Sleep and Immune Correlates: Translational Research in Clinical Populations

  • Sarosh J. Motivala
  • Michael Irwin


Substantial evidence demonstrates that sleep and the immune system interact via bidirectional pathways (Krueger et al. 1995; Opp 2005). Experimental strategies that target sleep (e.g., sleep deprivation) or modify the immune system (via the cytokine network) are beginning to identify the mechanisms that link sleep and immunity. Basic studies show that inflammatory cytokine administration alters sleep macroarchitecture and continuity (Spath-Schwalbe et al. 1998; Späth-Schwalbe, Lange, Perras, Fehm, and Born 2000; Hogan, Morrow, Smith, and Opp 2003). Conversely, sleep behavior influences immunity; with as few as 4 h of sleep loss altering lymphocyte trafficking, cytokine expression, and effector cell activity (Motivala and Irwin 2005); furthermore, prolonged sleep deprivation in rats (>2 weeks) results in death due to poor host defense of normally controlled bacterial pathogens that progressively penetrate into multiple organ systems (Everson and Toth 2000). These studies suggest that chronic sleep impairments show a reciprocal relationship with immune dysregulation. There is growing interest in testing the impact of chronic loss of sleep on the immune system in clinical disorders in which there are marked sleep impairments. Such studies have the potential to provide insights into the reciprocal influence of cytokines on sleep, and whether increases in inflammatory markers in many of these disorders might contribute to abnormalities in sleep continuity or sleep depth in these populations. In addition, immune dysregulation due to sleep impairments may impact the incidence of infectious diseases and the development of inflammatory disorders in these vulnerable populations. This chapter focuses on these clinical populations who have disordered sleep and/or inflammation and examines the hypothesis that sleep impairments initiate increased expression of inflammatory cytokines that are part of a positive feedback loop that promotes and perpetuates sleep impairments and low-grade inflammatory processes.


Rheumatoid Arthritis Patient Sleep Deprivation Poor Sleep Chronic Insomnia Primary Insomnia 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. American Psychiatric Association and American Psychiatric Association Task Force on DSMIV (1994) Diagnostic and Statistical Manual of Mental Disorders: DSM-IV. American Psychiatric Association, Washington, DC.Google Scholar
  2. Ancoli-Israel, S. (2000) Insomnia in the elderly: A review for the primary care practitioner. Sleep 23(Suppl 1), S23–S30; discussion S36–S38.PubMedGoogle Scholar
  3. Association, A.P. (2000) Diagnostic and Statistical Manual of Mental Disorders. American Psychiatric Association, Washington, DC.Google Scholar
  4. Balasekaran, R., Bulterys, M., Jamal, M.M., Quinn, P.G., Johnston, D.E., Skipper, B., Chaturvedi, S., and Arora, S. (1999) A case-control study of risk factors for sporadic hepatitis C virus infection in the southwestern United States. Am J Gastroenterol 94(5), 1341–1346.PubMedCrossRefGoogle Scholar
  5. Bauer, J., Hohagen, F., Ebert, T., Timmer, J., Ganter, U., Krieger, S., Lis, S., Postler, E., Voderholzer, U., and Berger, M. (1994) Interleukin-6 serum levels in healthy persons correspond to the sleep-wake cycle. Clin Invest 72(4), 315.CrossRefGoogle Scholar
