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Cleveland Clinic Basic and Clinical Immunology for the Busy Clinician Online Series

Sleep and Immunity: Partners in Sickness and in Health

Michael R. Irwin, MD

Introduction

Sleep problems and insomnia affect nearly one quarter of adults in the United States 1 . Difficulties with sleep increase the risk of inflammatory disorders and infectious disease, as well as all-cause mortality2. Sleep, inflammatory cytokines and anti-viral immune responses are interconnected, and it is thought that one of the functions of sleep is to promote host defense. In this brief summary, I present evidence that sleep is homeostatically linked to the immune system and to the circadian timing of inflammatory cytokine release. Furthermore, the normally adaptive function of sleep can become dysregulated, and such sleep disturbance leads to increased inflammation at the expense of antiviral immune responses. The potential of interventions that treat insomnia and reverse inflammation to restore the homeostatic balance between sleep processes and immunity are considered.

Sleep and its functions in the regulation of immunity

Sleep, a naturally recurring state of arousal of the brain and body, has multiple functions to promote physiological homeostasis and resilience. For example, it is well known that sleep aids in recovery from infectious and other disease states, and this function may have evolutionary value as sleep is a period low metabolic need and bodily quiescence3 which provides the resources to support high metabolic demands of an immunological response.

  Naturally occurring sleep dynamically influences immune cell distribution and the production of inflammatory cytokines. In humans, nocturnal sleep seems to be necessary for the nocturnal increases in IL-6 levels and production of tumor necrosis factor (TNF) by Toll-like receptor 4 (TLR4)-stimulated monocytes4,5. For example, experimental sleep deprivation induces an undersecretion of IL-6 during the nocturnal period6, delays the nocturnal increase of IL-6 levels7, and attenuates monocytic production of TNF during the night4, which then shifts the pattern of secretion of IL-6 from night-time to daytime and an oversecretion of inflammatory cytokines during the day6. Moreover, different stages of sleep differentially regulate nocturnal changes in inflammatory cytokine activity. During sleep stages dominated by slow wave sleep activity, inflammatory cytokines peak, although other data indicate that higher levels of IL-6 occur during REM sleep. The survival advantage of sleep is suggested by models of acute threat which increases sleep duration and further augments host defenses, although this concept has so far only been evaluated in invertebrate model systems8.

Sleep disturbance and inflammation.

  When a threat is perceived by the CNS as chronic, a maladaptive profile of sleep occurs, i.e., sleep disturbance. Such perceived threats also induce increases in inflammation9, along with disturbances in sleep continuity, loss of slow wave sleep, and increased duration of REM sleep10. Such sleep disturbance initially induces a shift in the temporal profile of inflammatory responses with increased levels of inflammatory cytokines during the day, rather than during the night6, which then leads to excessive levels of inflammation.

  Experimental studies have shown that loss of sleep activates inflammatory signaling pathways, such as those involving nuclear factor-κB (NF-κB), activator protein 1 (AP-1), and signal transducer and activator of transcription (STAT) family proteins2,11-13; increases levels of mRNAs encoding proinflammatory cytokines; and increases TLR4-stimulated monocyte production of IL-6 and TNF13. Moreover, the activation of NF-κB following sleep deprivation is conserved across species and also occurs in neural tissues including the lateral hypothalamus, basal forebrain cholinergic neurons, and cerebral cortex14.

  Persistent sleep disturbance leads to sustained activation of the inflammatory response. In a meta-analysis of ~50,000 adults15, sleep disturbance was associated with higher levels of C- reactive protein (CRP) and IL-6, with further evidence that increased levels of CRP occur even in individuals who have high variability in sleep duration between nights16. Longitudinal prospective findings confirm that sleep disturbance contributes to increased levels of inflammation. In a five-year longitudinal study of ~3,000 African–American and white adults, increases in CRP and IL-6 levels were predicted by sleep disturbance, as well as subjectively reported short sleep duration17.

