Physiol Rev 99: 1325–1380, 2019

Published March 27, 2019; doi:10.1152/physrev.00010.2018

THE SLEEP-IMMUNE CROSSTALK IN HEALTH AND

DISEASE
Luciana Besedovsky, X Tanja Lange, and Monika Haack

Institute of Medical Psychology and Behavioral Neurobiology, University of Tübingen, Tübingen, Germany;
Department of Neurology, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston,
Massachusetts; and Department of Rheumatology and Clinical Immunology, University of Lübeck, Lübeck,
Germany

Besedovsky L, Lange T, Haack M. The Sleep-Immune Crosstalk in Health and Disease.

L
Physiol Rev 99: 1325–1380, 2019. Published March 27, 2019; doi:10.1152/physrev.
00010.2018.—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 inflamma-
tory 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.

I. INTRODUCTION 1325 be the bacterial cell wall component muramyl peptide, and
II. THE SLEEP RESPONSE TO IMMUNE ... 1333 like more than 2,000 yr ago, it was assumed that it derives
III. SLEEP EFFECTS ON HOST DEFENSE 1340 from the gastrointestinal tract (304). By activating the im-
IV. IMMUNE SYSTEM CHANGES ... 1352 mune system and the release of sleep regulatory substances
V. SLEEP TO REINSTATE IMMUNE BALANCE 1357 like the cytokines tumor necrosis factor (TNF) and interleu-
VI. CONCLUSIONS AND FUTURE DIRECTIONS 1360 kin (IL)-1␤, these muramyl peptides and other microbial
products were shown in animal models to contribute to the
homeostatic regulation of slow-wave sleep (SWS), the deep-
I. INTRODUCTION
est form of sleep. We now know that both cytokines like-
wise mediate the SWS response to an infectious challenge
Sleep-immune interactions are well-known phenomena in
(353). With respect to the sleep-to-immune directionality,
everyday life and folk wisdom. There is no doubt that an
early studies in the late 19th century showed that total sleep
infection makes us tired and increases the desire to sleep,
deprivation in dogs leads to death after several days (re-
and a good night’s sleep is commonly recommended as “the
best medicine” for an infectious disease. Along this line, it is viewed in Ref. 38). Later studies using more controlled
assumed that prolonged sleep loss weakens our body’s de- approaches found that sleep deprivation of rats is lethal
fense system and thus renders us more prone to catch a cold after ~2–3 wk (459), and a breakdown of host defense
or any other infection. The scientific analyses of these no- indicated by a systemic bacterial infection was reported
tions started in 350 BC, when Artistotle elaborated in his after applying the same method of sleep deprivation (172,
book On Sleep and Sleeplessness that sleep is induced by 175). Together with other experiments from recent times,
hot vapors that arise from the stomach during digestion, these findings suggest an important role of sleep for immune
and that a similar sleep response can be observed in feverish defense (47, 79).
patients (16). In the early 20th century, researchers postu-
lated a hypnotoxin that increases during wakefulness, in- This review is based on findings from experimental, in-
duces sleep, and is cleared again during sleep (265, 333). laboratory animal and human models that manipulate sleep
The first hypnotoxin, discovered in the 1980s, turned out to or components of the immune system, as well as human

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 BESEDOVSKY ET AL.

field studies conducted in populations with various habitual possible countermeasures to reinstate immune balance, in-
sleep durations, chronic sleep disturbances, or chronic in- cluding recovery sleep following total or partial sleep depri-
fectious or inflammatory diseases. It aims to summarize vation, napping, extension of sleep duration, and cognitive
sleep changes in response to infectious and noninfectious behavioral therapy. Finally, in section VI, we provide con-
challenges and to describe, on the other hand, the role of clusions on the available data, highlight the problems and
sleep in fine-tuning the immune system to foster immune pitfalls in this scientific field, and propose some questions
defense. We start in section I by introducing basic aspects of open for future research. See FIGURE 1 for an overview of
sleep and the immune system and the means by which they the topics covered by this review and the sections in which
can interact with each other. In section II, we outline how they are described.
the components of the immune system signal to the brain
and how sleep is altered during acute and chronic infectious
or inflammatory diseases. Section III summarizes research A. Sleep Characteristics, Regulation, and
that was performed mainly in the last two decades and Measurement
assessed the sleep-to-immune directionality, including the
impact of sleep on immune parameters and function, vacci- Sleep is not a passive condition; the brain and the body are
nation responses, and infection outcome and risk. This sec- highly active during this particular behavioral state. Sleep
tion includes mainly experimental studies in which sleep can be characterized by a prototypical posture (usually re-
was actively manipulated. In section IV we focus on obser- cumbency), an increased arousal threshold with a reduced
vational studies investigating the association between responsiveness to external stimuli, and a loss of conscious-
chronic sleep deficiency and immune parameters and de- ness. In contrast to coma, it can be easily reversed. Sleep is
scribe how this association may contribute to increased dis- regulated homeostatically, meaning that sleep increases in
ease risk. Section V summarizes data on studies examining duration and intensity after a prolonged period without

Experimental studies ZZ
Z
Z

Sleep changes induced by: Acute (1 night of total or partial SD) and subchronic
• cytokines (II B) (several nights of total or partial SD) effects of sleep/SD on:
• prostaglandins (II B) • single immune parameters (III A)
• LPS/infection (II C) • vaccination response (III B)
• infection outcome and risk (III C)

Field studies Influencing factors

Duration and Time points of
Z ZZ method of SD specimen sampling
Z

Method of sleep Type of immune

assessment assay
Z ZZ
Z

Psychosocial Circadian
• Sleep changes during chronic immune activation (II D)
stress system
• Associations of habitual sleep with vaccination
response (III B) and infection risk (III C)
• Immune measures associated with habitual sleep Age and health Analyzed
duration (IV A) and chronic sleep disturbances (IV B) related factors Environmental species
factors, e.g., light

FIGURE 1. Research approaches for investigating sleep-immune interactions and potential influencing fac-
tors. Experimental studies investigate causal relationships between sleep and immune parameters by manip-
ulating sleep or immunological factors, but have low ecologic validity (i.e., they cannot be easily translated into
everyday situations). Field studies investigate naturally existing associations between sleep characteristics and
immune parameters; however, causality cannot be inferred. Several factors (summarized in sect. VIB) influ-
ence the results of studies, including specifics of the study design, methods, and environmental factors.
Orange numbers in brackets refer to the section dealing with the denoted topic. SD, sleep deprivation; LPS,
lipopolysaccharide.

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 THE SLEEP-IMMUNE CROSSTALK

sleep. In addition to this homeostatic component, a second characteristic patterns like the so-called saw tooth waves.
process that is independent from prior wakefulness modu- Most of the dreaming episodes seem to occur during REM
lates the timing of sleep, namely, the circadian system. This sleep and muscle activity is actively suppressed, presumably
system is responsible for imposing and synchronizing a to hinder acting out dreaming episodes. REM sleep makes
close to 24-h rhythm on several behaviors and body func- up ~20% of total sleep time. Stages N1, N2, and N3 are
tions, including the propensity to sleep or be awake along collectively also termed non-REM (NREM) sleep as op-
the 24-h sleep-wake cycle. The homeostatic and circadian posed to REM sleep. They typically occur in succession
components constitute the two factors of the so-called two- from light to deep sleep (i.e., from N1 to N3 with an in-
process model describing the regulation of sleep (64, 65). creasing arousal threshold) followed by an episode of REM
Several brain mechanisms are involved in this regulation, sleep. An average night with 8 h of sleep contains around
which have been reviewed in detail elsewhere (76). five of these NREM-REM sleep cycles, which each last ~90
min (representing an ultradian rhythm). Whereas NREM
The sleeping brain shows a characteristic pattern of activa- sleep is predominantly under homeostatic control, REM
tion, which can be measured by electroencephalography sleep is mainly under circadian control. SWS predominates
(EEG). Together with the measurements of eye movements during the first half of the night and becomes reduced as
(electrooculography, EOG) and muscle activity (electro- sleep progresses. In contrast, REM sleep episodes are typi-
myography, EMG), the EEG is used to discriminate be- cally short at the beginning of the night and become longer
tween four stages of sleep (FIGURE 2). Sleep stage N1 refers and more frequent in the second sleep half.
to a transitionary state between sleep and wake and often
includes slowly rolling eye movements. It is typically fol- Besides the different sleep stages, various other aspects of
lowed by sleep stage N2, which makes up ~50% of total sleep can be determined, such as how fragmented the sleep
sleep time in healthy young adults. N2 is characterized by period is (sleep fragmentation), how long a person needs to
the frequent occurrence of so-called sleep spindles (waxing fall asleep (sleep onset latency), how long a person is asleep
and waning waves of 12–15 Hz) and K-complexes (single, during the time in bed (sleep efficiency), and how much time
high negative deflections) in the EEG. Around 20% of total a person spends awake after falling asleep until the final
sleep time is composed of sleep stage N3. It is distinguished wake up (wake after sleep onset, WASO). All these features
from the other stages by a high incidence of low-frequency of sleep, which are interrelated, determine the quality of
(ⱕ4 Hz), high-amplitude (⬎75 ␮V) waves, called slow sleep. In addition, the density of the different EEG frequen-
waves, and is therefore also referred to as SWS. Originally, cies that characterize single sleep parameters like spindles
this sleep stage was subdivided into two stages (S3 and S4), and slow waves can be quantified by spectral analyses.
depending on the percentage of slow waves occurring (460), Slow-wave activity (SWA), a measure of the density and
but this distinction has been abandoned in newer guidelines amplitude of slow waves, is considered to reflect the inten-
(8a). The fourth sleep stage is denoted rapid-eye-movement sity of sleep and is increased during sleep episodes that
(REM) sleep due to the typical rapid eye movements that follow a prolonged period of wakefulness.
occur only during this sleep stage. Brain activity during
REM sleep is very different from stages N2 and N3. It Sleep can be measured in several ways (TABLE 1). Polysom-
resembles more the waking brain activity, but also includes nography (PSG) is the gold standard for objectively measur-

EEG FIGURE 2. Prototypical hypnogram with EEG

characteristics and sleep laboratory setting. Sleep
is divided into stages N1, N2, N3 (formerly further
subdivided into S3 and S4), and rapid-eye-move-
EEG ment (REM) sleep based on specific patterns of
brain activity [measured with electroencephalog-
raphy (EEG)], eye movements [measured with elec-
EOG troocculography (EOG)], and muscle activity [mea-
sured with electromyography (EMG)]. N1, N2, and
N3 are collectively referred to as non-REM
EMG (NREM) sleep. The course of the different sleep
stages across a sleep period is typically visualized
REM in a hypnogram (bottom right). The typical sleep
1 laboratory setting for measuring blood parame-
2 ters during sleep includes a hole-through-the-wall
NREM 3 system, allowing the blood sample to be collected
4 from an adjacent room through a long tube with-
out disturbing the participant’s sleep. (Adapted
11 PM 7 AM
Slow wave sleep from Tanja Lange.)
(N3)

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 BESEDOVSKY ET AL.

Table 1. Most common methods for measuring and experimentally manipulating sleep
Methods for sleep measurement
Polysomnography (PSG) Gold standard for objectively measuring sleep in the laboratory setting in humans. Consists of
electrodes measuring brain activity (electroenephalography, EEG), eye movements
(electrooculography, EOG), and muscle activity (electromyography, EMG). In the clinical setting,
further measurements may include heart rate (electrocardiogram, ECG), respiratory events,
snoring activity, blood oxygen saturation, and body position. Portable polysomnography (PSG)
devices also exist for the ambulatory recordings in the home environment. While in humans the
EEG electrodes are attached to the scalp, in animal experiments, the EEG electrodes are
surgically implanted into the brain.
Actigraphy Commonly used method to objectively estimate sleep parameters such as bedtimes, sleep duration,
sleep onset latency, and sleep fragmentation over periods of multiple days in humans; it consists
of a device that is typically worn on the wrist and that monitors motor activity (some models also
measure light exposure and heart rate), based on which the various sleep parameters are
estimated. It can be easily performed in the home environment.
Sleep diaries Participants complete a sleep diary after awakening in the morning (and sometimes before going to
bed to capture daytime functioning). These diaries allow subjective estimates of sleep duration,
sleep onset latency, wake after sleep onset (WASO), number of awakenings, and sleep quality,
among others.
Sleep questionnaires Sleep questionnaires obtain information on sleep quantity and quality of the previous night or they
can be filled in to retrospectively inform about average sleep quantity and quality and other sleep
parameters over the last weeks.
Methods for experimental sleep manipulations
Total sleep deprivation Sleep is suppressed entirely for a certain period, typically for one entire night and the subsequent
day in humans. Ideally, body posture, light exposure, and food and fluid consumption are
controlled to resemble sleep conditions.
Partial sleep Sleep is suppressed only partly for a certain period, e.g., between 11 PM and 3 AM for one or
deprivation ⫽ sleep restriction several nights.
Sleep disruption Sleep is interrupted repeatedly by forced awakenings of the participant or the animal for a limited
time period (e.g., 30-min-long awakenings) and is used as a model for resembling sleep in, e.g.,
maintenance insomnia or parenting small children. Sleep can be also disrupted through frequent
exposures to acoustic or mechanical stimuli, leading to frequent and brief EEG arousals (generally
⬍10 s in length) and stage shifts into lighter sleep stages. This method is also referred to as
sleep fragmentation and intends to model sleep that is characteristic for, e.g., breathing-related
disorders or restless-leg syndrome.
Selective deprivation of single Slow-wave sleep (SWS) and rapid-eye movement (REM) sleep can be suppressed or reduced
sleep stages selectively. Selective SWS suppression is typically induced by delivering sounds to the sleeping
participants as soon as the EEG shows certain features of SWS. The aim is to induce a shift into
a lighter sleep stage without awakening the participant. Selective REM sleep suppression is
performed more rarely in humans and participants typically have to be woken up if signs of REM
sleep occur, as it is difficult to induce a shift to another sleep stage out of REM sleep. One of the
most commonly used methods for long-term sleep deprivation in animal research, the multiple
platform technique (see below), mainly suppresses REM sleep, while SWS is concomitantly
reduced only to a certain extent.
Selective enhancement of single So far, a selective enhancement of single sleep stages is well established only for SWS. Certain
sleep stages aspects of SWS can be enhanced by delivering short sounds (e.g., pink noise) to sleeping
participants, by applying weak electrical stimulation, or by using transcranial magnetic stimulation
(TMS). These methods enhance or synchronize the occurrence of slow waves. Listening to
specific hypnotic suggestions while falling asleep can increase the time spent in SWS.
Sleep extension Sleep extension in humans can be performed by increasing the time allocated for the nighttime
sleep period. Generally, time to go to bed will be advanced (e.g., from 11 PM to 10:30 PM) and
time to get out of bed will be delayed (e.g., from 7 AM to 7:30 AM).
Daytime napping Naps of different lengths (generally 30 min to ⱕ2 h) are scheduled during the daytime period to
increase sleep duration across the 24-h day.
Disk-over-water method Developed by Rechtschaffen and Bergmann in 1989 to induce sleep deprivation in rats. An
experimental animal and a yoked control animal are housed on opposite sides of a divided disk
suspended over water. Whenever the experimental animal falls asleep or reaches a specified
sleep stage (as defined by EEG measures), the disk starts to rotate, forcing the animal to move to
avoid falling into the water. The yoked control animal is allowed to sleep ad libitum, while
experiencing the same amount of physical stimulation. This method can be used for total sleep
deprivation or for deprivation of specific sleep stages, typically REM sleep.
Continued

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 THE SLEEP-IMMUNE CROSSTALK

Table 1.—Continued
Single platform technique Originally developed for cats and later adapted for rats, this method involves the placement of the
experimental animal on a small platform that is surrounded by water. Whenever REM sleep
occurs, the animal partly or entirely falls into the water due to the muscle atonia occurring during
REM sleep. Besides suppressing REM sleep, this method also suppresses SWS to a certain
extent. The severe movement restriction, contact with water, and social isolation are factors that
might induce a certain degree of stress in the exposed animals.
Multiple platform technique Modification of the single platform technique including several platforms to limit the substantial
movement restriction of the single platform technique. To reduce social isolation, in a modified
version of this method, several animals are placed together in large tanks. This method has been
also adapted for experiments in mice.
Gentle handling techniques Animals are kept awake by receiving gentle physical stimulation by the experimenter (e.g., by gentle
touching, cage tapping, cage movement, or exposure to novel objects). This method is typically
used for shorter sleep deprivation protocols. It is suggested to be the least stressful method for
depriving animals of sleep in the short term. However, longer periods of sleep deprivation are
difficult to induce with this method because the handling by an experimenter is labor intensive and
because it becomes increasingly difficult to keep animals awake over time.
Genetic modifications of sleep Specific genetic modifications lead to a reduction or an increase of spontaneous sleep duration.
duration This method is mainly used in Drosophila models.

ing sleep in the laboratory. In addition to EEG, EMG, and the unspecific, natural, innate immune system such as
EOG, PSG often includes measurements of heart rate, granulocytes (neutrophils, eosinophils, or basophils that
breathing functions, and blood oxygen saturation, espe- develop into tissue mast cells), blood monocytes that
cially in the clinical setting. Portable PSG devices allow the develop into tissue macrophages [e.g., Langerhans cells
recording of sleep in the natural home environment. Actig- in the skin, microglia-like macrophages in the brain
raphy, the most common method for recording over periods (586)], dendritic cells (DCs), and unspecific lymphocytes
of multiple days or weeks, employs an activity monitoring such as natural killer (NK) cells; 2) cells of the specific,
device (usually worn on the wrist) that estimates basic sleep acquired, adaptive immune system, which either develop
parameters, such as sleep duration, sleep onset latency, and in the bone marrow (B lymphocytes or B cells) or in the
sleep fragmentation. To date, sleep stages cannot be differ- thymus (T lymphocytes or T cells), and express unique
entiated using this method, and it is difficult to discriminate receptors [B cell receptor, T cell receptor (TCR)] that
between sleep and immobility during wakefulness. How- recognize a specific antigenic peptide. Leukocytes origi-
ever, actigraphy is practical for long-term recordings in the nate, develop, and interact in primary (bone marrow,
natural environment and provides an estimate of habitual thymus) and secondary (lymph nodes, spleen, mucosa
sleep duration and day-to-day variability of various sleep associated lymphatic tissue) lymphoid organs, and traffic
parameters. A number of sleep parameters, such as sleep among these lymphoid organs and tissues throughout the
duration, sleep onset latency, WASO, number of nocturnal body via the bloodstream and lymphatic vessels. They
awakenings, as well as sleep quality (e.g., how refreshed do communicate with each other and other non-immune
you feel this morning?) can also be assessed subjectively cells via soluble mediators (cytokines, chemokines, shed
using diaries administered in electronic or paper form daily surface molecules, vesicles, etc.) and direct cell-to-cell
over a week or longer, or with standard questionnaires, contact (involving surface molecules). Their defense
such as the Pittsburgh Sleep Quality Index (PSQI) (87), mechanisms can be classified into humoral (soluble me-
which asks participants to report on their sleep habits in the
diators) and cellular immunity (phagocytosis, cytotoxic-
past month. However, subjectively and objectively assessed
ity) and involve multiple escalation levels with increasing
sleep parameters can differ substantially (26, 327), which
specificity.
must be considered when evaluating sleep.
At the body’s inner and outer surfaces, mucosal and skin
B. Cells, Mediators, and Tissues Involved in epithelia are physical barriers protected by antimicrobial
Host Defense peptides, and complement factors that can also be produced
by non-immune cells. If a pathogen nevertheless manages to
The immune system is our body’s defense system, which invade the body by breaking these barriers, tissue resident
detects and eliminates internal and external threats. It is macrophages or DCs recognize the challenge with pattern
distributed throughout the body, and its cells, termed recognition receptors (PRRs), which are specialized innate
leukocytes or white blood cells (WBCs), are classified immune sensors that are encoded in the germline. PRRs
according to their ontogenetic origin, structural charac- detect “non-self” conserved pathogen-associated molecular
teristics, surface markers, functions, and level of specific- patterns (PAMPs) from microbes like bacteria or viruses
ity. They are divided into two broad categories: 1) cells of [e.g., bacterial lipopolysaccharide (LPS); viral double-

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 BESEDOVSKY ET AL.

stranded ribonucleic acid (RNA)] or endogenous danger/ swelling, heat, and pain (rubor et tumor cum calore et
damage-associated molecular patterns (DAMPs), which are dolore). They were first described by Celsus in the 1st
released by stressed or injured cells [e.g., heat-shock pro- century. Much later, in the 19th century, Virchow added
teins (HSPs)] (51, 113, 368). PRRs in turn activate inflam- the fifth cardinal sign of inflammation, i.e., loss of func-
matory signaling pathways like the inflammasome or tion (function laesa), referring to the restricted function
NF-␬B followed by the release of acute phase cytokines such of inflamed tissue (reviewed in Ref. 354). The typical
as IL-1, IL-6, and TNF, of interferons (IFNs) with anti-viral inflammatory response is triggered by a local infection or
activity, of vasoactive mediators like prostaglandins (PGs), tissue injury, involving PAMPs and DAMPs, and is tra-
and of chemokines that attract further leukocytes (che- ditionally thought of as a protective reaction that defends
motaxis). Locally, these processes result in the clinical signs and restores physiological functions (111, 296). The in-
of inflammation (redness, swelling, warming, pain, im- flammatory mediators involved in this response are cyto-
paired function) and prompt innate defense mechanisms of kines, chemokines, vasoactive amines, and PGs, which
phagocytosis or the release of antimicrobial substances that induce a variety of local biological processes (e.g., re-
destroy the pathogen [e.g., reactive oxygen species (ROS)] cruitment of neutrophils from the circulation to tissues at
(368, 378). Systemically, this acute phase response prompts the site of infection/injury, vascular changes) with the
central nervous symptoms like fever and sickness behavior goal of restoring homeostasis (378). In some cases, these
(see sects. ID and IIA). inflammatory mediators may become detectable in the
circulation and may act systemically (e.g., induce fever).
If the microbe evades this first line of defense, the adap-
tive immune system, consisting of T and B cells, can The function of restoring homeostasis can get lost if in-
provide tailored, specific responses that are initiated in flammation persists. In the past few decades, conditions
secondary lymphatic tissues but take several days to characterized by mild systemic elevations of inflamma-
emerge. First, antigen-presenting cells (APCs) like DCs tory markers have drastically increased, including obe-
take up the antigen in tissues and migrate to secondary sity, type 2 diabetes, cardiovascular diseases, asthma,
lymphoid organs like the lymph nodes. There, they pres- some chronic pain conditions, some forms of cancer, and
ent the antigenic peptide together with the major histocom- neurodegenerative diseases. Furthermore, increases of in-
patibility complex (MHC) II (peptide-MCHII, pMHCII) on flammatory markers accompany the process of aging, a
their surface to naive CD4 T cells. This activates antigen-spe- phenomenon termed inflammaging (96, 197). In these
cific CD4 T cells (i.e., those cells with the matching TCR for conditions, elevations of inflammatory markers are of
the specific antigen), which then proliferate and differenti-
low magnitude and the cardinal signs of local inflamma-
ate into specialized effector CD4 T-helper (Th) cells (e.g.,
tion are generally absent. Such mild and often chronic
Th1, Th2, Th17). These cells in turn help macrophages,
elevations are most frequently referred to as low-grade
CD8 T cells, and B cells eliminate the pathogen. Cytotoxic
inflammation; sometimes terms such as unresolved, ster-
CD8 T cells recognize pMHCI (e.g., on virus-infected cells)
ile, meta-, sub-, or para-inflammation have been used. To
and kill the target cell by releasing cytotoxins (perforin,
assess low-grade inflammation, various measures usually
granzyme, granulosin). Activated B cells develop into
associated with the innate immune system have been uti-
plasma cells producing antibodies (immunoglobulins, Ig)
lized, including C-reactive protein (CRP), IL-6, WBC
that can specifically neutralize soluble antigens or mark
counts, neutrophil counts, and platelet counts. The mag-
cell-bound antigens for elimination. Depending on the type
nitude of the response may be defined as a two- to three-
of infection and the pattern of PAMPs and DAMPs, APCs
fold elevation of such markers (297, 437). However,
release certain cytokines, thereby determining CD4 T cell
there is currently no consistent definition. Furthermore,
lineage commitment and eventually the class of antibodies
[in humans, e.g., intracellular (viral and bacterial) infection: the inducers of low-grade inflammation are not well un-
type I IFNs/IL-12, Th1, IgG1, IgG3; helminth infection: derstood. They do not appear to involve the classical
IL-4, Th2, IgG4, IgE; fungal infection: IL-23, Th17], hall- inducers of the typical inflammatory response [i.e., infec-
marking the close interplay between the innate and adaptive tion or tissue injury (377)], but rather cellular stress or
arm of the immune system (266, 368, 566). After elimina- malfunction that leads to activation of PRRs by the re-
tion of the pathogen in the effector phase, most activated lease of DAMPs (e.g., HSPs) (68, 100). Additional induc-
antigen-specific B and T cells die, but some persist as mem- ers of low-grade inflammation are nutrients and metab-
ory cells that allow a faster and more efficient response olites acting as DAMPs (e.g., free fatty acids, oxidized
upon re-encounter of the antigen, and therefore represent lipoproteins) and commensal bacteria representing a
immunological memory (181, 395, 577) (FIGURE 3). source of PAMPs [sometimes also described with the
more global term microbe-associated molecular patterns
(MAMPs), as they are not necessarily pathogenic] (189,
C. Low-Grade Inflammation
240, 244, 295, 329, 347). Important ramifications of
As mentioned in the previous section, the four cardinal low-grade inflammation are insulin resistance, endothe-
signs of the typical inflammatory response are redness, lial dysfunction, atherosclerosis, and neuroinflammation

