ArticlePDF AvailableLiterature Review

Sleep, Immunity, and Circadian Clocks: A Mechanistic Model


Abstract and Figures

The lack of sufficient amounts of sleep is a hallmark of modern living, and it is commonly perceived that in the long run this makes us sick. An increasing amount of scientific data indicate that sleep deprivation has detrimental effects on immune function. Conversely, immune responses feedback on sleep phase and architecture. Several studies have investigated the impact of short-term sleep deprivation on different immune parameters, whereas only a few studies have addressed the influence of sleep restriction on the immune system. In many cases, sleep deprivation and restriction impair immune responses by disrupting circadian rhythms at the level of immune cells, which might be a consequence of disrupted endocrine and physiological circadian rhythms. Little is known about the mechanisms underlying the circadian regulation of immunity, but recent studies have suggested that local as well as central circadian clocks drive the rhythms of immune function. In this review, we present a mechanistic model which proposes that sleep (through soluble factors and body temperature) primes immune cells on the one hand, and, on the other hand, provides a timing signal for hematopoietic circadian clocks. We hypothesize that chronic sleep disruption desynchronizes these clocks and, through this mechanism, deregulates immune responses.
Content may be subject to copyright.
Fax +41 61 306 12 34
DOI: 10.1159/000281827
Sleep, Immunity, and Circadian Clocks:
A Mechanistic Model
Thomas Bollinger a Annalena Bollinger b Henrik Oster c Werner Solbach a
a Institute of Medical Microbiology and Hygiene, University of Luebeck, Luebeck ,
b Institute for Immunobiology,
Research Center Borstel, Borstel , and
c Circadian Rhythms Group, Max Planck Institute of Biophysical Chemistry,
Goettingen , Germany
nal for hematopoietic circadian clocks. We hypothesize that
chronic sleep disruption desynchronizes these clocks and,
through this mechanism, deregulates immune responses.
Copyright © 2010 S. Karger AG, Bas el
Over the last 25 years, the modern urban lifestyle has
led to a constant decrease in average sleeping time
[1] , re-
sulting in what has been called an ‘epidemic of sleep re-
striction’ ( table 1 ). In the USA and Europe, approximate-
ly 15–20% of the population work at night
[2] , which fre-
quently leads to reduced sleep
[3] . An increasing body of
evidence suggests detrimental effects of chronic sleep
disruption on health and life expectancy. For example,
Kripke et al.
[4] showed in a study of 1.1 million men and
women that both shortened and extended sleep times are
associated with a significantly increased mortality haz-
ard. Furthermore, the common perception that sleep loss
makes us more susceptible to infections is supported by
human and animal studies
[5–7] . On the other hand, in-
fections can also feedback to t he re gulation of sleep, most
likely via proinf lammatory cytokines [for a review, see
8 ].
Strikingly, a comparative analysis of mammalian sleep,
immunity, and parasitism found a strong association be-
Key Words
Sleep Immune Clock Circadian Rhythm Diurnal
The lack of sufficient amounts of sleep is a hallmark of mod-
ern living, and it is commonly perceived that in the long run
this makes us sick. An increasing amount of scientific data
indicate that sleep deprivation has detrimental effects on
immune function. Conversely, immune responses feedback
on sleep phase and architecture. Several studies have inves-
tigated the impact of short-term sleep deprivation on differ-
ent immune parameters, whereas only a few studies have
addressed the influence of sleep restriction on the immune
system. In many cases, sleep deprivation and restriction im-
pair immune responses by disrupting circadian rhythms at
the level of immune cells, which might be a consequence of
disrupted endocrine and physiological circadian rhythms.
Little is known about the mechanisms underlying the circa-
dian regulation of immunity, but recent studies have sug-
gested that local as well as central circadian clocks drive the
rhythms of immune function. In this review, we present a
mechanistic model which proposes that sleep (through sol-
uble factors and body temperature) primes immune cells on
the one hand, and, on the other hand, provides a timing sig-
Received: July 2, 2009
Accepted: October 20, 20 09
Published online: Feb ruary 3, 2010
Thomas Bolli nger, MD
Institute of Med ical Microbiolog y and Hygiene, University of Luebeck
Ratzeburger A llee 160
DE–23538 Luebeck (Germany)
Tel. +49 451 50 0 2818, Fax +49 451 500 2808, E-Mail Thomas.Bollinger
© 2010 S. Karger AG, Basel
Accessible online at:
Bollinger /Bollinger /Oster /Solbach
tween longer sleep duration and reduced levels of para-
sitic infections
[9] .
Little is known about how sleep affects immune func-
tion, but we know from long-term sleep deprivation and
restriction in experimental animal models and short-
term sleep deprivation or restriction in human vaccina-
tion studies that sleep improves the immune response
10, 11] . Furthermore, the analysis of several immune pa-
rameters has shown that sleep loss alters the normal cir-
cad ia n rhy th m s ee n i n man y of these meas ures
[8, 12–15] .
Hence, sleep seems to influence the processes underlying
the circadian immune rhythm. Such rhythms are gener-
ated by cell-autonomous molecular oscillators that con-
trol physiology v ia the orchestration of hundreds of clock-
controlled genes
[16] . Circadian clocks have been de-
scribed in various types of immune cells and the network
properties of the circadian timing system make it a prime
candidate for communication between sleep and im-
mune regulation. In this review, we summarize the cur-
rent knowledge of the interaction between sleep, circa-
dian clocks, and the immune system, and present a mod-
el of how sleep (loss) may affect immune function at
different levels.
Sleep-Immune Interactions
Two basic questions arise: do immune responses mod-
ulate sleep and does sleep, or the lack thereof, influence
the course of an immune response? Several studies have
shown that infections as we ll a s low-do se l ipop olysac cha-
ride administration increase sleep in humans and mam-
mals, most likely through induction of proinflammatory
cytokines [for a review, see
8 ]. Additionally, it was dem-
onstrated that neutralizing tumor necrosis factor-
(TNF- ), a key proinflammatory cytokine, causes sub-
stantially reduced sleepiness in obstructive sleep apnea
[17] . By contrast, in humans, infections with rhi-
noviruses and, to a lesser extent, with Trypanosoma bru-
cei, decrease sleeping times
[18 , 19] . However, rhinovi-
ruses often cause respiratory problems which themselves
can affect sleep. Moreover, Trypanosoma brucei infects
the brain, which might mask the primary effects on sleep
by the infection itself. Nevertheless, from these data it
seems clear that infections affect sleep.
Toth et al. [20] demonstrated that the morbidity and
the mortality of experimentally infected rabbits are de-
creased with a longer sleep duration after the infective
challenge. Furthermore, it was shown that long-term
sleep deprivation as well as restriction in animals leads to
septicemia and can even be fatal [6, 7] . Hence, sleep has a
protective role. Conflicting data have been published on
the impact of sleep on experimental influenza infection
in mice: while some authors found benefits of sleep on the
immune response, other authors observed the opposite
or no effect
[21–23] .
In humans, it has been shown that one night of sleep
deprivation after a hepatitis A vaccination results in de-
creased antibody responses
[10] , and that 4 days of sleep
restriction prior to influenza vaccination also substan-
tially decreased antibody responses
[11] . Furthermore, it
was shown in a correlational study by Cohen et al.
that reduced sleep increases the risk of acquiring a com-
mon cold. From this experimental evidence, it seems
clear that sleep has beneficial effects in most infections or
vaccination responses.