  6. Benca, R.M., Obermeyer, W.H., Thisted, R.A., and Gillin, J.C., (1992) Sleep and psychiatric disorders. A meta-analysis. Arch Gen Psychiatry 49(8), 651–668; discussion 669–670.PubMedGoogle Scholar
  7. Ben-Eliyahu, S., Shakhar, G., Page, G.G., Stefanski, V., and Shakhar, K. (2000) Suppression of NK cell activity and of resistance to metastasis by stress: A role for adrenal catecholamines and beta-adrenoceptors. Neuroimmunomodulation 8(3), 154–164.PubMedCrossRefGoogle Scholar
  8. Boos, C.J., and Lip, G.Y. (2006) Is hypertension an inflammatory process? Curr Pharm Des 12(13), 1623–1635.PubMedCrossRefGoogle Scholar
  9. Born, J., Lange, T., Hansen, K., Molle, M., and Fehm, H.L. (1997) Effects of sleep and circadian rhythm on human circulating immune cells. J Immunol 158(9), 4454–4464.PubMedGoogle Scholar
  10. Brower, K.J. (2001) Alcohol's effects on sleep in alcoholics. Alcohol Res Health 25(2), 110–125.PubMedGoogle Scholar
  11. Burgos, I., Richter, L., Klein, T., Fiebich, B., Feige, B., Lieb, K., Voderholzer, U., and Riemann, D. (2006) Increased nocturnal interleukin-6 excretion in patients with primary insomnia: a pilot study. Brain Behav Immun 20(3): 246–253.PubMedCrossRefGoogle Scholar
  12. Buskin, S.E., Gale, J.L., Weiss, N.S., and Nolan, C.M. (1994) Tuberculosis risk factors in adults in King County, Washington, 1988 through 1990. Am J Pub Health 84(11), 1750–1756.PubMedCrossRefGoogle Scholar
  13. Carr, D., Goudas, L., Lawrence, D., Pirl, W., Lau, J., DeVine, D., Kupelnick, B., and Miller, K. (2002) Management of cancer symptoms: Pain, depression, and fatigue. Evid Rep Technol Assess (Summ)(61), 1–5.Google Scholar
  14. Charles, P., Elliott, M.J., Davis, D., Potter, A., Kalden, J.R., Antoni, C., Breedveld, F.C., Smolen, J.S., Eberl, G., deWoody, K., Feldmann, M., and Maini, R.N. (1999) Regulation of cytokines, cytokine inhibitors, and acute-phase proteins following anti-TNF-alpha therapy in rheumatoid arthritis. J Immunol 163(3), 1521–1528.PubMedGoogle Scholar
  15. Collado-Hidalgo, A., Bower, J.E., Ganz, P.A., Cole, S.W., and Irwin, M.R. (2006) Inflammatory biomarkers for persistent fatigue in breast cancer survivors. Clin Cancer Res 12(9), 2759–2766.PubMedCrossRefGoogle Scholar
  16. Cover, H., and Irwin, M. (1994) Immunity and depression: Insomnia, retardation, and reduction of natural killer cell activity. J Behav Med 17(2), 217–223.PubMedCrossRefGoogle Scholar
  17. Crum, R.M., Galai, N., Cohn, S., Celentano, D.D., and Vlahov, D. (1996) Alcohol use and Tlymphocyte subsets among injection drug users with HIV-1 infection: A prospective analysis. Alcohol Clin Exp Res 20(2), 364–371.PubMedCrossRefGoogle Scholar
  18. Curtis, J.L. (2005) Cell-mediated adaptive immune defense of the lungs. Proc Am Thorac Soc 2(5), 412–416.PubMedCrossRefGoogle Scholar
  19. Drewes, A.M. (1999) Pain and sleep disturbances with special reference to fibromyalgia and rheumatoid arthritis. Rheumatology (Oxford) 38(11), 1035–1038.CrossRefGoogle Scholar
  20. Drewes, A.M., Svendsen, L., Taagholt, S.J., Bjerregard, K., Nielsen, K.D., and Hansen, B. (1998) Sleep in rheumatoid arthritis: A comparison with healthy subjects and studies of sleep/wake interactions. Br J Rheumatol 37, 71–81.PubMedCrossRefGoogle Scholar
  21. Ehlers, C.L., and Kupfer, D.J. (1997) Slow-wave sleep: Do young adult men and women age differently? J Sleep Res 6(3), 211–215.PubMedCrossRefGoogle Scholar
