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Cited by 1,479Sleep and Wakefulness ResearchCircadian rhythm and melatoninSleep and related disorders

The Sleep-Immune Crosstalk in Health and Disease

Open access
Besedovsky, Luciana, Lange, Tanja, Haack, Monika·2019·Physiological Reviews
DOI 10.1152/physrev.00010.2018PMC PMC6689741
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Abstract

Sleep and immunity are bidirectionally linked. Immune system activation alters sleep, and sleep in turn affects the innate and adaptive arm of our body’s defense system. Stimulation of the immune system by microbial challenges triggers an inflammatory response, which, depending on its magnitude and time course, can induce an increase in sleep duration and intensity, but also a disruption of sleep. Enhancement of sleep during an infection is assumed to feedback to the immune system to promote host defense. Indeed, sleep affects various immune parameters, is associated with a reduced infection risk, and can improve infection outcome and vaccination responses. The induction of a hormonal constellation that supports immune functions is one likely mechanism underlying the immune-supporting effects of sleep. In the absence of an infectious challenge, sleep appears to promote inflammatory homeostasis through effects on several inflammatory mediators, such as cytokines. This notion is supported by findings that prolonged sleep deficiency (e.g., short sleep duration, sleep disturbance) can lead to chronic, systemic low-grade inflammation and is associated with various diseases that have an inflammatory component, like diabetes, atherosclerosis, and neurodegeneration. Here, we review available data on this regulatory sleep-immune crosstalk, point out methodological challenges, and suggest questions open for future research.

AI snapshot

Written from the paper’s full text.

TL;DR

This review synthesizes evidence that sleep and the immune system are bidirectionally linked: immune mediators such as IL-1, TNF, and PGD2 regulate NREM sleep, while sleep loss alters immune parameters and infection/vaccination outcomes. It concludes that adequate sleep supports immune homeostasis and that chronic sleep deficiency is associated with low-grade inflammation and increased disease risk.

Key findings

  • Sleep and immunity interact in both directions: IL-1 and TNF, and PGD2, regulate physiological NREM sleep in animals and mediate infection-induced increases in NREM sleep and suppression of REM sleep; human evidence is weaker but supportive.
  • Sleep strongly supports vaccination responses: restricting bedtime to 4 h/night for 4 days before and 2 days after influenza vaccination resulted in influenza-specific antibody titers more than doubled in the usual-sleep group; a single night without sleep after hepatitis A, hepatitis B, or H1N1 vaccination reduced antigen-specific antibody responses; in a hepatitis B field study, each additional hour of sleep was associated with an ~50% increase in antibody levels.
  • Short sleep is linked to infection risk and worse outcomes: self-reported habitual sleep ≤5 h/night was associated with increased pneumonia risk within 2 years and higher reports of respiratory infection; experimental rhinovirus studies found short sleep increased risk of developing a clinical cold; animal studies show sleep deprivation can impair host defense, induce bacterial translocation, and increase mortality after sepsis.
  • Chronic sleep deficiency is associated with low-grade inflammation: short or disturbed sleep is linked to elevated CRP and IL-6, increased WBC counts, reduced NK-cell activity, and shorter leukocyte telomere length; insomnia disorder has been associated with inflammatory dysregulation and attenuated influenza antibody responses.

Methods

  • Narrative review based on experimental in-laboratory animal and human models that manipulate sleep or immune components, plus human field/population studies in people with varied habitual sleep durations, chronic sleep disturbances, or chronic infectious/inflammatory diseases.
  • The main analysis is a qualitative synthesis across sections, supported by tables summarizing sleep measurement/manipulation methods, sleep effects on immune parameters, and cellular sources of humoral immune molecules; no new primary data or meta-analysis are presented.

Limitations

  • The paper states that sleep-manipulation methods vary greatly (total vs. partial deprivation, sleep disruption, selective stage deprivation, duration, species, assays), and some animal methods induce stress that can independently affect immune parameters; field studies often rely on a single self-report sleep question, rarely use objective multi-day sleep assessment, and often lack standardized, time-stamped blood collection, limiting causal inference.
  • The paper states that many conclusions rest on animal research and require confirmation in humans, that human evidence for cytokine regulation of physiological sleep is still weak, and that sex differences, lifespan effects, disease-stage effects, and time-of-day effects are understudied.
  • Evident from the text: as a narrative review, it does not systematically quantify effect sizes or assess risk of bias, and some human insomnia/immune findings come from small studies (e.g., n = 11–29) with mixed or conflicting results.

Model-written summary. Check it against the paper before relying on it.

Integrity signals

Registry

Crossref · 10.1152/physrev.00010.2018

Cites

606 of 606 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

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  • Findingcitation

    Observed sleep improvements with tocilizumab in active RA could not be explained by a reduction in disease activity.

    “Observed sleep improvements could not be explained by a reduction in disease activity”
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  • Findingcitation

    Some reports show increased numbers of lymphocyte subsets (CD4 T cells, CD8 T cells, and NK cells), particularly when measured in the evening after a regular night of sleep.

    “However, there are some reports of increased numbers of lymphocyte subsets (i.e., CD4 T cells, CD8 T cells, and NK cells), particularly when measured in the evening after a regular night of sleep (152, 234, 418, 556, 580).”
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  • Findingcitation

    Treatment with the IL-6 receptor inhibitor tocilizumab in RA patients with active disease improves self-reported sleep quality and daytime sleepiness.

    “Furthermore, treatment with an IL-6 receptor inhibitor (tocilizumab) in RA patients with active disease improved self-reported sleep quality (assessed by the PSQI) and daytime sleepiness.”
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  • Findingcitation

    Cellular inflammation, indicated by spontaneous or stimulated production of TNF or IL-6 by monocytes, is higher in RA patients than in matched healthy controls.

    “In a recent investigation, cellular inflammation, as indicated by spontaneous or stimulated production of TNF or IL-6 by monocytes, was higher in RA patients compared with matched healthy controls”
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  • Findingcitation

    Basophils and eosinophils were not found to be affected by sleep.

    “As for granulocyte subsets, basophils and eosinophils were not found to be affected by sleep (67, 152, 287, 338, 480, 580).”
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    Findingcitation

    In a noncontrolled study of RA patients with active disease, anti-TNF treatment with infliximab decreased sleep latency, increased sleep efficiency, reduced sleep stage transitions, and increased REM sleep.

    “In a noncontrolled study in RA patients with active disease, anti-TNF treatment (infliximab) resulted in decreased sleep latency, increased sleep efficiency, fewer sleep stage transitions, and increased REM sleep.”
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    Findingcitation

    Anti-TNF therapy in RA patients with high disease activity improves self-reported sleep quality without affecting PSG-derived sleep parameters.

    “In contrast, treatment with anti-TNF therapy in RA patients with high disease activity resulted in an improvement of self-reported sleep quality, without affecting PSG-derived sleep parameters (283).”
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    Findingnone given

    Studies of sleep disturbances in chronic infectious or inflammatory diseases demonstrate that sleep changes are common and can vary greatly, including shortened, prolonged, disrupted, or displaced sleep.

    “Collectively, studies devoting attention to sleep disturbances in chronic infectious or inflammatory diseases demonstrate that sleep changes are common and can vary greatly, including shortened, prolonged, disrupted, or displaced sleep.”
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    Findingcitation

    Higher sleep efficiency is associated with lower stimulated monocytic TNF production in the morning but with higher production in the evening.

    “For example, higher sleep efficiency was associated with lower stimulated monocytic TNF production in the morning, but with higher production when assessed in the evening.”
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    Findingcitation

    Intracellular IL-6 production is not altered acutely during sleep compared with nocturnal wakefulness, but is increased in the morning after one night of partial sleep loss in healthy humans.

    “Intracellular IL-6 production was not altered acutely during sleep compared with nocturnal wakefulness (147), but was increased in the morning after one night of partial sleep loss in healthy humans (89, 256, 262, 264).”
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    Findingcitation

    Prolonged total sleep deprivation of four consecutive nights increases levels of soluble TNF receptor I, which may reflect a homeostatic response to increased TNF production by leukocytes.

    “In contrast, prolonged total sleep deprivation of four consecutive nights increased levels of the soluble TNF receptor I (506), which may reflect a homeostatic response to increased TNF production by leukocytes; this, however, was not investigated in the study.”
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    Findingcitation

    Stimulated IL-2 production seems to be acutely enhanced by sleep in healthy humans, although other studies did not find such an effect when assessing stimulated IL-2 production specifically in CD4 T cells.

    “In contrast, stimulated IL-2 production seems to be acutely enhanced by sleep in healthy humans (67, 254, 552), although other studies did not find such an effect when assessing stimulated IL-2 production specifically in CD4 T cells (62, 149).”
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    Findingcitation

    Stimulated TNF production in humans is acutely reduced during sleep compared with nocturnal wakefulness when measured in supernatant or intracellularly in CD8 T cells, but increased when measured in monocytes.

    “Stimulated production of TNF in humans has been found to be acutely reduced during sleep compared with nocturnal wakefulness when measured in the supernatant (552) or intracellularly in CD8 T cells (149), but increased when measured in monocytes (146).”
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    Findingcitation

    Several studies found that sleep reduces neutrophil counts, although some studies did not find any changes.