Several studies have reported immunological altera-
tions related to sleep by using sleep deprivation or restric-
tion paradigms, but the underlying mechanisms remain
elusive. One limitation of human studies is that immune
cells or cytokines in the peripheral blood have been ana-
lyzed, and these might not reflect the changes taking
place in the spleen and lymph nodes. Unfortunately, there
is no good alternative in humans. Most studies have ad-
dressed the influence of sleep on the changes in absolute
and relative leukocyte counts in the blood and the rate of
cytokine-producing cells after polyclonal stimulation
13–15 ; for a review, see 8 ]. These studies have elegantly
Tab le 1. Definitions of key terms used in this report
an endogenous rhythm with a period of approxi-
mately 24 h that persists in the absence of external
timing signals (zeitgeber) such as the light-dark cy-
cle, temperature, or social rhythms
a 24-hour rhythm that is tied to an external zeitgeber;
a diurnal rhythm is the representation of a circadian
rhythm under synchronized (entrained) conditions
experimental paradigm in which a subject is prevent-
ed from sleeping for an extended period of time; in
this review, we use the term for experiments in which
sleep was deprived for a least 24 h
a sleep time reduction below the physiologically re-
quired amount of sleep
For the sake of simplicity, we have not differentiated between
‘circadian’ and ‘diurnal’ rhythms, but have always used the term
‘circadian’ when referring to 24 h rhythms under both free-run-
ning and entrained conditions.
Sleep, Immunity, and Circadian Clocks Gerontology
demonstrated circadian rhythms for counts of several
leukocyte subpopulations, including neutrophils, mono-
cytes, dendritic cells, natural killer (NK) cells, B cells, T
cells, and regulatory T cells which are (T cells, B cells, NK
cells, dendritic cells, monocytes) or are not (neutrophils,
regulatory T cells) modulated by sleep. In most of these
cases, sleep loss flattens existing circadian rhythms. This
clearly demonstrates that the analysis of sleep-dependent
changes requires sequential measurements for a period of
at least 24 h. Therefore, studies which investigated sleep
and immune parameters are only cited in this review if
such time-course measurements were performed. How-
ever, one limiting factor remains: the blood only contains
2–3% of all leucocytes. Hence, it is questionable whether
changes in leukocyte counts in the blood faithfully mim-
ic fu nctiona l processes at sin gle cel l le vel or r ather chang-
es in leukocy te distribution. In order to investigate wheth-
er a defined immune cell population is functionally al-
tered by sleep, it would be necessary to analyze the
function of purified immune cell populations or, as an
example, the measurement of function on single cell lev-
el in non-separated leukocytes in sleep deprivation/
restriction experiments. We have demonstrated that
purified and polyclonally stimulated T helper cells
(CD4 + CD25–) proliferate more and that the rhythmic
activity of regulatory T cells, which suppress detrimental
immune responses, was only observed in the condition of
normal sleep compared to sleep deprivation
[13] , whereas
cytokine secretion by T cells follows a circadian rhythm,
which was not altered by sleep [Bollinger T. , unpublished
work]. Figure 1 shows that the circadian rhythms of pro-
lactin and T cell proliferation are significantly inf luenced
by sleep, whereas the circadian rhythms of IL-2 and cor-
tisol are not. Additionally, in human experiments with
sleep restriction for several days, it has been shown that
proinflammatory substances like IL-6 and TNF- are in-
[12] . Hence, sleep seems to be an important regu-
lator of immunological homeostasis.
Most of the above-mentioned studies demonstrated
circadian rhythms in the analyzed immune parameters
which were modified by sleep. The overall finding is that
sleep improves immune responses and that most immune
cells, with the exception of NK cells, have their peak pro-
inflammatory activity at night. Therefore, in order to un-
derstand the influence of sleep on immune responses, it is
essential to understand the basis of circadian rhythms of
imm une f un ct ions . Mo re ove r, t o d isti ng ui sh be twee n sys -
temically driven (e.g. circadian rhythms of hormones)
and cellular rhythms (cellular circadian clock), future
studies should address the analysis of circadian and sleep-
dependent immune functions in distinct and purified cell
populations or at the single cell level.
Interestingly, immunological changes seen in sleep
loss and those observed in aged humans bear several sim-
ilarities, such as attenuated T cell immunity, increased
innate immune activation, and reduced adaptive im-
mune responses after vaccination
[25] . Furthermore, it is
known that the circadian timing system (explained later)
changes with age, resulting in phase advances of the
sleep-wake cycle and attenuated rhythms of hormones
Cortisol (µg/dl)
a8:00 20:00
IL-2 (pg/ml)
c8:00 20:00
Prolactin (ng/ml)
b8:00 20:00
T cell
proliferation (%)
d8:00 20:00
Fig. 1. Influence of sleep on rhythmic hor-
monal and immune parameters. Periph-
eral blood wa s drawn from 7 hea lthy young
men who either slept normally (solid line)
or were sleep deprived for 1 day (dashed
line). Average circadian serum profiles of
cortisol (
a ) and prolactin ( b ) under both
conditions are shown. The secretion of IL-
2 (
c ) and the proliferation ( d ) of polyclon-
ally stimulated CD4 + CD25 T cells is de-
picted (modified from Bollinger et al.
[13] ).
Bollinger /Bollinger /Oster /Solbach
such as cortisol and growth hormone [25] . Even though
there is no mechanistic link between the immunological
changes brought about by sleep loss or aging, it seems re-
markable that both processes deregulate circadian tim-
ing and circadian endocrine rhythms. Therefore, the
principles of the proposed model might also be true for
at least some of the age-related changes of the immune
Circadian Clock and Immune Responses
Circadian rhythms a re an external manifestation of an
internal clock that measures daytime
[26] . Circadian
clocks are found in most species and allow the organism
to anticipate reoccurring daily variations in environmen-
tal conditions. They regulate a wide range of biological
functions from behavior (such as the sleep/wake cycle
[27–30] ) down to molecular processes including chroma-
tin modifications and DNA repair. The latter and the cir-
cadian influence on immune function are important fac-
tors in the regulation of cellular homeostasis and, hence,
of development and aging
[26] . Mutations in clock genes
can lead to sleep disorders
[27] . Hence, the circadian
clock, together with a homeostatic component of un-
known origin, directly regulates sleep/wake patterns a nd,
therefore, sleep can be seen as an integral manifestation
of the circadian timing system.
In mammals, a master circadian pacemaker is located
in the hypothalamic suprachiasmatic nuclei (SCN). The
SCN synchronizes semi-autonomous peripheral clocks
found in most central and peripheral tissues
[28] with the
external light/dark cycle. The means of this synchroniza-
tion are not yet fully understood, but likely involve SCN
regulation of hormone release (e.g. melatonin, glucocor-
ticoids), body temperature rhythms
[29, 30] , and signal-
ing via the autonomic nervous system
[30] . Conversely,
behavioral and physiological signals may feedback to the
brain and ultimately the SCN, resetting clock phase by
so-called non-phot ic cues
[28] . At the molecular level, cir-
cadian clocks are based on cellular oscillators built from
a set of interlocked transcriptional/translational autoreg-
ulatory feedback loops in which the protein products of
particular clock genes negatively feedback on their own
transcription, resulting in mRNA and protein rhythms
with a period length of approximately 24 h
[26] ( fig. 2 ).