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 THE SLEEP-IMMUNE CROSSTALK

Defense system Cells and tissues Mechanisms (selected)

First line of defense Physical barriers

Anti-microbial peptides
Complement factors

Epithelium
Innate immunity NK cell Phagocytosis
Neutrophil Acute phase response
(cytokines, chemokines, prostaglandins, fever)
Inflammation
Cytotoxicity

Dendritic
cell Monocyte
pMHC
pMHC

Effector T cell Antigen presentation

TCR
Adaptive immunity T and B cell activation
Effector T and B cells, Antibodies
Antibody-secreting Plasma cells, Memory B and T cells
Naïve T cell (Immunological memory)
Antigen
exposure
Secondary immune
Antibodies B cell response (memory)
Primary immune
response
Plasma cell

FIGURE 3. Major components of the immune system, a prototypical immune response to an infectious
challenge, and immunological memory. The first line of defense against an infectious challenge are physical
barriers and antimicrobial peptides. If a pathogen manages to pass these barriers, the innate immune system
is activated. It includes phagocytotic and cytotoxic responses of leukocytes like neutrophils and natural killer
cells (NK cells). If the pathogen cannot be cleared, the adaptive immune system becomes involved. Antigen-
presenting cells (APCs, such as dendritic cells) present fragments of the pathogen (consisting of peptides)
together with the major histocompatibility complex II (peptide-MHCII, pMHCII) to naive T cells. Those T cells with
the matching T cell receptor (TCR) for the specific antigen then differentiate into effector T cells. Together with
antigen-specific memory T and B cells, antigen-specific antibodies constitute the basis of immunological
memory. Whereas the primary adaptive immune response to a pathogen takes several days to develop, the
secondary (memory) response develops much faster and is more efficient (bottom right). The borders between
the first line of defense, the innate immune response, and the adaptive immune response are fluid.

(109, 244, 336, 485, 572), as well as immunodeficiency stimuli, generate appropriate responses, and commit this
due to impaired DC, T, and B cell functions (80, 199, knowledge to memory such that the organism is prepared
422), which in turn can promote failure of tumor and for stimulus re-encounter and continuously adapts to its
pathogen defense (123, 426) (reviewed in Ref. 198). As environment. In performing these tasks, the two systems
will be summarized in section IV, sleep deficiency, either closely interact: an acute mental or physical stressor that
in the form of short sleep duration or sleep disturbance, primarily activates systems under CNS control, i.e., the neu-
appears to be one behavioral trigger of low-grade inflam- roendocrine hypothalamus-pituitary-adrenal (HPA) axis
mation and associated diseases. and the autonomic nervous system (ANS), will also induce
an inflammatory response (52, 525). On the other hand, a
D. Basic Mechanisms of Neuro-immune microbial challenge that primarily activates the immune
Interactions system will also prompt neurobehavioral, neuroendocrine,
and ANS responses (42, 132). A reasonable interpretation
The central nervous system (CNS) and the immune system of the first phenomenon is the idea that in ancestral times
are the two super-systems that can sense environmental any kind of stressor (e.g., facing a predator or a conspecific

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 BESEDOVSKY ET AL.

enemy) also challenged the body’s integrity and that the by immune cells and act on neurons, astrocytes, and micro-
immediate activation of the immune system along with glia of the peripheral nervous system (PNS) or the CNS via
the freeze, fight, or flight response (which is initiated by the respective receptors. These chemicals and other inflamma-
ANS) helped to ward off pathogens invading the wound tory agents like PGs, PAMPs, and DAMPs can reach the
and to initiate the healing process (383). The second phe- PNS or CNS by crossing the blood-brain barrier via trans-
nomenon reflects the concept of the immune system being porter systems or at leaky sites of circumventricular organs.
our sixth sense that recognizes stimuli that we otherwise Alternative routes of immune-to-brain signaling are immu-
cannot see, hear, taste, touch, or smell and signals this in- nomediators that can activate vagal and other neural affer-
formation to the brain (56, 58). To optimize ensuing de- ents, as well as cerebral endothelial and perivascular cells or
fense mechanisms, the CNS in turn generates a set of mea- the directed traffic of leukocytes to the brain (70, 503, 523,
surable changes in body functions and behavior, such as 586). All these pathways may induce microglial activation
fever, activation of neuroendocrine axes and the ANS, as and neuroinflammation in response to peripheral inflam-
well as sickness behavior, which is characterized by inactiv- mation, thereby initiating CNS responses including fever
ity, fatigue, sleep alterations, anhedonia, reduced respon- and sickness behavior (486, 493). Autoreactive T and B
siveness to external stimuli, social withdrawal, anorexia, cells add an additional level of complexity, as they can
adipsia, and increased pain sensitivity (130, 372). regulate inflammatory processes in the brain (291, 499) and
might represent a reflection of “our self,” the “immuncu-
Research in the interdisciplinary field of (psycho)neuroim- lus,” to restore homeostasis of tissues and organs (441).
munology elucidated anatomic and molecular mechanisms Neurons, glia cells, and nerve fibers themselves can synthe-
underlying these bidirectional brain-immune interactions size cytokines and chemokines, demonstrating a further
that were summarized in comprehensive reviews in previ- pathway of brain-to-immune signaling (70, 592). In sum,
ous issues of Physiological Reviews (57, 129, 350, 549). the outlined results show that there is a common biochem-
Therefore, we will only briefly outline basic principles of ical language for intra- and intersystem communication be-
this crosstalk. The CNS and the immune system are linked tween the CNS and the immune system, and the classifica-
by nerve fibers, soluble mediators, and leukocyte traffic to tion into neurotransmitters, neuropeptides, hormones, and
the brain and the spinal cord. Primary and secondary lym- immunomediators is based on the chronology of their dis-
phoid organs are innervated by sympathetic, peptidergic, covery rather than on the unique assignment to a system.
and sensory nerve fibers (182). Numerous neurotransmit-
ters and neuropeptides of efferent nerves (like cat- The final outcomes of these brain-to-immune or immune-
echolamines or neuropeptide Y) can be recognized by to-brain signaling pathways are determined by the specific
matching receptors on immune cells, and leukocytes them- experimental setup employed to measure the neuro-im-
selves can synthesize and release these neuronal messengers mune interactions of interest. For example, activation of the
(e.g., Refs. 190, 414, 436). The cholinergic innervation of classical HPA and ANS stress axes can support or suppress
immune organs is still a matter of debate (206, 400), yet a inflammatory and adaptive immune responses in human
non-neuronal cholinergic system in T cells can locally pro- and animal models, depending, among other factors, on
vide acetylcholine release in the periphery (99, 203). Apart whether it occurs before or after the immunological chal-
from lymphoid organs, tissue-resident leukocytes like mac- lenge (274, 371, 474). Some neurotransmitters, neuropep-
rophages can directly sense neurotransmitters and neuro- tides, and hormones can therefore not be classified in gen-
peptides that are released by local nerve endings (414). In eral as either immunosuppressive or immunosupportive,
contrast to this fast communication pathway through nerve but rather act in one or the other way depending on the
fibers, the neuroendocrine axes provide an additional, specific situation. The general picture suggests that the bi-
somewhat slower control of the immune system. Leuko- directional brain-immune crosstalk serves to fine-tune the
cytes can sense and synthesize a plethora of neuroendocrine immune response that is normally characterized by four Rs:
mediators of the hypothalamic, pituitary, and glandular recognition, response, regulation, and resolution. Recogni-
level [e.g., corticotropin releasing hormone, adrenocortico- tion and response take place during the early immediate
tropic hormone, cortisol; growth hormone releasing hor- pro-inflammatory phase that is supported by actions of the
mone, growth hormone (GH), insulin-like growth factor-1; stress axes, such as priming of immune cells and inflamma-
dopamine, prolactin] and can even form an own, local neu- tion, and mobilization of energy substrates to fuel the im-
roendocrine axis in an autocrine and paracrine manner mune system (86, 288, 528). Regulation and resolution re-
(e.g., Refs. 39, 155, 401, 414, 576). fer to subsequent counter-inflammatory measures that limit
the inflammatory process in time and space. During this
The capability of leukocytes to produce neurotransmitters, phase, the immune system has two levels of regulation. At
neuropeptides, and hormones allows them to signal to the one level, the immune system monitors itself by various
brain via afferent nerve fibers and the bloodstream. Further intrinsic control mechanisms and pro-resolving mediators
mediators of immune-to-brain signaling are immunopep- [e.g., regulatory T cells (Treg), indoleamine 2,3-dioxyge-
tides including cytokines and chemokines that are produced nase, M2 macrophages, IL-10, resolution-associated molec-

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 THE SLEEP-IMMUNE CROSSTALK

ular patterns (RAMPs), and specialized pro-resolving lipid the production of cytokines by macrophages (332). Over
mediators] (381, 483, 501, 507, 510). At the other level, the the following years, the role of cytokines (in particular IL-1
CNS exerts a superordinate extrinsic control through its and TNF) in homeostatic NREM sleep regulation has been
efferent pathways (i.e., HPA and ANS stress axes) (44, intensively studied in animals. To be considered a sleep
164). This balanced and coordinated control ensures a regulatory substance, administration of the substance
highly efficient, short-lasting, local immune response at low should increase sleep amount, whereas inhibiting the bio-
energy costs and with minimal collateral damage (139, logical action or production should result in a decrease of
526). spontaneous sleep, and the diurnal variations in the endog-
enous synthesis should parallel sleep-wake behavior (118).
II. THE SLEEP RESPONSE TO IMMUNE To investigate sleep-regulatory properties of cytokines, cy-
ACTIVATION tokine antagonists [e.g., IL-1 receptor antagonist (IL-1ra)
or anti-IL-1 antibody] have been used to prevent their bio-
logical actions. To summarize the findings, blocking the
A. Fever and Sickness Behavior biological actions of the cytokines IL-1 and TNF resulted in
a reduction of physiological NREM sleep amount or
As outlined above, acute infectious illnesses cause CNS re- NREM sleep rebound after sleep deprivation. On the other
sponses such as fever (230) and a set of common symptoms hand, increasing the availability of those cytokines pro-
of sickness, including fatigue, sleepiness, social withdrawal, moted NREM sleep amount and intensity and suppressed
negative mood (depression, anxiety), pain hypersensitivity, REM sleep amount. These findings established both cyto-
and decreased appetite (131). These changes are considered kines, IL-1 and TNF, as substances involved in the homeo-
adaptive responses of the CNS and presumably aid the re- static regulation of sleep (for review, see Refs. 299, 411). Of
covery from infections. For example, fatigue and sleepiness note, increased and intensified NREM and decreased REM
promote a less active behavioral state, thereby likely facili- sleep depend on several factors, such as time of day, route,
tating recovery from infection by conserving energy (560). and dose of administration. For example, in rats, NREM
Over the last 30 yr, it has been well established that fever sleep-increasing effects of IL-1 occur only within a small
and sickness behavior in response to infection or inflamma- dose-window: lower doses of IL-1 increase NREM sleep
tory diseases are mediated by inflammatory mediators, in- without inducing fever; higher doses of IL-1 accompanied
cluding cytokines and PGs that signal to the brain (131, by fever increase and fragment NREM but decrease REM
487). In the following, the role of these mediators in sleep sleep; and even higher doses decrease both (412) (as re-
modulation will be reviewed in the context of spontaneous, viewed in Ref. 300).
physiological sleep (sect. IIB), acute immune activation fol-
lowing infectious or inflammatory challenges (sect. IIC), Other cytokines, including IFN, IL-2, IL-4, IL-6, IL-10, IL-
and chronic immune activation related to infectious and 13, IL-15, and IL-18 also appear to have some sleep regu-
inflammatory diseases (sect. IID). latory properties. The anti-inflammatory cytokines IL-4, IL-
10, and IL-13 have been reported to attenuate NREM sleep
B. Inflammatory Mediators Involved in amount in rabbits (308, 314, 315), while the pro-inflamma-
Physiological Sleep Regulation tory acting cytokines IFN-␥, IL-2, IL-6, IL-15, and IL-18
have NREM sleep-promoting actions in animal models
1. Cytokines (238, 306, 307, 309). However, these cytokines have re-
ceived much less attention than IL-1 or TNF (411). Thus
The first discovery suggesting the existence of a central their role in physiological sleep regulation is much less clear.
sleep-promoting substance dates back to 1909, when Ishi- Overall, animal studies suggest that most pro-inflammatory
mori in Japan and Piéron in France reported that sleep in cytokines are NREM sleep promoting, while anti-inflam-
well-rested dogs can be induced by injecting cerebrospinal matory cytokines are NREM sleep reducing.
fluid (CSF) from sleep-deprived dogs (265, 333). These
early findings were supported by numerous follow-up stud- In humans, only very few studies have investigated the in-
ies using EEG recordings to objectively quantify sleep in volvement of cytokines in the regulation of physiological
various animal species (66). In parallel, scientists were sleep. Circulating levels of IL-1, TNF, and IL-6 have often
searching for a sleep-promoting substance in brain and been found to peak during sleep or in the early morning
body fluids. In 1975, Pappenheimer finally extracted a sub- hours (reviewed in Refs. 95, 321). Such findings may sug-
stance from the CSF and brain tissue of sleep-deprived an- gest the involvement of these cytokines in the regulation of
imals, which he called “factor S” (S stands for sleep pro- physiological sleep-wake behavior. Studies comparing the
moting) (424). Shortly afterwards, this factor was identified sleep period against a wake period at night clarify to what
as a muramyl peptide (304), which is produced during degree such diurnal variations are sleep-wake dependent or
phagocytosis of bacteria by macrophages (272). At that result from a circadian, sleep-independent process (see sect.
time, it was already known that muramyl peptides induce III). While there is clear evidence that administration of

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 BESEDOVSKY ET AL.

cytokines (in particular IFNs and IL-2) to patients suffering dents, as a potent, sleep-promoting substance in rats and
from various forms of cancer, multiple sclerosis, rheuma- mice (reviewed in Refs. 246, 551). Infusion of PGD2 into
toid arthritis (RA), human immunodeficiency virus (HIV), the intracerebroventricular (ICV) (particularly the sub-
or hepatitis may result in increased subjective sleepiness and arachnoid) space in rats induced substantial increases of
other sickness behavior symptoms, changes in objectively NREM sleep (252, 366). Inhibition of PG production by
assessed sleep in these patients have not been studied (4, COX-2 inhibitors reduced spontaneous and TNF-induced
382). Administration of IFN-␣ (520) or IL-2 (324) in increases in NREM sleep in the animal model (538, 595),
healthy participants did not change PSG-derived sleep pa- supporting the role of PGs in sleep modulation. Further-
rameters the following night. With respect to the cytokine more, moderate sleep deprivation caused an increase in CSF
IL-6, subcutaneous administration before sleep initiation in levels of PGD2, E2, and F2␣ in rats (455). Such upregulation
healthy participants resulted in a delayed REM sleep la- of various PGs suggests that sleep loss may target COX
tency and reduced REM sleep amount, without a change in enzymes, the precursor of all functional PGs, rather than a
total NREM sleep amount (519). Intranasal administration specific PG.
of IL-6 in healthy participants, however, intensified SWS in
the second half of the night (increased SWA), although no In humans, PGs have rarely been studied in the context of
overall changes in the amount of NREM sleep were ob- sleep. This may relate to difficulties in the reliable assess-
served (36). A reduction of SWS amount and intensity has ment of PGs in the blood, given the short half-life and rapid
been observed in the beginning of the night following ad- metabolization of PGs (498). However, precursors (e.g.,
ministration of granulocyte colony-stimulating factor, synthases) or metabolic products of PG appear to be more
which in parallel led to an increase of the plasma levels of biologically stable and therefore provide a reliable estimate
endogenous antagonists of IL-1 and TNF, i.e., IL-1ra and of PG production. In healthy participants, serum concen-
soluble TNF receptors, respectively (497). These findings trations of lipocalin-type PGD synthase, which catalyzes
suggest the involvement of IL-1 and TNF in the physiolog- the conversion from PGH2 to PGD2, have been reported to
ical regulation of sleep in humans. However, two recent vary throughout the day, with highest levels at night (sleep
studies in healthy participants revealed an increase, rather period) and lowest levels in the afternoon. Total sleep de-
than the expected decrease, in SWA following administra- privation blunted the nocturnal increase at night and ele-
tion of the anti-inflammatory drugs anakinra, an IL-1ra
vated levels during the daytime (275), suggesting a role of
(495), and minocycline (50), a tetracycline that among
PGD2 in human sleep physiology. With the use of a model
many other actions suppresses central nervous TNF pro-
of prolonged experimental sleep restriction of 10 days, a
duction (210). These human findings contrast with studies
nonsignificant increase of PGD2 and PGE2 metabolites of
in animals showing that pro-inflammatory, rather than anti-
~20% has been reported in healthy participants (223),
inflammatory, activity enhances sleep. Such discrepancies
while total sleep deprivation of 3 days produced increases of
highlight the need to further investigate the role of pro- and
PGE2 of almost 30% when compared with control sleepers
anti-inflammatory activities in human models, as their sleep
(221). A few studies have also addressed whether inhibition
modulatory effects may differ from those observed in animal
of PG production through NSAIDs affected sleep. Indeed,
models.
acute administration of aspirin at the recommended daily
2. Prostaglandins dose range in healthy participants disrupted sleep (i.e., de-
creased sleep efficiency, increased number of awakenings)
Sleep regulatory effects have also been reported for PGs. (398) and decreased SWS (241). Acute administration of
PGs are lipid mediators that are synthesized de novo from ibuprofen, in addition to its sleep disrupting effect, also led
the omega-6 fatty acid arachidonic acid through actions of to a delay of SWS (398). While these findings suggest the
cyclooxygenase (COX)-1 and COX-2 enzymes and specific involvement of the PG system in human sleep physiology,
synthases. PGs mediate some of the cardinal symptoms of the exact mechanisms and PGs involved remain unknown.
inflammation, such as fever and pain. Their involvement in The effects of chronic administration of NSAIDs on sleep
the production of such symptoms is demonstrated by the are also unknown. Given that a large proportion of the
therapeutic effects of nonsteroidal anti-inflammatory drugs population uses NSAIDs on a regular basis (135), future
(NSAIDs), e.g., ibuprofen or acetylsalicylic acid (aspirin), research may address the long-term effects on sleep physi-
which primarily prevent the synthesis of PGs through inhi- ology. In addition, in light of more recent findings that the
bition of COX enzymes (558). More recently, the PG sys- PG system not only promotes inflammation, but also plays
tem has also been shown to play a critical role in the reso- an essential role in resolving inflammation (502), blocking
lution of inflammation (502, 531) and therefore may also this system through NSAIDs may contribute to ongoing,
contribute to unresolved or chronic low-grade inflamma- unresolved inflammation in response to sleep deficiency.
tion if dysregulated. Thus further investigations of the PG system may be of
critical importance in elucidating mechanisms underlying
In the 1980s, work by Hayaishi and colleagues identified the association between sleep deficiency and low-grade in-
PGD2, the most abundant prostanoid in the brain of ro- flammation in humans, which is described in section IV.

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 THE SLEEP-IMMUNE CROSSTALK

3. Upstream signals of sleep regulatory substances involved in physiological REM sleep regulation (250, 551).
Other substances, such as IL-6, have received much less
A muramyl peptide was identified as the upstream signal of attention, and their role in sleep regulation is therefore less
sleep regulatory substances, in particular IL-1 and TNF understood. PAMPs, DAMPs, and respective PRRs may
(304). Although it is still unknown why muramyl peptides form a mechanism underlying the release of sleep-regula-
increase during sleep deprivation, it was assumed that com- tory substances; however, further investigations are war-
mensal gut bacteria contribute to their systemic release ranted on this topic. See FIGURE 4 for a conceptual sum-
(304). This notion is supported by animal studies showing mary. During an infectious challenge, increases in NREM
reduced NREM sleep in rats treated with antibiotics target- sleep amount or intensity (i.e., increased SWA) and de-
ing gut bacteria (74) and of altered sleep in rats and mice creases in REM sleep amount (353) have been observed. As
following the dietary supplementation of commensals (385, outlined in the next section, the release of IL-1 and TNF
542). Furthermore, recent data support a key role of gut appear to be key mediators of this effect. It is worth men-
microbiota and corresponding microbiota-derived PAMPs tioning that a number of other factors are involved in the
in central nervous processes like mood, cognition, pain, and regulation of sleep and may interact with the immune sys-
eating behavior in animals, and there is also first evidence tem to promote or inhibit sleep. These include, among oth-
for such a relationship in humans (85, 150, 151, 394). It is ers, hormones of the HPA and the somatotropic axes; neu-
tempting to speculate that increases in systemic levels of mi- rotransmitters such as acetylcholine, serotonin, norepi-
crobiota-derived PAMPs and inflammatory mediators follow- nephrine, histamine, and dopamine; neuropeptides such as
ing food intake likewise mediate post-prandial sleep changes orexin; the nucleoside adenosine; and the hormone melato-
(415, 599). Apart from microbiota-derived PAMPs, low levels nin. The interested reader is referred to Reference 76 for a
of PAMPs that are recognized during the daily, asymptomatic comprehensive review on sleep regulation.
confrontation of our immune system with numerous infec-
tious bacteria, viruses, or fungi could trigger subtle increases
in systemic cytokine and PG levels. Finally, DAMPs are C. Sleep Response to Acute Immune
released into the extracellular space not only during cell Activation Following an Infectious or
damage, but also during regular cellular activity. For exam- Inflammatory Challenge
ple, they increase in the brain during synaptic firing (305)
and in the periphery during acute mental (52, 273) or phys- One-hundred years ago, during World War I, the neurolo-
ical stress (13). Furthermore, in humans, DAMPs increase gist Constantin Freiherr von Economo described for the
in the brain (509), CSF (410), and blood (35) following first time the disease “encephalitis lethargica” (568), which
acute sleep deprivation. Conceivably any interaction of an spread across the world from ~1916 into the 1930s and was
organism with the environment, including learning, stress, frequently characterized by pathologically increased sleep.
social contacts, physical activity, and food intake, prompts Von Economo initially assumed that an infectious virus and
the release of PAMPs and/or DAMPs (FIGURE 4). They can related inflammatory processes were the cause of Encepha-
activate the immune system through binding to respective litis Lethargica. This was supported by findings showing
PRRs, which likely leads to systemic increases of sleep reg- that the disease could be transmitted via brain tissue from a
ulatory substances, such as TNF and IL-1 (303, 305). These deceased patient to a monkey (569). Although the majority
substances appear to keep track of the organisms’ prior of recent findings deputed the infectious disease hypothesis
activity and, upon reaching a certain threshold, contribute (reviewed in Ref. 40), the idea that an infection per se can
to the induction of sleepiness and eventually NREM sleep. alter sleep behavior found support in later studies in hu-
This view may help to explain findings of inflammatory mans and animals.
responses (18) and sleep changes, such as an increase in
NREM sleep amount (2, 555) observed in laboratory ani- Starting in the 1980s, the sleep response to infectious
mals housed in enriched or novel environments. However, challenges has been intensively studied in animal models,
the causal link between immune and sleep responses in the including rats, rabbits, mice, and, more recently, flies.
context of enriched environments still needs to be estab- Substantial evidence has accumulated over the last de-
lished in future research. The involvement of PRRs in this cades supporting the view that pathogens, including bac-
“use-dependent” NREM sleep induction (305) is supported teria, viruses, fungi, and parasites increase the amount
by findings in mice devoid of two important classes of PRR: and intensity of NREM sleep while decreasing the
the Toll-like receptors (TLRs) (585) and the nucleotide- amount of REM sleep (for comprehensive review, see
binding oligomerization domain-like receptors (Nod-like Refs. 299, 353). Of note, pathogen-induced effects on
receptors, NLRs) (605). NREM and REM sleep amount and intensity are com-
plex and depend on the pathogen structure, the dose
Collectively, there is ample evidence that IL-1 and TNF, administered, and time of day of administration. In ad-
in particular, and PGD2, play a critical role in the regu- dition, a biphasic time course of changes in NREM and
lation of physiological, spontaneous NREM sleep in ani- REM sleep amount has been reported after inoculation
mals, and potentially in humans, while they may not be with bacteria (Staphylococcus aureus) in rabbits (544)

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 BESEDOVSKY ET AL.

