  Article  Google Scholar 

  37. Kiecolt-Glaser JK, Marucha PT, Malarkey WB, Mercado AM, Glaser R (1995) Slowing of wound healing by psychological stress. Lancet 346(8984):1194–1196

    PubMed  CAS  Article  Google Scholar 

  38. Kiecolt-Glaser JK, Glaser R, Gravenstein S, Malarkey WB, Sheridan J (1996) Chronic stress alters the immune response to influenza virus vaccine in older adults. Proc Natl Acad Sci USA 93(7):3043–3047

    PubMed  CAS  Article  Google Scholar 

  39. Kiecolt-Glaser JK, Page GG, Marucha PT, MacCallum RC, Glaser R (1998) Psychological influences on surgical recovery. Perspectives from psychoneuroimmunology. Am Psychol 53(11):1209–1218

    PubMed  CAS  Article  Google Scholar 

  40. Kiecolt-Glaser JK, Preacher KJ, MacCallum RC, Atkinson C, Malarkey WB, Glaser R (2003) Chronic stress and age-related increases in the proinflammatory cytokine IL-6. Proc Natl Acad Sci USA 100(15):9090–9095

    PubMed  CAS  Article  Google Scholar 

  41. Kiecolt-Glaser JK, Loving TJ, Stowell JR, Malarkey WB, Lemeshow S, Dickinson SL, Glaser R (2005) Hostile marital interactions, proinflammatory cytokine production, and wound healing. Arch Gen Psychiatry 62(12):1377–1384

    PubMed  Article  Google Scholar 

  42. Laichalk LL, Thorley-Lawson DA (2005) Terminal differentiation into plasma cells initiates the replicative cycle of Epstein–Barr virus in vivo. J Virol 79(2):1296–1307

    PubMed  CAS  Article  Google Scholar 

  43. Leserman J, Jackson ED, Petitto JM, Golden RN, Silva SG, Perkins DO, Cai J, Folds JD, Evans DL (1999) Progression to AIDS: the effects of stress, depressive symptoms, and social support. Psychosom Med 61(3):397–406

    PubMed  CAS  Google Scholar 

  44. Levy S, Herberman R, Lippman M, d'Angelo T (1987) Correlation of stress factors with sustained depression of natural killer cell activity and predicted prognosis in patients with breast cancer. J Clin Oncol 5(3):348–353

    PubMed  CAS  Google Scholar 

  45. Marucha PT, Kiecolt-Glaser JK, Favagehi M (1998) Mucosal wound healing is impaired by examination stress. Psychosom Med 60(3):362–365

    PubMed  CAS  Google Scholar 

  46. Mehta SK, Stowe RP, Feiveson AH, Tyring SK, Pierson DL (2000) Reactivation and shedding of cytomegalovirus in astronauts during spaceflight. J Infect Dis 182(6):1761–1764

    PubMed  CAS  Article  Google Scholar 

  47. Mehta SK, Cohrs RJ, Forghani B, Zerbe G, Gilden DH, Pierson DL (2004) Stress-induced subclinical reactivation of varicella zoster virus in astronauts. J Med Virol 72(1):174–179

    PubMed  Article  Google Scholar 

  48. Mercado AM, Padgett DA, Sheridan JF, Marucha PT (2002a) Altered kinetics of IL-1 alpha, IL-1 beta, and KGF-1 gene expression in early wounds of restrained mice. Brain Behav Immun 16(2):150–162

    PubMed  CAS  Article  Google Scholar 

  49. Mercado AM, Quan N, Padgett DA, Sheridan JF, Marucha PT (2002b) Restraint stress alters the expression of interleukin-1 and keratinocyte growth factor at the wound site: an in situ hybridization study. J Neuroimmunol 129(1–2):74–83

    PubMed  CAS  Article  Google Scholar 

  50. Miller GE, Cohen S, Pressman S, Barkin A, Rabin BS, Treanor JJ (2004) Psychological stress and antibody response to influenza vaccination: when is the critical period for stress, and how does it get inside the body? Psychosom Med 66(2):215–223

    PubMed  Article  Google Scholar 

  51. Morag M, Morag A, Reichenberg A, Lerer B, Yirmiya R (1999) Psychological variables as predictors of rubella antibody titers and fatigue—a prospective, double blind study. J Psychiatr Res 33(5):389–395

    PubMed  CAS  Article  Google Scholar 

  52. Padgett DA, Glaser R (2003) How stress influences the immune response. Trends Immunol 24(8):444–448

    PubMed  CAS  Article  Google Scholar 

  53. Padgett DA, Marucha PT, Sheridan JF (1998a) Restraint stress slows cutaneous wound healing in mice. Brain Behav Immun 12(1):64–73

    PubMed  CAS  Article  Google Scholar 

  54. Padgett DA, Sheridan JF, Dorne J, Berntson GG, Candelora J, Glaser R (1998b) Social stress and the reactivation of latent herpes simplex virus type 1. Proc Natl Acad Sci USA 95(12):7231–7235

    PubMed  CAS  Article  Google Scholar 

  55. Padgett DA, Hotchkiss AK, Pyter LM, Nelson RJ, Yang E, Yeh PE, Litsky M, Williams M, Glaser R (2004) Epstein–Barr virus-encoded dUTPase modulates immune function and induces sickness behavior in mice. J Med Virol 74(3):442–448

    PubMed  CAS  Article  Google Scholar 

  56. Patriarca PA (1994) A randomized controlled trial of influenza vaccine in the elderly. Scientific scrutiny and ethical responsibility. JAMA 272(21):1700–1701