Hundreds of clock-controlled genes that are regulated in
a similar fashion, but have no feedback function, trans-
late time information into a physiologically meaningful
[28] .
Interestingly, it has been demonstrated that rat NK
cells, mouse macrophages, and human leukocytes show
rhyth mic expression of c loc k ge nes , w ith t he l atter sho wn
to be associated wit h sleep-wake patterns
[31–33] . In rats,
NK-cell inhibition of the clock gene Per2 (Period2, nega-
tive limb; fig. 2 ) leads to a decrease in expression of the
immune effectors granzyme-B and perforin, whereas in-
hibition of the clock gene Bmal1 ( Arntl , positive limb;
fig. 2 ) has t he opposite effect
[32] . Surprisingly, the knock-
down of Per2 in NK cells only marginally alters the
rhythm of interferon- (IFN- ), an important cytokine
for the cellular adaptive immune response. In contrast, in
Per2 -deficient mice, the rhythm of IFN- is severely
[34] , indicating that the rhythmic expression of
IFN- might be driven by systemic circadian signals such
as hormones or core body temperature. The fact that
D-box CCGs
E-box CCGs
Fig. 2. Molecular model of the circadian clock. Cellular oscilla-
tions of circadian clocks are driven by a set of transcriptional/
translational feedback loops. At the positive limb, CLOCK (or in
some tissues: NPAS2) and BMAL1 activate transcription of Per
and Cry genes. PER/CRY protein complexes negatively feedback
on CLOCK/BMAL1 (negative limb). This core oscillator is stabi-
lized by ancillary loops including Rev-erb
/Rora and E4bp4 / Dbp .
Timing signals from core and ancillary loops are translated into
physiological signals via transcriptional regulation of clock-con-
trolled genes (CCGs) via E-box, D-box and RORE promoter ele-
ments. Dashed lines = Inhibitory sig nals; gray arrows = activating
signals. This model of the circadian clock was modified from
Hastings et al.
[42] .
Sleep, Immunity, and Circadian Clocks Gerontology
rhythmically secreted hormones, e.g. glucocorticoids or
melatonin, or autonomic activation can modulate im-
mune functions has been previously demonstrated
38] . Per2 mutant mice respond less severely to lipopoly-
saccharide-induced septic shock than wild-type animals
[39] . Furthermore, deletion of Bmal1 causes impaired B
cell development
[40] . Together, these data strongly indi-
cate that circadian clocks are key regulators of immune
functions. Because of the tight entanglement of circadian
rhythms, sleep, and the mutual effect of both factors on
immunity, it seems likely that the 3 processes are caus-
ally linked and interact with each other.
Hypothesis: Circadian Clocks – Master Regulators of
Immune Rhythms
The circadian rhythm of immune responses is driven
by the interplay of master (SCN) and peripheral clocks
(immune cells). The SCN drives the release of rhythmic
soluble factors (hormones) which affect immune cell
function (hormonal priming) as well as the circadian
clock of immune cells [Bollinger T., unpublished work].
Furthermore, the SCN may affect immune cells through
the sympathetic nervous system as well as core body tem-
perature. We suggest a model ( fig. 3 ) in which factors re-
leased in relationship to the circadian rhyt hm – which are
(e.g. prolactin, growth hormone) or are not (e.g. cortisol
and melatonin) modulated by sleep – regulate the hor-
monal priming of immune cells and subsequently their
immune function. Furthermore, we predict that such fac-
tors, the sympathetic nervous system, and core body tem-
perature synchronize the peripheral circadian clocks of
immune cells and thereby drive the functional rhythm of
immunity at the cellular level. Conversely, immune cells
are able to modulate sleep and circadian clocks
[8, 41] .
Our model predicts that immune cells would be able to
sustain a rhythm, but need signals from the master clock
(SCN) in order to stay synchronized to other peripheral
clocks and to maintain clock synchrony within the leu-
kocyte subpopulations. We further predict that immune
cell cultures would gradually lose their synchrony in vi-
tro due to the lack of such synchronizing factors. Adding
these synchronizing factors should re-synchronize these
cultures in a similar way to what has been shown for fi-
broblasts and other cell lines
[29] . Since the circadian
clock is redundantly stabilized, short-term sleep depriva-
tion/restriction will have only minor effects on leukocyte
clock synchrony, but it will affect the circadian immune
rhythm through sleep-modulated circadian signals such
as prolactin and growth hormone (hormonal priming of
immune cells). Furthermore, we speculate that long-term
sleep deprivation/restriction will disrupt the synchrony
amongst different leukocyte clocks, leading to a desyn-
chronization of immune functions and, ultimately, de-
regulated immune responses. Clock desynchrony has al-
ready been shown to be detrimental for metabolic ho-
meostasis, for example
[42] . If our assumption is right,
then the effects of acute sleep loss on circadian immune
rhythms should be reversible through the mimicry of cir-
cadian rhythms of prolactin and growth hormone serum
levels, e.g. by timed infusion of these hormones. The dis-
ruption of circadian synchrony by long-term sleep depri-
vation/restriction can most likely be experimentally
amended by enforcing a normal sleep/wake cycle or by
timed exposure to circadian synchronizers such as light.
A good model to monitor clock changes at tissue levels
are circadian clock reporter mice
[43] . We speculate that
clock desynchrony in the leukocyte subpopulations due
Master clock
Peripheral clocks
(immune cells)
Cytokines ?
Soluble factors
Soluble factors
Soluble factors
(prolactin, GH)
Cytokines (IL-1 , TNF- )␤␣
Soluble factors (prolactin, GH)
Soluble factors
Fig. 3. Clock-sleep-immune model. The SCN is a key regulator of
sleep and synchronizes peripheral clocks all over the body, in-
cluding the cellular oscillators of immune cells. Sleep might feed-
ba ck t o t he c irc ad ian tim ing sy ste m – m ost li kel y by neu ron al and
humoral factors and by modulation of core body temperature –
thereby stabilizing the SCN as well as the periphera l clocks of im-
mune cells. Furthermore, sleep and the SCN together modulate
the function of immune cells through soluble factors (hormonal
priming). Immune cells, on the other hand, affect sleep via the
s ec re ti on of c y to ki n es , s uc h a s I L-1 , IL-6, and TNF- . The secre-
tion of cytokines might further modulate SCN and peripheral
clock rhythms. CBT = Core body temperature; SNS = sympathet-
i c n e r v e s y s t e m ; C C G s = c l o c k - c o n t r o l l e d g e n e s .
Bollinger /Bollinger /Oster /Solbach
1 Jean-Louis G, Kripke DF, Ancoli-Israel S,
Klauber MR, Sepulveda RS: Sleep duration,
illumination, and activity patterns in a pop-
ulation sample: effects of gender and ethnic-
ity. Biol Psychiatry 2000;
47: 921–927.
2 Wi llyard C: Hung ry for sleep. Nat Med 2008 ;
14: 477–480.
3 Ursin R, Baste V, Moen BE: Sleep duration
and sleep-related problems in different oc-
cupations in the Hordaland Health Study.