  Sleep disturbance has effects that are equivalent to effects of age, body mass index, and physical activity on inflammation15,18. In turn, when insomnia is treated, decreases in levels of CRP, TLR4-stimulated monocytic production of IL-6 and TNF, and transcriptional inflammatory profiles are found19,20, and these changes are comparable to the anti-inflammatory effects of a healthy diet and exercise21,22.

Sleep and Antiviral Immune Response

  Sleep also supports antiviral immune response profiles. During normal sleep, there is a redistribution of antigen-presenting cells (APCs) and T cells from the circulation to lymphoid tissue3,23, with activation of T cells leading to increased production of IL-2 and IFNγ5, which have a crucial role in inducing TH1-type adaptive immune responses5,24. It is thought that sleep serves to synchronize accumulation and maturation of APCs in lymphoid tissues and thereby enhances the diversity of T cell receptors that are available to be recruited into the immune response3.

  When sleep is experimentally disturbed, there is decreased production of IL-2 by T cells23,25, a shift towards TH2-type cytokine activity24,26, decreased IL-12 production by monocytes, and increased IL-10 expression24. Similar alterations in the adaptive immune response profile are found in humans with chronic sleep disturbance27. Additionally, sleep loss impairs vaccine responses. For example sleep deprivation reduces antibody response to trivalent A and B types of influenza virus vaccine, the antibody response to H1N1 swine influenza virus, IgG1 response to hepatitis A virus vaccination28,29, and TH1 cell-mediated and antibody responses to hepatitis B virus (HBV) vaccine29. The timing of sleep deprivation in relation to vaccination suggest that sleep loss might alter the interactions between APCs and T cells before the differentiation of effector T cells, possibly by disrupting the coordinated recruitment of APCs and T cells to lymphoid tissue, as well as the strength of the TH1-type cytokine signal. Finally, naturally occurring sleep disturbance such as short sleep duration is associated with decreased likelihood of clinical protection with the HBV vaccine30, as well as lower resting antibody titers to influenza virus in individuals with insomnia31. Indeed, short sleep duration predicts pneumonia risk (<5 hours sleep per night) 32 and susceptibility to the common cold (<6 hours sleep per night)33,34.

Summary

Bidirectional interactions between the CNS and the immune system show that naturally occurring sleep acutely enhances the expression of immune markers implicated in immune defense and that inflammatory signals can promote sleep. One of the most striking implications is that the metabolically quiescent period of sleep serves to prepare the immune system or anticipate infectious or other environmental exposures during the day, making the immune system more responsive to the microbial and host cell environment that will be encountered following waking.

  When sleep is disrupted and the beneficial crosstalk between sleep and the immune system becomes misaligned10, the immune system is steered towards a pro-inflammatory profile and away from an antiviral profile35. Such changes in sleep patterns can lead to inflammation-related morbidities. Fortunately, the ability to harness reciprocal sleep–immune regulation through pharmacological or behavioral interventions redirects a misaligned inflammatory transcriptional program to accommodate to the social and infectious threats that are perceived.

Annotated Bibliography

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    This theoretical treatise proposes that sleep benefits the consolidation of psychological memory, and likewise supports immunological memory formation, which is conveyed by the same sleep-associated processes.

  4. Dimitrov S, Besedovsky L, Born J, Lange T. Differential acute effects of sleep on spontaneous and stimulated production of tumor necrosis factor in men. Brain Behav Immun. 2015;47:201-210.
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  8. Davis KC, Raizen DM. A mechanism for sickness sleep: lessons from invertebrates. J Physiol. 2017;595(16):5415-5424.
  9. Slavich GM, Irwin MR. From stress to inflammation and major depressive disorder: a social signal transduction theory of depression. Psychol Bull. 2014;140(3):774-815.

    10. This review coined the social signal transduction hypothesis of depression and provided one of most detailed descriptions of the relationships between stress-induced activation of inflammatory responses and sensitivity to psychosocial stressors, which can lead to depression.