Sleep

NREM NREM NREM

REM REM

Sleep
regulatory
substances:
IL-1
TNF
PGD2

PRRs

DAMPs/PAMPs

Stress

Environmental stimuli Commensals Pathogens

FIGURE 4. Conceptual model of sleep changes in response to immune activation and underlying mech-
anisms. Environmental stimuli (e.g., food intake, stress), commensal bacteria, and infectious pathogens
(here illustrated as viruses) are recognized by the immune system as damage- and pathogen-associated
molecular patterns (DAMPs and PAMPs, green stars), which activate pattern recognition receptors
(PRRs, orange polygon) on innate leukocytes. This PRR activation induces an inflammatory response with
the production of sleep regulatory substances, such as interleukin (IL)-1 and tumor necrosis factor (TNF)
(both represented by orange dots), which reach the brain and promote non-rapid-eye-movement (NREM)
sleep (left arrow). In higher doses (e.g., during an infection; middle arrow), these sleep regulatory
substances may also suppress rapid-eye-movement (REM) sleep. Prostaglandin (PG) D2 is shown as a
potential further mediator of sleep changes in response to immune activation. These sleep responses to
immune activation are assumed to be adaptive. Subtle immune activation may be involved in homeostatic
NREM sleep regulation that in turn could serve to restore immune homeostasis. More pronounced
immune activation during an infection can induce a sleep response that in turn may support host defense
and immunological memory formation. However, an extreme immune activation (e.g., during severe
infection; right arrow) seems to disrupt both NREM and REM sleep, often accompanied by sleep fragmen-
tation, feelings of nonrestorative sleep, and daytime fatigue. Notably, most of our knowledge is based on
animal research, and confirmation in humans is still needed.

and bacterial cell wall components (endotoxin) in rats pathways like the transcription factor NF-␬B and inflam-
(318), such that the initial increase in NREM and sup- masomes, all of which are known to induce cytokines and
pression in REM sleep were reversed at later time points. PGs (301, 352, 605). As reviewed in section IIB, IL-1 and
Detection of such a biphasic pattern of NREM and REM TNF are key mediators of sleep-wake alterations and exert
sleep require long EEG recording times (e.g., up to 48 h) their NREM sleep-enhancing and intensifying effects also
and suggest a counterregulatory response to the initial during an infectious challenge. Using knockout mice for
sleep changes induced by pathogens. various PG receptors and the COX inhibitor meloxicam, a
recent study concluded that the LPS-mediated increases in
The mediators underlying this sleep-modulating effect are NREM sleep are only partially dependent on PGs (407),
components and/or decomposition products of these patho- corroborating the view that the sleep response to an infec-
gens, including PAMPs such as endotoxins (e.g., LPS), lipid tion is mainly triggered by IL-1 and TNF. Given that in-
A, muramyl peptides, viral double-stranded RNA, respec- creases in core body temperature can promote NREM sleep
tive PRRs like TLRs and NLRs, as well as downstream (488), it is important to note that the infection-driven

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 THE SLEEP-IMMUNE CROSSTALK

NREM sleep response is independent from the fever re- such as headache, muscle pain, and nausea. These endotox-
sponse (303). in-induced responses return to baseline after 8 to 12 h (for
comprehensive reviews, see Refs. 443, 493). Collectively,
Due to ethical reasons, there are only a few research studies these studies have shown that in humans, NREM sleep
where live pathogens have been administered to humans. enhancing or intensifying effects are restricted to times of
Smith and colleagues found in a series of experiments in the very mild host response activation, whereas stronger re-
late 1980s that experimentally induced influenza A and B sponses characterized by large cytokine increases and fever
and rhinovirus-induced common colds in healthy partici- caused sleep disruption (224, 396, 442).
pants led to an increase of self-reported sleep duration in the
symptomatic phase of the illness (517). Interestingly, In summary, findings in both animals and humans show
changes in self-reported sleep duration were also evident in that pathogens or their components are able to alter
the incubation phase of the illness, before symptom devel- sleep. Observations of enhanced or intensified sleep in
opment (for review, see Ref. 517). In the only study that, to response to acute infectious challenges have led to the
our knowledge, recorded sleep using PSG in this context, hypothesis that sleep is beneficial for host defense mech-
rhinovirus-type-23-induced common colds disrupted sleep anisms and/or host recovery. Findings by Toth et al.
in symptomatic individuals, as evidenced by reduced total (546) support this hypothesis. They reported that rabbits
sleep time and reduced sleep efficiency in the active phase of inoculated with Escherichia coli bacteria had less mor-
the illness (158). bidity and mortality when NREM sleep was enhanced in
response to the infectious challenge. A potential explana-
Most human studies investigating the role of sleep in host tion for this immune-supportive effect is that sleep may
defense mechanisms have employed experimental models of facilitate energy allocation to the immune system (496).
acute infections with well-characterized host responses, In contrast to the infection-driven increase in NREM
such as those induced by vaccines and bacterial endotoxins. sleep duration and intensity, animal and human studies
While most vaccination studies have examined the effects of have repeatedly shown a concomitant suppression of
naturally occurring or experimentally induced sleep loss on REM sleep. As REM sleep is incompatible with thermo-
immunological responses (reviewed in sect. IIIB), studies regulatory effector responses like shivering, REM sleep
investigating alterations of sleep itself in response to vacci-
suppression may promote the generation of fever that in
nation are rare. Salmonella typhi (typhoid) vaccination ad-
turn boosts immunity (250). In humans, the hypothesis
ministered in the late afternoon in healthy participants led
of a beneficial effect of sleep on host defense mechanisms
to a mild inflammatory response with elevated IL-6 levels 2
has been mostly studied in the context of sleep loss, either
h post-vaccination, and while well tolerated, PSG assessed
naturally occurring or experimentally induced. These
sleep in the night following vaccination was characterized
studies, together with respective animal experiments, will
by sleep disturbances (e.g., increased number of nighttime
be reviewed in section III, with a major focus on studies
awakenings) compared with those who received a placebo
using experimental modulation of sleep.
injection (505). 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 D. Sleep Changes During Chronic Immune
in the night following the vaccination, but there was no
Activation Related to Infectious or
comparison of sleep data to a placebo-vaccinated control
Inflammatory Diseases
group in these studies. However, specific sleep parameters,
such as SWS intensity, were predictive of the magnitude of
the antibody response (320). Thus intensity of SWS may While most investigations in this area have reported on
play a critical role in the optimal formation of an antigen- prevalence rates of sleep disturbances or focused on the
specific immune response (see sect. IIIB). In the 1990s, characterization of the sleep-wake profile, studies specifi-
Pollmächer and colleagues performed a series of experi- cally linking observed sleep changes to immunopathology
ments on the effects of low-dose endotoxin challenge on are still rare. In the following, a number of chronic infec-
sleep in humans (e.g., Refs. 224, 396, 442). Endotoxins are tious and inflammatory diseases will be reviewed to exem-
the major cell wall component of gram-negative bacteria plify the variety of self-reported and objective sleep changes
and important PAMPs that activate the innate immune sys- observed among different diseases, and to report on the
tem during the initial phase of bacterial infection through relationship between sleep changes and immunopathology.
TLRs. When injected intravenously, endotoxin induces a We here mainly focus on human diseases, as the relation-
host response that includes increases in TNF and TNF re- ship between sleep and immunopathology has been less
ceptors within the first hour of injection; increases in IL-6, frequently addressed in animal models, and for some
IL-10, IL-1ra, and other cytokines; and increases in leuko- chronic infectious or inflammatory diseases, animal models
cytes, GH, cortisol, body temperature, and heart rate. It do not exist, such as for myalgic encephalomyelitis/chronic
also dose-dependently leads to flulike sickness symptoms fatigue syndrome (ME/CFS).

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 BESEDOVSKY ET AL.

1. Chronic infectious diseases suggesting that the PGD2 system contributes to hypersom-
nia in HAT (435). In the rat model of HAT, it has been
With respect to HIV infection, two recent systematic re- reported that sleep alterations, including circadian sleep-
views revealed a prevalence rate of self-reported sleep dis- wake disruption, sleep fragmentation, and decreased REM
turbances of ~60% in people living with HIV, which is sleep latency, start early after infection and become increas-
much higher than the prevalence rate of 10% in the general ingly severe at the time of neuroinvasion of the parasite
population (97, 591). Based on objective polysomno- (170).
graphic assessment, sleep structure changes existed during
the early asymptomatic stage of the disease, characterized Sleep disturbances are also commonly observed in chronic
by a robust increase in SWS in particular during the latter infection with the hepatitis C virus (HCV), with more than
part of the sleep period. In the advanced stages of HIV 50% of patients reporting fatigue, daytime sleepiness, and
infection, typical PSG findings were sleep disruption with poor sleep quality (reviewed in Ref. 388). Based on objec-
frequent nighttime awakenings and arousals, resulting in tive sleep assessment using actigraphy, increased nocturnal
low sleep efficiency (reviewed in Ref. 134). Inflammatory wake time and reduced sleep efficiency have been found in
cytokines (e.g., IL-1 and TNF) appear to be likely candi- women infected with HCV (232). Of note, sleep alterations
dates in mediating sleep changes observed in HIV infection, in this study were independent of the viremic state, suggest-
given their sleep modulating role in animal models (see sect. ing that the sleep-immune relationship in HCV is complex.
IIB1) and upregulation in HIV-infected patients (195, 477, In patients with an infectious illness linked to the Epstein
540). Indeed, some of the very few studies conducted in this Barr virus (EBV), such as infectious mononucleosis, self-
area reported an association between sleep parameters (i.e., reported sleep duration was markedly increased (349) and
SWA, sleep duration) and pro-inflammatory cytokine dys-
debilitating daytime sleepiness persisted over many years
regulation in HIV-infected individuals (133, 195). Such as-
(218). T-cell activation and cytokine production, in partic-
sociations appear to be influenced by disease severity and
ular IFN-␥ and TNF, are thought to be responsible for the
duration. For example, the correlation between TNF and
clinical symptoms of infectious mononucleosis (21, 194,
SWA has been shown to weaken as a function of days since
581). However, whether such immune alterations also con-
seroconversion (133). Furthermore, in a recent study per-
tribute to the observed sleep changes has yet to be ad-
formed in low-income ethnic minority women living with
dressed.
HIV, greater self-reported sleep disturbances were related
to lower CD4 T-cell counts. This relationship persisted after
Long-lasting consequences of an infectious challenge may
adjusting for the effects of mood, stress, and disease status,
also play a pathogenic role in ME/CFS, where a viral etiol-
suggesting that the relationship was independent of such
ogy is still debated (29). Subjective complaints of disturbed,
factors (500). Of note, even after the initiation of antiretro-
viral therapy, HIV-positive patients continue to report nonrestorative, and unrefreshing sleep are among the many
lower sleep quality (359, 539, 591), and in a recent study in symptoms in ME/CFS. Based on conventional sleep param-
a South African-treated HIV-positive population, an in- eters assessed by PSG, several, though not all, studies re-
crease in CD4 T-cell counts was associated with lower sleep ported increased sleep onset latency, increased number of
quality (461). In animals, injection of the HIV envelope nocturnal awakenings, and reduced sleep efficiency in ME/
glycoprotein 120 in the brain of rats caused an increase of CFS patients compared with healthy control participants
hypothalamic mRNA expression of IL-1 and IL-10 and an (for review, see Ref. 269). Using nonconventional EEG
increase of NREM sleep, further suggesting that alteration sleep analysis approaches, a few studies also found altera-
in cytokine concentrations may underlie sleep alterations tions in SWA, such as lower SWA in the ultra-low delta
observed in HIV infections (413). range (i.e., slow oscillatory activity) (330) or a blunted SWA
response to a sleep onset delay in ME/CFS patients (17), as
In human African trypanosomiasis (HAT), a parasitic dis- well as alterations of cyclic alternating patterns, indicating
ease also known as sleeping sickness, circadian sleep-wake increased sleep instability (219). A number of immunolog-
disruption is characteristic, with sleep and wake periods ical and inflammatory parameters have been found to be
distributed throughout the 24-h day (77, 83). In compari- abnormal in ME/CSF, including altered cytokine profiles,
son to Encephalitis Lethargica, there is a certain overlap of increased numbers of activated cytotoxic CD8 T cells, re-
brain structures affected by both disorders, including hypo- duced T-cell responses to mitogens, and impaired function
thalamic centers, where many sleep-wake regulatory cir- of NK cells; however, findings across studies are often con-
cuits are located (for comprehensive reviews on the patho- flicting (reviewed in Ref. 342). With respect to circulating
physiology of Encephalitis Lethargica and HAT, see Refs. cytokine profiles, a recent systematic review reported an
361, 570). It has been shown that the parasite trypanosoma increase in transforming growth factor (TGF)-␤ as the most
can produce PGs, including PGD2 with known somnogenic consistent finding across studies (59). With the use of a
properties, and triggers the release of pro-inflammatory cy- comprehensive immune profiling approach in ME/CSF pa-
tokines (298). Increased PGD2 levels have been found in the tients, elevated TGF-␤ levels were confirmed, in addition to
CSF of patients in the late stages of the disease, further findings of lower resistin levels (390), a protein participat-

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 THE SLEEP-IMMUNE CROSSTALK

ing in the inflammatory response and able to activate TNF 456). Based on objective PSG and actigraphy assessment,
in monocytes and macrophages (for review, see Ref. 187). various indicators of disrupted sleep have been reported in
In the same study, 17 cytokines, most of them pro-inflam- RA patients compared with healthy control participants,
matory, correlated with symptom severity in ME/CFS including increases in ␣-EEG intrusion, arousals, sleep stage
(390), while another recent investigation reported an acti- shifts, sleep fragmentation, and nocturnal wake time (54,
vation of a number of pro- and anti-inflammatory cytokines 160, 237, 351, 472). Alterations in sleep architecture, such
during the early stage of the disorder only, suggesting that as changes in the amount or distribution of SWS, have often
immunopathology in ME/CFS fluctuates depending on dis- not been found or show little consistencies between studies
ease duration (242). The complexity of the relationship be- (reviewed in Ref. 53). A few studies investigated the link
tween immune parameters and symptoms in ME/CSF is also between sleep disturbances with immune alterations in this
suggested by a recent study showing that peripheral inhibi- disorder. The immunopathology in RA is reasonably well
tion of IL-1 by the IL-1ra anakinra over a 4-wk period did understood and is characterized by inappropriate produc-
not lead to clinically significant reduced fatigue in women tion of various cytokines, in particular TNF, among several
with ME/CSF compared with a placebo group (473). Un- other immunological abnormalities (94, 188). In a recent
fortunately, reports of sleep disturbance and nonrestorative investigation, cellular inflammation, as indicated by spon-
sleep were not solicited in this study. taneous or stimulated production of TNF or IL-6 by mono-
cytes, was higher in RA patients compared with matched
2. Chronic inflammatory diseases healthy controls, and showed a complex time-of-day-de-
pendent association with sleep efficiency and SWS amount.
Sleep disturbances are also commonly found in diseases For example, higher sleep efficiency was associated with
with inflammatory pathophysiology, such as inflammatory
lower stimulated monocytic TNF production in the morn-
bowel diseases (IBD). IBD are chronic inflammatory disor-
ing, but with higher production when assessed in the eve-
ders of the intestine with unknown pathogenesis, including
ning. As stated by the authors, these findings may suggest a
Crohn’s disease and ulcerative colitis. In a recent study, half
feedback loop between sleep parameters and cellular pro-
of the IBD patients reported sleep disturbances as assessed
duction of pro-inflammatory cytokines (54). In a large co-
by the PSQI (550), with strongest associations in patients
hort of over 8,000 patients from the National Data Bank of
with active disease (10, 209). Based on data from the
Rheumatic Diseases, self-reported sleep disturbances, in-
Nurses’ Heath Survey with over 400 IBD cases, self-re-
cluding trouble falling asleep, trouble getting back to sleep,
ported sleep duration of ⬍6 h and ⬎9 h per night increased
and not getting enough sleep to feel rested, did not differ
risk of ulcerative colitis (11). The association between IBD
between those who received anti-TNF therapy and those
and sleep disturbances is thought to be bidirectional, such
that increased disease activity leads to sleep disturbances, who did not (587). In contrast, treatment with anti-TNF
which in turn exacerbates inflammation. Supporting such therapy in RA patients with high disease activity resulted in
an association, subjective sleep quality [assessed with the an improvement of self-reported sleep quality, without af-
National Institutes of Health Patient-Reported Outcome fecting PSG-derived sleep parameters (283). However, at
Measurement Information System (PROMIS)], was in- least three studies reported PSG-derived sleep improve-
versely correlated with CRP levels in well-phenotyped IBD ments in response to anti-TNF therapy. In a noncontrolled
patients (584). In a prospective cohort, anti-inflammatory study in RA patients with active disease, anti-TNF treat-
therapies with anti-integrin (vedolizumab) and anti-TNF ment (infliximab) resulted in decreased sleep latency, in-
agents (infliximab or adalimumab) resulted in improved creased sleep efficiency, fewer sleep stage transitions, and
sleep quality (assessed with PROMIS) within 6 wk of ther- increased REM sleep. These sleep improvements did not
apy initiation (527). This suggests a modulatory influence relate to joint pain amelioration, and therefore may inde-
of cytokines on subjectively assessed sleep quality. In mice, pendently reflect inhibition of raised circulating TNF levels
using a dextran sodium sulfate colitis model, a worsening of (598). In another study in RA patients treated with anti-
colonic inflammation and colitis severity has been observed TNF therapy, PSG-assessed sleep improved, as indicated by
following chronic intermittent sleep deprivation (534), increased sleep efficiency and less WASO (535). PSG-de-
demonstrating a causal involvement of sleep in aggravating rived increases in sleep efficiency and total sleep time were
this disease. paralleled by a reduction of CRP levels in patients with
active disease treated with anti-TNF therapy (141). Fur-
One of the most extensively investigated chronic inflamma- thermore, treatment with an IL-6 receptor inhibitor (tocili-
tory disorders with respect to sleep is RA. This chronic zumab) in RA patients with active disease improved self-
inflammatory autoimmune disease primarily affects joints, reported sleep quality (assessed by the PSQI) and daytime
leading to pain and potentially to joint destruction and sleepiness. Observed sleep improvements could not be ex-
deformation, if left untreated. About 50% of RA patients plained by a reduction in disease activity, further suggesting
report sleep disturbances, including symptoms such as dif- that the cytokine-sleep relationship is not secondary to clas-
ficulties falling asleep and maintaining sleep, nonrestorative sical disease symptoms, in particular pain (196). To sum-
sleep, and excessive daytime sleepiness (reviewed in Ref. marize, investigations on cytokine inhibition in RA suggest

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 BESEDOVSKY ET AL.

that TNF, in particular, plays a role in sleep modulation, is sleep deprivation, and the studies differ largely in the
although the independence of this association from other methods used to prevent sleep. Some studies induced total
factors, such as disease activity, pain, and comorbid disor- sleep deprivation; others partially deprived sleep, i.e., re-
ders has often not been addressed in detail. Subjective and stricted sleep to a few hours per night or selectively sup-
objectively verified sleep disturbances have been also re- pressed REM sleep, using different methods that are more
ported in a number of other rheumatic disorders, including or less inherently stressful (TABLE 1). In addition, the dura-
Sjögren’s syndrome, systemic lupus erythematosus, sys- tion of the sleep modification procedure differed largely
temic sclerosis, osteoarthritis, and other chronic diseases between studies, ranging from only a few hours to several
with an inflammatory involvement, such as migraines. weeks. A limited number of studies employed an alternative
Comprehensive reviews can be found in References 1, 53, approach to sleep deprivation. Some of those studies extended
456. the opportunity to sleep [e.g., by a daytime nap (178 –180), or
by extending bedtime (i.e., increasing the nighttime sleep pe-
Collectively, studies devoting attention to sleep distur- riod) (103), see sect. V, B and C], while others intensified sleep
bances in chronic infectious or inflammatory diseases dem- [e.g., by acoustic stimulation (49)]. Because of the large meth-
onstrate that sleep changes are common and can vary odological differences, it is difficult to compare across studies,
greatly, including shortened, prolonged, disrupted, or dis- and inconsistencies between studies are in part due to this
placed sleep. Such variations in the sleep response likely methodological variety. TABLE 2 gives a broad overview of
depend on the type of immunopathology involved in the the research results and indicates how often a specific find-
disease, disease activity, symptom severity, and disease ing has been replicated. We define sleep manipulation of
stage. To date, only a few studies have specifically addressed one day or less as acute sleep deprivation/restriction in con-
the pathophysiological mechanisms responsible for sleep trast to protocols using more prolonged sleep manipula-
disturbances in chronic infectious or inflammatory diseases. tion. The idea behind this distinction is that experiments
This may relate to several challenges in this area of research: employing acute sleep manipulation are usually performed
chronic infectious or inflammatory diseases frequently oc- to assess the active role of sleep for the immune system (i.e.,
cur in conjunction with comorbid medical conditions, in- viewed from a sleep perspective) compared with a condition
cluding depression, anxiety, obesity, cardiovascular dis- without sleep. In contrast, studies using prolonged sleep
ease, and pain, all of which alter sleep and immune system deprivation are intended to examine the impact of a lack of
markers and thereby increase the complexity of the sleep- sleep on immune parameters. In TABLE 2, we therefore dis-
immune relationship. Furthermore, the immunopathology tinguish between acute effects of sleep (viewed from the
in chronic diseases may not be static over time. Depending sleep perspective) and effects of prolonged sleep loss
on disease duration, the association between symptoms and (viewed from the perspective of sleep loss).
immune parameters may differ in early versus late stages of
a disease. Nonetheless, in light of basic research supporting There are also several studies that measured changes in
a bidirectional relationship between sleep and the immune immune parameters across 24 h without experimentally
system (see next sections), it is most likely that such a link manipulating sleep. However, it is beyond the scope of the
also exists in the context of chronic infectious and inflam- current review to elaborate on these studies. The interested
matory diseases. However, the strength and independence reader is therefore referred to other recent reviews about
of such an association from the many factors comorbid with circadian rhythms in the immune system (e.g., Refs. 95,
chronic diseases (in particular pain) still needs to be deter- 207, 494). Finally, several studies employed sleep depriva-
mined. tion in combination with exercise, psychological stress, or
energy depletion (71, 220, 369, 402, 579, 588). Unless the
effects of sleep were clearly distinguishable from those of
III. SLEEP EFFECTS ON HOST DEFENSE the other manipulations (e.g., Refs. 122, 251, 469), results
of those studies are not included in the following sections.
A. Experimental Studies Investigating Sleep 1. Leukocyte and leukocyte subset numbers and
Effects on Immune Parameters distribution

A number of experimental studies have investigated the In sleep studies involving healthy humans, the numbers of
impact of experimental sleep manipulation on various im- various leukocyte subsets in the blood are among the most
mune parameters. These parameters include numbers of often investigated parameters. Many leukocytes display
leukocytes and leukocyte subsets in the blood and various strong migratory capacity and are constantly recirculating
tissues, circulating cytokine levels, cytokine production in between various tissues and organs, using the blood and the
specific leukocytes, concentration of antibodies and com- lymphatic system as traveling routes. This migration leads
plement factors in the blood, as well as functional aspects to acute changes in the blood count of leukocyte subsets and
like cell cytotoxicity, to name only the most frequently in- has a very pronounced circadian component (95, 494). On
vestigated parameters. The main type of sleep manipulation top of this strong circadian rhythm, sleep exerts an overall

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 THE SLEEP-IMMUNE CROSSTALK

Table 2. Sleep effects on immune parameters

Effect of
Prolonged
Acute Effect of Sleep Wakefulness Reference Nos.