Scand J Work Environ Health 2009;
35: 193–
4 Kripke DF, Garfinkel L , Wingard DL, Klau-
ber MR, Marler MR: Morta lity associated
with sl eep duration and i nsomnia. Arch G en
Psychiatry 2002;
59: 131–136.
5 Mohren DC, Jansen NW, Kant IJ, Galama J,
van den Brandt PA, Swaen GM: Prevalence
of common infections among employees in
different work schedules. J Occup Environ
Med 2002;
44: 1003–1011.
6 Everson CA: Sus tained sleep depr ivation im-
pairs host defense. Am J Physiol 1993;
7 Everson CA, Toth LA: Systemic bacterial in-
vasion induced by sleep deprivation. Am J
Physiol Regul Integr Comp Physiol 2000;
8 Bryant PA, Trinder J, Curtis N: Sick and
tired: Does sleep have a vital role in the im-
mune system? Nat Rev Immunol 2004;
9 Pres ton BT, Capel lini I, McNa mara P, Barton
RA, Nunn CL: Parasite resistance and the
ad ap ti ve s ig ni fi ca nc e o f sl ee p. B MC E vol Bi ol
9: 7.
10 Lange T, Perras B, Fehm HL, Born J: Sleep
enhances the human antibody response to
hepatitis A vaccination. Psychosom Med
65: 831–835.
11 Spiegel K, Sheridan JF, Van CE: Effect of
sleep deprivation on response to immuniza-
tion. JAMA 2002;
288: 1471–1472.
12 Vgontzas AN, Zoumakis E, Bixler EO, Lin
HM, Follett H, Kales A, Chrousos GP: Ad-
verse effects of modest sleep restriction on
sleepiness, performance, and inf lammatory
cytokines. J Cli n Endocrinol Metab 20 04;
13 Bol linger T, Bollinger A, Sk rum L, Dimitrov
S, Lange T, Solbach W: Sleep-dependent ac-
tivity of T cells and reg ulatory T cells. Clin
Exp Immunol 2009;
155: 231–238.
14 Dimitrov S, Lange T, Nohroudi K, Born J:
Number and function of circulating human
antigen presenting cells regulated by sleep.
Sleep 2007;
30: 401–411.
15 L an ge T, D im it r ov S , F eh m H L , We st er m an n
J, Born J: Shift of monocyte function toward
cellular immunit y during sleep. Arch Intern
Med 2006;
166: 1695 –1700.
16 L owrey PL, Takaha shi JS: Mamma lian circa-
dian biolog y: elucidating genome-wide lev-
els of tempora l organization. Annu Rev Ge-
nomics Hum Genet 2004;
5: 407–441.
17 Vgontzas AN, Zoumakis E, Lin HM, Bix ler
EO, Trakada G, Chrousos GP: Marked de-
cr eas e i n sle ep ine ss i n pa tie nts wit h s lee p ap -
nea by etanercept, a tumor necrosis factor-
alpha antagonist. J Clin Endocrinol Metab
89: 4409–4413.
18 Dra ke CL, Roehrs TA, Royer H, Koshorek G,
Turner RB, Roth T: Effects of an experimen-
tally induced rhinovirus cold on sleep, per-
formance, and daytime alertness. Physiol
Behav 200 0;
71: 75–81.
19 Buguet A, Bert J, Tapie P, Tabaraud F, Doua
F, Lonsdorfer J, Bogui P, Dumas M: Sleep-
wake c ycle in human Af rican tr ypanosom ia-
sis. J Clin Neurophysiol 1993;
10: 190–196.
20 Toth LA, Tolley EA, Krueger JM: Sleep as a
prognostic indicator during infectious dis-
ease in rabbits. Proc Soc Exp Biol Med 1993;
203: 179–192.
21 Brown R, Pang G, Husband AJ, King MG:
Suppression of immunity to inf luenza virus
infection in the respiratory tract following
sleep dis turbance . Reg Immunol 1989;
2: 321–
22 Renegar KB, Floyd RA, Krueger JM: Effects
of short-term sleep deprivation on murine
immunity to inf luenza virus in young adult
and senescent mice. Sleep 1998;
21: 241–248.
23 Toth LA, Rehg JE: Effects of sleep depriva-
tion and other stressors on the immune and
inf lammatory responses of influenza-in-
fected mice. Life Sci 1998;
63: 701–709.
24 Cohen S, Doyle WJ, Alper CM, Janicki-De-
verts D, Turner RB: Sleep habits and suscep-
tibility to the common cold. Arch Intern
Med 2009;
169: 62–67.
25 Perras B, Born J: Sleep associated endocrine
and immu ne changes in the eld erly. Adv Cell
Aging Gerontol 2005;
17: 113 –154 .
26 Reppert SM, Weaver DR: Coordination of
circadian timing in mammals. Nature 2002;
418: 935–941.
27 Toh KL, Jones CR, He Y, Eide EJ, Hinz WA,
Virshup DM, Ptacek LJ, Fu YH: An hPer2
phosphorylation site mutation in familial
advanced sleep phase syndrome. Science
291: 1040 –1043.
28 Schibler U, Sassone-Corsi P: A web of circa-
dian pacemakers. Cell 2002;
111: 919 –922.
29 Balsalobre A, Damiola F, Schibler U: A se-
rum shock induces circadian gene expres-
sion in mammalian tissue culture cells. Cel l
93: 929–937.
30 Terazono H, Mutoh T, Yamaguchi S, Ko-
bayashi M, Akiyama M, Udo R, Ohdo S,
Okamura H, Shibata S: Adrenergic regula-
tion of clock gene expression in mouse liver.
Proc Natl Acad Sci USA 2003;
100: 6795–
to chronic sleep disturbances will promote immune-re-
lated diseases such as autoimmunity, allergy, and tumors.
If this is true, then sleep-loss-induced clock desynchrony
could be seen as a learned response and, hence, represent
a form of peripheral memory of sleep loss.
In summary, it has become clear that sleep is essential
for immune homeostasis and that the deprivation/re-
striction of sleep leads to altered immune functions. Our
model proposes that the circadian timing system is the
underlying mechanism which simultaneously regulates
the sleep/wake cycle and, in consequence, the synchrony
of circadian immune rhythms and thereby immune ho-
meostasis. We speculate that long-term sleep depriva-
tion/restriction deregulates the circadian timing system
and subsequently disrupts immune homeostasis.
A c k n o w l e d g m e n t s
We thank Tanja Lange (Neuroendocrinology, University of
Luebeck) for helpful discussions. We also t hank Tim Hinch liff for
carefully reading and editing the manuscript. H.O. is an Emmy
Noether fellow of the DFG. This work was supported by a grant
of the DFG, SFB 654, projects B5 & C8.
Sleep, Immunity, and Circadian Clocks Gerontology
31 Archer SN, Viola AU, Kyriakopoulou V, von
SM, Dijk DJ: Inter-individual differences in
habitua l sleep timing a nd entrained phas e of
endogenous circadian rhythms of BMAL1,
PER2 a nd PER3 mRNA in human leuko-
cytes. Sleep 2008;
31: 608–617.
32 Arjona A, Sarkar DK: Ev idence supporting a
circadian control of natural kil ler cell func-
tion. Brain Behav Immun 20 06;
20: 469–476.
33 Hay ashi M, Sh imba S, Tez uka M : Cha racter-
ization of t he molecular clo ck in mouse peri-
toneal macrophages. Biol Pharm Bull 2007;
30: 621–626.