  10. Irwin MR. Why sleep is important for health: a psychoneuroimmunology perspective. Annu Rev Psychol. 2015;66:143-172.
  11. Irwin MR, Opp MR. Sleep Health: Reciprocal Regulation of Sleep and Innate Immunity. Neuropsychopharmacology. 2017;42(1):129-155.
  12. Irwin MR, Wang M, Ribeiro D, et al. Sleep loss activates cellular inflammatory signaling. Biol Psychiatry. 2008;64(6):538-540.
  13. Irwin MR, Wang M, Campomayor CO, Collado-Hidalgo A, Cole S. Sleep deprivation and activation of morning levels of cellular and genomic markers of inflammation. Arch Intern Med. 2006;166(16):1756-1762.

    14. This experimental study is the first to show that sleep deprivation induces an activation of cellular inflammation and inflammatory transcriptional profiles, owing to increased signalling through NF-kB and AP-1 inflammatory signaling pathways.

  14. Krueger JM. The role of cytokines in sleep regulation. Curr Pharm Des. 2008;14(32):3408-3416.
  15. Irwin MR, Olmstead R, Carroll JE. Sleep disturbance, sleep duration, and inflammation: a systematic review and meta-analysis of cohort studies and experimental sleep deprivation. Biol Psychiatry. 2016;80(1):40-52.

    16. This systematic review provided the first comprehensive assessment of the global evidence linking sleep disturbance, sleep duration, and inflammation in adult humans, and showed that sleep disturbance and long sleep duration should be regarded as behavioral risk factors for inflammation.

  16. Park H, Tsai KM, Dahl RE, et al. Sleep and Inflammation During Adolescence. Psychosom Med. 2016;78(6):677-685.
  17. Cho HJ, Seeman TE, Kiefe CI, Lauderdale DS, Irwin MR. Sleep disturbance and longitudinal risk of inflammation: Moderating influences of social integration and social isolation in the Coronary Artery Risk Development in Young Adults (CARDIA) study. Brain Behav Immun. 2015;46:319-326.
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  19. Irwin MR, Olmstead R, Breen EC, et al. Cognitive behavioral therapy and tai chi reverse cellular and genomic markers of inflammation in late-life insomnia: a randomized controlled trial. Biol Psychiatry. 2015;78(10):721-729.

    20. This report describes the results of the first randomized controlled trial to treat insomnia and reverse transcriptional, cellular and systemic profiles of inflammation over a long-term, one- year follow-up in older adults.

  20. Irwin MR, Olmstead R, Breen EC, et al. Tai chi, cellular inflammation, and transcriptome dynamics in breast cancer survivors with insomnia: a randomized controlled trial. Journal of the National Cancer Institute Monographs. 2014;2014(50):295-301.
  21. Neale EP, Batterham MJ, Tapsell LC. Consumption of a healthy dietary pattern results in significant reductions in C-reactive protein levels in adults: a meta-analysis. Nutr Res. 2016;36(5):391-401.
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    25. References 23 and 24 are among the first that experimentally examined the role of nocturnal sleep and its relation to circadian rhythm in the regulation of the immune system, to show that sleep supports ongoing immune defences in extravascular lymphoid tissue during a time of diminished acute antigenic challenge.

  25. Irwin M, Thompson J, Miller C, Gillin JC, Ziegler M. Effects of sleep and sleep deprivation on catecholamine and interleukin-2 levels in humans: clinical implications. J Clin Endocrin Metab. 1999;84(6):1979-1985.
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    29. This experimental study interrogated the role of sleep in promoting antigen-specific T cell immunity to a vaccination, and also provided novel evidence that slow wave sleep activity immediately after vaccination drives TH1 cell-mediated immune responses that persist over the following year.

  29. Prather AA, Hall M, Fury JM, et al. Sleep and antibody response to hepatitis B vaccination. Sleep. 2012;35(8):1063-1069.

    30. This study is the first to show that objective measures of short sleep duration are associated with increased susceptibility to the common cold after experimental viral exposure.

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