Leukocyte numbers in blood (sect. IIIB1)

WBC 222 ⫽ ⫽ ⫽ 111 ⫽ 3, 67, 69, 103, 122, 152, 178, 224, 234,
254, 287, 326, 338, 469, 480, 580
Lymphocytes 22 ⫽ ⫽ ⫽ 1(evening after normal sleep) 1⫽⫽⫽ 3, 24, 67, 69, 103, 122, 152, 178, 224,
234, 251, 254, 326, 338, 480, 580
Monocytes 222 ⫽ ⫽ ⫽ 1(4 days after partial SD) 111 ⫽ ⫽ 3, 24, 67, 69, 103, 146, 147, 152, 178,
224, 254, 263, 287, 326, 480, 580
T cells, CD4 T cells, CD8 T 222 ⫽ ⫽ ⫽ 11(mainly evening after sleep) ⫽ ⫽ ⫽ 3, 46, 67, 148, 152, 234, 251, 263, 418,
cells 469, 480, 556, 580
B cells 2⫽⫽⫽ 1⫽⫽ 3, 67, 152, 234, 418, 480, 556
NK cells 222 ⫽ ⫽ 111 12 3, 67, 152, 178, 234, 251, 263, 418,
556, 580
Neutrophils 222 ⫽ ⫽ ⫽ 1 111 ⫽ 67, 69, 103, 112, 122, 178, 287, 326,
338, 469, 480, 580
Basophils, eosinophils ⫽⫽⫽ ⫽⫽ 67, 152, 287, 338, 480, 580
Cytokines/cytokine receptors (sect. IIIB2)
IL-6
Plasma/saliva levels 22 ⫽ ⫽ ⫽ 11 111 ⫽ ⫽ ⫽ 67, 104, 147, 180, 200, 223, 224, 236,
245, 248, 261, 334, 464, 480, 489,
506, 541, 547, 556, 562–564, 594
Production (intracellular or 222 ⫽ 1(after partial SD) 11 ⫽ 89, 147, 245, 256, 262, 264, 356, 512,
in supernatant) 556
Tissue expression 2⫽ 11 ⫽ ⫽ 285, 290, 559, 604
TNF
Plasma levels 22 ⫽ ⫽ ⫽ 1(daytime after normal sleep) 111 ⫽ ⫽ ⫽ 104, 146, 224, 236, 245, 248, 261, 334,
480, 489, 506, 541, 564, 594
Production (intracellular or 24, 67, 146, 149, 256, 262, 264, 543,
in supernatant) 222 ⫽ 11(mostly after partial SD) 2⫽⫽1 552, 556
Tissue expression 22 ⫽ ⫽ 1 11 ⫽ ⫽ 18, 19, 162, 285, 290, 356, 553, 559,
604, 606
Soluble TNF receptor ⫽⫽ 1⫽ 104, 222, 224, 506
IL-1
Plasma levels 22 ⫽ ⫽ ⫽ 11 171, 200, 236, 245, 386, 480, 541, 547,
594
Production (intracellular or
in supernatant) 2⫽⫽ ⫽ ⫽ 11 24, 67, 103, 245, 552, 556
Tissue expression 22 ⫽ ⫽ 11 11 ⫽ ⫽ 18, 19, 162, 281, 290, 348, 356, 547,
553, 604
IL-1ra 2⫽ 1 200, 224, 245
IL-2
Plasma levels ⫽ ⫽⫽ 236, 248, 480, 547
Production (intracellular or
in supernatant) ⫽ ⫽ 11 2 24, 62, 67, 149, 254, 552
Soluble IL-2 receptor ⫽⫽ 21 149, 222, 506
IL-12
Intracellular production 2 11 148, 323, 465
IL-4, IL-10
Plasma levels ⫽ ⫽⫽⫽ 171, 236, 248, 480, 506, 547, 594
Production (intracellular or
in supernatant) 22 ⫽ ⫽ 24, 149, 323, 543
Th1/Th2 ratio
Production (intracellular or
in supernatant) 1 2(2nd half of night) 2 24, 149
Continued

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 BESEDOVSKY ET AL.

Table 2. Continued
Effect of
Prolonged
Acute Effect of Sleep Wakefulness Reference Nos.

Immune cell activity and proliferation (sect. IIIB3)

NK-cell activity ⫽ 11 1⫽2 137, 152, 253, 254, 386
Lymphocyte proliferation ⫽ ⫽ 11 1⫽⫽2 33, 62, 152, 243, 386, 482, 556, 580
Neutrophil function 2⫽⫽1 ⫽⫽ 112, 122, 421, 469
nTreg function 1 62
Antibodies, complement and other immune parameters (sect. IIIB4)
Total IgG, IgM, or IgA 22 ⫽ ⫽ 1 2 ⫽ ⫽ ⫽ 11 122, 171, 247, 418, 480, 596
antibody levels
Complement 2⫽⫽1 ⫽⫽1 247, 465, 480, 596
Adhesion molecules 22 ⫽ ⫽ 200, 489
Inflammatory gene 11 6, 387
expression

The number of icons represents the number of studies supporting the respective finding (3 icons, ⬎3 studies; 2 icons, 2–3 studies; 1 icon, 1
study). Please note that the depiction of the studies is very simplified, as differences in designs are not considered. Most studies measured
samples taken in the daytime after normal sleep or sleep deprivation, but not at night. Hence, some seemingly contradictory findings emerge
because opposite results are found for nighttime and daytime values. The left column shows the acute effects of sleep (one night of sleep
compared with one night of total/partial sleep deprivation), whereas the right column shows the effects of prolonged sleep loss (several nights
with total or partial sleep deprivation). Refer to section IIIA for details. SD, sleep deprivation; WBC, white blood cells; NK cells, natural killer cells;
IL-1ra, interleukin-1 receptor antagonist; nTreg, natural regulatory T cells.

weaker, but still significant, influence on leukocyte numbers found to be affected by sleep (67, 152, 287, 338, 480, 580).
in blood. Several studies in humans have found a reducing In contrast, several studies found that sleep reduces neutro-
effect of sleep on total leukocyte count when compared with phil counts (69, 112, 178, 287, 326, 338, 480, 580), al-
total sleep deprivation or sleep restriction for either only a though again some studies did not find any changes (67,
few hours or up to several days (67, 69, 152, 178, 287, 326, 103, 122, 469).
338, 480). Other studies failed to detect this reduction (3,
103, 122, 224, 234, 254, 469, 580). Such discrepancies Since most studies have reported that sleep reduces numbers
could be due to the fact that most studies assessed cell of various leukocyte subsets in the blood, the question con-
numbers only at a single or just a few time points across the cerning the fate of these cells arises. An impact on cell pro-
day, and often not during sleep. This reduces the chances of liferation is unlikely, given that the effects of sleep already
detecting transient changes in cell counts. Of note, none of emerge within 3 h of sleep, or even earlier, whereas changes
the studies found that sleep increases leukocyte numbers. in proliferation would take significantly longer to become
Therefore, it may be concluded that sleep reduces numbers evident (67, 148). Therefore, a redistribution of the cells
of leukocytes in the blood, albeit only transiently, which from the circulation to different tissues and organs is most
enhances the risk of missing those changes. probable. Animal studies have assessed cell numbers in dif-
ferent tissues, mainly primary and secondary lymphoid or-
Similarly, total monocyte counts, lymphocyte counts, and gans, after experimental manipulation of sleep. However, a
the major lymphocyte subsets (i.e., B cells, CD4 and CD8 T unifying picture cannot easily be drawn. One study in mice
cells, NK cells), have been found to be either reduced by found an increase in total splenic cells during sleep com-
sleep (46, 67, 148, 251, 254, 480, 556, 580) or unchanged pared with prolonged wakefulness, but leukocyte numbers
(3, 69, 103, 122, 152, 178, 224, 234, 263, 338, 418, 463, in the blood were unchanged, which contrasts with the
469) when compared with acute or prolonged sleep reduc- findings in humans (346). Other rodent studies found an
tion in humans. However, there are some reports of in- increase in numbers of leukocytes and lymphocytes in the
creased numbers of lymphocyte subsets (i.e., CD4 T cells, blood after normal sleep compared with forced wakeful-
CD8 T cells, and NK cells), particularly when measured in ness, whereas there were no changes in cell numbers in the
the evening after a regular night of sleep (152, 234, 418, lymph nodes, spleen, or bone marrow (171, 217, 596, 597).
556, 580). As suggested by Born et al. (67), these increases Using a skin allograft model, Ruiz et al. (479) recently
could reflect a homeostatic response, as numbers of lym- showed that numbers of total T cells, CD4 T cells, and CD8
phocytes and various subsets were acutely reduced during T cells in the lymph nodes and spleen were higher after
sleep, but increased in the afternoon or evening following undisturbed sleep than after prolonged sleep restriction,
regular sleep compared with nocturnal wakefulness. As for which was accompanied by an increased allograft rejection.
granulocyte subsets, basophils and eosinophils were not Interestingly, whereas Zager et al. (596) found no immedi-

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 THE SLEEP-IMMUNE CROSSTALK

ate changes in lymphocyte numbers in secondary lymphoid on IL-6 levels in plasma or saliva when compared with one
organs after acute sleep deprivation, they showed increased night with no or restricted sleep in healthy participants. Of
lymphocyte counts in lymph nodes after recovery sleep. note, measurements of IL-6 in saliva do not seem to reflect
This finding suggests that the typical increase in sleep inten- systemic levels of this cytokine in plasma (127), but differ-
sity following sleep deprivation can lead to an accumulation ences in the body fluid used to measure IL-6 are not suffi-
of lymphocytes in this tissue. The most consistent findings cient to explain the discrepancies between these studies.
with respect to the effect of sleep on leukocyte distribution More consistent findings are observed if sleep is diminished
have been observed for B cells and NK cells, which were for longer than one night: plasma levels of IL-6 or CRP
shown to be increased in numbers in the murine spleen after (which is produced by the liver in response to IL-6 secre-
normal sleep (137, 346, 360, 597). However, to summarize, tion) mostly increase in such conditions, likely reflecting a
findings on the effects of sleep on leukocyte distribution are systemic, unspecific inflammatory response to prolonged
far from conclusive. This may partly be due to methodolog- sleep loss (223, 506, 556, 564) (see also sect. IV). These
ical issues; for example, some studies investigated only one increases are in line with results of enhanced IL-6 levels in
or a few tissues in parallel, and studies applying in vivo animal studies, all of which used prolonged sleep depriva-
tracking of the cells are missing so far. In addition, compar- tion protocols (245, 541, 594). On the other hand, there are
ing the findings obtained in animal models with those from also studies reporting no effect of prolonged sleep restric-
human studies is difficult. Animal studies mostly investi- tion on IL-6 or CRP levels in humans (69, 334, 480, 506)
gated cell numbers in different tissues, but not in the blood, and animals (236, 248), suggesting that the effect is tran-
which is the compartment on which studies in healthy hu- sient and may not be detectable if samples are only mea-
mans have so far focused on. Therefore, it has not been sured at a single time point.
possible yet to relate changes in cell numbers in the blood
circulation to changes in other tissues. Furthermore, redis- Intracellular IL-6 production was not altered acutely during
tribution kinetics of leukocytes may be different in humans sleep compared with nocturnal wakefulness (147), but was
and animals given the large differences in body size between increased in the morning after one night of partial sleep loss
species. Consequently, while sleep appears to affect the cir- in healthy humans (89, 256, 262, 264). This effect was also
culating number and migration of almost all leukocyte sub-
found at the mRNA level, measured in peripheral blood
sets, the question as to where leukocytes redistribute during
lymphocytes of mice after 36 h of sleep deprivation (245).
sleep remains largely open.
Increased stimulated intracellular IL-6 production was also
shown after prolonged sleep restriction for several days in
2. Cytokine levels, cytokine production, and cytokine
humans (512, 556), although one of the studies found the
receptors
increase only at the mRNA, but not the protein level (556).
The most often investigated cytokines in the context of sleep Animal studies measuring IL-6 protein or mRNA expres-
research are the acute phase cytokines IL-6, TNF, and IL-1. sion in different tissues, especially the brain, found either
Fewer studies have investigated the role of sleep in modu- increases (285, 290, 356, 559) or no changes (285, 553,
lating other cytokines, such as IL-2 and IL-12 (which are 604) after shortened sleep.
essential for the formation of adaptive immunity), the anti-
B) TNF. Plasma levels of TNF were mostly unchanged during
inflammatory cytokine IL-10, or the Th2 cytokine IL-4.
There are several ways to measure cytokines. Basal levels or on the day after acute sleep deprivation/restriction in
can be measured in blood (plasma) or saliva, although the healthy humans (224, 261, 334, 480, 489, 506). One study
concentration of most cytokines in healthy participants is found TNF levels to be reduced during sleep, but to be
usually very low and not always detectable. Cytokine pro- enhanced on the day after normal sleep compared with a
duction by leukocytes (or other cells/tissues) can also be nocturnal vigil (146), potentially reflecting a homeostatic
measured, either unstimulated or after stimulation (e.g., regulation of this cytokine. However, another study found
with PAMPs like LPS), intracellularly on a single-cell level reduced levels in the evening following regular sleep (104).
using flow cytometry or in bulk analyses across numerous As to prolonged sleep curtailment, a mild reduction of sleep
cells at protein or mRNA level, or in the supernatant of in to 6 h per night for 1 wk led to an increase in TNF plasma
vitro cultures. It seems that sleep has a differential effect on levels in one study (564), although other studies in humans
cytokines depending on which type of cytokine is assessed found no effect after prolonged sleep deprivation or restric-
through which method and at which time of the day. Be- tion (334, 480, 506). Similarly, some rodent studies found
cause of the large methodological differences between stud- enhanced plasma levels of TNF following 36 and 72 h of
ies, findings on the effects of sleep on cytokines are very sleep restriction (245, 594), whereas other studies reported
mixed, especially for the effects of sleep when compared unchanged TNF plasma levels after sleep restriction for 48
with acute sleep loss. h and 8 days in mice and rats (236, 541). One recent study
found increased TNF levels after 10 days of sleep restriction
Sleep can show enhancing (180, 200, 464), decreasing
A) IL-6. in C57BL/6 mice, but not in BALB/c mice (248). This find-
(541, 562, 563) or no effects (67, 104, 147, 224, 261, 489) ing corresponds to the results of the two studies mentioned

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 BESEDOVSKY ET AL.

above, which used these different strains (236, 245), and sleep deprivation did not find an effect of sleep in healthy
might at least partly explain the divergent findings. Overall, participants (480). In rodents, three studies found increases
compared with the results for IL-6 levels in plasma, which in IL-1 plasma levels after sleep deprivation (171, 245,
mostly showed an increase with prolonged exposure to 594), although other studies failed to substantiate these
sleep deprivation or restriction, possible increments in TNF findings (236, 541, 547), which is similar to the mixed
levels after longer sleep deprivation seem to be more diffi- findings in humans. IL-1 production and mRNA expression
cult to detect in humans and animals. were mostly found to be unchanged by both acute and
prolonged sleep manipulation in healthy humans (24, 67,
Stimulated production of TNF in humans has been found to 103, 556). However, an increase at the mRNA level after
be acutely reduced during sleep compared with nocturnal prolonged sleep restriction has been reported in humans
wakefulness when measured in the supernatant (552) or (556), as well as in animal studies measuring gene expres-
intracellularly in CD8 T cells (149), but increased when sion in peripheral blood lymphocytes (245), and in the
measured in monocytes (146). Other studies, however, spleen, liver, CNS, heart, and adipose tissue (18, 162, 281,
failed to find an acute effect of sleep on TNF production 290, 348). Some animal studies found unchanged (19, 162,
assessed in the supernatant (67, 543). Following sleep de- 356, 553, 604) or reduced (19, 547) IL-1 levels in different
privation in the first night half, TNF production in mono- tissues other than the blood after sleep loss. Although find-
cytes and TNF mRNA were shown to be increased in the ings are mixed, none of the human and animal studies mea-
morning (256, 262, 264). These findings stand in contrast suring IL-1 levels either in plasma or intracellularly in cir-
to the sleep-induced increase in TNF production in mono- culating leukocytes reports a reduction of this cytokine fol-
cytes reported by Dimitrov et al. (146). Hence, the findings lowing acute or prolonged sleep deprivation or restriction.
of increased TNF production in the morning after sleep The receptor antagonist IL-1ra, which is a natural inhibitor
deprivation by Irwin et al. (256) may reflect a rebound of IL-1 signaling, was increased after sleep deprivation in
effect of sleep, as participants were allowed to sleep in the
humans and animals (200, 245). Similarly to the soluble
second night half before blood was collected in the morn-
TNF receptor I, the increase in IL-1ra might reflect a ho-
ing. Interestingly, Irwin et al. (256) found striking sex dif-
meostatic response following increased IL-1 levels.
ferences, with further increases of TNF in the evening in
women, but decreases in men. After prolonged sleep restric-
Other cytokines have been reported less
D) OTHER CYTOKINES.
tion of more than one night, stimulated TNF production
frequently, although they are no less physiologically sig-
was reduced in the supernatant in one study in humans
nificant. IL-12 and IL-2, for example, are essential for the
(556), but increased in another (24). Most animal studies
formation and maintenance of adaptive immunity, such
measured TNF protein or mRNA levels in different tissues
as in the context of a vaccination response, which will be
with or without stimulation using several methods for sleep
discussed in section IIIB. Studies attempting to measure
manipulation, which renders the results difficult to compare
IL-2 levels in plasma have failed to find an effect of sleep
with each other. Overall, most studies found either in-
manipulation in humans (480) and animals (236, 248,
creased (18, 161, 285, 356, 553, 559, 606) or unchanged
(19, 162, 290, 604) TNF levels in the various tissues, in- 547). In contrast, stimulated IL-2 production seems to be
cluding the spleen, liver, brain, adipose tissue, and perito- acutely enhanced by sleep in healthy humans (67, 254,
neum after sleep loss. These findings are an important ad- 552), although other studies did not find such an effect
dition to the studies in humans, in which cytokine levels when assessing stimulated IL-2 production specifically in
were mainly assessed in the blood circulation. CD4 T cells (62, 149). Five nights of partial sleep depri-
vation led to a reduction of stimulated IL-2 production in
Finally, a handful of studies in healthy humans investigated healthy humans (24), which is in line with the studies
the effect of experimental sleep manipulation on the soluble manipulating sleep for only one night. The effect of sleep
TNF receptors I and II, which act as inhibitors and regula- on the soluble IL-2 receptor, which may be used as a
tors of TNF signaling. One night without sleep did not surrogate marker of T-cell activation (392), was also
change the plasma levels of these receptors (104, 222). In investigated. Two studies in humans found no change in
contrast, prolonged total sleep deprivation of four consec- this receptor after one night without sleep (149, 222),
utive nights increased levels of the soluble TNF receptor I whereas another study revealed an increase across several
(506), which may reflect a homeostatic response to in- days of sleep deprivation (506). In contrast, one recent
creased TNF production by leukocytes; this, however, was animal experiment showed a reduction following pro-
not investigated in the study. longed sleep deprivation in a skin allograft model (479).
As for IL-12, two human studies found a striking increase
C) IL-1. As for plasma levels of IL-1, two human studies found of IL-12 producing cells during sleep compared with noc-
an acute increase in IL-1 following one night of sleep depri- turnal wakefulness (148, 323), although this increase
vation (200, 386), while another study employing either seems to be reversed when the cells are primed with
two nights of total sleep deprivation or four nights of REM IFN-␥ before LPS stimulation (465).