    “In contrast, several studies found that sleep reduces neutrophil counts (69, 112, 178, 287, 326, 338, 480, 580), although again some studies did not find any changes (67, 103, 122, 469).”
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    Findingcitation

    In an experimental model with five nights of sleep restriction (4 h of sleep/night) followed by two nights of recovery sleep (8 h of sleep/night), numbers of B lymphocytes, but not T lymphocytes, increased in response to sleep restriction and were restored to normal values after the two recovery nights.

    “Using an experimental model in which five nights of sleep restriction (4 h of sleep/night) were followed by two nights of recovery sleep (8 h of sleep/night), numbers of B lymphocytes, but not T lymphocytes, increased in response to sleep restriction, and were restored to normal values after the two recovery nights (556).”
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    Findingcitation

    In rats undergoing prolonged sleep restriction for 21 consecutive days, a decrease in total leukocyte counts normalized after 24 h of recovery sleep, but did not normalize after recovery sleep following a REM sleep deprivation protocol over 4 consecutive days.

    “In rats undergoing prolonged sleep restriction for 21 consecutive days, a decrease in total leukocyte counts normalized after 24 h of recovery sleep, but did not normalize after recovery sleep following a REM sleep deprivation protocol over 4 consecutive days (596).”
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    Findingcitation

    In over 5,000 older participants, self-reported napping was associated with higher CRP levels, particularly in older participants, but the relationship was attenuated after adjusting for health-related variables such as pre-existing diseases, blood pressure, and depression.

    “Self-reported napping assessed in over 5,000 older participants was also associated with higher CRP levels, particularly in older participants, but the relationship was attenuated after adjusting for health-related variables such as pre-existing diseases, blood pressure, and depression (335).”
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    Findingcitation

    Spontaneous production of IL-6 and TNF by monocytes was increased in the morning after a night of sleep restriction, and this increase persisted in those monocytes that co-produced IL-6 and TNF after a night of recovery sleep.

    “Spontaneous production of IL-6 and TNF by monocytes was increased in the morning after a night of sleep restriction, and this increase persisted in those monocytes that co-produced IL-6 and TNF after a night of recovery sleep (264).”
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    Findingcitation

    Sleep restriction flattened the diurnal rhythms of WBC and neutrophil numbers, which appeared exaggerated at the end of the recovery period, as indicated by a higher amplitude of the diurnal curves.

    “Furthermore, this is one of the few studies utilizing frequent blood sampling throughout the day and found a flattening of the diurnal rhythms of WBC and neutrophil numbers in response to sleep restriction, which appeared to be exaggerated at the end of the recovery period, as indicated by a higher amplitude of the diurnal curves (326).”
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    Findingcitation

    In mice, 48 h of recovery sleep reversed the reduction in survival of a malaria infection induced by prolonged REM sleep deprivation, whereas 24 h of recovery sleep were not enough.

    “A recovery sleep period of 48 h reversed the reduction in survival of a malaria infection, induced by prolonged REM sleep deprivation in mice; in contrast, 24 h of recovery sleep were not enough to reverse the sleep-deprivation-induced effects (345).”
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    Findingcitation

    Lymphocyte counts nonsignificantly decreased in response to sleep restriction, with a further significant decrease following 8 h of recovery sleep.

    “Monocyte counts, in contrast, were not affected by either sleep restriction or recovery sleep, while lymphocyte counts nonsignificantly decreased in response to sleep restriction, with a further significant decrease following 8 h of recovery sleep.”
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    Findingcitation

    In a population-based study with over 300 participants, self-reported nappers had increased circulating CRP and IL-6 levels compared with non-nappers, but this relationship was influenced by nap frequency, nighttime sleep duration and quality, and health status.

    “For example, in a study with over 300 participants, self-reported nappers had increased circulating CRP and IL-6 levels compared with non-nappers, but this relationship was influenced by a number of factors, including nap frequency, nighttime sleep duration and quality, and health status (142).”
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    Findingcitation

    This increase of habitual sleep duration by ~10% per day resulted in a substantial decrease in blood pressure, while inflammatory markers (WBC counts and circulating levels of CRP and IL-6) nonsignificantly decreased from pre- to post-intervention.

    “This increase of habitual sleep duration by ~10% per day resulted in a substantial decrease in blood pressure, while inflammatory markers (i.e., WBC counts and circulating levels of CRP and IL-6) nonsignificantly decreased from pre- to post-intervention.”
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    Findingcitation

    The percentages of monocytes producing TNF alone or in combination with IL-6 were lower 2 mo post-treatment, but not during later follow-up time points.

    “Furthermore, the percentages of monocytes producing TNF alone or in combination with IL-6 were lower 2 mo post-treatment (257), but not during later follow-up time points.”
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    Findingcitation

    In peritoneal dialysis and hemodialysis patients, CBT-I improved sleep quality compared with a sleep hygiene education intervention, which was paralleled by a decrease of serum levels of inflammatory markers, including IL-1, CRP, and IL-18.

    “In peritoneal dialysis and hemodialysis patients, CBT-I improved sleep quality compared with a sleep hygiene education intervention, which was paralleled by a decrease of serum levels of inflammatory markers, including IL-1 (102), CRP, and IL-18 (101).”
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    Findingcitation

    Sleep disturbances can increase allergic reactions and worsen tumor-related immune responses.

    “For instance, sleep disturbances can increase allergic reactions and worsen tumor-related immune responses (138, 226, 289, 404), which indicates that patients with these diseases could profit from sleep improvements.”
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    Findingcitation

    One study reported prolonged allograft survival after sleep deprivation, accompanied by a reduced number of graft-infiltrating CD4 T cells.

    “One study reported a prolonged allograft survival after sleep deprivation, which was accompanied by a reduced number of graft-infiltrating CD4 T cells (479).”
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    Findingcitation

    In one of the largest CBT-I studies with over 100 older adults suffering from primary insomnia, CBT-I resulted in lower levels of CRP throughout the 16-mo follow-up period compared with adults receiving sleep education, and this decrease was associated with remission of insomnia.

    “In one of the largest CBT-I studies with over 100 older adults suffering from primary insomnia, CBT-I resulted in lower levels of CRP throughout the 16-mo follow-up period compared with adults receiving sleep education, and this decrease was associated with remission of insomnia (258).”
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    Findingcitation

    Genes downregulated after CBT-I included transcripts involved in inflammation, while upregulated genes included transcripts involved in IFN and antibody responses.

    “Using a genome-wide transcriptional profiling approach, genes that were downregulated after CBT-I included transcripts involved in inflammation, while upregulated genes included transcripts involved in IFN and antibody responses (257).”
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    Premisenone given

    The inducers of low-grade inflammation are not well understood.

    “Furthermore, the inducers of low-grade inflammation are not well understood.”
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    Premisecitation

    The homeostatic and circadian components constitute the two factors of the two-process model describing sleep regulation.

    “The homeostatic and circadian components constitute the two factors of the so-called two-process model describing the regulation of sleep (64, 65).”
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    • cites [65] Borbély AA, 1999, J Biol Rhythms

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    Premisenone given

    Actigraphy cannot differentiate sleep stages and has difficulty discriminating between sleep and immobility during wakefulness.

    “To date, sleep stages cannot be differentiated using this method, and it is difficult to discriminate between sleep and immobility during wakefulness.”
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    Study design and conductnone given

    Polysomnography is the gold standard for objectively measuring sleep in the laboratory.

    “Polysomnography (PSG) is the gold standard for objectively measuring sleep in the laboratory.”
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    Premisenone given

    Slow-wave activity reflects the intensity of sleep and is increased during sleep episodes that follow a prolonged period of wakefulness.

    “Slow-wave activity (SWA), a measure of the density and amplitude of slow waves, is considered to reflect the intensity of sleep and is increased during sleep episodes that follow a prolonged period of wakefulness.”
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    Premisecitation

    Sleep is regulated homeostatically, such that sleep increases in duration and intensity after a prolonged period without sleep.

    “Sleep is regulated homeostatically, meaning that sleep increases in duration and intensity after a prolonged period without sleep.”
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    There is currently no consistent definition of low-grade inflammation.

    “However, there is currently no consistent definition.”
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    Premisecitation

    Important ramifications of low-grade inflammation include insulin resistance, endothelial dysfunction, atherosclerosis, neuroinflammation, and immunodeficiency due to impaired dendritic cell, T, and B cell functions, which can promote failure of tumor and pathogen defense.

    “Important ramifications of low-grade inflammation are insulin resistance, endothelial dysfunction, atherosclerosis, and neuroinflammation (109, 244, 336, 485, 572), as well as immunodeficiency due to impaired DC, T, and B cell functions (80, 199, 422), which in turn can promote failure of tumor and pathogen defense (123, 426) (reviewed in Ref. 198).”
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    Premisecitation

    Additional inducers of low-grade inflammation are nutrients and metabolites acting as DAMPs and commensal bacteria representing a source of PAMPs/MAMPs.