  22. Everson, C.A., and Toth, L.A. (2000) Systemic bacterial invasion induced by sleep deprivation. Am J Physiol Regul Integr Comp Physiol 278(4), R905–R916.PubMedGoogle Scholar
  23. Feldmann, M., and Maini, R.N. (2001) Anti-TNF alpha therapy of rheumatoid arthritis: What have we learned? Annu Rev Immunol 19, 163–196.PubMedCrossRefGoogle Scholar
  24. Fleming, W.E., and Pollak, C.P. (2005) Sleep disorders in multiple sclerosis. Semin Neurol 25(1), 64–68.PubMedCrossRefGoogle Scholar
  25. Friedman, E.M., and Irwin, M. (1997) Modulation of immune cell function by the autonomic nervous system. Pharmacol Ther 74, 27–38.PubMedCrossRefGoogle Scholar
  26. Glaser, R., and Kiecolt-Glaser, J.K. (2005) Stress-induced immune dysfunction: Implications for health. Nat Rev Immunol 5(3), 243–251.PubMedCrossRefGoogle Scholar
  27. Gonzalez-Quintela, A., Dominguez-Santalla, M.J., Perez, L.F., Vidal, C., Lojo, S., and Barrio, E. (2000) Influence of acute alcohol intake and alcohol withdrawal on circulating levels of IL-6, IL-8, IL-10 and IL-12. Cytokine 12(9), 1437–1440.PubMedCrossRefGoogle Scholar
  28. Hall, M., Baum, A., Buysse, D.J., Prigerson, H.G., Kupfer, D.J., and Reynolds, C.F. (1998) Sleep as a mediator of the stress-immune relationship. Psychosom Med 60, 48–51.PubMedGoogle Scholar
  29. Hirsch, M., Carlander, B., Verge, M., Tafti, M., Anaya, J.M., Billiard, M., and Sany, J. (1994) Objective and subjective sleep disturbances in patients with rheumatoid arthritis. A reappraisal. Arthritis Rheum 37(1), 41–49.PubMedCrossRefGoogle Scholar
  30. Hogan, D., Morrow, J.D., Smith, E.M., and Opp, M.R. (2003) Interleukin-6 alters sleep of rats. J Neuroimmunol 137(1/2), 59–66.PubMedCrossRefGoogle Scholar
  31. Irwin, M. (2002) Effects of sleep and sleep loss on immunity and cytokines. Brain Behav Immun 16(5), 503–512.PubMedCrossRefGoogle Scholar
  32. Irwin, M., and Miller, C. (2000) Decreased natural killer cell responses and altered interleukin-6 and interleukin-10 production in alcoholism: An interaction between alcohol dependence and African-American ethnicity. Alcohol Clin Exp Res 24(4), 560–569.PubMedCrossRefGoogle Scholar
  33. Irwin, M.R., and Rinetti, G. (2004) Disordered sleep, nocturnal cytokines, and immunity: Interactions between alcohol dependence and African-American ethnicity. Alcohol 32(1), 53–61.PubMedCrossRefGoogle Scholar
  34. Irwin, M., Mascovich, A., Gillin, J.C., Willoughby, R., Pike, J., and Smith, T.L. (1994) Partial sleep deprivation reduces natural killer cell activity in humans. Psychosom Med 56, 493–498.PubMedGoogle Scholar
  35. Irwin, M., Clark, C., Kennedy, B., JC, G., and Ziegler, M. (2003) Nocturnal catehcolamines and immune function in insomniacs, depressed patients, and control subjects. Brain Beh Immun 17, 365–372.CrossRefGoogle Scholar
  36. Irwin, M., Miller, C., Gillin, J.C., Demodena, A., and Ehlers, C.L. (2000) Polysomnographic and spectral sleep EEG in primary alcoholics: An interaction between alcohol dependence and African-American ethnicity. Alcohol Clin Exp Res 24(9), 1376–1384.PubMedCrossRefGoogle Scholar
  37. Irwin, M., Gillin, J.C., Dang, J., Weissman, J., Phillips, E., and Ehlers, C.L. (2002) Sleep deprivation as a probe of homeostatic sleep regulation in primary alcoholics. Biol Psychiatry 51(8), 632–641.PubMedCrossRefGoogle Scholar