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A few studies have also investigated the impact of sleep on measuring cytokine production is that they do not reflect
the anti-inflammatory cytokine IL-10 and the Th2 cytokine normal physiology. Cells are often incubated for several
IL-4. Studies in both humans and animals did not find hours and stimulated with high, non-physiological doses of
changes in plasma levels of IL-4 and IL-10 after sleep ma- stimulants. Given that the effects of sleep on cytokine pro-
nipulation, although these cytokines are often below detec- duction are potentially mediated by humoral factors (322),
tion limits without stimulation (171, 236, 248, 480, 506, using isolated cells instead of measuring cells in whole
547, 594). In contrast, human studies measuring stimulated blood (i.e., their natural physiological environment) hardly
cytokine production found a sleep-dependent drop in IL-10 reflects the real in vivo situation. Another important issue is
production by monocytes (323) and in IL-4 production by that results can be biased, as sleep does not only affect
CD4 T cells (149) if assessed at a cell-subset specific level in cytokine production itself, but also the numbers of circulat-
whole blood, but not if measured in a cell-subset specific ing leukocytes that produce these cytokines. A selective ex-
level in isolated T cells (61), or in the supernatant of whole travasation of certain leukocyte subsets can therefore have
blood or peripheral blood mononuclear cell (PBMC) cul- an impact on the results of cytokine measurements. Further-
tures (24, 543). The study by Dimitrov et al. (149) found an more, there are also other sources of cytokine production
acute rise in the Th1/Th2 cytokine ratio (measured as the besides immune cells, such as endothelial cells (see TABLE 3
ratio of IFN-␥ to IL-4) during early sleep compared with for an overview of sources of production of humoral im-
nocturnal wakefulness. This change, however, reversed in mune molecules). Hence, it is important to view the effects
the second half of sleep. After 5 days of sleep restriction, of sleep on cytokines in the context of the potential sources
Axelsson et al. (24) observed a shift in the Th1/Th2 cyto- producing the cytokine of interest. Cytokines are also often
kine balance (measured in this study as the ratio of IL-2 to produced only locally and for a short period, and have short
IL-4) towards Th2 activity that was strongest during day- half-lives, which makes it difficult to detect changes, espe-
time after sleep restriction in humans. These findings sug- cially when measured in the blood. Finally, many studies
gest that sleep, and especially the early sleep period, is re- did not collect blood during the sleep manipulation itself,
sponsible for establishing a predominant Th1 cytokine but rather on the day after, and only at single or very few
response. time points. Being a homeostatic system, the healthy body is
expected to attempt to reach a homeostatic state, thus coun-
Altogether, the results on the impact of sleep on cytokine teracting any effects occurring acutely during sleep depriva-
levels and production are complex, which is not only due to tion. It is therefore not surprising that the observed effects
the differences in the methods used for inducing sleep de- of sleep can differ depending on the exact time point of
privation mentioned above, but also because of method- measurement. Nonetheless, in general, it seems that sleep
ological differences in the measurement of cytokine produc- acutely favors pro-inflammatory and Th1 cytokine produc-
tion. A major problem with the assays usually employed for tion over anti-inflammatory and Th2 cytokine production,

Table 3. Humoral immune molecules and their cellular sources of production

Molecule Cell Source

IL-6 Monocytes, macrophages, T cells, B cells, granulocytes, mast cells, thymocytes, endothelial cells, fibroblasts,
smooth muscle cells, chondrocytes, osteoblasts, glia cells, keratinocytes, pancreatic cells
TNF Monocytes, macrophages, CD4⫹ T cells, B cells, neutrophils, NK cells, mast cells, fibroblasts, astrocytes,
microglia, endothelial cells, smooth muscle cells, intrinsic renal cells, keratinocytes
IL-1 Monocytes, macrophages, lymphocytes, neutrophils, keratinocytes, microglia, megakaryocytes, fibroblasts,
synovial lining cells, DCs, endothelial cells, smooth muscle cells
IL-1ra Monocytes, macrophages, neutrophils, fibroblasts, endothelial cells, epithelial cells, keratinocytes,
hepatocytes, astrocytes, bone marrow cells
IL-2 CD4⫹ and CD8⫹ T cells, DCs, NK cells, NKT cells, mast cells, innate lymphoid cells
IL-12 Monocytes, macrophages, neutrophils, microglia, DCs, B cells, NK cells, keratinocytes
IFN-␥ NK and NKT cells, macrophages, Th1 cells, cytotoxic CD8 T cells, B cells, DCs, neutrophils, endothelial cells
IL-4 Th2 cells, basophils, eosinophils, mast cells, NKT cells, ␥/␦ T cells, monocytes/macrophages, neutrophils, B
cells
IL-10 T cells, B cells, monocytes, macrophages, DCs, mast cells, thymocytes, keratinocytes
Immunoglobulins B cells
Complement proteins Hepatocytes, endothelial cells, epithelial cells, neutrophils, mast cells, monocytes, macrophages, DCs,
lymphocytes

NK cells, natural killer cells; DCs, dendritic cells; NKT cells, natural killer T cells; Th1, type 1 helper T cells; Th2, type 2 helper T cells. See
References 7, 344 for further details on cellular sources of cytokine and complement production, respectively. Note that this table includes only
the most commonly reported cellular sources of production.

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 BESEDOVSKY ET AL.

with both being tightly regulated by a homeostatic response pensatory processes that may take place with more chronic
that reverses this effect at later time points (e.g., during the forms of sleep loss.
second half of sleep or the daytime period in humans). This
delicate balance can be disturbed following prolonged re- A few human studies have investigated neutrophil func-
ductions in sleep duration, which may lead to a chronic tions, mostly by assessing markers of degranulation.
imbalance favoring a pro-inflammatory response that is Whereas two studies did not find an effect of sleep on neu-
likely to have deleterious health consequences over the long trophil function (421, 469), one study reported a transient
term (see sect. IV). increase in neutrophil degranulation after one, but not two
nights without sleep (122). In contrast, ROS production in
3. Immune cell activity and proliferation neutrophils was reduced after one night without sleep, but
no change was evident in phagocytosis or the percentage of
Besides measuring leukocyte numbers and cytokine produc- phagocytizing neutrophils (112). Finally, the suppressive
tion, the impact of sleep on functional parameters, espe- capacity of natural Tregs was shown to be higher during
cially on NK-cell activity and lymphocyte proliferation, has sleep as compared with a nocturnal vigil (62). However,
also been investigated. During both the night of and the because of the very low number of studies, the results con-
morning after total sleep deprivation or restriction, NK-cell cerning neutrophil and Treg cell function have to be inter-
activity was reduced in healthy humans (253, 254, 386), preted with caution.
suggesting a supportive effect of sleep on this functional
immune parameter. In contrast, no change was evident in 4. Circulating levels of antibody classes, complement
the evening following sleep deprivation for one night (152). factors, and other immune parameters
Interestingly, this latter study found increased NK-cell ac-
tivity in the evening after two nights without sleep, possibly Research on the effect of sleep on the humoral immune
reflecting a slowly evolving counterbalancing response to system (including total IgG, IgM, and IgA antibody levels
NK-cell activity reductions reported during and in the and complement factors) is very scarce so far, and results
morning after acute sleep loss (253, 254, 386). However, should therefore be considered as preliminary. One study
differences in the findings between these studies could also found increases in circulating IgG, IgM, and IgA levels in
be due to differences in the time the assays were performed the morning after one night of total sleep deprivation in
(morning vs. evening). One study in mice found a reduction humans (247), which might reflect a change in the binding
in the cytotoxicity of NK cells after 24 and 48 h of sleep or consumption of antibodies rather than a de novo synthe-
deprivation, which was not evident after a more prolonged sis. Two other studies could, however, not replicate this
deprivation of 72 h (137). It thus seems that sleep is impor- finding (418, 480). Following four days of selective REM
tant for optimal NK cell functioning, since acute depriva- sleep deprivation, circulating IgA, but not IgG and IgM,
tion or restriction of sleep may transiently dampen this levels were reduced (480). Another study found an increase
function in humans and mice. However, if sleep deprivation in secretory IgA in saliva following one and two days with-
or restriction is prolonged, adaptive processes of NK-cell out sleep; however, this might reflect an accumulation of the
activity may commence, as suggested by an increase or nor- antibody due to a decreased saliva flow rate (122). Animal
malization, rather than further reduction, of the response. studies have found enhanced levels of circulating antibod-
ies, especially for IgM, after sleep restriction for 10 days or
Similarly complex is the impact of sleep on lymphocyte longer, but not after shorter periods (171, 596). Overall,
proliferation. Again, during and in the morning or after- results so far are divergent, and the functional significance
noon following acute sleep deprivation of a single night in of changes in antibody levels is difficult to assess.
healthy humans, mitogen-stimulated cell proliferation was
reduced (62, 386, 580), whereas no changes were detected The complement system consists of several plasma proteins
in the evening after one and two nights of total sleep depri- that are produced in a cascade of sequential cleavages by
vation (152). However, following several nights with re- proteases and supports several other immune parameters in
stricted sleep, an increase in PBMC proliferation was re- attacking pathogens. Inappropriate activation of the com-
ported (556). Hence, as for NK-cell activity, adaptive pro- plement system has been shown to play a deleterious role in
cesses (over-)compensating for the effect of sleep loss seem a number of rare diseases (e.g., Neuromyelitis Optica), but
to occur. Animal studies have reported reductions in lym- also in more common diseases, including autoimmune (e.g.,
phocyte proliferation after sleep deprivation for 48 h and RA), neurodegenerative (e.g., Alzheimer’s disease), acute
72 h, but not 24 h (243). However, other experiments failed inflammatory diseases (e.g., sepsis), and various roles for
to find such an effect after prolonged sleep deprivation of 72 the complement system have been proposed in cancer and
h or several days (33, 482). Overall, human and animal cancer therapies (reviewed in Ref. 239). Presumably due to
experiments suggest a general supportive influence of nor- its large complexity, only a few studies have investigated the
mal sleep on lymphocyte proliferation, although the effects effect of sleep on this aspect of the immune system. The
may depend on the duration and type of sleep loss. Further complement factors C3 and C5 were increased after acute
research is needed to better understand adaptive or com- sleep deprivation in one human study (247), whereas others

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found no change in C3, C4, or the receptors C3aR and ings on the cellular expression of molecules should be inter-
C5aR after either acute total sleep deprivation or prolonged preted with caution.
REM sleep deprivation (465, 480). Complement activation,
as indicated by plasma levels of C3a, was even found to be Finally, another more general approach to investigate the
higher during sleep than during nocturnal wakefulness impact of sleep on the immune system is to measure the
(465). The only animal study to our knowledge measuring change in global gene expression in leukocytes after sleep
effects of sleep on the complement system revealed a tran- manipulation. The findings of human studies using this
sient increase in C3 levels after 96 h of REM sleep depriva- technique are generally in line with other results showing
tion, but not after shorter or longer periods of sleep restric- that sleep loss for longer periods enhances inflammatory
tion (596). C4 levels remained unchanged regardless of the pathways (6, 387) and can reduce the functional capacity of
duration of sleep manipulation. leukocytes (433). In addition, sleep restriction has been
found to change the circadian rhythm of genes associated
Cell adhesion molecules are essential for cell-to-cell con- with immune and inflammatory responses; these pertur-
bances in rhythmicity are likely to be also associated with
tacts, for example, between circulating immune cells and
health problems related to sleep disturbances (15, 387) as
endothelial cells, which is an essential step in the migration
described in section IV.
process of leukocytes. These molecules can be found as
soluble forms in the blood or expressed on the surface of
cells. Two human studies investigated the impact of sleep on B. Sleep Effects on Immunological Memory
circulating levels of three different soluble adhesion mole-
cules: intercellular adhesion molecule (ICAM)-1, vascular 1. Vaccination studies
adhesion molecule (VCAM)-1, and E-selectin (200, 489).
E-selectin and ICAM-1 levels were increased following one The findings summarized in the previous section show that
night without sleep, whereas VCAM-1 levels remained un- sleep affects a variety of immune parameters in the steady
changed. The increases were interpreted as indicators of state. However, an effective immune response relies on the
enhanced pro-inflammatory processes and endothelial acti- complex interplay between several immune cells and medi-
vation, which could be linked to the development of cardio- ators. Therefore, it is essential to also consider the impact of
vascular disease (489) (see also sect. IV). Another study sleep on an ongoing immune response. Vaccination is an
measured the expression of L-selectin and the integrin mac- optimal experimental model to tackle this question, as it
rophage-associated antigen (Mac-1) on monocytes and mimics an infection and can be delivered at defined points in
lymphocytes (463). It found that the increase in the percent- time to healthy humans. In contrast to the plethora of data
age of Mac-1-positive lymphocytes observed during a night on the impact of sleep on isolated immune parameters, only
with undisturbed sleep was prevented by depriving partici- a few studies have investigated the direct effect of sleep on
pants of sleep between 11 PM and 3 AM. This was inter- the immune response to vaccination. The very first human
preted as a reduced ability of the cells to migrate to sites of study in this context examined the influence of restricting
infection after sleep restriction. In contrast, sleep restriction bed time to 4 h per night for 4 days before and 2 days after
enhanced the nocturnal increase of L-selectin-positive lym- vaccination against influenza. Influenza-virus-specific anti-
phocytes and monocytes that was evident during normal body titers measured 10 days after vaccination were more
sleep. The lower number of L-selectin-positive cells during than doubled in participants that were allowed to keep their
usual bed time of 7.5– 8 h compared with those with re-
sleep compared with partial sleep deprivation was inter-
stricted sleep (522). Further studies showed that also a sin-
preted as an enhanced activation of immune cells during
gle night without sleep on the night following vaccination
sleep, because L-selectin is shed following cell activation.
against hepatitis A, hepatitis B, and H1N1 (swine flu) re-
However, a reduced expression could also be interpreted as
duces the antigen-specific antibody response (which reflects
a lower migration potential of the cells, as L-selectin is
immunological memory) to a similar extent (34, 320, 325).
necessary for the first step in the migration cascade, which The only study that measured the effect of sleep on cellular
includes the slow rolling of the cells along the vessel walls. immune parameters showed that sleep also enhances the
The results are complicated further by the fact that those number of antigen-specific CD4 T cells, as well as their
cell subsets with a higher expression of L-selectin and production of the Th1 effector cytokine IFN-␥ (320). These
Mac-1 might leave the bloodstream faster than cell subsets results demonstrate that sleep not only supports the mem-
with lower expressions. Therefore, the reduced number of ory phase of the immune response to vaccination, but also
L-selectin-positive leukocytes during sleep could simply re- the effector phase. Of note, three participants from the
flect a selective extravasation of cell subsets with a high Wake group had to receive an additional vaccination be-
expression of this molecule. Although the authors’ interpre- cause their titers were below levels for clinical protection,
tations of the results are in line with the notion that sleep whereas all participants from the Sleep group had sufficient
enhances the migration capacity of leukocytes and their protection, showing the clinical significance of the findings.
activation, the study is also important in showing that find- All vaccines that were employed in these human sleep stud-

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 BESEDOVSKY ET AL.

ies are known to induce mainly Th1-dependent IgG1 and which include the development of low-grade inflammation.
IgG3 responses, which were selectively enhanced by sleep This chronic inflammatory state is associated with an in-
compared with nocturnal wakefulness (320). It is presently creased risk for several diseases and with a decreased ability
unknown, however, whether sleep likewise supports Th2 or to mount adaptive immune responses (198), which might at
CD8 T cell responses. least partly explain the above-mentioned findings of Prather
and colleagues (317, 447).
Of note, in all of these studies the magnitude of the sleep
effect was similarly strong, i.e., on average sleep doubled Results from animal studies are overall less consistent. Most of
the response to vaccination when compared with the wake the experiments are not readily comparable to the studies in
or sleep-restricted groups. In contrast, the persistence of the humans, as they focused on the secondary immune response
sleep effect varied between experiments. Some studies failed (i.e., sleep deprivation took place after a secondary challenge
to reveal any statistically significant differences between in previously immunized animals). In a very early study, mice
groups 4 weeks after vaccination (34, 522), whereas one that had been recently immunized with the influenza virus
study found a pronounced sleep effect even 1 year after the received a challenge, after which they were deprived of sleep
initial vaccination (320). In addition, those studies includ- by gentle handling for 7 h. In contrast to mice that were al-
ing male and female participants either found no sex differ- lowed to sleep, these animals had a lower influenza-specific
ences (325) or a dramatic difference between sex, such that antibody titer and could not clear the virus, thus resembling
only men were affected by the sleep manipulation (34). nonimmunized mice (73). A further study by the same group
These discrepancies might be related to differences in study found comparable effects after immunization with sheep red
designs and virus type, but on the whole, the few available blood cells (75). Other studies, however, did not find such
studies in humans provide convincing evidence for sleep dramatic effects of sleep or even found increased antigen-spe-
strongly supporting vaccination outcomes. cific antibody titers after repeated sleep deprivation (466 –
468, 545). These discrepancies between studies could stem
These experimental studies are also well in line with one from differences in mice and virus strains, as well as differences
prospective study that found habitual sleep duration (as in study design, especially in the timing of the sleep deprivation
measured by wrist actigraphy) to be related to the vaccina- procedure in relation to the antigen challenge and the route of
tion response against hepatitis B (447). Longer sleep dura- antigen administration. Renegar et al. (468) argued that in the
tion in the 7 days surrounding the first of three vaccinations early study by Brown and colleagues (73), animals had not
was associated with higher secondary antibody levels. developed complete immunity against the virus because of the
When sleep duration was divided into the three categories different routes of antigen administration during immuniza-
“less than 6 h,” “6 –7 h,” and “more than 7 h” of sleep per tion (orally) and later challenge (intranasally). Sleep depriva-
night, each additional hour of sleep was associated with an tion might have impaired the migration of lymphocytes to the
~50% increase in antibody levels. Clinical protection sta- respiratory tract in that study, thus interfering with the devel-
tus, which was assessed 6 months after the final vaccination, opment of mucosal immunity. In contrast, in other studies that
was achieved less frequently in participants with a short did not show an impairing effect of sleep deprivation, robust
sleep duration, demonstrating the clinical significance of immunological memory had already developed by the time of
these findings. Sleep efficiency, as assessed by actigraphy, as sleep manipulation (468). It therefore seems that sleep does
well as self-reported sleep quality and duration, as assessed not primarily affect existing immunity but rather supports the
by sleep diaries, were not associated with the immune re- development of immunological memory to a new antigen.
sponse. Interestingly, this study found no association be- This conclusion is indeed well in line with the findings from the
tween sleep duration around the time of the first vaccination human studies in which sleep was manipulated at a time at
and the primary antibody response, but only with the re- which immunological memory was still developing.
sponse after the second and the third vaccination. This
stands in contrast to the experimental studies in which the Some of the studies in animals measured the effect of sleep
effect of sleep was already evident for the primary immune deprivation on virus titers in previously nonimmunized
response. However, habitual sleep duration measures the control mice. However, this was measured only a few days
cumulative effect of sleep loss instead of the acute effect of after the challenge (i.e., during the expansion phase), but
a single night without sleep. As outlined below, SWS seems not during the memory phase, which did not allow for
to be the most relevant sleep stage in mediating the acute measurement of the antigen-specific antibody or T-cell re-
effect of sleep (compared with one night without sleep) on sponse as it was done in the human studies. Most of these
the immune system. However, habitual short sleep is not animal studies did not find an effect of sleep on virus titers
necessarily associated with a reduction in SWS (574); there- (73, 467, 545), although one experiment reported reduced
fore, other mechanisms might underlie the immune conse- virus shedding in the respiratory tract after sleep depriva-
quences of sustained reductions in sleep duration observed tion (466). Hence, sleep does not contribute to the acute
by Prather and colleagues (447). In section IV, we will take suppression of viral replication. As already suggested by
a closer look at the consequences of habitual short sleep, Renegar et al. (468), sleep might rather support the migra-

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tion of lymphocytes, thus supporting the formation of im- memory formation. Although there are clear differences in
munological memory. Indeed, the studies described in sec- memory formation in the CNS and the immune system, e.g.,
tion IIIA showing a sleep-induced reduction in circulating as to the forms of information storage, there seem to be
lymphocyte numbers, together with other studies suggest- some striking similarities. Analogously to the formation of
ing an accumulation of APCs and lymphocytes in lymphatic memory in the CNS, memory in the immune system may be
tissues during the rest phase, support this notion (63, 67, subdivided into three phases (FIGURE 5). 1) Encoding: dur-
143, 148, 169). Further mechanisms presumably mediating ing the encoding phase, the information to be remembered
the positive effect of sleep on the development of immuno- first has to be sensed by our body. In the immune system, the
logical memory include an increase in the production of relevant information is the antigen, which is sensed by APCs
proinflammatory and Th1 cytokines, which are relevant for of the innate immune system. These cells take up the patho-
the early phase of immunological memory formation. Spe- gen at the site of entry and represent an initial store for the
cifically, stimulated production of IL-12 and IL-2, which antigenic information. 2) Consolidation: during the consol-
support the interaction between APCs and T cells and the idation phase, the sensed information is transferred from
subsequent Th1 cell differentiation and proliferation, re- the initial store into a longer-lasting store. In the CNS, the
spectively, was shown to be increased by sleep (67, 148, initial and long-term stores are represented by different
323). The following section discusses possible mechanisms brain regions. In the immune system, the long-term store is
of the supportive effect of sleep on the vaccination response represented by memory T and B cells and plasma cells of the
viewed from the perspective of a general role of sleep in adaptive immune system. The transfer of the information
supporting memory formation in the CNS as well as in the from APCs to T cells takes place in secondary lymphatic
immune system. tissues, where APCs present antigens to T cells. Activated T
cells then proliferate and differentiate into effector and
2. The memory function of sleep memory cells and support the activation of B cells. 3) Re-
call: this phase represents the retrieval of the memory for
Although it is very likely that sleep does not serve only a the encoded information. Memory recall in the immune
single function, one assumed general role of this behavioral system occurs mainly by activation of memory T and B cells
state is to support memory formation. For the CNS, this has upon re-encounter of the antigen and by antibody-driven
been established in numerous studies (see Ref. 457 for a effector mechanisms.
comprehensive review on that topic). Interestingly, sleep
seems to play the same role for immunological memory, as As stated in section IIIB1, sleep supports the formation of
shown by the vaccination studies described above. Compar- new immunological memory rather than affecting existing
ing the role of sleep for memory formation in the CNS and immunity. Thus, rather than supporting the recall phase,
the immune system might help to understand mechanisms sleep seems to foster either the encoding or consolidation
underlying the supportive role of sleep in immunological phase. Almost all of the human studies that demonstrated a

Memory can be subdivided into three processes...

Encoding Consolidation Recall

FIGURE 5. Sleep supports memory consolidation in the brain and

the immune system. Memory processes in the brain are usually
subdivided into three phases, which may also be used to categorize
memory processes in the immune system. During the Encoding
phase, the information to be remembered is taken up. In the immune
system, this phase refers to the uptake of the pathogen by antigen-
presenting cells (APCs). In the Consolidation phase, the initially labile
Uptake of Transfer to Retrieval of information is transferred from the initial store to a long-term store.
information long-term store stored memory For memories in the brain, the information is moved from certain
brain regions to others; for memories in the immune system, the
information (i.e., the antigen) is transferred from APCs to T cells.
During recall, the remembered information can be retrieved, which is
represented in the immune system by the activation of memory T and
B cells. For both the brain and the immune system, sleep and espe-
cially slow-wave sleep seem to be most important for the consolida-
Uptake of Transfer of Facilitated tion phase of memory processes. (Adapted from Tanja Lange.)
antigen by antigenic response
antigen- information upon antigen
presenting cells to T cells re-encounter

Slow-wave sleep

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 BESEDOVSKY ET AL.