    “Additional inducers of low-grade inflammation are nutrients and metabolites acting as DAMPs (e.g., free fatty acids, oxidized lipoproteins) and commensal bacteria representing a source of PAMPs [sometimes also described with the more global term microbe-associated molecular patterns (MAMPs), as they are not necessarily pathogenic] (189, 240, 244, 295, 329, 347).”
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    Premisenone given

    NREM sleep is predominantly under homeostatic control, whereas REM sleep is mainly under circadian control.

    “Whereas NREM sleep is predominantly under homeostatic control, REM sleep is mainly under circadian control.”
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    Premisecitation

    Increasing the availability of IL-1 and TNF promotes NREM sleep amount and intensity and suppresses REM sleep amount.

    “increasing the availability of those cytokines promoted NREM sleep amount and intensity and suppressed REM sleep amount.”
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    Interpretationreasoning

    The bidirectional brain-immune crosstalk serves to fine-tune the immune response, which is normally characterized by four Rs: recognition, response, regulation, and resolution.

    “The general picture suggests that the bidirectional brain-immune crosstalk serves to fine-tune the immune response that is normally characterized by four Rs: recognition, response, regulation, and resolution.”
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    Premisecitation

    A non-neuronal cholinergic system in T cells can locally provide acetylcholine release in the periphery.

    “yet a non-neuronal cholinergic system in T cells can locally provide acetylcholine release in the periphery (99, 203).”
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    Premisecitation

    Alternative routes of immune-to-brain signaling include activation of vagal and other neural afferents, cerebral endothelial and perivascular cells, and directed traffic of leukocytes to the brain.

    “Alternative routes of immune-to-brain signaling are immunomediators that can activate vagal and other neural afferents, as well as cerebral endothelial and perivascular cells or the directed traffic of leukocytes to the brain (70, 503, 523, 586).”
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    Premisecitation

    All these pathways may induce microglial activation and neuroinflammation in response to peripheral inflammation, thereby initiating CNS responses including fever and sickness behavior.

    “All these pathways may induce microglial activation and neuroinflammation in response to peripheral inflammation, thereby initiating CNS responses including fever and sickness behavior (486, 493).”
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    Premisecitation

    Leukocytes can sense and synthesize neuroendocrine mediators of the hypothalamic, pituitary, and glandular level and can form their own local neuroendocrine axis in an autocrine and paracrine manner.

    “Leukocytes can sense and synthesize a plethora of neuroendocrine mediators of the hypothalamic, pituitary, and glandular level [e.g., corticotropin releasing hormone, adrenocorticotropic hormone, cortisol; growth hormone releasing hormone, growth hormone (GH), insulin-like growth factor-1; dopamine, prolactin] and can even form an own, local neuroendocrine axis in an autocrine and paracrine manner”
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    Premisecitation

    Acute infectious illnesses cause CNS responses such as fever and common sickness symptoms including fatigue, sleepiness, social withdrawal, negative mood, pain hypersensitivity, and decreased appetite.

    “acute infectious illnesses cause CNS responses such as fever (230) and a set of common symptoms of sickness, including fatigue, sleepiness, social withdrawal, negative mood (depression, anxiety), pain hypersensitivity, and decreased appetite (131).”
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    Premisecitation

    Numerous neurotransmitters and neuropeptides of efferent nerves can be recognized by matching receptors on immune cells, and leukocytes themselves can synthesize and release these neuronal messengers.

    “Numerous neurotransmitters and neuropeptides of efferent nerves (like catecholamines or neuropeptide Y) can be recognized by matching receptors on immune cells, and leukocytes themselves can synthesize and release these neuronal messengers (e.g., Refs. 190, 414, 436).”
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    • cites [436] Pert CB, 1985, J Immunol source

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    Premisecitation

    In rats, the NREM sleep-increasing effects of IL-1 occur only within a small dose-window: lower doses increase NREM sleep without fever; higher doses accompanied by fever increase and fragment NREM but decrease REM sleep; even higher doses decrease both.

    “in rats, NREM sleep-increasing effects of IL-1 occur only within a small dose-window: lower doses of IL-1 increase NREM sleep without inducing fever; higher doses of IL-1 accompanied by fever increase and fragment NREM but decrease REM sleep; and even higher doses decrease both (412)”
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  • May combine two claims.

    Premisecitation

    Acute administration of aspirin at the recommended daily dose range in healthy participants disrupted sleep (decreased sleep efficiency, increased number of awakenings) and decreased SWS.

    “acute administration of aspirin at the recommended daily dose range in healthy participants disrupted sleep (i.e., decreased sleep efficiency, increased number of awakenings) (398) and decreased SWS (241).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [398] source

      Not checked in the free run.

    • cites [241] source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Administration of granulocyte colony-stimulating factor reduced SWS amount and intensity at the beginning of the night and increased plasma levels of IL-1ra and soluble TNF receptors.

    “A reduction of SWS amount and intensity has been observed in the beginning of the night following administration of granulocyte colony-stimulating factor, which in parallel led to an increase of the plasma levels of endogenous antagonists of IL-1 and TNF, i.e., IL-1ra and soluble TNF receptors, respectively (497).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [497] source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Recent data support a key role of gut microbiota and corresponding microbiota-derived PAMPs in central nervous processes like mood, cognition, pain, and eating behavior in animals, with first evidence for such a relationship in humans.

    “recent data support a key role of gut microbiota and corresponding microbiota-derived PAMPs in central nervous processes like mood, cognition, pain, and eating behavior in animals, and there is also first evidence for such a relationship in humans (85, 150, 151, 394).”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [85] source

      Not checked in the free run.

    • cites [150] source

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    • cites [151] source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In healthy participants, serum concentrations of lipocalin-type PGD synthase vary throughout the day, with highest levels at night and lowest in the afternoon; total sleep deprivation blunted the nocturnal increase and elevated daytime levels.

    “serum concentrations of lipocalin-type PGD synthase, which catalyzes the conversion from PGH2 to PGD2, have been reported to vary throughout the day, with highest levels at night (sleep period) and lowest levels in the afternoon. Total sleep deprivation blunted the nocturnal increase at night and elevated levels during the daytime (275)”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [275] source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Acute administration of ibuprofen led to a delay of SWS in addition to its sleep-disrupting effect.

    “Acute administration of ibuprofen, in addition to its sleep disrupting effect, also led to a delay of SWS (398).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [398] source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Intranasal administration of IL-6 in healthy participants intensified SWS in the second half of the night (increased SWA), although no overall changes in the amount of NREM sleep were observed.

    “Intranasal administration of IL-6 in healthy participants, however, intensified SWS in the second half of the night (increased SWA), although no overall changes in the amount of NREM sleep were observed (36).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [36] source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    Overall, animal studies suggest that most pro-inflammatory cytokines are NREM sleep promoting, while anti-inflammatory cytokines are NREM sleep reducing.

    “Overall, animal studies suggest that most pro-inflammatory cytokines are NREM sleep promoting, while anti-inflammatory cytokines are NREM sleep reducing.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Pathogens, including bacteria, viruses, fungi, and parasites, increase the amount and intensity of NREM sleep while decreasing the amount of REM sleep.

    “pathogens, including bacteria, viruses, fungi, and parasites increase the amount and intensity of NREM sleep while decreasing the amount of REM sleep (for comprehensive review, see Refs. 299, 353).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [299] source

      Not checked in the free run.

    • cites [353] source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Subcutaneous administration of IL-6 before sleep initiation in healthy participants resulted in delayed REM sleep latency and reduced REM sleep amount, without a change in total NREM sleep amount.

    “subcutaneous administration before sleep initiation in healthy participants resulted in a delayed REM sleep latency and reduced REM sleep amount, without a change in total NREM sleep amount (519).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [519] source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    These findings suggest the involvement of the prostaglandin system in human sleep physiology, but the exact mechanisms and prostaglandins involved remain unknown.

    “While these findings suggest the involvement of the PG system in human sleep physiology, the exact mechanisms and PGs involved remain unknown.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    During an infectious challenge, increases in NREM sleep amount or intensity and decreases in REM sleep amount have been observed.

    “During an infectious challenge, increases in NREM sleep amount or intensity (i.e., increased SWA) and decreases in REM sleep amount (353) have been observed.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [353] source

      Not checked in the free run.

  • May combine two claims.

    Interpretationcitation

    Collectively, there is ample evidence that IL-1 and TNF, in particular, and PGD2 play a critical role in the regulation of physiological, spontaneous NREM sleep in animals, and potentially in humans, while they may not be involved in physiological REM sleep regulation.

    “Collectively, there is ample evidence that IL-1 and TNF, in particular, and PGD2, play a critical role in the regulation of physiological, spontaneous NREM sleep in animals, and potentially in humans, while they may not be involved in physiological REM sleep regulation (250, 551).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [250] source

      Not checked in the free run.

    • cites [551] source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    The parasite trypanosoma can produce prostaglandins, including PGD2 with known somnogenic properties, and triggers the release of pro-inflammatory cytokines.

