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Sick and tired: does sleep have a vital role in the immune system?

Key Points

  • The relationship between sleep and immunity is important because in recent decades there has been a documented decrease in the mean duration of sleep and an increase in shift work. With ever-increasing pressures to work longer hours, sleep loss and sleep disruption have become occupational hazards. As well as those who are ill with infections, chronic disease, depression or sleep apnoea, sleep disturbance is also suffered by shift workers, military personnel, new parents and carers.

  • There is good evidence, mainly from animal studies, that various infections are associated with increased sleep. This has been shown for both infection with whole microorganisms or exposure to their component virulence factors, such as lipopolysaccharide.

  • The host immune response (specifically, the production of cytokines) is responsible for the increased sleep associated with infection. Certain pro-inflammatory cytokines, in particular tumour-necrosis factor (TNF) and interleukin-1β (IL-1β), usually increase sleep, and anti-inflammatory cytokines inhibit sleep.

  • Certain cytokines are regulated endogenously during sleep. The fact that some cytokines show circadian rhythm indicates that they have a role in physiological sleep. This is supported by experiments using knockout mice, showing that both TNF- and type 1 IL-1 receptor-deficient mice have either decreased baseline sleep or do not show enhanced sleep after administration of TNF or IL-1β, respectively.

  • Sleep-deprivation experiments in both animals and humans provide the best evidence for a crucial role of sleep in the immune response. The results of these experiments show some inconsistencies, thereby underlining the complexities of measuring the interaction between different durations of sleep deprivation and different immune components. However, in humans, general patterns emerge, indicating that sleep deprivation has detrimental effects on immune-cell number, function and cytokine production.

  • There is also emerging evidence that chronic partial sleep loss might be more detrimental to immune function than short-term total sleep loss. This is important because it is chronic partial sleep loss that burdens the current population, through shift work, pressured lifestyles, and other stresses and changes in society.

  • The final piece of evidence for a reciprocal relationship between sleep and immunity is provided by clinical situations (for example, depression or narcolepsy) in which sleep disorders are associated with changes in the immune system.

  • The effects of sleep deprivation on the immune response might have important implications for protecting the population against infection and malignancy.

Abstract

It is a common belief that we are more susceptible to infections when deprived of sleep. Consistent with this, there is increasing evidence that sleep deprivation has detrimental effects on the immune response, indicating that sleep should be considered a vital part of the immune system and that there is a reciprocal relationship between sleep and immunity. This relationship is important because, over recent decades, there has been a documented decrease in the mean duration and quality of sleep in the population. The concept that lack of sleep might be compromising immunity in the population has far-reaching public-health implications for both individuals and society.

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Figure 1: Stages of sleep in humans.
Figure 2: Putative pathways of immune-system involvement in sleep.
Figure 3: Relationship between sleep, circadian rhythm, and the neuroendocrine, autonomic nervous and immune systems.

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Acknowledgements

The authors thank R. Robins-Browne, J. McCluskey and D. Ventor for helpful comments on the manuscript. P.A.B. is the recipient of a European Society of Paediatric Infectious Diseases Fellowship Award.

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Correspondence to Nigel Curtis.

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DATABASES

Entrez Gene

ACTH

CRH

GHRH

growth hormone

IL-1β

orexin

prolactin

TNF

FURTHER INFORMATION

National Sleep Foundation

Sleep Research Society

European Sleep Research Society

American Academy of Sleep Medicine

Glossary

ELECTROENCEPHALOGRAM

Graphical representation of the electrical activity of the brain, recorded by attaching electrodes to the scalp. The shape, frequency and amplitude of the waveforms provide information about the stage and intensity of sleep.

MURAMYL PEPTIDES

Fragments of peptidoglycans, from the cell walls of Gram-positive bacteria, that are thought to have a crucial role in the generation of the immune response to Gram-positive bacterial infection.

LIPOPOLYSACCHARIDE

A constituent of the cell walls of Gram-negative bacteria that is thought to be important for eliciting the immune response to Gram-negative bacterial infection. Also known as endotoxin.

PYROGENIC RESPONSE

The response to infection that leads to fever. Cytokines induced by microbial products — particularly tumour-necrosis factor and interleukins — function to increase the 'set point' for body temperature (through eliciting prostaglandin synthesis in the hypothalamus) and consequently produce fever.

ACUTE-PHASE RESPONSE

The early immune response to infection, which results in the production of cytokines and other mediators and an increase in the number of peripheral leukocytes.

CIRCADIAN RHYTHMICITY

Having an approximately 24-hour variation. This can be a property of biological or behavioural processes. It can be a direct consequence of an endogenous circadian mechanism or be secondary to other processes, such as the sleep–wake cycle. From the Latin words circa meaning 'about' and dies meaning 'day'.

OBSTRUCTIVE SLEEP APNOEA

A medical condition in which the obstruction of upper airways causes episodes of breathing cessation during sleep, leading to recurrent arousals from sleep and other complications.

CIRCADIAN OSCILLATOR

The biological clock responsible for organizing many of the circadian rhythms of the body. It is a function of the suprachiasmatic nucleus in the brain.

CACHEXIA

Severe weight loss, muscle wasting and debility caused by prolonged disease. It is thought to be mediated through neuroimmunoendocrine interactions.

CHRONIC FATIGUE AND FIBROMYALGIA

Clinical conditions characterized by debilitating fatigue, often following a viral illness. In the latter, fatigue occurs together with chronic pain and tenderness in muscles.

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Bryant, P., Trinder, J. & Curtis, N. Sick and tired: does sleep have a vital role in the immune system?. Nat Rev Immunol 4, 457–467 (2004). https://doi.org/10.1038/nri1369

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