    PubMed  CAS  Article  Google Scholar 

  57. Payne DA, Mehta SK, Tyring SK, Stowe RP, Pierson DL (1999) Incidence of Epstein–Barr virus in astronaut saliva during spaceflight. Aviat Space Environ Med 70(12):1211–1213

    PubMed  CAS  Google Scholar 

  58. Penninx BW, Kritchevsky SB, Yaffe K, Newman AB, Simonsick EM, Rubin S, Ferrucci L, Harris T, Pahor M (2003) Inflammatory markers and depressed mood in older persons: results from the Health, Aging and Body Composition study. Biol Psychiatry 54(5):566–572

    PubMed  CAS  Article  Google Scholar 

  59. Petrella T, Yaziji N, Collin F, Rifle G, Morlevat F, Arnould L, Fargeot P, Depret O (1997) Implication of the Epstein–Barr virus in the progression of chronic lymphocytic leukaemia/small lymphocytic lymphoma to Hodgkin-like lymphomas. Anticancer Res 17(5B):3907–3913

    PubMed  CAS  Google Scholar 

  60. Pierson DL, Stowe RP, Phillips TM, Lugg DJ, Mehta SK (2005) Epstein–Barr virus shedding by astronauts during space flight. Brain Behav Immun 19(3):235–242

    PubMed  CAS  Article  Google Scholar 

  61. Rojas IG, Padgett DA, Sheridan JF and Marucha PT (2002) Stress-induced susceptibility to bacterial infection during cutaneous wound healing. Brain Behav Immun 16(1):74–84

    PubMed  Article  Google Scholar 

  62. Roy S, Khanna S, Yeh PE, Rink C, Malarkey WB, Kiecolt-Glaser J, Laskowski B, Glaser R, Sen CK (2005) Wound site neutrophil transcriptome in response to psychological stress in young men. Gene Expr 12(4–6):273–287

    PubMed  CAS  Google Scholar 

  63. Sanders VM, Kohm AP (2002) Sympathetic nervous system interaction with the immune system. Int Rev Neurobiol 52:17–41

    PubMed  CAS  Article  Google Scholar 

  64. Schmader K, Studenski S, MacMillan J, Grufferman S, Cohen HJ (1990) Are stressful life events risk factors for herpes zoster? J Am Geriatr Soc 38(11):1188–1194

    PubMed  CAS  Google Scholar 

  65. Schulz R, Belle SH, Czaja SJ, McGinnis KA, Stevens A, Zhang S (2004) Long-term care placement of dementia patients and caregiver health and well being. JAMA 292(8):961–967

    PubMed  CAS  Article  Google Scholar 

  66. Segerstrom SC, Miller GE (2004) Psychological stress and the human immune system: a meta-analytic study of 30 years of inquiry. Psychol Bull 130(4):601–630

    PubMed  Article  Google Scholar 

  67. Sheridan JF, Feng NG, Bonneau RH, Allen CM, Huneycutt BS, Glaser R (1991) Restraint stress differentially affects anti-viral cellular and humoral immune responses in mice. J Neuroimmunol 31(3):245–255

    PubMed  CAS  Article  Google Scholar 

  68. Sheridan JF, Stark JL, Avitsur R, Padgett DA (2000) Social disruption, immunity, and susceptibility to viral infection. Role of glucocorticoid insensitivity and NGF. Ann NY Acad Sci 917:894–905

    PubMed  CAS  Article  Google Scholar 

  69. Sieber WJ, Rodin J, Larson L, Ortega S, Cummings N, Levy S, Whiteside T, Herberman R (1992) Modulation of human natural killer cell activity by exposure to uncontrollable stress. Brain Behav Immun 6(2):141–156

    PubMed  CAS  Article  Google Scholar 

  70. Sternberg EM (2006) Neural regulation of innate immunity: a coordinated nonspecific host response to pathogens. Nat Rev Immunol 6(4):318–328

    PubMed  CAS  Article  Google Scholar 

  71. Stone AA, Bovbjerg DH, Neale JM, Napoli A, Valdimarsdottir H, Cox D, Hayden FG, Gwaltney JM Jr (1992) Development of common cold symptoms following experimental rhinovirus infection is related to prior stressful life events. Behav Med 18(3):115–120

    PubMed  CAS  Article  Google Scholar 

  72. Touitou R, Arbach H, Cochet C, Feuillard J, Martin A, Raphael M, Joab I (2003) Heterogeneous Epstein–Barr virus latent gene expression in AIDS-associated lymphomas and in type I Burkitt's lymphoma cell lines. J Gen Virol 84(Pt 4):949–957

    PubMed  CAS  Article  Google Scholar 

  73. Vedhara K, Cox NK, Wilcock GK, Perks P, Hunt M, Anderson S, Lightman SL, Shanks NM (1999) Chronic stress in elderly carers of dementia patients and antibody response to influenza vaccination. Lancet 353(9153):627–631

    PubMed  CAS  Article  Google Scholar 

  74. Weaver JD, Huang MH, Albert M, Harris T, Rowe JW, Seeman TE (2002) Interleukin-6 and risk of cognitive decline: MacArthur studies of successful aging. Neurology 59(3):371–378

    PubMed  CAS  Google Scholar 

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Godbout, J.P., Glaser, R. Stress-Induced Immune Dysregulation: Implications for Wound Healing, Infectious Disease and Cancer. Jrnl Neuroimmune Pharm 1, 421–427 (2006). https://doi.org/10.1007/s11481-006-9036-0

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Key words

  • stress
  • immunity
  • cytokines
  • behavior