    “the parasite trypanosoma can produce PGs, including PGD2 with known somnogenic properties, and triggers the release of pro-inflammatory cytokines (298).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [298] source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In humans, NREM sleep enhancing or intensifying effects are restricted to times of very mild host response activation, whereas stronger responses characterized by large cytokine increases and fever caused sleep disruption.

    “in humans, NREM sleep enhancing or intensifying effects are restricted to times of very mild host response activation, whereas stronger responses characterized by large cytokine increases and fever caused sleep disruption (224, 396, 442).”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [224] source

      Not checked in the free run.

    • cites [396] source

      Not checked in the free run.

    • cites [442] source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In people living with HIV, the prevalence rate of self-reported sleep disturbances is about 60%, much higher than the prevalence rate of 10% in the general population.

    “two recent systematic reviews revealed a prevalence rate of self-reported sleep disturbances of ~60% in people living with HIV, which is much higher than the prevalence rate of 10% in the general population (97, 591).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [97] source

      Not checked in the free run.

    • cites [591] source

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  • May combine two claims.

    Premisecitation

    In early asymptomatic HIV infection, PSG shows a robust increase in SWS particularly during the latter part of the sleep period; in advanced HIV infection, typical PSG findings are sleep disruption with frequent nighttime awakenings and arousals, resulting in low sleep efficiency.

    “sleep structure changes existed during the early asymptomatic stage of the disease, characterized by a robust increase in SWS in particular during the latter part of the sleep period. In the advanced stages of HIV infection, typical PSG findings were sleep disruption with frequent nighttime awakenings and arousals, resulting in low sleep efficiency (reviewed in Ref. 134).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [134] source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Increased PGD2 levels have been found in the CSF of patients in the late stages of human African trypanosomiasis, suggesting that the PGD2 system contributes to hypersomnia in HAT.

    “Increased PGD2 levels have been found in the CSF of patients in the late stages of the disease, further suggesting that the PGD2 system contributes to hypersomnia in HAT (435).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [435] source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Actigraphy shows increased nocturnal wake time and reduced sleep efficiency in women infected with hepatitis C virus.

    “Based on objective sleep assessment using actigraphy, increased nocturnal wake time and reduced sleep efficiency have been found in women infected with HCV (232).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [232] source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Vaccinations with hepatitis A virus and influenza A H1N1 virus in healthy participants appeared not to cause gross sleep changes in the night following vaccination, but there was no comparison of sleep data to a placebo-vaccinated control group.

    “Vaccinations with hepatitis A virus (320, 325) and influenza A H1N1 (swine flu) virus (34) in healthy participants appeared to not cause any gross sleep changes in the night following the vaccination, but there was no comparison of sleep data to a placebo-vaccinated control group in these studies.”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [320] source

      Not checked in the free run.

    • cites [325] source

      Not checked in the free run.

    • cites [34] source

      Not checked in the free run.

  • May combine two claims.

    Interpretationcitation

    REM sleep suppression may promote the generation of fever that in turn boosts immunity.

    “As REM sleep is incompatible with thermoregulatory effector responses like shivering, REM sleep suppression may promote the generation of fever that in turn boosts immunity (250).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [250] source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Nonconventional EEG sleep analysis studies found alterations in SWA, such as lower SWA in the ultra-low delta range or a blunted SWA response to a sleep onset delay, and alterations of cyclic alternating patterns indicating increased sleep instability in ME/CFS patients.

    “a few studies also found alterations in SWA, such as lower SWA in the ultra-low delta range (i.e., slow oscillatory activity) (330) or a blunted SWA response to a sleep onset delay in ME/CFS patients (17), as well as alterations of cyclic alternating patterns, indicating increased sleep instability (219).”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [330] source

      Not checked in the free run.

    • cites [17]

      Not checked in the free run.

    • cites [219] source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In patients with Epstein Barr virus-linked infectious mononucleosis, self-reported sleep duration was markedly increased and debilitating daytime sleepiness persisted over many years.

    “In patients with an infectious illness linked to the Epstein Barr virus (EBV), such as infectious mononucleosis, self-reported sleep duration was markedly increased (349) and debilitating daytime sleepiness persisted over many years (218).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [349] source

      Not checked in the free run.

    • cites [218] source

      Not checked in the free run.

  • May combine two claims.

    Interpretationcitation

    Sleep alterations in hepatitis C virus infection were independent of the viremic state, suggesting that the sleep-immune relationship in HCV is complex.

    “sleep alterations in this study were independent of the viremic state, suggesting that the sleep-immune relationship in HCV is complex.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [232] source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    T-cell activation and cytokine production, in particular IFN-γ and TNF, are thought to be responsible for the clinical symptoms of infectious mononucleosis.

    “T-cell activation and cytokine production, in particular IFN-γ and TNF, are thought to be responsible for the clinical symptoms of infectious mononucleosis (21, 194, 581).”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [21] source

      Not checked in the free run.

    • cites [194] source

      Not checked in the free run.

    • cites [581] source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Half of IBD patients reported sleep disturbances as assessed by the PSQI, with strongest associations in patients with active disease.

    “In a recent study, half of the IBD patients reported sleep disturbances as assessed by the PSQI (550), with strongest associations in patients with active disease (10, 209).”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [550] source

      Not checked in the free run.

    • cites [10] source

      Not checked in the free run.

    • cites [209] source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Comprehensive immune profiling in ME/CFS patients confirmed elevated TGF-β levels and lower resistin levels, and 17 cytokines, most of them pro-inflammatory, correlated with symptom severity.

    “With the use of a comprehensive immune profiling approach in ME/CSF patients, elevated TGF-β levels were confirmed, in addition to findings of lower resistin levels (390), a protein participating in the inflammatory response and able to activate TNF in monocytes and macrophages (for review, see Ref. 187). In the same study, 17 cytokines, most of them pro-inflammatory, correlated with symptom sever”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [390] source

      Not checked in the free run.

    • cites [187] source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    Investigations on cytokine inhibition in RA suggest that TNF in particular plays a role in sleep modulation, although the independence of this association from disease activity, pain, and comorbid disorders has often not been addressed in detail.

    “To summarize, investigations on cytokine inhibition in RA suggest that TNF, in particular, plays a role in sleep modulation, although the independence of this association from other factors, such as disease activity, pain, and comorbid disorders has often not been addressed in detail.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationreasoning

    The association between IBD and sleep disturbances is thought to be bidirectional, such that increased disease activity leads to sleep disturbances, which in turn exacerbates inflammation.

    “The association between IBD and sleep disturbances is thought to be bidirectional, such that increased disease activity leads to sleep disturbances, which in turn exacerbates inflammation.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationreasoning

    Sleep reduces numbers of leukocytes in the blood, albeit only transiently, which enhances the risk of missing those changes.

    “Therefore, it may be concluded that sleep reduces numbers of leukocytes in the blood, albeit only transiently, which enhances the risk of missing those changes.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationreasoning

    Sleep appears to affect the circulating number and migration of almost all leukocyte subsets, but where leukocytes redistribute during sleep remains largely open.

    “Consequently, while sleep appears to affect the circulating number and migration of almost all leukocyte subsets, the question as to where leukocytes redistribute during sleep remains largely open.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationreasoning

    In general, sleep acutely favors pro-inflammatory and Th1 cytokine production over anti-inflammatory and Th2 cytokine production, with both tightly regulated by a homeostatic response that reverses this effect at later time points.

    “Nonetheless, in general, it seems that sleep acutely favors pro-inflammatory and Th1 cytokine production over anti-inflammatory and Th2 cytokine production, with both being tightly regulated by a homeostatic response that reverses this effect at later time points (e.g., during the second half of sleep or the daytime period in humans).”
    Quote in the paperSubstantial claim
    • Rests on an assumption: The healthy body attempts to maintain homeostasis, counteracting acute effects of sleep deprivation.

  • May combine two claims.

    Interpretationreasoning

    Sleep might support the migration of lymphocytes, thus supporting the formation of immunological memory.

    “sleep might rather support the migration of lymphocytes, thus supporting the formation of immunological memory.”
    Quote in the paperSubstantial claim0 of 6 sources checked
    • cites [468] Renegar KB, 1998, Sleep

      Not checked in the free run.

    • cites [63] source

      Not checked in the free run.

    • cites [67] source

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    • cites [143] source

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    • cites [148] source

      Not checked in the free run.

    • cites [169] Engeset A, 1977, Lymphology

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    The delicate balance of sleep and cytokine production can be disturbed following prolonged reductions in sleep duration, which may lead to a chronic imbalance favoring a pro-inflammatory response that is likely to have deleterious health consequences over the long term.

    “This delicate balance can be disturbed following prolonged reductions in sleep duration, which may lead to a chronic imbalance favoring a pro-inflammatory response that is likely to have deleterious health consequences over the long term (see sect. IV).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationcitation

    Sleep restriction changes the circadian rhythm of genes associated with immune and inflammatory responses, and these perturbances in rhythmicity are likely to be associated with health problems related to sleep disturbances.

    “In addition, sleep restriction has been found to change the circadian rhythm of genes associated with immune and inflammatory responses; these perturbances in rhythmicity are likely to be also associated with health problems related to sleep disturbances (15, 387)”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [15] source

      Not checked in the free run.