  38. Irwin, M., McClintick, J., Costlow, C., Fortner, M., White, J., and Gillin, J.C. (1996) Partial night sleep deprivation reduces natural killer and cellular immune responses in humans. FASEB J 10, 643–653.PubMedGoogle Scholar
  39. Irwin, M., Rinetti, G., Redwine, L., Motivala, S., Dang, J., and Ehlers, C. (2004) Nocturnal proinflammatory cytokine-associated sleep disturbances in abstinent African American alcoholics. Brain Behav Immun 18(4), 349–360.PubMedCrossRefGoogle Scholar
  40. Irwin, M., Smith, T.L., and Gillin, J.C. (1992) Electroencephalographic sleep and natural killer activity in depressed patients and control subjects. Psychosom Med 54, 107–126.Google Scholar
  41. Isomaki, P., and Punnonen, J. (1997) Pro- and anti-inflammatory cytokines in rheumatoid arthritis. Ann Med 29(6), 499–507.PubMedGoogle Scholar
  42. Kanel, R., Dimsdale, J.E., Ancoli-Israel, S., Mills, P.J., Patterson, T.L., McKibbin, C.L., Archuleta, C., and Grant, I. (2006) Poor sleep is associated with higher plasma proinflammatory cytokine interleukin-6 and procoagulant marker fibrin D-Dimer in older caregivers of people with Alzheimer's disease. J Am Geriatr Soc 54(3), 431–437.CrossRefGoogle Scholar
  43. Kripke, D.F., Simons, R.N., Garfinkel, L., and Hammond, E.C. (1979) Short and long sleep and sleeping pills. Is increased mortality associated? Arch. Gen. Psychiatry 36, 103–116.PubMedGoogle Scholar
  44. Krueger, J.M., Takahashi, S., Kapás, L., Bredow, S., Roky, R., Fang, J., Floyd, R., Renegar, K.B., Guha-Thakurta, N., and Novitsky, S. (1995) Cytokines in sleep regulation. Adv Neuroimmunol 5, 171–188.PubMedCrossRefGoogle Scholar
  45. Lavie, P., Nahir, M., Lorber, M., and Scharf, Y. (1991) Non-steroid anti-inflammatory drug therapy in RA patients. Lack of association between clinical improvement and effects on sleep. Arthritis Rheum 34, 655–659.PubMedCrossRefGoogle Scholar
  46. Lentz, M.J., Landis, C.A., Rothermel, J., and Shaver, J.L. (1999) Effects of selective slow wave sleep disruption on musculoskeletal pain and fatigue in middle-aged women. J Rheumatol 26(7), 1586–1592.PubMedGoogle Scholar
  47. Lesperance, F., Frasure-Smith, N., Theroux, P., and Irwin, M. (2004) The association between major depression and levels of soluble intercellular adhesion molecule 1, interleukin-6, and C-reactive protein in patients with recent acute coronary syndromes. Am J Psychiatry 161(2), 271–277.PubMedCrossRefGoogle Scholar
  48. Liukkonen, T., Silvennoinen-Kassinen, S., Jokelainen, J., Rasanen, P., Leinonen, M., Meyer-Rochow, V.B., and Timonen, M. (in press) The association between C-reactive protein levels and depression: Results from the Northern Finland 1966 Birth Cohort Study. Biol Psychiatry (Corrected Proof).Google Scholar
  49. Mahowald, M.W., Mahowald, M.L., Bundlie, S.R., and Ytterberg, S.R. (1989) Sleep fragmentation in rheumatoid arthritis. Arthritis Rheum 32(8), 974–983.PubMedCrossRefGoogle Scholar
  50. Mallon, L., Broman, J.E., and Hetta, J. (2002) Sleep complaints predict coronary artery disease mortality in males: A 12-year follow-up study of a middle-aged Swedish population. J Intern Med 251(3), 207–216.PubMedCrossRefGoogle Scholar
  51. Miller, G.E., Stetler, C.A., Carney, R.M., Freedland, K.E., and Banks, W.A. (2002) Clinical depression and inflammatory risk markers for coronary heart disease. Am J Cardiol 90(12), 1279–1283.PubMedCrossRefGoogle Scholar
