Download Sleep and Host Defenses: A Review

Sleep, 20(11): 1027-1037
© 1997 American Sleep Disorders Association and Sleep Research Society
Sleep and Host Defenses: A Review
*Ruth M, Benca and tJose Quintans
*Department of Psychiatry, University of Wisconsin-Madison, Madison, Wisconsin; and
tDepartment of Pathology and Committee on Immunology, University of Chicago, Chicago, Illinois, U.S.A.
Summary: Although the specific functions of sleep are not known, an increasing body of literature has suggested
that sleep is important for the proper functioning of host defense systems. Sleep loss is associated with changes in
some parameters of host defense, whereas pathogenic challenge leads to alterations in sleep patterns, probably
mediated by activation of host defense systems. However, whether sleep-host defense relationships represent physiologically important regulatory interactions vs. nonspecific cross-reactivity between the two systems remains an
open question. In either case, it is unlikely that sleep or sleep loss have global effects on host defenses or vice
versa. Further work is needed to understand the role of sleep in health and disease. Key Words: Sleep--Sleep
deprivation-Host defenses-Immune system-Cytokines.
It is a commonly held belief that sleep loss makes
an individual more susceptible to disease, and, conversely, that sleep is important for recovery from iilness. One hypothesis that has been proposed is that
sleep is essential for the proper functioning of host
defense systems, and that sleep loss leads to impairment of host defenses, thus rendering an organism
more susceptible to pathogens (1,2). It has also been
suggested that host defense systems, particularly the
immune system, may increase sleep in a positive feedback manner upon activation by pathogens.
The brain and host defense systems are capable of
bidirectional communication, which provides a mechanism for changes in sleep-wake behavior to impact
on host defenses and vice versa (3-5). Sleep is a behavior comprising several substates that are regulated
by multiple brain regions and neurotransmitters;
changes in sleep are thus reflections of changes in
brain activity. Nervous system changes can affect host
defense systems through a variety of mechanisms,
such as direct innervation of the immune system, control of cellular recirculation patterns, and by effects on
host defense cells through receptors for neurotransmitters. Conversely, neurons and glial cells have specific receptors for regulatory substances produced by
host defense systems. For the purpose of this review,
it is assumed that the reader is familiar with the basic
Accepted for publication July 1997.
Address correspondence and reprint requests to Ruth M. Benca,
M.D., Ph.D., Department of Psychiatry, University of WisconsinMadison, 6001 Research Park Boulevard, Madison, WI 53719-1179,
U.S.A.
aspects of sleep physiology. General aspects of host
defense function are reviewed below.
HOST DEFENSE SYSTEMS
Host defenses in higher organisms are complex and
multilayered. They involve anatomical barriers such as
skin, mucosal surfaces, secretions, and ciliary action,
as well as active components. Active defenses include
nonspecific and specific defenses, which are further
subdivided into cellular and humoral components.
Nonspecific defenses include various inflammatory
cells (e.g. polymorphonuclear cells, natural killer cells,
basophils, eosinophils, etc.) and humoral factors (e.g.
opsonins, complement, lectins, etc.). Vertebrates also
have lymphocyte-mediated immunity, which provides
targeted responses to specific pathogens. Immune responses are carried out by clonal populations of T and
B lymphocytes, which become activated upon recognition of specific antigens. B cells produce antibodies
(immunoglobulins), whereas T cells secrete cytokines
and mediate cytotoxicity. Antibodies can be considered state-of-the-art opsonins (molecules that bind to
antigens and are recognized by phagocytic cells) that
interact with most cellular components of nonspecific
defenses via the class-specific, immunoglobulin-heavy
chain receptors (Fc receptors).
B-cell responses evolved to operate as tightly regulated, antigen-driven processes. The initiation, maintenance, and termination of specific immune responses
is dependent on processing and presentation of antigens and on costimulatory signals provided by non-
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R. M. BENCA AND 1. QUINTANS
specific lymphoid cells. Conversely, components of
specific immunity such as cytokines also greatly affect
nonspecific defenses. Thus, specific and nonspecific
host defenses are interdependent and work cooperatively. In general, both the quality and the magnitude
of host defense responses are actively regulated to
maximize their effectiveness.