supporting role of sleep in vaccination responses manipu- 1970s suggest that sleep improves processes of antigen up-
lated sleep in the night immediately after vaccination (34, take and phagocytosis (93, 420). However, since then, no
320, 325). It is therefore unlikely that sleep affected antigen studies have further studied the specific impact of sleep on
uptake by APCs (i.e., the encoding phase), which should the encoding phase of immunological memory formation.
already have happened before the time of sleep. The sleep Measuring habitual sleep in the 7 nights surrounding a vac-
manipulation occurred within 24 h post-vaccination, i.e., cination did not reveal any single night as uniquely predic-
the time window during which APCs and T cells interact in tive of the humoral antigen-specific response (447). How-
secondary lymphatic tissues. Therefore, sleep seems to sup- ever, this null effect might be due to a small variance be-
port the consolidation phase of immunological memory tween the individual nights within participants. Therefore,
formation. Several findings discussed in section III back up experimental studies that manipulate sleep in the night be-
this idea. Sleep reduces the number of APCs and T cells in fore vaccination are needed to unravel whether the encod-
the blood, probably by redistributing these cells to lymph ing phase of immunological memory does also profit from
nodes (67, 143, 148, 169), thus increasing the chances of adequate sleep.
encounter of both cell types. In addition, sleep, by favoring
pro-inflammatory and Th1 cytokine production, further To summarize, one important function of sleep and espe-
supports the interaction between APCs and T cells and the cially SWS might be to support the formation of memory in
subsequent differentiation and proliferation of Th1 cells, the two super systems, i.e., the nervous and the immune
eventually leading to the formation of IgG1 and IgG3 anti- system, which allows an optimal adaptation of the organ-
bodies (24, 67, 148, 254, 320). ism to the environment. For the immune system, this has
been demonstrated by several vaccination studies in hu-
In the CNS, sleep also supports memory formation during mans, showing that sleep after vaccination doubles the an-
the consolidation phase. A further parallel between the effect tigen-specific immune response. While the impact of sleep
of sleep on CNS and immunological memory is the predomi- has been best investigated for the consolidation phase of
nant role of SWS. Although REM sleep might also support memory formation in the CNS and the immune system, the
adaptive immune functions, the pro-inflammatory endocrine impact of sleep on the encoding and recall phases of immu-
nological memory needs further investigation.
milieu present during SWS (including high levels of GH, pro-
lactin, and aldosterone and nadir levels of cortisol) is optimally
suited for promoting APC-T cell interactions. GH, prolactin, C. Sleep Effects on Infection Outcome and
and aldosterone are known to support T-cell migration, the Risk
release of pro-inflammatory and Th1 cytokines, cell prolifer-
ation, and lymphocyte responses to a microbial challenge (43, Based on the finding that infections can increase and
45, 48, 117, 126, 286, 355, 362–365, 380, 389, 478, 516, intensify NREM sleep, the hypothesis emerged that sleep
518, 524, 575, 583, 601). On the other hand, low levels of is an important acute phase response of the body to help
cortisol during SWS could allow efficient APC-T cell interac- fight infections (544). An early study found that rabbits
tions (157, 211, 417, 427, 438). In line with this idea, the inoculated with different microbes not only exhibited
amount of SWS and SWA in the slow oscillation range (i.e., increased SWS, but that the sleep response was an indi-
slow frequencies of ⱕ1 Hz), as well as the accompanying in- cator of survival chance. Those animals exhibiting a
creases in GH and prolactin and reduction in cortisol levels in stronger enhancement in NREM sleep amount and inten-
the night following vaccination, correlated with the percent- sity had a more favorable prognosis and less severe clin-
age of antigen-specific CD4 T cells measured up to 1 year later ical signs following infection with Eschericia coli, Staph-
(320). Thus the general idea is that SWS, by inducing this ylococcus aureus, and Candida albicans (546). Experi-
unique endocrine constellation, supports the interaction be- mental studies manipulating sleep in animals support the
tween APCs and T cells, which results in a stronger immuno- notion that sleep affects the outcome of an infection. Kuo
logical memory (578). Evidence for the association between and Williams (311) showed that prolonging sleep dura-
SWS and the pro-inflammatory endocrine milieu was so far tion using a genetic approach in Drosophila increased
correlational in nature (98, 216, 521). However, a recent resistance to bacterial infection, as measured by bacterial
study showed that specifically enhancing slow oscillation ac- load, and improved survival compared with flies with
tivity during sleep in healthy participants intensified the hor- normal sleep duration. Interestingly, genetically reducing
monal milieu during SWS (especially by further increasing al- sleep duration did not affect the survival rate, but unex-
dosterone and decreasing cortisol levels) and reduced circulat- pectedly reduced bacterial load. This was interpreted as a
ing lymphocyte counts (49). These findings indicate that SWS reduced tolerance to infection, as the flies showed the
actively induces these endocrine and immunological changes same survival rate as control animals, even though they
rather than being simply a correlate. had a lower bacterial load. A reducing effect of sleep loss
on bacterial load was also found after sleep deprivation
At present, little is known about sleep’s effect on the encod- for between 4 h and 3 days in normal flies (310, 582). The
ing phase of immunological memory. Two studies from the latter study also found an increased survival outcome

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 THE SLEEP-IMMUNE CROSSTALK

following sleep deprivation, seemingly contradicting the poorer ratings of sleep quality, but did not differ in sleep
findings from the same group using a genetic approach to duration compared with participants reporting a normal
manipulate sleep duration. A thorough analysis and se- immune status (154). Using an experimental infection, Co-
ries of experiments, however, revealed that the improved hen et al. (119) showed that people reporting a short sleep
survival outcome was due to the rebound sleep that fol- duration in the weeks before they received nasal drops con-
lowed the sleep deprivation procedure, such that the taining a rhinovirus had an increased risk of developing a
sleep-deprived animals experienced enhanced sleep com- clinical cold. This finding was replicated in a study in which
pared with the nondeprived group. Flies lacking two sleep duration was measured objectively for 7 days using
transcription factors necessary for the development of actigraphy (448). Another study measuring sleep with ac-
rebound sleep did not show an improved survival rate to tigraphy in adolescents showed that short sleep duration
bacterial infection following sleep deprivation (310). was associated with a higher number of reported illness
This supports the conclusion that it was not sleep depri- events, which included symptoms of cold, flu, and gastro-
vation per se that was responsible for the improved sur- enteritis (416). In contrast to these consistent findings, a
vival outcome, but rather the enhanced sleep following recent study found no association between self-reported
sleep deprivation (310). Together, these studies in flies sleep duration and quality and the incidence of self-reported
indicate a positive effect of sleep on the outcome of a upper-respiratory tract infections (208).
bacterial infection. Consistent with this conclusion, one
study in mice found an increased mortality after experi- Interestingly, the study by Patel et al. (428) reporting an
mentally induced sepsis in mice that underwent sleep association between short sleep duration and pneumonia
interruption compared with a control group with undis- risk revealed that participants sleeping 9 or more hours also
turbed sleep (202). Studies in rats have shown that sleep had an increased infection risk. This finding is interesting in
deprivation for several days can even induce a transloca- light of epidemiological studies demonstrating an enhanced
tion of commensal bacteria, which are harmless under mortality not only in short, but also in long sleepers (e.g.,
normal conditions, into several extra-intestinal sites (41, Refs. 22, 88, 235, 340). However, longer sleep may not be
175). This translocation of bacteria has been postulated
directly linked to increased mortality; it is thought that
to eventually lead to general sepsis and death if sleep
confounding variables such as (subclinical) disease mediate
deprivation is prolonged (175). Hence, sleep is not only
this association (22, 88, 340). The other studies mentioned
important for fighting infections induced by invading
above either did not investigate the association between
bacteria, but is also essential to keep in check usually
long sleep and infection risk or did not find such a relation-
harmless bacteria that naturally inhabit our body.
ship (119, 448, 449). It therefore would be too early to
draw any conclusions about the role of long sleep duration
Recent studies have also investigated the impact of sleep on
in infection risk.
parasitic infection, including protozoa and helminths. Sleep
deprivation for 72 h did not affect the number of intestinal
In sum, the literature on short sleep duration and infection
worms in Trichinella spiralis-infected rats or the survival
rate of mice after infection with Trypanozoma cruzi (249, risk in humans convincingly demonstrates an association
482). However, sleep deprivation before malaria infection between both variables (although these studies did not ma-
increased the death rate and number of infected cells in nipulate sleep), and experimental studies in animals have
mice, an effect that was reversed after animals had experi- proven causality for the role of sleep in infection outcome.
enced rebound sleep (345). Taking an evolutionary approach, Preston et al. (453) re-
vealed that evolutionary increases in mammalian sleep du-
Studies in humans have focused on the association between ration are associated with a higher number of circulating
sleep and infection risk rather than infection outcome. Self- immune cells and reduced levels of parasitic infections (en-
reported short habitual sleep (ⱕ5 h per night) was associ- compassing viral, bacterial, and macroparasitic infections).
ated with an increased risk for the development of pneumo- These findings point to an important role of sleep for opti-
nia within the next 2 years (428) and with a higher inci- mal immune defense and may explain why sleep survived
dence of reporting a respiratory infection within the past evolution, despite being a potentially dangerous state of
month (449) compared with 7– 8 h sleepers. Interestingly, prolonged unconsciousness. Several aspects of the influence
participants reporting a habitual sleep duration of ⱕ5 h per of sleep on the immune system remain to be explored, in-
night, but indicating that they feel their sleep duration is cluding how the sleep-induced changes in single immune
adequate, did not have an increased pneumonia risk (428). parameters described in section IIIA relate to the positive
This finding suggests that there are inter-individual differ- influence of sleep on vaccination responses and infection.
ences in sleep needs, and that a short sleep duration can be However, the various studies described in this and the pre-
sufficient for optimal immune function in people with lower vious section clearly indicate that sleep’s effect on immune
sleep needs. This notion is in line with a study showing that parameters does indeed have functional relevance and is
participants reporting a perceived reduced immunity had critical for optimal immune competence.

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IV. IMMUNE SYSTEM CHANGES for these variables); the association with long sleep duration
ASSOCIATED WITH CHRONIC SLEEP was predominantly explained by lifestyle and health status
DEFICIENCY factors, but less so by inflammatory markers (228). Find-
ings from a study in over 2,500 older men followed over a
Over the last decade, a broad spectrum of disorders char- 7-yr period also suggest an inflammatory mechanism un-
acterized by low-grade inflammatory upregulation has been derlying the sleep duration-mortality relationship (515).
identified, including neurological and neuropsychiatric dis- Critically, this study assessed sleep objectively in the home
orders, degenerative diseases, cardiovascular disorders, environment through at-home actigraphy, recorded over a
metabolic disorders, and chronic pain conditions (100, 153, period of at least 5 days, in addition to a single-night PSG.
337). The initiating trigger of inflammatory upregulation in Blood was collected fasted at a standardized time in the
these disorders is not well defined (377) (see also sect. IC). morning, thus controlling for inflammatory variations due
However, substantial evidence (mentioned in sect. IIIA) has to time of day effects and fasting status. Short sleep dura-
accumulated showing that sleep deficiency could be a po- tion of ⬍5 h was related to an increase in all-cause mortality
tent risk factor. In the following two sections, we will re- risk through elevated inflammatory burden (i.e., composite
view studies on the association of immune measures with measure of levels of CRP, IL-6, TNF, sTNF-RII, IFN-␥), as
chronic sleep deficiency in the form of habitual short sleep evidenced by a substantial attenuation of this relationship
duration and chronic sleep disturbances in population- when adjusted for inflammatory burden. The inflammatory
based studies, including reports on insomnia disorder. Po- mediation appeared to be specific to short sleep duration,
tential mechanisms through which chronic forms of sleep since the association between other sleep characteristics
deficiency may lead to a chronic state of low-grade inflam- (e.g., sleep latency or time awake at night) was independent
mation will be discussed in section IVC. Studies investigat- of the inflammatory burden. On a related note, elevated
ing the association between sleep duration and infection CRP has been well established as a clinically useful marker
risk are discussed in section IIIC and are therefore not re- for cardiovascular risk prediction (470) and, therefore, may
viewed in this section. not only underlie the association between deficient sleep
and mortality, but also the association between deficient
A. Immune Measures Associated With sleep and increased risk for cardiovascular diseases (213).
Habitual Sleep Duration
A number of population-based studies have investigated the
association between habitual sleep duration and inflamma-
There is ample evidence that a short habitual sleep duration
tory status independent of their mediating role in mortality
in population-based studies is related to adverse health out-
and other health risks. In most of those studies, inflamma-
comes (i.e., obesity, diabetes, cardiovascular disease, neu-
ropsychiatric symptoms, pain) as well as mortality risk (for tory status was measured by CRP or IL-6 levels in the sys-
review, see Refs. 212, 573). A recent meta-analytic investi- temic circulation, with some studies also assessing IL-1,
gation of 40 prospective cohort studies enrolling over two IL-2, IL-4, IL-5 IL-10, TNF, IFN-␥, fibrinogen, adhesion
million participants reported that shorter sleep duration molecules (e.g., sICAM, E-selectin), WBC counts and sub-
(⬍7 h) in women and longer sleep duration (⬎8 h) in both sets, T cell subsets, and cell function. Sleep duration has
women and men were associated with increased all-cause generally been assessed by self-report through a single ques-
mortality risk (340). The relationship between longer sleep tion (e.g., how many hours of sleep do you usually get at
duration and mortality, while unexpected, has been re- night during a normal work week?), with very few studies
ported in previous reviews and meta-analyses (88, 205, utilizing objective sleep assessment methods (e.g., PSG, ac-
214). It is thought to be due to residual confounders, such as tigraphy). Collectively, findings are variable: with respect to
uncontrolled comorbidities (429), illness-related longer cytokines and other inflammatory proteins (for recent re-
sleep duration in the last months of life (537), among many views, see Refs. 259, 511), some studies reported an asso-
other factors (313). ciation of these markers with short sleep duration, generally
defined as ⬍5 or 6 h of sleep compared with a reference
Inflammatory dysregulation has been suggested as a poten- range of 7– 8 h of sleep (92, 105, 186, 367, 384, 430). Based
tial mechanism linking sleep duration and mortality, given on the longitudinal Whitehall II study in over 5,000 middle-
that inflammatory markers appear to be independent pre- aged adults, higher levels of CRP and IL-6 were not only
dictors of mortality risk in older populations (78, 567). associated with shorter sleep duration, but also with a re-
However, to date, only two investigations exist in this area. duction of sleep duration assessed 5 yr apart (186). A num-
In a prospective cohort study including over 3,000 older ber of studies, however, also reported an association be-
adults followed over a 9-yr period, inflammatory markers tween elevated inflammatory markers and long sleep dura-
(levels of IL-6, TNF, and CRP), lifestyle, and health status tion, defined as more than 8 or 9 h of sleep per night (92,
factors explained the association between higher mortality 114, 156, 430, 452). Although associations between long
risk and self-reported short sleep duration (as indicated by sleep duration and elevated inflammatory status have been
an attenuated mortality hazard ratio in the model adjusted statistically adjusted for a number of factors (including de-

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 THE SLEEP-IMMUNE CROSSTALK

mographic variables, health behaviors, medication, and investigations are needed to further insights of the relation
medical comorbidities), uncontrolled disease processes are between sleep duration and processes of cellular senescence.
still thought to mediate this relationship. Of note, several The variability of findings reported for the relation of sleep
studies did not find an association between inflammatory duration to inflammatory cytokines, as reviewed earlier, is
markers and sleep duration (268, 373, 450, 529, 533), add- also true for the relation to immune cell counts, cell func-
ing to the heterogeneity of findings. tion, and telomere length. Of note, far fewer studies mea-
suring these latter parameters have been conducted, and in
While most studies have focused on the assessment of cyto- some of those studies, habitual short sleep duration has
kines and inflammatory proteins as indicators of inflamma- been found to be unrelated to WBC counts (156, 405),
tory status, a few studies have examined immune cell NK-cell activity (391), and telomere length (451).
counts, cell function/activity, and cell telomere length in the
context of habitual sleep duration. A study in over 600 Inconsistencies in study findings are not surprising given the
adolescents reported an association between high WBC methodological limitations specific to population-based
counts and short self-reported sleep duration (⬍8 h/night) studies as well as methodological differences across studies.
(136). Likewise, in another study in adolescents (n ⫽ 933), While population-based studies can give an estimate of the
short sleep duration (⬍8 h/night) was associated with inflammatory consequences or correlates of habitual sleep
higher cell counts of total WBC, neutrophils, and mono- duration, thus providing critical information beyond the
cytes, as well as higher counts of total T cells, CD4 T cells, effects of acute or subchronic experimentally induced short
memory T cells (CD3⫹RO⫹), and memory CD4 T cells sleep duration in the laboratory setting, experimental stud-
(CD4⫹RO⫹) (435a). A reduction in naive T cell numbers ies can manipulate sleep in the controlled environment, thus
was recently reported to be related to short sleep (⬍6 helping to get insights into the directionality of the sleep-
h/night) in a study with over 2,000 female participants (91). inflammatory relationship.
Such a decline in naive T cells may negatively affect the early
immune response to novel antigens, and may underlie find- A major limitation of almost all of these population-based
ings of a decreased antibody response after vaccination in studies is the lack of a refined and objective sleep assessment
short sleepers (447)(see also sect. IIIB). With respect to cell methodology. Generally, sleep duration is obtained once by
functions, which are generally assessed by the proliferation a single question; other sleep characteristics, including cir-
response of cells induced by antigens or mitogens, self-re- cadian misaligned or mistimed sleep (14, 589), and com-
ported short sleep duration (⬍7 h) the night before blood mon sleep disorders such as apnea (140) or insomnia (191,
collection in healthy adults was related to higher T cell 565) are generally not assessed, although they can substan-
proliferation in response to phytohemagglutinin as well as tially alter inflammatory status, in addition to habitual sleep
to lower NK-cell activity (192). In accordance with the duration. Furthermore, objective assessment methods (i.e.,
latter findings, a decrease in NK-cell activity across two actigraphy, PSG) are rarely used. However, sleep duration
measuring time points has been found to be associated with evaluated by self-report questionnaires and diaries may not
a decrease in self-reported sleep duration in healthy women agree with the results of actigraphy and PSG. In healthy
(504). These findings complement results of experimental populations, self-reported sleep duration appears to be lon-
studies showing a role of sleep in the regulation of lympho- ger compared with actigraphy estimates, while in popula-
cyte proliferation and NK-cell activity (see sect. IIIA3). Re- tions with sleep disturbances, self-reported sleep duration
cent studies linked sleep duration to immune cell telomere tends to be shorter (327, 375). In addition, the length of the
length, which is considered a measure of cellular aging (106, sleep assessment period matters, and single day sleep assess-
284). In more than 400 healthy, middle to early old age ments do not accurately reflect habitual sleep behavior
participants drawn from the Whitehall II Cohort study, (293). Depending on methods used for the assessment of
self-reported short sleep duration in men, but not in sleep duration, findings on its relation to inflammatory
women, was related to shorter leukocyte telomere length markers may vary. For example, in the same study, sleep
(267). A similar association was found in older, but not duration assessed by self-report correlated with levels of
middle-aged, adults (n ⫽ 154) (125) and was recently also CRP and IL-6, while sleep duration assessed objectively by
reported in children (n ⫽ 1,567) (271). Ongoing inflamma- PSG correlated inversely with levels of TNF (430). Another
tion has been shown to contribute to telomere dysfunction, methodological concern contributing to the heterogeneity
although the exact interactions between inflammatory pro- of findings within and across studies is the lack of standard-
cesses, including NF-␬B activity and PRR activation, with ized blood collection times. The production of many in-
telomere functioning are still not well understood and are flammatory markers varies across the 24-h day (95). Unfor-
currently under investigation (276). It is thought that tunately, blood collections are frequently not time-
shorter telomere length may reflect a mechanism or indicate stamped; thus this information cannot be utilized for
a biological pathway by which shorter sleep duration is adjustment in analyses. Future population-based studies
linked to long-term negative health consequences. How- should therefore implement objective, multiple-day long
ever, research in this field is still relatively new, and future sleep assessment methods to gain an accurate estimate of

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habitual sleep duration, and time-stamped blood collec- With respect to the acute phase protein CRP, a longitudinal
tions to control for diurnal variability of inflammatory prediction of CRP levels by sleep disturbances in a general
markers. population was first demonstrated in a study including
nearly 3,000 young adults (108). Using cross-sectional
In summary, many, but not all, studies investigating habit- study designs, a study in more than 8,500 participants
ual short sleep duration support an association with alter- showed that self-reported complaints of difficulty initiating
ations in immune measures, including increased inflamma- sleep and feelings of nonrestorative sleep were associated
tory proteins (in particular CRP, IL-6), increased WBC with CRP levels in men only (328). A sex-specific associa-
counts, reduced NK cell activity, and shortened telomere tion was also found in a cohort of more than 4,000 partic-
length. These alterations may contribute to increased mor- ipants, where self-reported indices of sleep disturbances
tality and disease risk reported for habitual short sleepers, were related to higher CRP levels among men only (341).
and their potential causal role will need to be addressed in Other studies reported such an association in women only
future studies. (268, 339, 445, 529). Furthermore, insomnia symptoms in
combination with objectively-verified sleep duration of ⬍7
B. Immune Measures Associated With h were associated with higher CRP levels as early as adoles-
Chronic Sleep Disturbances cence (n ⫽ 378) (183). A number of smaller scale studies
(⬍200 participants) also support an association between
The use of the term sleep disturbance ranges from the pres- self-reported indices of sleep disturbances and CRP levels
ence of a single sleep complaint (e.g., difficulty falling asleep (373, 408). The sleep disturbance-CRP relationship in the
or frequent nighttime awakenings) up to the presence of above-mentioned studies remained significant even after
insomnia disorder, in which a combination of sleep com- adjusting for several interfering factors, including age,
plaints is present for a certain time. In the general popula- smoking, obesity, cardiovascular risk factors, and depres-
tion, the one-year incidence rate is ~30% for sleep com- sion. However, some studies reported a loss of association
plaints and 7% for new-onset insomnia disorder (331). De- after adjustment for interfering factors (602), or did not
spite high incidence rates of sleep disturbances, the detect a significant association between indices of sleep dis-
immunological consequences and how they translate into turbances and CRP (156, 231, 367, 452).
increased disease risk are still not well understood. A recent
meta-analytic review concluded that sleep disturbances With respect to inflammatory cytokines, a longitudinal
show a stronger association with inflammatory upregula- study including nearly 3,000 participants reported that
tion (i.e., CRP and IL-6) than short sleep duration (259), sleep disturbances (indexed by 6 components, such as sleep
supporting the importance of a better understanding of the onset and sleep maintenance problems) predicted IL-6 lev-
inflammatory consequences of disturbed sleep. This section els measured 5 yr later (108). A cross-sectional study in
will first review the association between immune markers fewer than 200 individuals found an association between
and sleep disturbances in population- and field-based stud- poorer subjective sleep quality (assessed by the PSQI) and
ies, followed by a review of studies addressing the associa- higher stimulated IL-1, TNF, and IL-6 production, of which
tion in individuals suffering from insomnia disorder. Im- only the association with IL-1 remained significant after
mune changes as they occur in breathing-related disorders adjustment for demographic and lifestyle factors (450). As
(e.g., obstructive sleep apnea) are not discussed, as they are with CRP, sex-specific associations have been demon-
strongly related with hypoxia (72, 294), making it difficult strated in a number of studies, including a longitudinal
to isolate the contribution of sleep disturbances to immune study in over 600 adults, in which lower subjective sleep
changes observed in this context. quality at baseline (assessed with the PSQI) was prospec-
1. Population-based studies tively associated with 5-yr increases in IL-6 levels in fe-
males, but not males (445). In accord with this finding, in
Similar to population-based studies focusing on sleep dura- another study only women showed an association between
tion, studies on sleep disturbance have most frequently ex- greater difficulty falling asleep and frequency of sleep dis-
amined cytokines and other inflammatory proteins (in par- turbances (both PSQI subcomponents) with higher levels of
ticular CRP and IL-6, reviewed in Ref. 259), with a few IL-6 (529). On the basis of objectively assessed sleep, lower
studies examining immune cell counts or functions. Assess- sleep efficiency was shown to predict higher IL-6 levels in 74
ments of sleep disturbances are generally based on subjec- older women (201). In a sample of 254 adult men recruited
tive judgement of sleep as good or poor using a graded scale, from a manufacturing company, self-reported insomnia
ratings of single or multiple sleep complaints (e.g., difficulty (defined as the perception of poor sleep combined with
initiating sleep, difficulty maintaining sleep, nonrestorative either difficulty falling asleep, difficulty maintaining sleep,
sleep), or sleep questionnaires, such as the PSQI (87). If or waking up too early one or more times during the past
assessed objectively through PSG or actigraphy, sleep effi- year) was associated with lower stimulated IFN-␥ produc-
ciency and the amount of WASO have been the most fre- tion and a lower IFN-␥/IL-4 ratio in the absence of other
quently used as indicators of sleep disturbances. medical disorders (484). This suggests that self-reported

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insomnia appears to result in a shift towards Th2 immunity. (⬍200 individuals) community sample, good sleep quality
Such a shift in the Th1/Th2 balance has been also observed (assessed by the PSQI) appeared to have a protective effect
for alcohol dependence-associated sleep changes (462) and on age-related shortening of PBMC telomere length, as in-
in response to experimental sleep deficiency (24, 320), and dicated by an attenuation of the age-telomere length asso-
may explain lower vaccine efficacy and increased infection ciation by better sleep quality (125). Such an age-specific
risk in the context of sleep deficiency (see sect. III, B and C). association has been also observed in another study, where
Of note, several studies did not find an association between only the oldest age group (⬎70 yr) had shorter PBMC telo-
cytokines (TNF, IL-6) and sleep disturbances (231, 408, mere length when diagnostic criteria of insomnia were ful-
452). filled (90).