34 Arjona A, Sarkar DK: The circadian gene
mPer2 regulates the daily rhythm of IFN-
gamma. J Interferon Cytokine Res 2006;
35 Straub RH: Complexity of the bi-directional
neuroim mune junction in t he spleen. Trends
Pharmacol Sci 2004;
25: 640–646.
36 Kin NW, Sanders VM: It take s nerve to tell T
and B cel ls what to do. J Leukoc Biol 20 06;
1093 –1104.
37 Dimitrov S, Lange T, Fehm HL, Born J: A
regulatory role of prolactin, growth hor-
mone, and corticosteroids for human T-cell
production of cytokines. Brain Behav Im-
mun 2004;
18: 368374.
38 Srinivasan V, Maestroni GJ, Cardinali DP,
Esquifino AI, Perumal SR, Miller SC: Mela-
tonin, immune function and aging. Immun
Ageing 2005;
2: 17.
39 Liu J, Malkani G, Shi X, Meyer M, Cunning-
ham-Runddles S, Ma X, Sun ZS: The circa-
dian clock Period 2 gene regulates gamma
interferon production of NK cells in host re-
sponse to lipopolysaccharide-induced endo-
toxic shock. Infect Immun 2006;
74: 4750–
4 0 Sun Y, Yang Z, Niu Z, Peng J, Li Q, Xiong W,
Lang nas AN, Ma MY, Zhao Y: MOP3, a com-
ponent of the molecular clock, reg ulates the
development of B cells. Immunology 2006;
119: 451–460.
41 Kwak Y, Lundk vist GB, Brask J, Davidson A,
Menaker M , Kristensson K, B lock GD: Inter-
feron-gamma alters electrical activity and
clock gene expression in suprachiasmatic
nucleus neurons. J Biol Rhythms 2008;
4 2 Ha stings M, O’Neil l JS, Maywood ES: Ci rca-
dian clocks: regulators of endocrine and
metabolic rhy thms. J Endocrinol 2007;
43 Davidson AJ, Castanon-Cervantes O, Leise
TL, Molyneux PC, Harrington ME: Visual-
izing jet lag in the mouse suprachiasmatic
nucleus and p eripheral circ adian tim ing sys-
tem. Eur J Neurosci 2009;
29: 171–180 .
... We found an association between sleep duration and pancreatic cancer (HR 6 vs. 7h , 2.67; 95% CI: 1.08-6.61). A linear relationship between sleep duration and colorectal cancer was observed Chinese Medical Journal 2021;134 (24) We found a U-shaped association between sleep duration and pancreatic cancer in the sensitivity analysis (HR 6vs.7h , 3.81; 95% CI: 1.30-11.16; ...
... [23] In previous studies among poor sleepers, we found that the changes in sleep duration may suppress immune function and change the balance of cytokine production. [24,25] The disruption of circadian rhythms is a possible mechanism. Disruption of circadian physiology, due to sleep loss or sleep disturbance, may lead to impaired glucose and appetite control [22] and various GI diseases. ...
... The large sample size permits sufficient power to assess associations with major GI cancer sites. In addition, its prospective design with a long follow-up time minimized the potential Chinese Medical Journal 2021;134 (24) selection or recall bias of sleep duration, and its questionnaire design that included relevant covariates allowed us to adjust for important potential confounders during the statistical analysis. ...
Background: Prospective analyses have yet to identify a consistent relationship between sleep duration and the incidence of gastrointestinal (GI) cancers. The effect of changes in sleep duration on GI cancer incidence has scarcely been studied. Therefore, we aimed to examine the association between baseline sleep duration and annual changes in sleep duration and GI cancer risk in a large population-based cohort study. Methods: A total of 123,495 participants with baseline information and 83,511 participants with annual changes in sleep duration information were prospectively observed from 2006 to 2015 for cancer incidence. Cox proportional-hazards models were used to calculate hazard ratios (HRs) and their confidence intervals (CIs) for GI cancers according to sleep duration and annual changes in sleep duration. Results: In baseline sleep duration analyses, short sleep duration (≤5 h) was significantly associated with a lower risk of GI cancer in females (HR: 0.31, 95% CI: 0.10-0.90), and a linear relationship between baseline sleep duration and GI cancer was observed (P = 0.010), especially in males and in the >50-year-old group. In the annual changes in sleep duration analyses, with stable category (0 to -15 min/year) as the control group, decreased sleep duration (≤-15 min/year) was significantly associated with the development of GI cancer (HR: 1.29; 95% CI: 1.04-1.61), especially in the >50-year-old group (HR: 1.32; 95% CI: 1.01-1.71), and increased sleep duration (>0 min/year) was significantly associated with GI cancer in females (HR: 2.89; 95% CI: 1.14-7.30). Conclusions: Both sleep duration and annual changes in sleep duration were associated with the incidence of GI cancer.
... Several studies investigated the relationship between the immune system and circadian machinery, highlighting the negative effect of circadian disruption on this system [70][71][72]. In particular, a combined influence of the circadian system and sleep may induce an increase in circulating naïve T-cells and the production of some proinflammatory cytokines, such as interleukin-12, during nighttime, and that of cytotoxic effector leukocytes and of interleukin-10 during daytime, with strong clinical implications [70]. ...
... In particular, a combined influence of the circadian system and sleep may induce an increase in circulating naïve T-cells and the production of some proinflammatory cytokines, such as interleukin-12, during nighttime, and that of cytotoxic effector leukocytes and of interleukin-10 during daytime, with strong clinical implications [70]. Moreover, chronic sleep deprivation or restriction desynchronizes central and peripheral clocks and impairs the immune response by disrupting circadian rhythms at the level of immune cells and, through this mechanism, deregulates the immune system [71]. Recent studies have clarified the molecular mechanisms by which the circadian clock controls the immune system. ...
Full-text available
Chronobiology is the scientific discipline which considers biological phenomena in relation to time, which assumes itself biological identity. Many physiological processes are cyclically regulated by intrinsic clocks and many pathological events show a circadian time-related occurrence. Even the pituitary–thyroid axis is under the control of a central clock, and the hormones of the pituitary–thyroid axis exhibit circadian, ultradian and circannual rhythmicity. This review, after describing briefly the essential principles of chronobiology, will be focused on the results of personal experiences and of other studies on this issue, paying particular attention to those regarding the thyroid implications, appearing in the literature as reviews, metanalyses, original and observational studies until 28 February 2021 and acquired from two databases (Scopus and PubMed). The first input to biological rhythms is given by a central clock located in the suprachiasmatic nucleus (SCN), which dictates the timing from its hypothalamic site to satellite clocks that contribute in a hierarchical way to regulate the physiological rhythmicity. Disruption of the rhythmic organization can favor the onset of important disorders, including thyroid diseases. Several studies on the interrelationship between thyroid function and circadian rhythmicity demonstrated that thyroid dysfunctions may affect negatively circadian organization, disrupting TSH rhythm. Conversely, alterations of clock machinery may cause important perturbations at the cellular level, which may favor thyroid dysfunctions and also cancer.