    • cites [387] source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    Sleep is important for optimal NK cell functioning, because acute deprivation or restriction of sleep may transiently dampen this function in humans and mice.

    “It thus seems that sleep is important for optimal NK cell functioning, since acute deprivation or restriction of sleep may transiently dampen this function in humans and mice.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationreasoning

    Sleep does not primarily affect existing immunity but rather supports the development of immunological memory to a new antigen.

    “It therefore seems that sleep does not primarily affect existing immunity but rather supports the development of immunological memory to a new antigen.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationreasoning

    Overall, results on antibody levels are divergent, and the functional significance of changes in antibody levels is difficult to assess.

    “Overall, results so far are divergent, and the functional significance of changes in antibody levels is difficult to assess.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationreasoning

    Overall, human and animal experiments suggest a general supportive influence of normal sleep on lymphocyte proliferation, although the effects may depend on the duration and type of sleep loss.

    “Overall, human and animal experiments suggest a general supportive influence of normal sleep on lymphocyte proliferation, although the effects may depend on the duration and type of sleep loss.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationcitation

    Sleep supports both the memory phase and the effector phase of the immune response to vaccination.

    “These results demonstrate that sleep not only supports the memory phase of the immune response to vaccination, but also the effector phase.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationreasoning

    Sleep is not only important for fighting infections induced by invading bacteria, but is also essential to keep in check usually harmless bacteria that naturally inhabit our body.

    “Hence, sleep is not only important for fighting infections induced by invading bacteria, but is also essential to keep in check usually harmless bacteria that naturally inhabit our body.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Sleep reduces the number of APCs and T cells in the blood, probably by redistributing these cells to lymph nodes.

    “Sleep reduces the number of APCs and T cells in the blood, probably by redistributing these cells to lymph nodes (67, 143, 148, 169)”
    Quote in the paperSubstantial claim0 of 4 sources checked
    • cites [67] source

      Not checked in the free run.

    • cites [143] source

      Not checked in the free run.

    • cites [148] source

      Not checked in the free run.

    • cites [169] Engeset A, 1977, Lymphology

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Habitual sleep duration, as measured by wrist actigraphy, is related to the vaccination response against hepatitis B, and each additional hour of sleep is associated with an approximately 50% increase in antibody levels.

    “one prospective study that found habitual sleep duration (as measured by wrist actigraphy) to be related to the vaccination response against hepatitis B (447).”
    • Also stated in: § B. Sleep Effects on Immunological Memory · plain
      “each additional hour of sleep was associated with an ~50% increase in antibody levels.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [447] source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Sleep enhances the number of antigen-specific CD4 T cells and their production of the Th1 effector cytokine IFN-γ.

    “sleep also enhances the number of antigen-specific CD4 T cells, as well as their production of the Th1 effector cytokine IFN-γ (320).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [320] source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    The relationship between longer sleep duration and mortality has been reported in previous reviews and meta-analyses.

    “The relationship between longer sleep duration and mortality, while unexpected, has been reported in previous reviews and meta-analyses”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [88] source

      Not checked in the free run.

    • cites [205] source

      Not checked in the free run.

    • cites [214] source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Shorter sleep duration (<7 h) in women and longer sleep duration (>8 h) in both women and men are associated with increased all-cause mortality risk.

    “shorter sleep duration (<7 h) in women and longer sleep duration (>8 h) in both women and men were associated with increased all-cause mortality risk”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [340] source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Self-reported short habitual sleep of 5 h per night or less is associated with an increased risk for the development of pneumonia within the next 2 years and with a higher incidence of reporting a respiratory infection within the past month compared with 7-8 h sleepers.

    “Self-reported short habitual sleep (≤5 h per night) was associated with an increased risk for the development of pneumonia within the next 2 years (428) and with a higher incidence of reporting a respiratory infection within the past month (449) compared with 7–8 h sleepers.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [428] source

      Not checked in the free run.

    • cites [449] source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    Sleep supports the formation of new immunological memory rather than affecting existing immunity.

    “As stated in section IIIB1, sleep supports the formation of new immunological memory rather than affecting existing immunity.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationcitation

    Sleep, by favoring pro-inflammatory and Th1 cytokine production, supports the interaction between APCs and T cells and the subsequent differentiation and proliferation of Th1 cells, eventually leading to the formation of IgG1 and IgG3 antibodies.

    “In addition, sleep, by favoring pro-inflammatory and Th1 cytokine production, further supports the interaction between APCs and T cells and the subsequent differentiation and proliferation of Th1 cells, eventually leading to the formation of IgG1 and IgG3 antibodies (24, 67, 148, 254, 320).”
    Quote in the paperSubstantial claim0 of 5 sources checked
    • cites [24] source

      Not checked in the free run.

    • cites [67] source

      Not checked in the free run.

    • cites [148] source

      Not checked in the free run.

    • cites [254] source

      Not checked in the free run.

    • cites [320] source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Sleep deprivation before malaria infection increased the death rate and number of infected cells in mice, an effect that was reversed after animals had experienced rebound sleep.

    “However, sleep deprivation before malaria infection increased the death rate and number of infected cells in mice, an effect that was reversed after animals had experienced rebound sleep (345).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [345] source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    Sleep's effect on immune parameters has functional relevance and is critical for optimal immune competence.

    “However, the various studies described in this and the previous section clearly indicate that sleep’s effect on immune parameters does indeed have functional relevance and is critical for optimal immune competence.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationcitation

    There are inter-individual differences in sleep needs, and a short sleep duration can be sufficient for optimal immune function in people with lower sleep needs.

    “This finding suggests that there are inter-individual differences in sleep needs, and that a short sleep duration can be sufficient for optimal immune function in people with lower sleep needs.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Self-reported short sleep duration (<7 h) the night before blood collection in healthy adults was related to higher T cell proliferation in response to phytohemagglutinin and lower NK-cell activity.

    “self-reported short sleep duration (<7 h) the night before blood collection in healthy adults was related to higher T cell proliferation in response to phytohemagglutinin as well as to lower NK-cell activity”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [192] source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Sleep duration evaluated by self-report questionnaires and diaries may not agree with actigraphy and PSG; in healthy populations self-reported sleep duration appears longer than actigraphy estimates, while in populations with sleep disturbances self-reported sleep duration tends to be shorter.

    “sleep duration evaluated by self-report questionnaires and diaries may not agree with the results of actigraphy and PSG. In healthy populations, self-reported sleep duration appears to be longer compared with actigraphy estimates, while in populations with sleep disturbances, self-reported sleep duration tends to be shorter”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [327] source

      Not checked in the free run.

    • cites [375] source

      Not checked in the free run.

  • Classified as probably not a substantial claim.

    Interpretationreasoning

    Shorter telomere length may reflect a mechanism or indicate a biological pathway by which shorter sleep duration is linked to long-term negative health consequences.

    “It is thought that shorter telomere length may reflect a mechanism or indicate a biological pathway by which shorter sleep duration is linked to long-term negative health consequences”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationcitation

    Elevated CRP may underlie the association between deficient sleep and mortality and the association between deficient sleep and increased risk for cardiovascular diseases.

    “may not only underlie the association between deficient sleep and mortality, but also the association between deficient sleep and increased risk for cardiovascular diseases”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [213] source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In the same study, sleep duration assessed by self-report correlated with levels of CRP and IL-6, while sleep duration assessed objectively by PSG correlated inversely with levels of TNF.

    “in the same study, sleep duration assessed by self-report correlated with levels of CRP and IL-6, while sleep duration assessed objectively by PSG correlated inversely with levels of TNF”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [430] source

      Not checked in the free run.

  • May combine two claims.

    Study design and conductcitation

    Sleep duration is generally obtained once by a single question, and other sleep characteristics including circadian misaligned or mistimed sleep and common sleep disorders such as apnea or insomnia are generally not assessed.

    “Generally, sleep duration is obtained once by a single question; other sleep characteristics, including circadian misaligned or mistimed sleep (14, 589), and common sleep disorders such as apnea (140) or insomnia (191, 565) are generally not assessed”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Based on the Whitehall II study in over 5,000 middle-aged adults, higher levels of CRP and IL-6 were associated with shorter sleep duration and with a reduction of sleep duration assessed 5 years apart.

    “Based on the longitudinal Whitehall II study in over 5,000 middle-aged adults, higher levels of CRP and IL-6 were not only associated with shorter sleep duration, but also with a reduction of sleep duration assessed 5 yr apart”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [186] source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    In the general population, the one-year incidence rate is approximately 30% for sleep complaints and 7% for new-onset insomnia disorder.

    “In the general population, the one-year incidence rate is ~30% for sleep complaints and 7% for new-onset insomnia disorder”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [331] source

      Not checked in the free run.

  • May combine two claims.

    Interpretationcitation

    A decline in naive T cells may negatively affect the early immune response to novel antigens and may underlie decreased antibody response after vaccination in short sleepers.

    “Such a decline in naive T cells may negatively affect the early immune response to novel antigens, and may underlie findings of a decreased antibody response after vaccination in short sleepers”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [447] source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    A similar association between short sleep duration and shorter leukocyte telomere length was found in older, but not middle-aged, adults (n = 154) and in children (n = 1,567).