Beyond examining inflammatory markers under basal or The link between sleep disturbances and immune measures
resting conditions, very few studies have focused on inflam- has been also investigated in depression (124, 227, 393,
matory reactivity to a stressful challenge. Inadequate reac- 532), schizophrenia (176), alcohol dependence (462), he-
tivity to physiological or psychological challenges likely modialysis (107, 458), organ transplantation (193), preg-
contributes to increased disease vulnerability (reviewed in nancy (55, 409), cervical cancer risk (491), and diabetes
Ref. 374), and while reactivity to such challenges has been (548), with most studies reporting a significant association
well studied for the classical stress systems (i.e., HPA axis between some aspects of sleep disturbances and immune
and sympathetic nervous system), less is known about in- measures.
flammatory reactivity, although inflammatory markers are
reliably activated by stressful challenges (475). Accord- Collectively, findings support a link between indices of self-
ingly, inflammatory reactivity could potentially be altered reported sleep disturbances as observed in general/clinical
by sleep disturbances (82, 379). Supporting this hypothesis, populations and dysregulation of inflammatory markers,
poorer sleep quality was recently found to be associated immune cell counts, and cellular aging markers. Similar to
with greater IL-6 reactivity following a psychosocial stres- habitual short sleep duration, this suggests that these dys-
sor in postmenopausal women (445). Furthermore, another regulations may constitute a potential mechanism through
which sleep disturbances influence disease risk.
study found that IL-6 reactivity following a series of cogni-
tive challenges was higher in men and postmenopausal
2. Insomnia disorder
women age 50 and older who reported poor sleep quality,
compared with those reporting good sleep quality (233).
Insomnia disorder is diagnosed if symptoms of difficulty
initiating sleep, disrupted sleep, or waking up too early,
With respect to immune cells, increased WBC counts in a combined with an impairment in daytime functioning, are
sample of over 200 male workers in a manufacturing plant present. Depending on diagnostic guidelines, insomnia
were associated with self-reported poor sleep (assessed by a symptoms must occur with a specific frequency (e.g., at least
single question), but not with sleep duration or shift work 3 times per week) and persist for a certain time (e.g., at least
patterns, suggesting a critical role of the perception of sleep 3 mo). While the diagnosis is based on subjective reporting,
as poor in WBC upregulation (403). Based on objective a recent meta-analysis showed that the objective PSG profile
sleep assessment through actigraphy, elevated WBC counts in individuals with primary insomnia (i.e., insomnia not
in a sample of almost 1,100 elderly individuals were asso- attributable to another disorder or substance abuse) is char-
ciated with lower sleep efficiency and higher nocturnal acterized by reduced total sleep time, longer sleep latency,
wake time in women only; this association held even after increased number of nocturnal awakenings per night, and
controlling for various confounders, such as age, obesity, increased wake time after sleep onset, resulting in a de-
and hypertension (405). Furthermore, advanced epigenetic creased sleep efficiency compared with healthy controls. In
age and higher counts of late differentiated CD8 T cells, addition, the amount of SWS and REM sleep appears to be
which are indicators of age-related changes in blood cell slightly, but significantly reduced (25). Such PSG-derived
composition and immune senescence, correlated with in- sleep impairments are generally of a much lesser magnitude
somnia symptoms in a study with nearly 2,100 women. than subjectively reported sleep impairments. For example,
Among insomnia symptoms, waking up at night was the total sleep time based on diary-based assessment is esti-
most strongly related to older epigenetic age (91). mated to be 50 min less compared with PSG-based assess-
ment (25).
In addition, shorter leukocyte telomere length, a proposed
marker of cellular senescence, has been linked with markers There is good evidence that insomnia increases the risk for
of sleep disturbances (assessed by the PSQI) in a sample of certain disorders including depression (439), hypertension
245 healthy midlife women (451) and of 87 obese adults (31), and type 2 diabetes (561). Dysregulations of immune
(446), with the latter study reporting a link with telomere markers have been suggested as a potential mechanism by
length of CD8 and CD4 T cells in particular. Among older which insomnia increases disease risk. However, while sev-
(but not middle-aged) adults from a healthy, small-scale eral studies (reviewed below) have pointed to immune dys-

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 BESEDOVSKY ET AL.

regulations in insomnia disorder, no investigations have yet as recently reported (536). In this study, the vaccination
addressed their mediating role in the association between response to influenza did not differ between 133 healthy
insomnia disorder and disease vulnerability. college students with or without insomnia (based on
DSM-V criteria), although the insomnia group had overall
In one of the first studies on immune system markers in lower antibody amounts pre- and post-vaccination. When
insomnia disorder, a shift of the peak levels of systemic IL-6 controlling for potential covariates, subjective sleep quality
and TNF from nighttime to daytime was observed in 11 (assessed by the PSQI) and insomnia status were predictive
individuals with insomnia without concomitant mental dis- of the influenza antibody response, which led the authors to
orders, compared with healthy age- and body-mass index- suggest that both may attenuate immunity to the influenza
matched control participants (565). The authors suggested virus (536). This complements findings of weaker vaccina-
that these daytime increases in inflammatory cytokines may tion responses in healthy participants with a short sleep
explain increased fatigue experienced during the day. Of duration (see sect. IIIB).
note, eligibility criteria for insomnia in this study included
an objective criterion of ⬍80% sleep efficiency during the Collectively, findings suggest that a diagnosis of insomnia is
screening PSG night. In contrast, another study reported an associated with immune dysregulations, ranging from in-
increase of IL-6 levels during the nighttime, rather than creased levels and diurnal rhythm changes of inflammatory
daytime, in 11 individuals with primary insomnia com- cytokines to decreased lymphocyte subsets to shorter telo-
pared with age- and sex-matched healthy sleepers (84). This mere length, and may potentially attenuate influenza anti-
insomnia sample also showed objective PSG-derived sleep body responses. Given that most studies excluded individ-
impairments, as indicated by increased sleep onset latency, uals with comorbid psychiatric and other disorders, many
reduced total sleep time, and decreased sleep efficiency com- of which are known to affect both sleep and the immune
pared with healthy sleepers. Furthermore, greater PSG-de- system, findings strongly suggest that the presence of insom-
rived nocturnal wake time was related to higher IL-6 levels nia itself is directly linked to immune and inflammatory
(84). A higher inflammatory composite score (IL-6, CRP, dysregulations. Furthermore, the magnitude of such dys-
and monocyte counts) was further reported in 29 individu- regulations may depend on the presence of objective sleep
als with chronic insomnia disorder who were otherwise impairments, which have been suggested as a marker indi-
cating the biological severity and the medical impact of the
healthy [based on Diagnostic and Statistical Manual of
disorder (184, 561).
Mental Disorders (DSM)-V criteria (20)] compared with
age- and sex-matched control sleepers (191). This inflam-
To conclude, habitual short sleep duration and chronic
matory effect was accompanied by objective sleep impair-
sleep disturbances are related to a variety of diseases, in-
ments, as indicated by a decrease in sleep duration (as mea-
cluding cardiovascular diseases, metabolic diseases, chronic
sured by actigraphy) of 45 min daily in those suffering from
pain conditions, some forms of cancer, and neuropsychiat-
insomnia disorder. In another study, counts of lymphocyte
ric disease (255), all of which involve immune dysregula-
subpopulations (i.e., total T cells, CD4 T cells, and CD8 T
tions. While such dysregulations have been found to be
cells) were found to be lower in 19 chronic primary insom-
associated with indicators of short or disturbed sleep in
nia patients (based on DSM-IV criteria) when compared
population-based studies and with the diagnosis of insom-
with healthy sleepers, but no differences were observed for nia in small-scale, well-controlled studies, it is still an open
total leukocyte counts, NK-cell activity, or production of question whether they function as mechanisms underlying
IL-1, IL-2, and IFN-␥ (490). Of note, in the same study, increased disease vulnerability in those suffering from short
individuals with insomnia and healthy sleepers also did not or disturbed sleep.
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 insom- C. Potential Mechanisms of Low-Grade
nia. Although speculative, this lack of difference in objec- Inflammation Associated With Sleep
tive sleep parameters might explain the lack of difference in Deficiency
several immune parameters between insomnia patients and
healthy controls in this study. To date, a single study has Sleep deficiency can induce low-grade inflammation, as in-
investigated telomere length in insomnia: In the oldest age dicated by increases in leukocyte counts and pro-inflamma-
group (⬎70 yr) within a sample of 126 older adults, a tory cytokines following experimental sleep deprivation or
diagnosis of primary insomnia (based on DSM-IV criteria) restriction (see sect. IIIA) or in the context of habitual short
was associated with shorter PBMC telomere length, sug- or disturbed sleep (see sect. IV, A and B). In section IIB3, we
gesting that the presence of insomnia may accelerate cellu- elaborated on the possibility that environmental interac-
lar aging in the later years of life (90). Sleep was not objec- tions can initiate an inflammatory response through PAMPs
tively assessed in this study. Such abnormalities reported for and DAMPs, which activate PRRs on immune and nonim-
basal immune and inflammatory markers in insomnia dis- mune cells. A simple explanation of how sleep loss might
order may underlie inadequate influenza vaccine responses promote low-grade inflammation could be that any addi-

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 THE SLEEP-IMMUNE CROSSTALK

tional time spent awake enhances environmental interac- adverse lifestyle habits like physical inactivity (431) and
tion, potentially leading to activation of PRRs by PAMPs unhealthy food (508), and psychosocial influences like
and DAMPs that will trigger inflammatory processes. In stress (121, 189, 454, 525), loneliness (120), and low so-
addition, SWS-dependent processes might actively counter- cioeconomic status (166). These are all factors that should
act inflammation in the brain (64, 65, 302). Supporting this be controlled for in studies linking short or disturbed sleep
hypothesis, a study in healthy humans found that CSF levels and inflammatory processes.
of amyloid beta, a DAMP (115) that is released during
synaptic firing, showed a rhythm parallel to the sleep-wake In sum, available evidence in animals and humans suggests
cycle (i.e., amyloid beta increases during the day and de- that sleep counteracts low-grade systemic inflammation
creases overnight) (280). Furthermore, amyloid beta was and in this way maintains immune homeostasis. In section
found to be lower following a night of regular sleep com- IID, we outlined that chronic inflammatory conditions are
pared with a night of total sleep deprivation (410, 509) or associated with sleep disturbances, and it is conceivable that
SWS disruption (278). It is assumed that the glymphatic physiological sleep regulation fails when inflammatory me-
system, a waste clearance pathway to eliminate soluble pro- diators are constantly elevated. However, sleep distur-
teins and metabolites from the CNS, flushes amyloid beta bances in inflammatory conditions presumably also have a
away from the brain parenchyma during sleep (60, 81). As negative effect on the underlying immune process, thus
shown in animals, this system allows the drainage of deep feeding into a vicious circle.
brain structures resulting from an increase of cortical inter-
stitial space, which expands by more than 60% during sleep V. SLEEP TO REINSTATE IMMUNE
(593). Disturbances in this metabolic clearance due to the BALANCE
lack of sleep can lead to neuroinflammation and, in the long
While recovery sleep has been well studied with respect to
term, to neurodegenerative diseases (60, 399). A parallel
the reversibility of neurobehavioral consequences of sleep
active clearance of IL-1 and TNF from the brain during
deficiency, the question of whether immune and inflamma-
NREM sleep has been suggested (116), but as yet awaits
tory consequences return to normal once recovery sleep has
experimental evidence. In the periphery, recumbency and
been obtained has only recently gained attention. Within
sleep-associated changes in the vasculature could likewise
the neurobehavioral domain, for example, various doses of
affect the draining of proteins from tissues and organs by
recovery sleep (0, 2, 4, 6, 8, and 10 h) following five nights
the lymphatic system (143, 167, 168, 312). Both the glym- of experimental sleep restriction resulted in a sleep-dose-
phatic and the lymphatic systems eventually redirect pro- dependent decrease of lapses (i.e., reaction times over 500
teins including sleep regulatory substances into lymph ms) in the psychomotor vigilance test (28) (reviewed in Ref.
nodes and then into the circulation for final clearance by the 30). Furthermore, performance did not return to baseline
liver or the kidneys (144, 145, 343). The role of sleep in levels after a single night with a 10-h sleep opportunity (28)
these processes, however, is completely obscure. In rats, or three nights with an 8-h sleep opportunity (32), suggest-
sustained sleep deprivation induced oxidative stress as well ing that a longer recovery sleep period is needed to fully
as DNA, cell, and tissue damage (173), likely representing a resolve any performance decrements due to experimental
condition of increased DAMP levels and DAMP-driven in- sleep deficiency. Although such elegant sleep-dose recovery
flammation. In this study, cell injury was most pronounced responses have not yet been conducted for immune and
in the intestine (173), which could result in increased intes- inflammatory processes, the following sleep recovery op-
tinal permeability (leaky gut) and, together with the impair- tions have been examined as potential countermeasures of
ment of host defense following sleep loss, to a translocation the inflammatory consequences of sleep deficiency and will
of commensal bacteria and PAMP-driven systemic inflam- be reviewed below: 1) recovery sleep following experimen-
mation (175, 303) (see also sect. IIIC). Whether sleep loss tally induced sleep deficiency, 2) daytime napping, and 3)
contributes in this way to intestinal dysbiosis and, conse- extension of habitual sleep duration. Furthermore, recent
quently, to low-grade inflammation is still unclear (12, 37, studies investigated the immune effects of cognitive behav-
425, 444, 603). Finally, the HPA axis, which is crucial in ioral therapy (CBT) in chronic sleep disturbances, such as
suppressing inflammatory processes, might become im- insomnia disorder. While the effects of recovery sleep have
paired by (prolonged) sleep loss (379). Indeed, one study been studied in both experimental animal and human mod-
found that the interplay between inflammatory and stress els, there are no animal models on the effects of nap behav-
markers at the cell level, as assessed in vitro by the sensitiv- ior, sleep extension, or interventions equivalent to human
ity of monocytes to the counter-inflammatory cortisol sig- CBT.
nal, was dysregulated following prolonged sleep restriction
in humans (512). A. Recovery Sleep Following Acute Sleep
Deficiency
Notably, chronic sleep disturbances may be the cause or the
consequence of other known triggers of low-grade inflam- In humans, one of the first studies investigating immune
mation, including circadian disruption (370), obesity (406), recovery from total sleep deprivation (i.e., 64 h continuous

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 BESEDOVSKY ET AL.

wakefulness) in healthy adults reported that monocytes still be exaggerated at the end of the recovery period, as indi-
tended to be increased after a single night of recovery sleep cated by a higher amplitude of the diurnal curves (326).
(duration not reported) compared with pre-deprivation lev- These findings suggest that restoration of not only the num-
els, while recovery levels of leukocyte counts, granulocyte ber, but also diurnal rhythms of some immune cell popula-
counts, and NK-cell activity returned to pre-deprivation tions require prolonged periods of recovery sleep.
levels (152). In a study using a total sleep deprivation pro-
tocol, increased numbers of leukocytes and monocytes as- Besides recovery of circulating immune cells from sleep de-
sessed once in the morning following 2 days of continuous ficiency, a few studies investigated recovery of cytokines
wakefulness in healthy young men normalized after a single and inflammatory proteins. Spontaneous production of
night of recovery sleep compared with control sleepers IL-6 and TNF by monocytes was increased in the morning
(480). However, increases in CD4 T cells remained elevated after a night of sleep restriction, and this increase persisted
even after three nights of recovery sleep (480). In a study in those monocytes that co-produced IL-6 and TNF after a
utilizing frequent blood sampling over 51 h in healthy night of recovery sleep (264). In another study, an increase
young men, recovery sleep following a single night of sleep of LPS-stimulated monocytes co-producing IL-6 and TNF
deprivation fully restored the sleep deprivation-induced in- after a night of sleep restriction persisted after a night of
crease in monocyte counts (67). Nocturnal increases in lym- recovery sleep in younger (⬍40 yr), but not older partici-
phocyte counts, including NK cells, CD4 and CD8 T cells, pants (⬎60 yr) (89). Mimicking sleep patterns of a common
and activated T cells, were reduced in the evening following week with 5 days of restricted sleep (4 h of sleep/night)
sleep deprivation compared with a sleep control group. A followed by 2 days of recovery sleep (limited to 8 h of
further reduction of NK cells and activated T cells was sleep/night), sleep restriction induced elevations of IL-1,
observed during recovery sleep, indicating a compensatory IL-6, and IL-17 (as assessed at the mRNA level of stimu-
decrease of those cell subsets (67). Furthermore, a single lated PBMCs) (556). These parameters were still elevated,
night of recovery sleep limited to 8 h following a single night though nonsignificantly, after two nights of recovery sleep.
of sleep restricted to 2 h was not able to recover increased Circulating CRP levels even continued to increase after re-
WBC counts (mainly due to elevated neutrophil subsets) covery sleep (556). However, another study showed that
assessed at 7 AM in healthy men (178). However, when when recovery sleep was extended to 10 h per night for
recovery sleep was extended to 10 h in healthy men, both three nights, elevated circulating IL-6 levels resulting from 6
WBC and neutrophil counts normalized. Monocyte counts, days of sleep restriction (6 h of sleep/night) returned to
in contrast, were not affected by either sleep restriction or normal in healthy adults (432). Such findings suggest that
recovery sleep, while lymphocyte counts nonsignificantly sleeping in on the weekend (i.e., extending habitual sleep
decreased in response to sleep restriction, with a further duration) and/or having multiple days of recovery sleep
significant decrease following 8 h of recovery sleep. Again, may help to resolve inflammatory modifications due to
extending the recovery night to 10 h appeared to dampen acute sleep deficiency.
the lymphocyte decrease observed after an 8-h recovery
night to nonsignificance (178). These findings suggest that In recent years, the chronicity of common patterns of sleep
increasing the amount of recovery sleep obtained in a single restriction with intermittent recovery sleep has been exper-
night can help to normalize consequences of sleep deficiency imentally modeled to examine processes of inflammatory
on cell counts. Using an experimental model in which five adaptation to the repeated exposure to such patterns. A
nights of sleep restriction (4 h of sleep/night) were followed common feature of many biological systems is to habituate
by two nights of recovery sleep (8 h of sleep/night), numbers (i.e., to decrease in response) when repeatedly exposed to
of B lymphocytes, but not T lymphocytes, increased in re- the same stressor or challenge (215). Whether this is also
sponse to sleep restriction, and were restored to normal true for the repeated exposure to sleep deficiency is not
values after the two recovery nights (556). A recent study known. Using an experimental model mimicking common
investigating immune cell subpopulations in healthy young patterns of sleep restriction during week days (4 h of sleep/
men employed a longer recovery period of 7 days (8 h of night) and recovery sleep during weekend days (8 h of sleep/
sleep/night) following 5 days of sleep restriction (4 h of night) over a 3-wk-long period in healthy young adults, one
sleep/night) (326). Counts of total WBC, monocytes, neu- study found that stimulated IL-6 expression by monocytes
trophils, and lymphocytes gradually increased across the increased during the second and third week of sleep restric-
days of sleep restriction. While counts of monocytes and tion and remained elevated above baseline levels after re-
lymphocytes returned to baseline levels after a single night covery sleep was obtained (512). These findings suggest that
of recovery sleep, neutrophil counts were not restored to the inflammatory system does not habituate to the repeated
pre-restriction levels even after 7 days of recovery sleep exposure of common sleep restriction-recovery patterns
(326). Furthermore, this is one of the few studies utilizing over a 3-wk period. The inflammatory consequences of ex-
frequent blood sampling throughout the day and found a posure to such patterns over a longer period of time (e.g.,
flattening of the diurnal rhythms of WBC and neutrophil years or decades), as are often experienced in real life, still
numbers in response to sleep restriction, which appeared to need to be addressed in future studies.

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 THE SLEEP-IMMUNE CROSSTALK

In animals, investigations on the effects of recovery sleep B. Daytime Napping

on immune parameters are rare. A recovery sleep period
of 48 h reversed the reduction in survival of a malaria Like research on nighttime recovery sleep, research on the
infection, induced by prolonged REM sleep deprivation pro- and/or anti-inflammatory consequences of daytime
in mice; in contrast, 24 h of recovery sleep were not nap behavior is still in its early stage. Within population-
enough to reverse the sleep-deprivation-induced effects based studies, the effects of habitual napping on inflamma-
(345). In rats, 48 h of recovery sleep following 10 days of tory markers appear to be complex. For example, in a study
sleep deprivation restored sleep deprivation-induced in- with over 300 participants, self-reported nappers had in-
creases of myeloperoxidase activity (an enzyme constitu- creased circulating CRP and IL-6 levels compared with non-
ent of neutrophils) in the lung and liver. However, my- nappers, but this relationship was influenced by a number
eloperoxidase activity in the intestines was increased of factors, including nap frequency, nighttime sleep dura-
after recovery sleep compared with baseline and sleep- tion and quality, and health status (142). Self-reported nap-
deprivation levels, suggesting ongoing reactive processes ping assessed in over 5,000 older participants was also as-
during recovery sleep subsequent to sleep deprivation sociated with higher CRP levels, particularly in older par-
(174). In rats undergoing prolonged sleep restriction for ticipants, but the relationship was attenuated after
21 consecutive days, a decrease in total leukocyte counts adjusting for health-related variables such as pre-existing
normalized after 24 h of recovery sleep, but did not nor- diseases, blood pressure, and depression (335). An associa-
malize after recovery sleep following a REM sleep depri- tion between increased napping and elevated CRP has been
vation protocol over 4 consecutive days (596). In light of also found in a young population of over 2,100 adolescents
a number of other immune measures modulated by these (358). Again, complex interactions among daytime nap be-
protocols (not reviewed), findings suggest that immune havior, nighttime sleep, health status, and CRP levels were
recovery depends on the type and duration of prior sleep found. The directionality of the relationship between day-
loss, with considerable response variation between dif- time napping and inflammatory markers remains unknown
ferent immune measures. in these non-laboratory population-based studies, although
it has been argued that nap behavior most likely results
In summary, while research on immune recovery is still in from underlying health problems (see also the review in Ref.
its early stages, current findings suggest that restoration of 177).
sleep deficiency-induced modifications of some (but not all)
immune markers, as well as their diurnal rhythmicity, takes In the controlled laboratory setting, a few studies have ex-
longer than a single or even a couple of nights of recovery amined the effect of daytime napping as a counter-measure
of the inflammatory effects of acute sleep deficiency. A mid-
sleep. Future studies are warranted to identify the amount
afternoon nap of 2 h has been shown to reverse the effects of
of recovery sleep required to gain full immune and inflam-
one night of total sleep deprivation on circulating IL-6 levels
matory restoration following exposure to sleep deficiency.
in young healthy participants (563). Similarly, two 30-min-
In light of current research findings, recovery needs will
long naps (in the morning and afternoon, respectively) nor-
likely differ for different immune and inflammatory mark-
malized daytime IL-6 decreases observed after a night of
ers, with some markers restoring quickly and others requir-
sleep restricted to 2 h (180). In another study, adding a
ing prolonged sleep recovery periods involving extended
short early afternoon nap of 30 min to a standard 8-h long
sleep per night or multiple nights of recovery sleep; based on sleep recovery night was sufficient to normalize increased
current findings, neutrophils and IL-6 likely fall into the neutrophil counts that resulted from prior exposure to a
latter category. night of sleep restricted to 2 h (178).

Future studies are also warranted to identify mechanisms Collectively, findings generated in the laboratory setting
contributing to slow or incomplete recovery of inflamma- suggest that napping appears to be an effective counter-
tory markers. Counter-inflammatory pathways likely play measure that supports the recovery of immune changes in-
an important role in establishing complete inflammatory duced by acute sleep deficiency. Opposing findings from
recovery. Signals with counter-inflammatory properties in- population-based studies, where napping appears to be as-
clude the classical stress hormone cortisol, anti-inflamma- sociated with elevated, rather than decreased or normal
tory cytokines (such as IL-10), and the newly discovered inflammatory markers, are thought to reflect underlying
omega-3- and -6-derived inflammatory lipid mediators health problems, a hypothesis that warrants future investi-
(such as resolvins and maresins), which actively resolve in- gations. A better understanding of the influence of nap char-
flammation (502). A better understanding of the role of acteristics, such as nap frequency, duration, placement dur-
counter-inflammatory pathways may help to develop phar- ing the daytime, as well as interactions of daytime nap be-
macological strategies to ameliorate the inflammatory con- havior with nighttime sleep behavior on inflammatory
sequences of sleep deficiency, thereby reducing inflamma- status will likely help to optimize nap behavior as a poten-
tory-related disease risk. tial inflammatory countermeasure of sleep deficiency.