... These results suggest that RAS and NPs may act as endogenous antagonists. Circadian clock controls many physiological functions, such as blood pressure, immune response, and metabolism, potentially through four "circadian clock" proteins: period 1-3 (Per 1-3), Bmal1, Clock cryptochrome 1-2, and Clock (Eckel-Mahan and Sassone-Corsi, 2009;Agarwal, 2010;Bollinger et al., 2010;Dibner et al., 2010). Per1 regulates expression of αENaC in both aldosterone-dependent and-independent manners (Gumz et al., 2009(Gumz et al., , 2010aRichards et al., 2013). ...
Full-text available
Aldosterone is a major mineralocorticoid steroid hormone secreted by glomerulosa cells in the adrenal cortex. It regulates a variety of physiological responses including those to oxidative stress, inflammation, fluid disruption, and abnormal blood pressure through its actions on various tissues including the kidney, heart, and the central nervous system. Aldosterone synthesis is primarily regulated by angiotensin II, K+ concentration, and adrenocorticotrophic hormone. Elevated serum aldosterone levels increase blood pressure largely by increasing Na+ re-absorption in the kidney through regulating transcription and activity of the epithelial sodium channel (ENaC). This review focuses on the signaling pathways involved in aldosterone synthesis and its effects on Na+ reabsorption through ENaC.
... The two-process model nicely illustrates that sleep is regulated by the circadian system. On the other hand, sleep can reset cellular clocks in the SCN [47] and the periphery [48], showing the strong bidirectional interaction between these two systems. ...
Full-text available
Twenty-four-hour rhythms in immune parameters and functions are robustly observed phenomena in biomedicine. Here, we summarize the important role of sleep and associated parameters on the neuroendocrine regulation of rhythmic immune cell traffic to different compartments, with a focus on human leukocyte subsets. Blood counts of “stress leukocytes” such as neutrophils, natural killer cells, and highly differentiated cytotoxic T cells present a rhythm with a daytime peak. It is mediated by morning increases in epinephrine, leading to a mobilization of these cells out of the marginal pool into the circulation following a fast, beta2-adrenoceptor-dependent inhibition of adhesive integrin signaling. In contrast, other subsets such as eosinophils and less differentiated T cells are redirected out of the circulation during daytime. This is mediated by stimulation of the glucocorticoid receptor following morning increases in cortisol, which promotes CXCR4-driven leukocyte traffic, presumably to the bone marrow. Hence, these cells show highest numbers in blood at night when cortisol levels are lowest. Sleep adds to these rhythms by actively suppressing epinephrine and cortisol levels. In addition, sleep increases levels of immunosupportive mediators, such as aldosterone and growth hormone, which are assumed to promote T-cell homing to lymph nodes, thus facilitating the initiation of adaptive immune responses during sleep. Taken together, sleep–wake behavior with its unique neuroendocrine changes regulates human leukocyte traffic with overall immunosupportive effects during nocturnal sleep. In contrast, integrin de-activation and redistribution of certain leukocytes to the bone marrow during daytime activity presumably serves immune regulation and homeostasis.
... Age-related neurodegenerative diseases such as Alzheimer's, Parkinson's, and Huntington's show signs of circadian disruption, which is indicative of older individuals having an increased susceptibility to circadian dysfunctionassociated clinical ailments including cancer risk (Blask, 2009;Abbott and Videnovic, 2016;Mattis and Sehgal, 2016). Generally, sleep helps maintain normal physiological processes such as brain development, plasticity, memory, learning and immunity (Bollinger et al., 2010;Abel et al., 2013; Figure 1). Circadian disruptions have been documented to have detrimental effects on an individual. ...
Full-text available
The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic has affected nearly 28 million people in the United States and has caused more than five hundred thousand deaths as of February 21, 2021. As the novel coronavirus continues to take its toll in the United States and all across the globe, particularly among the elderly (>65 years), clinicians and translational researchers are taking a closer look at the nexus of sleep, circadian rhythms and immunity that may contribute toward a more severe coronavirus disease-19 (COVID-19). SARS-CoV-2-induced multi-organ failure affects both central and peripheral organs, causing increased mortality in the elderly. However, whether differences in sleep, circadian rhythms, and immunity between older and younger individuals contribute to the age-related differences in systemic dysregulation of target organs observed in SARS-CoV-2 infection remain largely unknown. Current literature demonstrates the emerging role of sleep, circadian rhythms, and immunity in the development of chronic pulmonary diseases and respiratory infections in human and mouse models. The exact mechanism underlying acute respiratory distress syndrome (ARDS) and other cardiopulmonary complications in elderly patients in combination with associated comorbidities remain unclear. Nevertheless, understanding the critical role of sleep, circadian clock dysfunction in target organs, and immune status of patients with SARS-CoV-2 may provide novel insights into possible therapies. Chronotherapy is an emerging concept that is gaining attention in sleep medicine. Accumulating evidence suggests that nearly half of all physiological functions follow a strict daily rhythm. However, healthcare professionals rarely take implementing timed-administration of drugs into consideration. In this review, we summarize recent findings directly relating to the contributing roles of sleep, circadian rhythms and immune response in modulating infectious disease processes, and integrate chronotherapy in the discussion of the potential drugs that can be repurposed to improve the treatment and management of COVID-19.
... As the underlying synergetic mechanisms of sleep and the immune system studied in other populations are worth to be mentioned, these will be discussed first before evaluating athletic studies. The central nervous system, where sleep regulation occurs in the suprachiasmatic nucleus, and the immune system are both influenced by circadian rhythms and interact through hormones 240 . ...
... Une autre piste qui reste à investiguer concerne l'effet modulateur de l'exercice sur le système immunitaire et le profil des cytokines. Plusieurs études suggèrent un lien bidirectionnel entre le sommeil et le système immunitaire (Bollinger et al., 2010;Gamaldo et al., 2012;Irwin and Opp, 2017). L'activité physique pourrait impacter le sommeil par son effet sur le système immunitaire. ...
Full-text available
Physical activity and ingested nutrients take part in the regulation of the internal clock and sleep physiology. Recently, there has been a surge of interest in this topic. However, studies remain almost exclusively limited to adults. Adolescence is marked by critical transitions that may trigger several behavioral disturbances particularly with regard to sleep. A problem compounded by an array of endogenous and exogenous factors forming the so called “Perfect Storm” of both altered sleep duration and quality. Obesity and elite sport are two factors that have been separately associated with sleep disturbances, and have a negative impact on holistic development, with lowered performance and altered health status of adolescents, both physical (recovery, metabolism, growth, weight control) and cognitive (learning, memory, decision-making, vigilance). Therefore, the purpose of this work was to explore the effect of physical activity and nutrition on sleep among these two distinct adolescent populations. Altered sleep pattern in young athletes seems to be more related to sport constraints such as competition and travel. However, acute exercise improves sleep duration in quality in both populations (athlete and with obesity). Moreover, dietary intake seems to be a promising alternative to improve sleep quality. Only three days under controlled feeding fixed at the recommended dietary allowance resulted in reduced sleep onset latency in adolescents with obesity compared to ad-libitum condition. Finally, randomized controlled studies are needed to support the effect of certain nutrients on sleep. PROTMORPHEUS study will bring a fuller understanding of the effect of protein tryptophan/large neutral amino acids ratio on sleep.