    “A similar association was found in older, but not middle-aged, adults (n = 154) (125) and was recently also reported in children (n = 1,567)”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [125] source

      Not checked in the free run.

    • cites [271] source

      Not checked in the free run.

  • May combine two claims.

    Interpretationcitation

    Many, but not all, studies investigating habitual short sleep duration support an association with alterations in immune measures, including increased inflammatory proteins (in particular CRP, IL-6), increased WBC counts, reduced NK cell activity, and shortened telomere length.

    “many, but not all, studies investigating habitual short sleep duration support an association with alterations in immune measures, including increased inflammatory proteins (in particular CRP, IL-6), increased WBC counts, reduced NK cell activity, and shortened telomere length”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Some studies reported a loss of association between sleep disturbances and CRP after adjustment for interfering factors, or did not detect a significant association.

    “some studies reported a loss of association after adjustment for interfering factors (602), or did not detect a significant association between indices of sleep disturbances and CRP”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [602] source

      Not checked in the free run.

    • cites [156] source

      Not checked in the free run.

    • cites [231] source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    A cross-sectional study in fewer than 200 individuals found an association between poorer subjective sleep quality (PSQI) and higher stimulated IL-1, TNF, and IL-6 production, of which only the association with IL-1 remained significant after adjustment for demographic and lifestyle factors.

    “A cross-sectional study in fewer than 200 individuals found an association between poorer subjective sleep quality (assessed by the PSQI) and higher stimulated IL-1, TNF, and IL-6 production, of which only the association with IL-1 remained significant after adjustment for demographic and lifestyle factors”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [450] source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    The link between sleep disturbances and immune measures has been investigated in depression, schizophrenia, alcohol dependence, hemodialysis, organ transplantation, pregnancy, cervical cancer risk, and diabetes, with most studies reporting a significant association between some aspects of sleep disturbances and immune measures.

    “The link between sleep disturbances and immune measures has been also investigated in depression (124, 227, 393, 532), schizophrenia (176), alcohol dependence (462), hemodialysis (107, 458), organ transplantation (193), pregnancy (55, 409), cervical cancer risk (491), and diabetes (548), with most studies reporting a significant association between some aspects of sleep disturbances and immune mea”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [124] source

      Not checked in the free run.

    • cites [227] source

      Not checked in the free run.

    • cites [393] source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    This insomnia sample showed objective PSG-derived sleep impairments, indicated by increased sleep onset latency, reduced total sleep time, and decreased sleep efficiency compared with healthy sleepers.

    “This insomnia sample also showed objective PSG-derived sleep impairments, as indicated by increased sleep onset latency, reduced total sleep time, and decreased sleep efficiency compared with healthy sleepers”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [84] source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    There is good evidence that insomnia increases the risk for depression, hypertension, and type 2 diabetes.

    “There is good evidence that insomnia increases the risk for certain disorders including depression (439), hypertension (31), and type 2 diabetes (561)”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [439] source

      Not checked in the free run.

    • cites [31] source

      Not checked in the free run.

    • cites [561] source

      Not checked in the free run.

  • May combine two claims.

    Interpretationcitation

    A shift in the Th1/Th2 balance has been observed for alcohol dependence-associated sleep changes and in response to experimental sleep deficiency, and may explain lower vaccine efficacy and increased infection risk in the context of sleep deficiency.

    “Such a shift in the Th1/Th2 balance has been also observed for alcohol dependence-associated sleep changes (462) and in response to experimental sleep deficiency (24, 320), and may explain lower vaccine efficacy and increased infection risk in the context of sleep deficiency”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [462] source

      Not checked in the free run.

    • cites [24] source

      Not checked in the free run.

    • cites [320] source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Increased WBC counts in a sample of over 200 male workers were associated with self-reported poor sleep, but not with sleep duration or shift work patterns.

    “increased WBC counts in a sample of over 200 male workers in a manufacturing plant were associated with self-reported poor sleep (assessed by a single question), but not with sleep duration or shift work patterns”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [403] source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    PSG-derived sleep impairments in primary insomnia are generally of a much lesser magnitude than subjectively reported sleep impairments; total sleep time based on diary-based assessment is estimated to be 50 min less compared with PSG-based assessment.

    “Such PSG-derived sleep impairments are generally of a much lesser magnitude than subjectively reported sleep impairments. For example, total sleep time based on diary-based assessment is estimated to be 50 min less compared with PSG-based assessment”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [25] source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S4 (based).

    Interpretationnone given

    Dysregulations of immune markers have been suggested as a potential mechanism by which insomnia increases disease risk.

    “Dysregulations of immune markers have been suggested as a potential mechanism by which insomnia increases disease risk”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Based on objective sleep assessment through actigraphy, elevated WBC counts in a sample of almost 1,100 elderly individuals were associated with lower sleep efficiency and higher nocturnal wake time in women only; this association held after controlling for age, obesity, and hypertension.

    “Based on objective sleep assessment through actigraphy, elevated WBC counts in a sample of almost 1,100 elderly individuals were associated with lower sleep efficiency and higher nocturnal wake time in women only; this association held even after controlling for various confounders, such as age, obesity, and hypertension”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [405] source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Shorter leukocyte telomere length has been linked with markers of sleep disturbances (PSQI) in a sample of 245 healthy midlife women and of 87 obese adults, with the latter study reporting a link with telomere length of CD8 and CD4 T cells in particular.

    “shorter leukocyte telomere length, a proposed marker of cellular senescence, has been linked with markers of sleep disturbances (assessed by the PSQI) in a sample of 245 healthy midlife women (451) and of 87 obese adults (446), with the latter study reporting a link with telomere length of CD8 and CD4 T cells in particular”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [451] source

      Not checked in the free run.

    • cites [446] source

      Not checked in the free run.

  • May combine two claims.

    Interpretationcitation

    Both subjective sleep quality and insomnia status may attenuate immunity to the influenza virus.

    “which led the authors to suggest that both may attenuate immunity to the influenza virus”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [536] source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In the same study, individuals with insomnia and healthy sleepers did not differ with respect to PSG-based sleep parameters, contrasting with subjective reports of higher nocturnal wake time and lower sleep efficiency in those with insomnia.

    “individuals with insomnia and healthy sleepers also did not differ with respect to PSG-based sleep parameters (490), contrasting with subjective reports of higher nocturnal wake time and lower sleep efficiency in those with insomnia”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [490] source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    Collectively, findings suggest that a diagnosis of insomnia is associated with immune dysregulations, ranging from increased levels and diurnal rhythm changes of inflammatory cytokines to decreased lymphocyte subsets to shorter telomere length, and may potentially attenuate influenza antibody responses.

    “Collectively, findings suggest that a diagnosis of insomnia is associated with immune dysregulations, ranging from increased levels and diurnal rhythm changes of inflammatory cytokines to decreased lymphocyte subsets to shorter telomere length, and may potentially attenuate influenza antibody responses”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationcitation

    Chronic sleep disturbances may be the cause or the consequence of other known triggers of low-grade inflammation, including circadian disruption, obesity, adverse lifestyle habits like physical inactivity and unhealthy food, and psychosocial influences like stress, loneliness, and low socioeconomic status.

    “chronic sleep disturbances may be the cause or the consequence of other known triggers of low-grade inflammation, including circadian disruption (370), obesity (406), adverse lifestyle habits like physical inactivity (431) and unhealthy food (508), and psychosocial influences like stress (121, 189, 454, 525), loneliness (120), and low socioeconomic status (166)”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [370] source

      Not checked in the free run.

    • cites [406] source

      Not checked in the free run.

    • cites [431] source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    The vaccination response to influenza did not differ between 133 healthy college students with or without insomnia, although the insomnia group had overall lower antibody amounts pre- and post-vaccination.

    “the vaccination response to influenza did not differ between 133 healthy college students with or without insomnia (based on DSM-V criteria), although the insomnia group had overall lower antibody amounts pre- and post-vaccination”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [536] source

      Not checked in the free run.

  • Classified as probably not a substantial claim. May combine two claims.

    Interpretationreasoning

    Any additional time spent awake enhances environmental interaction, potentially leading to activation of PRRs by PAMPs and DAMPs that will trigger inflammatory processes.

    “any additional time spent awake enhances environmental interaction, potentially leading to activation of PRRs by PAMPs and DAMPs that will trigger inflammatory processes”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationcitation

    Disturbances in metabolic clearance due to the lack of sleep can lead to neuroinflammation and, in the long term, to neurodegenerative diseases.

    “Disturbances in this metabolic clearance due to the lack of sleep can lead to neuroinflammation and, in the long term, to neurodegenerative diseases”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [60] source

      Not checked in the free run.

    • cites [399] source

      Not checked in the free run.

    • The authors state this as an assumption: The glymphatic system flushes amyloid beta away from the brain parenchyma during sleep.

  • May combine two claims.

    Premisecitation

    Habitual short sleep duration and chronic sleep disturbances are related to a variety of diseases, including cardiovascular diseases, metabolic diseases, chronic pain conditions, some forms of cancer, and neuropsychiatric disease, all of which involve immune dysregulations.