  52. Moldofsky, H. (2001) Sleep and pain. Sleep Med Rev 5(5), 385–396.PubMedCrossRefGoogle Scholar
  53. Moldofsky, H., and Scarisbrick, P. (1976) Induction of neurasthenic musculoskeletal pain syndrome by selective sleep stage deprivation. Psychosom Med 38(1), 35–44.PubMedGoogle Scholar
  54. Moldofsky, H., Lue, F.A., and Smythe, H.A. (1983) Alpha EEG sleep and morning symptoms in rheumatoid arthritis. J Rheumatol 10(3), 373–379.PubMedGoogle Scholar
  55. Morin, C.M., Bastien, C., Guay, B., Radouco-Thomas, M., Leblanc, J., and Vallieres, A. (2004) Randomized clinical trial of supervised tapering and cognitive behavior therapy to facilitate benzodiazepine discontinuation in older adults with chronic insomnia. Am J Psychiatry 161(2), 332–342.PubMedCrossRefGoogle Scholar
  56. Motivala, S., and Irwin, M. (2005) Intrinsic changes affecting sleep loss/deprivation: Immunologic changes. In: C. Kushida (Ed.), Sleep Deprivation: Basic Science, Physiology and Behavior. Marcel Dekker, New York, pp. 192, 359–386.Google Scholar
  57. Motivala, S.J., Sarfatti, A., Olmos, L., and Irwin, M.R. (2005) Inflammatory markers and sleep disturbance in major depression. Psychosom Med 67(2), 187–194.PubMedCrossRefGoogle Scholar
  58. Nelson, S., and Kolls, J.K. (2002) Alcohol, host defence and society. Nat Rev Immunol 2(3), 205–209.PubMedCrossRefGoogle Scholar
  59. Nicassio, P.M., Moxham, E.G., Schuman, C.E., and Gevirtz, R.N. (2002) The contribution of pain, reported sleep quality, and depressive symptoms to fatigue in fibromyalgia. Pain 100(3), 271–279.PubMedCrossRefGoogle Scholar
  60. Nicassio, P.M., and Wallston, K.A. (1992) Longitudinal relationships among pain, sleep problems, and depression in rheumatoid arthritis. J Abnorm Psychol 101(3), 514–520.PubMedCrossRefGoogle Scholar
  61. NIH (2005) National Institutes of Health State of the Science Conference statement on manifestations and management of chronic insomnia in adults, June 13–15, 2005. Sleep 28(9), 1049–1057.Google Scholar
  62. O'Donnell, J.F. (2004) Insomnia in cancer patients. Clin Cornerstone 6(Suppl 1D), S6–S14.PubMedCrossRefGoogle Scholar
  63. Opp, M.R. (2005) Cytokines and sleep. Sleep Med Rev 9(5), 355–364.PubMedCrossRefGoogle Scholar
  64. Petit, L., Azad, N., Byszewski, A., Sarazan, F.F., and Power, B. (2003) Non-pharmacological management of primary and secondary insomnia among older people: Review of assessment tools and treatments. Age Ageing 32(1), 19–25.PubMedCrossRefGoogle Scholar
  65. Pross, H.F., and Lotzova, E. (1993) Role of natural killer cells in cancer. Nat Immun 12(4–5), 279–292.PubMedGoogle Scholar
  66. Redwine, L., Dang, J., Hall, M., and Irwin, M. (2003) Disordered sleep, nocturnal cytokines, and immunity in alcoholics. Psychosom Med 65(1), 75–85.PubMedCrossRefGoogle Scholar
  67. Redwine, L., Hauger, R.L., Gillin, J.C., and Irwin, M. (2000) Effects of sleep and sleep deprivation on interleukin-6, growth hormone, cortisol, and melatonin levels in humans. J Clin Endocrinol Metab 85(10), 3597–603.PubMedCrossRefGoogle Scholar
  68. Reichenberg, A., Yirmiya, R., Schuld, A., Kraus, T., Haack, M., Morag, A., and Pollmächer, T. (2001) Cytokine-associated emotional and cognitive disturbances in humans. Arch Gen Psychiatry 58(5), 445–452.PubMedCrossRefGoogle Scholar