Background: Stress and sleep disturbance have been found to be associated with numerous adverse health outcomes, including cancer. Our study aimed to measure the association between quality of sleep, short-temperedness, and stress in life with the risk of thyroid cancer. Methods: The present study is conducted on 361 newly diagnosed TC patients and 347 sex-age frequency matched controls. Control and case participants were registered with the same health centers. We used multiple logistic regression to investigate the association between TC risk and the interested factors. Results: Based on the results of the multivariate analysis, stress (ORalways stressful/often calm = 3.07, 95% CI 1.42-6.63) and short-temperedness (ORnervous/calm = 2.00, 95% CI 1.28-3.11) were directly associated with the risk of TC. On the other hand having a quality sleep (ORsometimes/never = 0.36, 95% CI 0.16-0.79) and quality sleep (ORoften/no = 0.45, 95% CI 0.21-0.96, P = 0.041) seems to be a protective factor. Conclusions: Some community-based interventions, e.g., lowering stress levels and improving sleep quality, may help in preventing different types of cancer, including TC. We suggest further evaluation of these important findings in the prevention of TC cancer.
Background The relationship between insomnia and lung cancer is scanty. The Mendelian randomization approach provides the rationale for evaluating the potential causality between genetically-predicted insomnia and lung cancer risk. Methods We extracted 148 insomnia-related single-nucleotide polymorphisms (SNPs) as instrumental variables (IVs) from published genome-wide association studies (GWASs). Summary data of individual-level genetic information of participants were obtained from the International Lung Cancer Consortium (ILCCO) (29,266 cases and 56,450 controls). MR analyses were performed using the inverse-variance-weighted approach, MR pleiotropy residual sum and outlier (MR-PRESSO) test, weighted median estimator, and MR-Egger regression. Sensitivity analyses were further performed using Egger intercept analysis, leave-one-out analysis, MR-PRESSO global test, and Cochran's Q test to verify the robustness of our findings. Results The results of the MR analysis indicated an increased risk of lung cancer in insomnia patients (OR = 1.1671; 95% CI 1.0754–1.2666, p = 0.0002). The subgroup analyses showed increased risks of lung adenocarcinoma (OR = 1.1878; 95% CI 1.0594–1.3317, p = 0.0032) and squamous cell lung cancer (OR = 1.1595; 95% CI 1.0248–1.3119, p = 0.0188). Conclusion Our study indicated that insomnia is a causal risk factor in the development of lung cancer. Due to the lack of evidence on both the epidemiology and the mechanism level, more studies are needed to better elucidate the results of the study.
Study objectives To prospectively investigate the association between sleep traits and lung cancer risk, accounting for the interactions with genetic predisposition of lung cancer. Methods We included 469,691 individuals free of lung cancer at recruitment from UK Biobank, measuring sleep behaviors with a standardized questionnaire and identifying incident lung cancer cases through linkage to national cancer and death registries. We estimated multivariable adjusted hazard ratios (HR) for lung cancer (2,177 incident cases) across four sleep traits (sleep duration, chronotype, insomnia and snoring), and examined the interaction and joint effects with a lung cancer polygenic risk score. Results A U-shaped association was observed for sleep duration and lung cancer risk, with a 18% higher risk (95% confidence interval (CI): 1.07-1.30) for short sleepers and a 17% higher risk (95%CI: 1.02-1.34) for long sleepers compared with normal sleepers (7-8 h/day). Evening preference was associated with elevated lung cancer risk compared with morning preference (HR: 1.25; 95%CI: 1.07-1.46), but no association was found for insomnia or snoring. Compared to participants with favorable sleep traits and low genetic risk, those with both unfavorable sleep duration (<7 hours or >8 hours) or evening preference and high genetic risk showed the greatest lung cancer risk (HRsleep duration: 1.83; 95%CI: 1.47-2.27; HRchronotype: 1.85; 95%CI: 1.34-2.56). Conclusions Both unfavorable sleep duration and evening chronotype were associated with increased lung cancer incidence, especially for those with low to moderate genetic risk. These results indicate that sleep behaviors as modifiable risk factors may have potential implications for lung cancer risk.
Full-text available
Sleep quality is thought to be an important predictor of immunity and, in turn, susceptibility to the common cold. This article examines whether sleep duration and efficiency in the weeks preceding viral exposure are associated with cold susceptibility. A total of 153 healthy men and women (age range, 21-55 years) volunteered to participate in the study. For 14 consecutive days, they reported their sleep duration and sleep efficiency (percentage of time in bed actually asleep) for the previous night and whether they felt rested. Average scores for each sleep variable were calculated over the 14-day baseline. Subsequently, participants were quarantined, administered nasal drops containing a rhinovirus, and monitored for the development of a clinical cold (infection in the presence of objective signs of illness) on the day before and for 5 days after exposure. There was a graded association with average sleep duration: participants with less than 7 hours of sleep were 2.94 times (95% confidence interval [CI], 1.18-7.30) more likely to develop a cold than those with 8 hours or more of sleep. The association with sleep efficiency was also graded: participants with less than 92% efficiency were 5.50 times (95% CI, 2.08-14.48) more likely to develop a cold than those with 98% or more efficiency. These relationships could not be explained by differences in prechallenge virus-specific antibody titers, demographics, season of the year, body mass, socioeconomic status, psychological variables, or health practices. The percentage of days feeling rested was not associated with colds. Poorer sleep efficiency and shorter sleep duration in the weeks preceding exposure to a rhinovirus were associated with lower resistance to illness.
Full-text available
Sleep is a biological enigma. Despite occupying much of an animal's life, and having been scrutinized by numerous experimental studies, there is still no consensus on its function. Similarly, no hypothesis has yet explained why species have evolved such marked variation in their sleep requirements (from 3 to 20 hours a day in mammals). One intriguing but untested idea is that sleep has evolved by playing an important role in protecting animals from parasitic infection. This theory stems, in part, from clinical observations of intimate physiological links between sleep and the immune system. Here, we test this hypothesis by conducting comparative analyses of mammalian sleep, immune system parameters, and parasitism. We found that evolutionary increases in mammalian sleep durations are strongly associated with an enhancement of immune defences as measured by the number of immune cells circulating in peripheral blood. This appeared to be a generalized relationship that could be independently detected in 4 of the 5 immune cell types and in both of the main sleep phases. Importantly, no comparable relationships occur in related physiological systems that do not serve an immune function. Consistent with an influence of sleep on immune investment, mammalian species that sleep for longer periods also had substantially reduced levels of parasitic infection. These relationships suggest that parasite resistance has played an important role in the evolution of mammalian sleep. Species that have evolved longer sleep durations appear to be able to increase investment in their immune systems and be better protected from parasites. These results are neither predicted nor explained by conventional theories of sleep evolution, and suggest that sleep has a much wider role in disease resistance than is currently appreciated.
This chapter discusses the sleep associated endocrine and immune changes in the elderly. The interaction of neuro-endocrine and neuro-endocrine–immune regulation with sleep are reviewed, first in young and then in aged humans. The chapter focuses on the hypothalamo-pituitary-adrenal (HPA) system, the somatotropic system, and the vasopressinergic system. Apart from “efferent” influences of the sleeping brain on the release of hormones into the blood stream, the “afferent” effects of circulating hormones and cytokines of the immune system on the sleeping brain are also discussed in the chapter. Early sleep is characterized by a trias of neuroendocrine phenomena, comprised of a predominance of SWS, a maximum inhibition of HPA activity, and a strong activation of somatotropic activity. During aging, there are distinct changes of this trias. It decreases slow wave sleep (SWS), disinhibits pituitary–adrenal activity, and reduces somatotropic activity during this time. In addition, sleep in the aged is less deep, fragmented by frequent awakenings and influenced by a phase advance of circadian sleep–wake regulation. Immunological measures reflect an acute sleep-related enhancement of signs of innate immune activity in the aged, beyond a general decline in T cell related immune function, which is not restricted to the sleep period.