    “habitual short sleep duration and chronic sleep disturbances are related to a variety of diseases, including cardiovascular diseases, metabolic diseases, chronic pain conditions, some forms of cancer, and neuropsychiatric disease (255), all of which involve immune dysregulations”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [255] source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In rats, sustained sleep deprivation induced oxidative stress as well as DNA, cell, and tissue damage.

    “In rats, sustained sleep deprivation induced oxidative stress as well as DNA, cell, and tissue damage”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [173] source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Performance did not return to baseline levels after a single night with a 10-h sleep opportunity or three nights with an 8-h sleep opportunity, suggesting that a longer recovery sleep period is needed to fully resolve performance decrements due to experimental sleep deficiency.

    “performance did not return to baseline levels after a single night with a 10-h sleep opportunity (28) or three nights with an 8-h sleep opportunity (32), suggesting that a longer recovery sleep period is needed to fully resolve any performance decrements due to experimental sleep deficiency”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [28] source

      Not checked in the free run.

    • cites [32] source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    Recovery needs will likely differ for different immune and inflammatory markers, with some markers restoring quickly and others requiring prolonged sleep recovery periods involving extended sleep per night or multiple nights of recovery sleep; based on current findings, neutrophils and IL-6 likely fall into the latter category.

    “In light of current research findings, recovery needs will likely differ for different immune and inflammatory markers, with some markers restoring quickly and others requiring prolonged sleep recovery periods involving extended sleep per night or multiple nights of recovery sleep; based on current findings, neutrophils and IL-6 likely fall into the latter category.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationreasoning

    Immune recovery depends on the type and duration of prior sleep loss, with considerable response variation between different immune measures.

    “In light of a number of other immune measures modulated by these protocols (not reviewed), findings suggest that immune recovery depends on the type and duration of prior sleep loss, with considerable response variation between different immune measures.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    A further reduction of NK cells and activated T cells was observed during recovery sleep, indicating a compensatory decrease of those cell subsets.

    “A further reduction of NK cells and activated T cells was observed during recovery sleep, indicating a compensatory decrease of those cell subsets”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [67] source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In humans, after 64 h continuous wakefulness, monocytes still tended to be increased after a single night of recovery sleep compared with pre-deprivation levels, while recovery levels of leukocyte counts, granulocyte counts, and NK-cell activity returned to pre-deprivation levels.

    “monocytes still tended to be increased after a single night of recovery sleep (duration not reported) compared with pre-deprivation levels, while recovery levels of leukocyte counts, granulocyte counts, and NK-cell activity returned to pre-deprivation levels”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [152] source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).

    Interpretationreasoning

    Sleep disturbances in inflammatory conditions presumably also have a negative effect on the underlying immune process, thus feeding into a vicious circle.

    “sleep disturbances in inflammatory conditions presumably also have a negative effect on the underlying immune process, thus feeding into a vicious circle”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationreasoning

    Available evidence in animals and humans suggests that sleep counteracts low-grade systemic inflammation and in this way maintains immune homeostasis.

    “available evidence in animals and humans suggests that sleep counteracts low-grade systemic inflammation and in this way maintains immune homeostasis”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).

    Interpretationreasoning

    It is conceivable that physiological sleep regulation fails when inflammatory mediators are constantly elevated.

    “it is conceivable that physiological sleep regulation fails when inflammatory mediators are constantly elevated”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationreasoning

    These immune dysregulations may constitute a potential mechanism through which sleep influences disease risk, which has been supported in more recent studies.

    “These immune dysregulations may constitute a potential mechanism through which sleep influences disease risk, which has been supported in more recent studies.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Study design and conductcitation

    Blood was assessed only once per day in the bedtime extension study, which may have reduced the chance of detecting transient changes in cell numbers.

    “Of note, blood was assessed only once per day, which may have reduced the chance of detecting transient changes in cell numbers.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [103] source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S4 (based). May combine two claims.

    Interpretationnone given

    Chronic sleep deficiency disturbs immune homeostasis, thereby presumably increasing the risk for the development and amplification of several diseases in which immune dysregulation is common (e.g., cardiovascular, metabolic, autoimmune, and neurodegenerative diseases).

    “Chronic sleep deficiency disturbs immune homeostasis, thereby presumably increasing the risk for the development and amplification of several diseases in which immune dysregulation is common (e.g., cardiovascular, metabolic, autoimmune, and neurodegenerative diseases).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationnone given

    These cytokines and PGs are potentially also involved in physiological sleep regulation and pathogen-induced sleep responses in humans, although experimental evidence is still weak.

    “These (and other) cytokines and PGs are potentially also involved in the physiological sleep regulation and pathogen-induced sleep responses in humans, although experimental evidence is still weak.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationreasoning

    This may lead to an improved adaptive immune response and stable immunological memory formation.

    “This may lead to an improved adaptive immune response and stable immunological memory formation.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationreasoning

    Recovery sleep following acute sleep deficiency, naps, extension of habitual sleep duration, and CBT-I may counteract sleep deficiency-induced changes of immune measures.

    “To conclude, recovery sleep following acute sleep deficiency, naps, extension of habitual sleep duration, and CBT-I may counteract sleep deficiency-induced changes of immune measures.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).

    Interpretationnone given

    Various medications can disturb sleep (e.g., beta-blockers, corticosteroids, analgetics, anti-depressants).

    “Various medications can disturb sleep (e.g., beta-blockers, corticosteroids, analgetics, anti-depressants), which needs to be considered in treatment decisions.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    CBT-I is considered the first-line treatment for insomnia and outperforms pharmacological interventions, particularly with respect to maintenance of therapeutic effects at long-term follow-up.

    “CBT for insomnia (CBT-I) is considered the first-line treatment for insomnia (557) and outperforms pharmacological interventions, in particular with respect to maintenance of therapeutic effects at long-term follow-up (270, 513).”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [557] source

      Not checked in the free run.

    • cites [270] source

      Not checked in the free run.

    • cites [513] source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    Overall, findings suggest that improving sleep disturbances has a beneficial effect on various immune parameters, which potentially may mediate the association between sleep disturbances and increased disease risk reported in epidemiological studies.

    “However, overall, findings suggest that improving sleep disturbances has a beneficial effect on various immune parameters, which potentially may mediate the association between sleep disturbances and increased disease risk reported in epidemiological studies (see sect. IVB).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationnone given

    Sleep deficiency induces immune system changes, and vice versa, the immune system modulates sleep.

    “As we have outlined in this review, sleep deficiency induces immune system changes, and vice versa, the immune system modulates sleep.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationnone given

    Experimental studies on the application of pathogens and components of pathogens in humans, as well as field studies in individuals with chronic infectious and inflammatory diseases, show that sleep changes are common, but can vary greatly, including enhanced, reduced, disrupted, or misplaced sleep.

    “Experimental studies on the application of pathogens and components of pathogens (e.g., endotoxins) in humans, as well as field studies in individuals with chronic infectious and inflammatory diseases, show that sleep changes are common, but can vary greatly, including enhanced, reduced, disrupted, or misplaced sleep.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationnone given

    Substances of the immune system, in particular the cytokines IL-1 and TNF, and PGD2, are involved in the regulation of spontaneous, physiological sleep in animals, and also mediate the increase of NREM sleep amount and intensity after the animal's host defense is challenged with pathogens.

    “Substances of the immune system, in particular the cytokines IL-1 and TNF, and PGD2 are involved in the regulation of spontaneous, physiological sleep in animals, and also mediate the increase of NREM sleep amount and intensity after the animal’s host defense is challenged with pathogens.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationreasoning

    Sleep influences infection outcome, as well as the response to vaccination as an experimental model of infection.

    “It is therefore not surprising that sleep influences infection outcome, as well as the response to vaccination as an experimental model of infection.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationreasoning

    Studies in flies and rodents suggest that sleep increases the survival of an infection, whereas several studies in humans indicate that sleep loss increases the susceptibility to infections and worsens the immune response to vaccination.

    “Studies in flies and rodents suggest that sleep increases the survival of an infection, whereas several studies in humans indicate that sleep loss increases the susceptibility to infections and worsens the immune response to vaccination.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S4 (based). May combine two claims.

    Interpretationnone given

    Adequate sleep duration can improve infection outcomes and is associated with reduced infectious disease risk.

    “Adequate sleep duration can improve infection outcomes and is associated with reduced infectious disease risk.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S2 (checkable), S3 (load-bearing), S4 (based).

    Interpretationnone given

    It is likely that different parameters act in concert to mediate the impact of sleep on the immune system and vice versa.

    “It is likely that different parameters act in concert to mediate the impact of sleep on the immune system and vice versa.”
    Quote in the paperNot a substantial claim

  • Classified as probably not a substantial claim.

    Premisecitation

    The effects of sleep on autoimmunity, allergy, tumor immunity, and graft rejection are under-studied.

    “The effects of sleep on some specific immune aspects, such as autoimmunity (see, e.g., Ref. 419), allergy, tumor immunity, and graft rejection, are under-studied.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Ref. 419

      Not checked in the free run.