  69. Ridker, P.M., Rifai, N., Stampfer, M.J., and Hennekens, C.H. (2000) Plasma concentration of interleukin-6 and the risk of future myocardial infarction among apparently healthy men. Circulation 101(15), 1767–1772.PubMedGoogle Scholar
  70. Sanders, S., and Adams, K.B. (2005) Grief reactions and depression in caregivers of individuals with Alzheimer's disease: Results from a pilot study in an urban setting. Health Soc Work 30(4), 287–295.PubMedGoogle Scholar
  71. Savard, J., Laroche, L., Simard, S., Ivers, H., and Morin, C.M. (2003) Chronic insomnia and immune functioning. Psychosom Med 65(2), 211–221.PubMedCrossRefGoogle Scholar
  72. Savard, J., Miller, S.M., Mills, M., O'Leary, A., Harding, H., Douglas, S.D., Mangan, C.E., Belch, R., and Winokur, A. (1999) Association between subjective sleep quality and depression on immunocompetence in low-income women at risk for cervical cancer. Psychosom Med 61(4), 496–507.PubMedGoogle Scholar
  73. Spath-Schwalbe, E., Hansen, K., Schmidt, F., Schrezenmeier, H., Marshall, L., Burger, K., Fehm, H.L., and Born, J. (1998) Acute effects of recombinant human interleukin-6 on endocrine and central nervous sleep functions in healthy men. J Clin Endocrinol Metab 83(5), 1573–1579.PubMedCrossRefGoogle Scholar
  74. Späth-Schwalbe, E., Lange, T., Perras, B., Fehm, H.L., and Born, J. (2000) Interferon-alpha acutely impairs sleep in healthy humans. Cytokine 12(5), 518–521.PubMedCrossRefGoogle Scholar
  75. Tench, C.M., McCurdie, I., White, P.D., and D'Cruz, D.P. (2000) The prevalence and associations of fatigue in systemic lupus erythematosus. Rheumatology 39(11), 1249–1254.PubMedCrossRefGoogle Scholar
  76. Van Cauter, E., Leproult, R., and Plat, L. (2000) Age-related changes in slow wave sleep and REM sleep and relationship with growth hormone and cortisol levels in healthy men. JAMA 284(7), 861–868.PubMedCrossRefGoogle Scholar
  77. Vgontzas, A.N., Papanicolaou, D.A., Bixler, E.O., Kales, A., Tyson, K., and Chrousos, G.P. (1997) Elevation of plasma cytokines in disorders of excessive daytime sleepiness: Role of sleep disturbance and obesity [see comments]. J Clin Endocrinol Metab 82(5), 1313–1316.PubMedCrossRefGoogle Scholar
  78. Vgontzas, A.N., Zoumakis, E., Bixler, E.O., Lin, H.M., Follett, H., Kales, A., and Chrousos, G.P. (2004a) Adverse effects of modest sleep restriction on sleepiness, performance, and inflammatory cytokines. J Clin Endocrinol Metab 89(5), 2119–2126.CrossRefGoogle Scholar
  79. Vgontzas, A.N., Zoumakis, E., Lin, H.M., Bixler, E.O., Trakada, G., and Chrousos, G.P. (2004b) Marked decrease in sleepiness in patients with sleep apnea by Etanercept, a tumor necrosis factor-alpha antagonist. J Clin Endocrinol Metab 89(9), 4409–4413.CrossRefGoogle Scholar
  80. Vgontzas, A.N., Zoumakis, M., Papanicolaou, D.A., Bixler, E.O., Prolo, P., Lin, H.M., Vela-Bueno, A., Kales, A., and Chrousos, G.P. (2002) Chronic insomnia is associated with a shift of interleukin-6 and tumor necrosis factor secretion from nighttime to daytime. Metabolism 51(7), 887–892.PubMedCrossRefGoogle Scholar
  81. Zamarron, F., Maceiras, F., Mera, A., and Gomez-Reino, J.J. (2004) Effects of the first infliximab infusion on sleep and alertness in patients with active rheumatoid arthritis. Ann Rheum Dis 63, 88–90.PubMedCrossRefGoogle Scholar

Copyright information

© Springer 2007

Authors and Affiliations

  • Sarosh J. Motivala
  • Michael Irwin

There are no affiliations available

Personalised recommendations