The aim of this study was to examine the relationship between occupation and sleep duration, sleepiness, insufficient sleep, and insomnia in day and shift workers (including night work and watches). The study was population-based and cross-sectional, and relied on self-administered questionnaires. It was conducted as part of the 1997-1999 Hordaland Health Study in collaboration with the Norwegian National Health Screening Service. Aged 40-45 years, 7782 participants answered a sleep questionnaire, reporting their occupation and whether or not they were employed in shift work. Our study found differences in sleep duration during the working week between occupational groups; in both shift and day workers. Craft workers, plant operators, and drivers slept less than leaders, and non-personal and personal service workers. Within some occupations (leaders, personal service workers, and plant operators), shift workers slept less than day workers. The mean sleep duration of shift workers was 15 minutes shorter than that of day workers. Rise times, but not bedtimes, were earlier in craft-and construction workers, plant operators, and drivers than in leaders and non-personal and personal service workers, particularly day workers. When adjusted for shift work and working hours - compared to leaders - craft workers, plant operators, and drivers had an increased risk of daytime sleepiness (odds ratio 1.5, 1.8, and 1.8 respectively) and of falling asleep at work (odds ratio 1.6, 2.1 and 2.0 respectively). Shift workers had an increased risk of falling asleep at work and insomnia. Occupation has separate effects on sleep duration and sleep-related problems, independent of the effects of shift work.
A number of immunological functions are dependent on circadian rhythms and regular sleep. This has impact on the type and magnitude of immune responses following antigenic challenge, for example in vaccination. Little is known about the underlying mechanisms. One possibility may be the circadian and sleep-dependent modulation of CD4(+)CD25(-) T cell responses by CD4(+)CD25(+) natural regulatory T cells (nT(reg)). In a variety of studies, nT(reg) have been shown to regulate T cell responses negatively. Thus, we investigated the influence of sleep and circadian rhythm on the number and function of nT(reg) as well as on the function of CD4(+)CD25(-) T cells. Seven healthy young men were examined under defined conditions on two occasions, i.e. during sleep and sleep deprivation. Venous blood was drawn periodically; numbers of nT(reg), suppressive activity of nT(reg), interleukin-2 production and proliferation of CD4(+)CD25(-) T cells were explored in vitro. nT(reg) counts revealed a significant circadian rhythm with highest levels during the night (mean 95 nT(reg)/microl) and lowest levels during the day (mean 55 nT(reg)/microl). During normal sleep, the suppressive activity of nT(reg) was highest at 02.00 h and somewhat lower at 15.00 h. Surprisingly, almost no suppressive activity was present at 07.00 h. Deprivation of sleep abrogated this rhythm. CD4(+)CD25(-) T cell proliferation was dampened significantly by sleep deprivation. This is the first study in human cells to show that nT(reg) number and function follow a rhythm across the 24-h period. Furthermore, sleep deprivation severely disturbs the functional rhythm of nT(reg) and CD4(+)CD25(-) T cells.
Circadian rhythms regulate most physiological processes. Adjustments to circadian time, called phase shifts, are necessary following international travel and on a more frequent basis for individuals who work non-traditional schedules such as rotating shifts. As the disruption that results from frequent phase shifts is deleterious to both animals and humans, we sought to better understand the kinetics of resynchronization of the mouse circadian system to one of the most disruptive phase shifts, a 6-h phase advance. Mice bearing a luciferase reporter gene for mPer2 were subjected to a 6-h advance of the light cycle and molecular rhythms in suprachiasmatic nuclei (SCN), thymus, spleen, lung and esophagus were measured periodically for 2 weeks following the shift. For the SCN, the master pacemaker in the brain, we employed high-resolution imaging of the brain slice to describe the resynchronization of rhythms in single SCN neurons during adjustment to the new light cycle. We observed significant differences in shifting kinetics among mice, among organs such as the spleen and lung, and importantly among neurons in the SCN. The phase distribution among all Period2-expressing SCN neurons widened on the day following a shift of the light cycle, which was partially due to cells in the ventral SCN exhibiting a larger initial phase shift than cells in the dorsal SCN. There was no clear delineation of ventral and dorsal regions, however, as the SCN appear to have a population of fast-shifting cells whose anatomical distribution is organized in a ventral-dorsal gradient. Full resynchronization of the SCN and peripheral timing system, as measured by a circadian reporter gene, did not occur until after 8 days in the advanced light cycle.
The extent to which sleep deprivation interferes with immunity in the respiratory tract to influenza virus has been assessed in mice. Mice were orally immunized with influenza virus on two occasions separated by a one week interval and challenged intranasally one week later. Some animals were deprived of sleep for a 7 h period immediately following challenge. Three days after challenge, virus clearance and virus specific antibody were determined in lungs of sleep deprived and normally sleeping mice and the results compared with unimmunized mice subjected to the same protocol. Whereas immunized, normal sleep mice achieved total virus clearance, sleep deprivation in immunized mice completely abrogated this effect such that sleep deprived animals behaved as though they had never been immunized. There was no difference in viral clearance in unimmunized mice whether sleep deprived or not, indicating that sleep deprivation did not itself have a direct effect on viral replication. The data reported here support the concept that sleep is a behavioral state which is essential for optimal immune function in the presence of a respiratory tract pathogen.
Prolonged sleep deprivation in rats causes an unexplained hypercatabolic state, secondary malnutrition symptoms, and mortality. The nature of the vital impairment has long been a mystery. Its determination would help to elucidate the type of organic dysfunction that sleep prevents. There are no gross detectable disturbances in intermediary metabolism, clinical chemistry, or hematological indexes that provide substantial clues to the mediation of sleep-deprivation effects. Furthermore, postmortem examinations reveal no systematic morphological or histopathological findings. Taken together, the cachexia and the absence of evidence of structural damage or organ dysfunction pointed to involvement of a regulatory system that was diffuse, possibly the immune system. Blood cultures revealed invasion by opportunistic microbes to which there was no febrile response. These results suggest that the life-threatening condition of prolonged sleep deprivation is a breakdown of host defense against indigenous and pathogenic microorganisms.
Sleeping sickness patients are classically described as sleepy by day and restless by night. Prior to this study, we had objectively confirmed this description by recording 24-h sleep patterns in a patient with human African trypanosomiasis. We report 24-h polysomnographic recordings (EEG, electrooculogram, electromyogram, electrocardiogram, and nasal, buccal, and thoracic respiratory traces) performed on two eight-channel electroencephalographs in eight patients with untreated sleeping sickness at an early stage of meningoencephalitis. As in our previously reported patient, there was no hypersomnia. The patients presented mainly a disorganization of the circadian alternation of sleeping and waking, with no or little alteration in the states of vigilance at this early stage of the disease. The disorganization was proportional to the degree of severity of the clinical symptoms. It may be due to an alteration in biological clock mechanisms.