150 of 150

  • The authors state this as an assumption.

    Prolonged sleep loss weakens the body's defense system and renders one more prone to catch a cold or any other infection.

    “Along this line, it is assumed that prolonged sleep loss weakens our body’s defense system and thus renders us more prone to catch a cold or any other infection.”

  • The authors state this as an assumption.

    Commensal gut bacteria contribute to the systemic release of muramyl peptides during sleep deprivation.

    “it was assumed that commensal gut bacteria contribute to their systemic release (304).”

  • The authors state this as an assumption.

    Sleep responses to immune activation are adaptive.

    “These sleep responses to immune activation are assumed to be adaptive.”

  • The paper relies on this without support.

    Fever and sickness behavior are adaptive responses of the CNS that presumably aid recovery from infections.

    “These changes are considered adaptive responses of the CNS and presumably aid the recovery from infections.”

  • The paper relies on this without support.

    Only a few studies have specifically addressed the pathophysiological mechanisms responsible for sleep disturbances in chronic infectious or inflammatory diseases.

    “To date, only a few studies have specifically addressed the pathophysiological mechanisms responsible for sleep disturbances in chronic infectious or inflammatory diseases.”

  • The paper relies on this without support.

    The healthy body attempts to maintain homeostasis, counteracting acute effects of sleep deprivation.

    “Being a homeostatic system, the healthy body is expected to attempt to reach a homeostatic state, thus counteracting any effects occurring acutely during sleep deprivation.”

  • The authors state this as an assumption.

    One general role of sleep is to support memory formation.

    “one assumed general role of this behavioral state is to support memory formation.”

  • The paper relies on this without support.

    Memory in the immune system can be subdivided into encoding, consolidation, and recall phases.

    “Analogously to the formation of memory in the CNS, memory in the immune system may be subdivided into three phases (FIGURE 5).”

  • The paper relies on this without support.

    Uncontrolled disease processes mediate the association between long sleep duration and elevated inflammatory status.

    “uncontrolled disease processes are still thought to mediate this relationship”

  • The authors state this as an assumption.

    The glymphatic system flushes amyloid beta away from the brain parenchyma during sleep.

    “It is assumed that the glymphatic system, a waste clearance pathway to eliminate soluble proteins and metabolites from the CNS, flushes amyloid beta away from the brain parenchyma during sleep”

  • The paper relies on this without support.

    The systematic investigation of the interactions between sleep and the immune system is a relatively new research area.

    “Although the assumption that sleep is important for immune functions has existed for a long time, the systematic investigation of the interactions between sleep and the immune system is a relatively new research area.”

  • The paper relies on this without support.

    The mechanisms underlying neuro-immune interactions are still not well understood.

    “The mechanisms underlying these complex neuro-immune interactions are still not well understood.”

  • The paper relies on this without support.

    Studies in humans relating sleep-induced changes in immune parameters to actual infection risk and outcome are lacking.

    “Importantly, studies in humans relating sleep-induced changes observed in several immune parameters, like immune cell numbers, to actual infection risk and outcome are lacking so far.”

  • The paper relies on this without support.

    Tregs are dysfunctional in autoimmunity, allergy, tumor immunity, and graft rejection.

    “Tregs, which dampen the immune response in an antigen-specific manner, are dysfunctional in these conditions”

  • The paper relies on this without support.

    Large interindividual differences exist in sleep need, preferred timing of sleep, and susceptibility to the physiological and perceptual consequences of sleep loss.

    “Large interindividual differences exist with regard to sleep need (the optimal sleep duration for an individual), preferred timing of sleep (the optimal time of day to sleep), and susceptibility to the physiological (and perceptual) consequences of sleep loss”

  • The paper relies on this without support.

    Not much is known about how interindividual differences in sleep relate to immune functions.

    “but not much is known about how these differences relate to immune functions.”

  • The paper relies on this without support.

    Basic interactions between the CNS and the immune system play an essential role in normal physiology and in many pathological conditions.

    “which play an essential role not only in normal physiology, but also in many pathological conditions.”
17 of 17

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

  • Sleep problems lead to a series of adverse outcomes, including decreased immune function, obesity, traffic accidents, substance abuse, depression, and suicidal tendency.

    “Sleep problems lead to a series of adverse outcomes, including decreased immune function, obesity, traffic accidents, substance abuse, depression, and suicidal tendency [1–3].”

    From Adolescents’ short-form video addiction and sleep quality: the mediating role of social anxiety (2024) · cites this paper as [1]

Cites

Flagged first, then by citations

2 of the 608 references couldn’t be matched to a known paper.

Research works printed but not linked: 35

  1. American Academy of Sleep Medicine, 2007, The AASM Manual for the Scoring of Sleep and Associated Events. Rules, Terminology and Technical Specifications
  2. Attarbaschi T, 2003, Eur Cytokine Netw, 14, 34
  3. Borbély AA, 1999, J Biol Rhythms, 14, 557
  4. Brown R, 1989, Reg Immunol, 2, 321
  5. Casey FB, 1974, J Reticuloendothel Soc, 15, 87
  6. Detert J, 2016, Clin Exp Rheumatol, 34, 848
  7. Dickstein JB, 2000, Sleep, 23, 185
  8. Dracott BN, 1979, Immunology, 38, 437
  9. Elenkov IJ, 2000, Pharmacol Rev, 52, 595
  10. Engeset A, 1977, Lymphology, 10, 198
  11. Hambrecht-Wiedbusch VS, 2017, Sleep, 40, zsx116
  12. Horohov DW, 2001, Comp Med, 51, 230
  13. Ishimori K, 1909, Tokyo Igaku Zasshi, 23, 423
  14. Kaszubowska L, 2008, J Physiol Pharmacol, 59, 169
  15. Leclerc C, 1982, Lymphokines, 7, 1
  16. Legendre R, 1913, Z. Physiologie, 14, 235
  17. Masocha W, 2018, Brain Res Bull, S0361-9230(18)3
  18. Matalka KZ, 2003, Neuro Endocrinol Lett, 24, 283
  19. Miller MA, 2009, Sleep, 32, 857
  20. Nezi M, 2000, Endotext
  21. Oztürk L, 1999, Sleep Res Online, 2, 107
  22. Poletaev A, 2011, Hippokratia, 15, 295
  23. Renegar KB, 1998, Sleep, 21, 19
  24. Renegar KB, 1998, Sleep, 21, 241
  25. Rovenský J, 1995, Arch Immunol Ther Exp (Warsz), 43, 221
  26. Smith A, 1992, Sleep, Arousal, and Performance, 233
  27. Späth-Schwalbe E, 1998, J Clin Endocrinol Metab, 83, 1573
  28. Spiegel K, 1995, Sleep, 18, 543
  29. Tesoriero C, 2018, Brain Res Bull, S0361-9230(18)3
  30. Trammell RA, 2015, Comp Med, 65, 173
  31. Von Economo C, 1917, Wien Klin Wochenschr, 30, 581
  32. Von Economo C, 1917, Neurol Centralbl, 5, 866
  33. Wang M, 2016, Am J Neurodegener Dis, 5, 171
  34. Wolfe F, 2006, J Rheumatol, 33, 1942
  35. Zammit GK, 1995, Sleep, 18, 229

Cited by

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Authors
Besedovsky, L., Lange, T., & Haack, M.
Affiliations
Beth Israel Deaconess Medical Center (US)
ORCID
Venue
Physiological Reviews
Publisher
American Physiological Society
Published
2019-07-01
Volume
99
Issue
3
Pages
1325-1380
ISSN
  • 0031-9333 (ISSN-L)
  • 1522-1210
DOI
10.1152/physrev.00010.2018
PMC
PMC6689741
OpenAlex
W2927147597
Cited by
1,479
References
608
Citations by year
2026: 206 · 2025: 276 · 2024: 254 · 2023: 232 · 2022: 204 · 2021: 166 · 2020: 124 · 2019: 16
FWCI
15.95
Type
journal article
Language
en
Open access
Locations
  • Physiological Reviews (publishedVersion)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
Funders
  • Deutsche Forschungsgemeinschaft (DFG) (BE 6319/1-1, TR/SFB 654 C6)
  • HHS | NIH | National Heart, Lung, and Blood Institute (NHBLI) (HL136310)
  • HHS | NIH | National Institute of Neurological Disorders and Stroke (NINDS) (NS091177)
Topics
  • Life Sciences › Neuroscience › Cognitive Neuroscience › Sleep and Wakefulness Research
  • Life Sciences › Neuroscience › Endocrine and Autonomic Systems › Circadian rhythm and melatonin
  • Social Sciences › Psychology › Experimental and Cognitive Psychology › Sleep and related disorders
Keywords
sleep and immunity, sleep deprivation, short sleep duration, sleep disorders, inflammation, cytokines, innate immunity, adaptive immunity, infection, vaccine response, sleep hormones, low-grade inflammation, diabetes mellitus, atherosclerosis, neurodegeneration
MeSH terms
Animals, Homeostasis, Humans, Immune System, Immunity, Immunity, Innate, Sleep, Sleep Deprivation

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Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

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