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 BESEDOVSKY ET AL.

C. Extending Habitual Sleep Duration lower levels of CRP throughout the 16-mo follow-up period
compared with adults receiving sleep education, and this
Considering that cutting back on sleep on a regular basis is a decrease was associated with remission of insomnia (258).
common behavior, extending habitual sleep duration may Furthermore, the percentages of monocytes producing TNF
help reduce immune/inflammatory changes associated with alone or in combination with IL-6 were lower 2 mo post-
habitual short sleep (i.e., sleep duration of ⱕ6 h/night). How- treatment (257), but not during later follow-up time points.
ever, to date, only a few studies have explored inflammatory Using a genome-wide transcriptional profiling approach,
changes after sleep extension. In one study, participants with genes that were downregulated after CBT-I included tran-
pre- or type 1 hypertension and habitual sleep duration of ⬍7 scripts involved in inflammation, while upregulated genes
h per night extended their bedtimes for 60 min every day over included transcripts involved in IFN and antibody re-
6 wk, which resulted in an actigraphy-based increase in sleep sponses (257). These immune effects suggest that CBT-I in
duration of ~35 min per day (225). This increase of habitual adults suffering from insomnia lowers inflammatory risk.
sleep duration by ~10% per day resulted in a substantial de- The impact of CBT-I on immune markers has also been
crease in blood pressure, while inflammatory markers (i.e., investigated in medical populations with sleep distur-
WBC counts and circulating levels of CRP and IL-6) nonsig- bances. In women with insomnia disorder secondary to
nificantly decreased from pre- to post-intervention. Given in- breast cancer, LPS-stimulated production of IL-1 and IFN
sufficient statistical power to detect inflammatory changes in in whole blood was increased from pre-to-post CBT-I treat-
this study, future studies with an adequate sample size need to ment (492), although whether these changes were paral-
substantiate these preliminary findings. A recent study in leled by CBT-I-induced sleep changes was not addressed. In
healthy young men increased bedtime by 1.5 h over 6 consec- peritoneal dialysis and hemodialysis patients, CBT-I im-
utive days (103). PSG-derived total sleep time between the proved sleep quality compared with a sleep hygiene educa-
extended bedtime condition (9 PM–7 AM) and habitual bed- tion intervention, which was paralleled by a decrease of
time condition (10:30 PM–7 AM) differed by ~100 min on serum levels of inflammatory markers, including IL-1 (102),
average, mainly due to increases of sleep stages 1, 2, and REM CRP, and IL-18 (101).
sleep in the extended bedtime condition. However, no differ-
ences were observed in lymphocyte, monocyte, or neutrophil Interpretation of immune changes in response to CBT-I can be
numbers in the blood (103). Of note, blood was assessed only challenging, in particular in clinical populations where the
once per day, which may have reduced the chance of detecting underlying medical disorder potentially interferes with the im-
transient changes in cell numbers. Furthermore, the amount of mune status. However, overall, findings suggest that improv-
SWS, which may play a critical role in leukocyte subset ing sleep disturbances has a beneficial effect on various im-
changes (49), was not changed by the bedtime extension con- mune parameters, which potentially may mediate the associa-
dition. In summary, research on the effects of sleep extension tion between sleep disturbances and increased disease risk
on immune parameters is still in its early stages, and further reported in epidemiological studies (see sect. IVB).
studies are needed to evaluate whether extending sleep dura-
tion is beneficial for the immune system. To conclude, recovery sleep following acute sleep defi-
ciency, naps, extension of habitual sleep duration, and
CBT-I may counteract sleep deficiency-induced changes of
D. Cognitive Behavioral Therapy for immune measures. Future research in this young field will
Insomnia need to investigate optimal strategies, for example, with
respect to placement and length of recovery sleep/naps, to
CBT for insomnia (CBT-I) is considered the first-line treatment successfully restore sleep deficiency-induced immune
for insomnia (557) and outperforms pharmacological inter- changes.
ventions, in particular with respect to maintenance of thera-
peutic effects at long-term follow-up (270, 513). In recent
years, studies on CBT-I have incorporated a physiological VI. CONCLUSIONS AND FUTURE
measuring arm, including the assessment of immune parame- DIRECTIONS
ters, which will be reviewed below. The impact of pharmaco-
logical sleep interventions, such as benzodiazepines (e.g., tria-
zolam) and nonbenzodiazepines (e.g., zolpidem) (reviewed in A. Conclusions
Ref. 159) on immune parameters has received very little atten-
tion and is not discussed here. The interested reader is referred 1. Immune-to-sleep directionality
to recent reviews on the effects of pharmacological sleep ther-
apeutics on specific immunological aspects (i.e., wound heal- Sleep and the immune system are bidirectionally related.
ing and infection risk) (163, 277). Substances of the immune system, in particular the cyto-
kines IL-1 and TNF, and PGD2 are involved in the regula-
In one of the largest CBT-I studies with over 100 older tion of spontaneous, physiological sleep in animals, and
adults suffering from primary insomnia, CBT-I resulted in also mediate the increase of NREM sleep amount and in-

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 THE SLEEP-IMMUNE CROSSTALK

tensity after the animal’s host defense is challenged with between those investigating immune correlates of habitual
pathogens. These (and other) cytokines and PGs are poten- sleep duration. As outlined in this review, this likely stems
tially also involved in the physiological sleep regulation and from a number of methodological differences, particularly the
pathogen-induced sleep responses in humans, although ex- lack of objective sleep assessment and standardized timing of
perimental evidence is still weak. Experimental studies on specimen collection in these studies. Implementing objective,
the application of pathogens and components of pathogens multiple-day-long sleep assessment methods (to gain an accu-
(e.g., endotoxins) in humans, as well as field studies in in- rate estimate of habitual sleep duration) and time-stamped
dividuals with chronic infectious and inflammatory dis- blood collections (to control for diurnal variability of inflam-
eases, show that sleep changes are common, but can vary matory markers) may diminish the variability of study findings
greatly, including enhanced, reduced, disrupted, or mis- in the future.
placed sleep. The type of sleep change likely reflects a com-
bination of various factors, including the type of pathogen 3. Clinical implications of the sleep-immune crosstalk
and severity of host defense responses. In the case of chronic
infectious or inflammatory diseases, disease activity, stage, In addition to infectious and chronic inflammatory condi-
symptom severity, and comorbid disorders play a role, too. tions that involve a clear immunopathology (e.g., HIV,
However, the immune system’s involvement in disease-as- RA), numerous other diseases emerged in the last decades
sociated sleep changes is probably best supported by recent for which mild systemic elevations of inflammatory mark-
research on the effects of immunotherapy (e.g., anti-TNF ers are characteristic, including cardiovascular (481) and
treatment) on sleep, which shows that dampening activity metabolic diseases (153), certain forms of chronic pain (23),
of certain inflammatory cytokines improves sleep quantity certain cancers (165), and neurodegenerative diseases (9).
and quality. While it has been shown that PAMPs are up- In all these diseases, deficient sleep is common (279). As we
stream molecules of the increase in sleep-regulatory sub- have outlined in this review, sleep deficiency induces im-
stances, the role of DAMPs in this context is still unknown. mune system changes, and vice versa, the immune system
modulates sleep. Consequently, targeting sleep will need to
2. Sleep-to-immune directionality be an integral part of disease prevention and treatment
strategies, while at the same time, research continues to
A) EXPERIMENTAL STUDIES. Several experimental studies in animals address the knowledge gaps (see next section). Examples of
and humans show that manipulation of sleep can affect a wide clinical translations of knowledge gained in the sleep-im-
array of immune parameters, including leukocyte migration mune field are outlined in the following (see also Box 1):
and distribution, cytokine production, leukocyte activity and • Given that sufficient sleep promotes an optimal vacci-
proliferation, antibody levels, complement activation, expres- nation response, individuals should be informed to
sion of cell adhesion molecules, and immune-related genes. It have sufficient sleep when receiving a vaccination. Vac-
is therefore not surprising that sleep influences infection out- cinations will likely benefit also from wiser timing.
come, as well as the response to vaccination as an experimen- Thus, depending on the type of antigen, the beneficial
tal model of infection. Studies in flies and rodents suggest that effects of sleep on vaccination outcomes may be more
sleep increases the survival of an infection, whereas several pronounced following vaccination either in the morn-
studies in humans indicate that sleep loss increases the suscep- ing or in the evening.
tibility to infections and worsens the immune response to vac- • The knowledge about the relationship between sleep
cination. Mechanisms underlying the effect of sleep on the and infection risk/outcome is most relevant for inpa-
immune system are not well understood. The current literature tients in hospitals, as infections are a serious risk factor
supports the hypothesis that SWS, by inducing an immune- for multi-morbid and immunocompromised patients.
supportive hormonal constellation, fosters and coordinates Sleep disruption is a well-studied and highly prevalent
the migration of T cells and APCs to lymphatic tissues as well problem in intensive care units (e.g., Refs. 204, 440).
as the communication between these cells. This may lead to an Reducing factors responsible for sleep disturbances in
improved adaptive immune response and stable immunologi- the hospital environment such as exposure to constant
cal memory formation. The effect of sleep on functional as- noise and light are likely to minimize complications
pects of the innate immune response has been less thoroughly and improve recovery (440).
investigated. • Sleep does not only affect immune functions related to
infection, but also those to several other immune-related
B) FIELD STUDIES.Findings of studies in the natural setting show pathologies. For instance, sleep disturbances can increase
that sleep duration (short and long) and sleep disturbances allergic reactions and worsen tumor-related immune re-
(including insomnia disorder) are linked to dysregulation of sponses (138, 226, 289, 404), which indicates that pa-
inflammatory markers, immune cell counts, and cellular aging tients with these diseases could profit from sleep improve-
markers. These immune dysregulations may constitute a po- ments. In other situations, however, patients may profit
tential mechanism through which sleep influences disease risk, from controlled, short-term sleep deprivation, in analogy
which has been supported in more recent studies. However, to employing sleep deprivation as antidepressive treat-
there is a considerable variability between studies, particularly ment in mood disorders (128). Organ transplantation

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 BESEDOVSKY ET AL.

might be such a clinical condition that could take advan-

tage of the immunosuppressive effects of sleep depriva- • Clinicians should be aware that many diseases are comorbid
tion: One study reported a prolonged allograft survival with sleep disturbances and encourage the patients to im-
after sleep deprivation, which was accompanied by a re- prove their sleep behavior and educate them about sleep
duced number of graft-infiltrating CD4 T cells (479). hygiene (i.e., good sleep habits). This may have a beneficial
effect on the severity and progression of the disease.
However, much research will be needed to investigate
• Various medications can disturb sleep (e.g., beta-blockers,
whether there is an optimal “dosage” of controlled sleep corticosteroids, analgetics, anti-depressants), which needs
deprivation in such specific contexts that outweighs the to be considered in treatment decisions.
widespread negative consequences of sleep loss.
• Postoperative pain is a major health care challenge that
remains undermanaged (590). In human and animal
B. Future Directions
models, sleep disturbances pre- and post-surgery have
been shown to be associated with prolonged postopera-
1. Variability in methods influence the outcome of
tive recovery time and increased pain (reviewed in Refs.
experimental studies
110, 229, 571), one of the cardinal signs of inflammation.
Hence, pre- and post-operative sleep management will As mentioned in the previous sections, several factors influ-
likely reduce postoperative pain and accelerate recovery ence the sleep-immune relationship (FIGURE 1). The meth-
processes. ods of manipulating sleep vary greatly, especially in animal
• A number of medications for the treatment of various studies. Some methods induce greater amounts of stress, as
diseases have sleep-disturbing effects, thereby potentially defined by HPA axis and sympathetic nervous system acti-
decreasing the immunosupportive effects of sleep. Sleep- vation, which can affect immune parameters independently
disturbing or -altering effects have not only been shown of the sleep manipulation (423, 530). Therefore, methods
for psychotropic medications (e.g., antidepressants), but keeping stress factors to a minimum or appropriately con-
also nonpsychotropic drugs, including cardiovascular trolling for them should be used in future animal studies.
drugs (e.g., beta-blocking agents), corticosteroids, and For short-term sleep deprivation, gentle handling tech-
analgetics (e.g., opioids, NSAIDs) (reviewed in Ref. 554). niques (see TABLE 1) may be considered the methods of
Appropriate dosage and timing of medications or medi- choice as they avoid possible stress effects associated with
cation change should be considered to keep associated movement restriction, forced activity, and contact with wa-
sleep-disturbing effects at a minimum. ter, which are inherent to other methods (8, 476).
• In disorders characterized by immune dysregulations, im-
mune-therapy may not only be used to improve disease Sleep can be deprived totally (no sleep allowed during the
activity, but also to directly improve sleep. As described in entire manipulation period) or partially (altering periods of
section IID2, treatment of RA patients with IL-6 or TNF forced wakefulness with opportunities for recovery sleep).
blockers improved sleep (196, 283, 535). Comparable Other methods induce disruptions of sleep continuity or
effects of anti-TNF therapy on sleep were found in pa- selectively deprive only single sleep stages. The duration of
tients with IBD and ankylosing spondylitis (282, 527). sleep manipulation also varies greatly between studies,
from only a couple of hours to several weeks. This can lead
Along a similar line, administration of a TNF antagonist
to different, and sometimes opposite, outcomes, as the body
to abstinent alcohol-dependent patients counteracted in-
may try to compensate for the effects of sleep loss. Environ-
creases in REM sleep, which are prospectively associated
mental factors, such as light exposure, ambient tempera-
with the risk of alcoholic relapse (260).
ture, body posture, food, and fluid intake, have been con-
trolled to different degrees in different studies. As described
in previous sections, the type of immune assay is also rele-
vant when assessing the outcome of sleep manipulation.
BOX 1. Callout box for clinicians Finally, sleep-immune interactions might also vary between
• Sleep is a biological need, and adequate sleep duration and different species.
quality help maintain immune health.
• Patients should be educated to attain sufficient sleep after
Taken together, all these factors can greatly influence ob-
receiving a vaccination to strengthen the vaccine response.
• Adequate sleep duration can improve infection outcomes and
served outcomes and might explain divergent results from
is associated with reduced infectious disease risk. different studies. Therefore, it is essential that future studies
• Chronic sleep deficiency disturbs immune homeostasis, thereby control for such factors and consider that different manip-
presumably increasing the risk for the development and amplifi- ulation techniques, species, and employed assays can influ-
cation of several diseases in which immune dysregulation is ence findings. In addition, only recently, approaches that
common (e.g., cardiovascular, metabolic, autoimmune, and enhance sleep (e.g., sleep extension, acoustic stimulation,
neurodegenerative diseases). long-sleeping fly mutants, see also TABLE 1) are becoming
more frequent. These methods are an important addition to

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 THE SLEEP-IMMUNE CROSSTALK

the sleep deprivation studies as they allow investigating the could potentially translate into targeting specific sleep com-
active role of sleep (rather than the effect of a lack of sleep). ponents to prevent or ameliorate an age-dependent decline
We therefore encourage employing such methods more fre- in immune functions.
quently in future studies.
Furthermore, when evaluating sleep and immune changes
2. Understanding the sleep-immune relationship in chronic infectious or inflammatory diseases, the associa-
across various time dimensions tion depends on disease duration. The sleep-immune asso-
ciation may not be static over time, but may differ depend-
Findings on the sleep-immune relationship also depend on a ing on the stage of a disease. This knowledge potentially
number of time dimensions, including time of day of param- benefits the optimization of therapeutic interventions at dif-
eter assessment or experimental intervention (e.g., morning, ferent stages of a disease.
evening, night hours), age of the animal/participant (e.g.,
infancy, adolescence, older age), duration of infectious or The effects of the chronicity of sleep deficiency (i.e., the time
inflammatory disease (e.g., early or late disease stages), and span, from a few days to years or even decades, over which
chronicity of sleep deficiency (e.g., acute, subchronic, sleep remains deficient) are also under-studied. Understand-
chronic; FIGURE 1). Understanding the influence of these ing the adaptive processes that take place within the im-
time dimensions on the relation between sleep and the im- mune system in the course of acute to more chronic forms of
mune system is valuable for developing pharmacological sleep deficiency are likely essential in elucidating the mech-
and behavioral strategies to support optimal immune and anisms by which long-term sleep deficiency increases dis-
sleep health. However, knowledge in these areas is still lim- ease risk. Given that a key feature of most biological sys-
ited. tems is the ability to adapt to ongoing adversity, the degree
to which immune responses adapt to ongoing or chronic
With respect to time-of-day effects, this review showed sleep loss warrants further research.
that the effects of sleep and sleep loss on various immune
parameters can vary considerably, partially due to differ- 3. Development of methods to assess physiological
ences between studies in the time and frequency of spec- sleep need for optimal immune homeostasis
imen sampling. Such time-of-day dependency is well-
known for the stress hormone cortisol, where the effects
Currently, categorization of habitual sleep duration as
of sleep loss result in increased, decreased, or unchanged
short, optimal, or long generally relies on common rec-
levels, depending on time of day of measurement (see, for
ommendations (573) and/or self-perception. Self-percep-
example, Refs. 27, 512). With exception of the major
tion, however, may not accurately reflect the sleep dura-
immune cell sets (e.g., leukocytes, monocytes), knowl-
tion needed for optimal health maintenance. This has
edge about diurnal variations of other immune parame-
been suggested by research in neurobehavioral perfor-
ters (particularly cytokines) and how they are affected by
mance domains, where performance increasingly deteri-
various challenges, including sleep modulation, is lim-
orates with prolonged total sleep deprivation, but subjec-
ited. Such knowledge may inform decisions in chrono-
tive sleepiness adapts to the sleep loss challenge. Thus,
therapy, which focuses on the optimal timing of the ad-
over time, the degree of performance decrement diverges
ministration of (e.g., immunomodulatory) drugs to max-
from the perception of sleepiness. Such dissociation has
imize therapeutic effectiveness.
been also shown for inflammatory markers, which re-
mained increased in the course of ongoing sleep restric-
Changes in the sleep-immune relationship across the life-
tion, while subjective estimates of sleepiness tended to
span are also poorly understood. Both sleep and the im-
decrease over time (512). Thus self-reported sleep need
mune system undergo complex changes across the lifespan.
may not accurately reflect sleep needed for optimal main-
For example, as the human body ages, both innate and
tenance of biological systems, including the immune sys-
adaptive responses functionally decline (357), a process
tem. Current active research in the biomarker field will
termed immunosenescence (5). With respect to sleep, its
hopefully lead to the discovery of a marker that can
duration shortens over the lifespan, and the amount and
measure inadequate sleep (316, 397), which may greatly
intensity of SWS starts to decline in adolescence (514). To
assist in determining the optimal habitual sleep duration
date, experimental knowledge on the immune-sleep rela-
for maintaining immune homeostasis.
tionship is primarily derived from studying young adults (or
young animals); generalizability to infants, children, ado-
lescents, middle-age, and the elderly is limited. Understand- 4. Investigating the imbalance between pro- and
ing the immune-sleep relationship in age groups other than counter-inflammatory signals
young adults may help answer important questions, such as
the degree to which the observed age-related functional im- Research investigating the interaction between sleep and
mune system decline is a consequence (or a cause) of sleep inflammation has mostly focused on the pro-inflammatory
changes observed in the elderly. Again, such knowledge side, while the balance between pro- and counter-inflam-

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 BESEDOVSKY ET AL.

matory signals, including anti-inflammatory cytokines (IL- causal involvement of sleep-related immune changes for the
10), pro-resolution lipid mediators (resolvins), and classical development or amplification of chronic inflammatory or
counter-inflammatory hormones (cortisol), has received lit- infectious diseases described in section IID also needs fur-
tle attention. Inflammatory balance is likely of key impor- ther investigation. In the clinical setting we should take the
tance in assessing the interaction between sleep and the opportunity to monitor sleep in conditions of acute and
immune system. In addition, research examining the rela- chronic immune activation and to assess the impact of spe-
tionship between sleep and the inflammatory system gener- cific immunomodulatory treatments to gain further insights
ally investigated only a single or very few immune out- into sleep-immune relationships. The effects of sleep on
comes. However, the inflammatory response is regulated by some specific immune aspects, such as autoimmunity (see,
a large number of pro- and counter-inflammatory media- e.g., Ref. 419), allergy, tumor immunity, and graft rejec-
tors. Advances in profiling a large number of signals tion, are under-studied. Tregs, which dampen the immune
through the use of omic approaches may lead to a more response in an antigen-specific manner, are dysfunctional in
complete understanding of the complexity of the sleep-im- these conditions, and studying the effects of sleep on these
mune relationship. cells offers high-yield research opportunities. Large interin-
dividual differences exist with regard to sleep need (the
5. Investigating sex differences in the sleep-immune optimal sleep duration for an individual), preferred timing
crosstalk of sleep (the optimal time of day to sleep), and susceptibility
to the physiological (and perceptual) consequences of sleep
Research on the relationship between sleep and the immune loss, but not much is known about how these differences
system has rarely addressed differences between females relate to immune functions. In addition, further research is
and males. Indeed, until recently, research in animals (and needed to understand how sleep can be improved to foster
in some laboratories also in humans) has been mostly per- its immunosupportive and inflammation-regulatory func-
formed in males, to avoid potential confounding effects of tions. Nevertheless, substantial knowledge accumulated
the female estrogen cycle. However, sex differences exist in over the last decades, showing that the sleep-immune cross-
the prevalence of sleep disturbances as well as in the prev- talk is a prime example of the research within the overar-
alence of various immune-related diseases or conditions: ching field of psychoneuroimmunology. Understanding
insomnia complaints are more common and severe in fe- these interactions in more detail will therefore also lead to a
males than males (reviewed in Ref. 434), and this prepon- better understanding of basic interactions between the CNS
derance emerges already after late puberty (600). Autoim- and the immune system, which play an essential role not
mune diseases (e.g., RA), chronic pain (e.g., fibromyalgia), only in normal physiology, but also in many pathological
and neurodegenerative diseases (e.g., Alzheimer’s disease) conditions.
are more common in females than males and can also man-
ifest and progress differently between sexes (reviewed in ACKNOWLEDGMENTS
Refs. 185, 292). With respect to infectious diseases, females
have a higher fatality of influenza A infection, a higher risk We thank Dr. Janet M. Mullington for helpful scientific
of developing AIDS, and stronger vaccine responses than advice and Richard Flynn for editorial work on this manu-
males (reviewed in Ref. 292). To understand differential script.
susceptibility to diseases and responses to vaccination be-
tween females and males, systematic investigation and re- Address for reprint requests and other correspondence: T.
porting of sex differences with regard to the sleep-immune Lange, Dept. of Rheumatology and Clinical Immunology,
crosstalk are warranted. Univ. of Lübeck, Lübeck, Germany (e-mail: tanja.lange
@uksh.de).
6. The future of sleep-immune research
GRANTS
Although the assumption that sleep is important for im-
mune functions has existed for a long time, the systematic This work was supported by Deutsche Forschungsgemein-
investigation of the interactions between sleep and the im- schaft Grants BE 6319/1–1 and TR/SFB 654 C6; National
mune system is a relatively new research area. Therefore, Heart, Lung, and Blood Institute Grant HL136310; and
several questions remain open for future studies in this field. National Institute of Neurological Disorders and Stroke
The mechanisms underlying these complex neuro-immune Grant NS091177.
interactions are still not well understood. It is likely that
different parameters act in concert to mediate the impact of
sleep on the immune system and vice versa. Importantly, DISCLOSURES
studies in humans relating sleep-induced changes observed
in several immune parameters, like immune cell numbers, to No conflicts of interest, financial or otherwise, are declared
actual infection risk and outcome are lacking so far. The by the authors.

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 THE SLEEP-IMMUNE CROSSTALK

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