Host defenses to pathogens usually involve interactions among multiple cellular and humoral components acting both locally and systemically. Local coordination of host defenses is achieved through direct
cell-cell interactions and via soluble product such as
chemotactic/vasoactive factors and cytokines. Systemic coordination involves the neuroendocrine and autonomic nervous systems as well as a complex proinflammatory cytokine network, including interleukin-l
(IL-l), IL-6, tumor necrosis factor (TNF), and others
by activated NK cells are as important for immune
competence as is their cytotoxicity. Antibody-dependent NK-mediated cytotoxicity may be of equal or
greater importance than NK cytotoxicity of tumor cell
targets. No studies dealing with sleep and immunity
have taken a comprehensive approach toward assessing these functions of NK cells.
Furthermore, many studies rely on the assessment
of cells from peripheral blood samples; this presents
serious problems for interpretation because conventional immune responses are launched from the secondary lymphoid organs (lymph nodes, spleen, etc.)
and not from cells in the circulation. Changes in functional activities of peripheral blood lymphocytes
(PBLs) might simply reflect a redeployment of cells to
sites where they are needed most. This point is well
documented in the recent studies of Dhabhar et al. (7)
(6).
and Dhabhar and McEwen (8) on stress-induced
Immune responses to pathogens are divided into two changes in lymphocyte biology.
major categories, defined by whether helper T cells of
An important fact overlooked in most studies of
type 1 (Thl) or type 2 (Th2) are involved. Intracellular sleep and immune function is that the Thl and Th2
pathogens induce cellular responses that are highly de- branches of the immune system exhibit a form of inpendent on Thl cells and the cytokines interferon traservice rivalry that is mutually inhibitory. In gen(IFN) gamma and interleukin-12 (IL-12). Th2 re- eral, the effects of IFN gamma (a Thl cytokine) and
sponses involve humoral responses against extracel- IL-4 (a Th2 cytokine) are antagonistic. Therefore, a
lular pathogens and rely on IL-4, IL-5, and IL-lO to net decrease in one branch often leads to an opportufacilitate B-cell activation and antibody production. nistic increase in the other. Furthermore, not all types
Humoral and cellular immune responses are interde- of immune responses are equally effective in dealing
pendent because antibodies engage multiple cellular with every pathogen; for example, Thl responses inactivities via the class-specific (Fc) antibody receptors clude cell-mediated reactions that are important for
found on phagocytes, natural killer (NK) cells, mast dealing with intracellular pathogens, whereas Th2 recells, basophils, eosinophils, and even platelets. NK sponses regulate production of antibodies in response
cells are often considered part of the Thl defensive to extracellular pathogens. It is thus extremely difficult
loop, but they also participate in antibody-dependent to make conclusions about the state of the immune
cytotoxicity to extracellular pathogens, a Th2 re- system from studies that measure few parameters and
sponse, because of the presence of Fc receptors.
follow responses to limited numbers of antigens.
To study effects of sleep on host defenses, it would
Finally, most studies in the field of psychoneuroimbe ideal to evaluate multiple components simulta- munology have also failed to distinguish between the
neously. In practice, this is quite difficult and generally recirculating pool of lymphocytes that mount immune
not done; most studies focus on sampling one or at responses in lymph nodes and the spleen vs. the more
most a few isolated host defense measures. Some of sessile, mucosal-associated lymphocytes. The failure
the more commonly studied parameters include mito- to assess mucosal immunity represents a major gap in
gen-induced proliferative responses and assays of NK our understanding of sleep-immune system interaccell activity. The popularity of these assays is largely tions because of the sheer size of the mucosal lymdue to their ease of performance rather than their rel- phocyte pool (20-50% of the body's total lymphoevance as indicators of overall immune function. Mi- cytes), the extensive autonomic innervation of mucosal
togen assays take advantage of the ability of polyclon- sites, and the local availability of neuropeptides. The
al activators to induce nonspecific proliferation of potential importance of nervous system regulation on
large numbers of lymphocytes but do not correlate the development of mucosal immunity is suggested by
well with immune responses to pathogens. NK cell the recent demonstration that thymic production of the
assays typically measure cytotoxicity against selected neuropeptide thyrotropin-releasing hormone (TRH) is
transformed cell lines maintained continuously by in essential for the development of gut T lymphocytes in
vitro passage, but the relevance of this type of assay the mouse (9). Development of intestinal T cells furto in vivo situations has also not been well established. ther depends on local production of thyroid-stimulatFor example, it is conceivable that cytokines released ing hormone (TSH), which exemplifies the cross-utiSleep. Vol. 20. No. 11. 1997
SLEEP AND HOST DEFENSES
lization of messenger molecules between the nervous
and immune systems (10).
SLEEP AND HOST DEFENSES
Increases in sleep often accompany infectious illnesses; this is generally considered to be one of the
major pieces of evidence in support of a connection
between sleep and host defenses. Humans with common viral infections such as influenza, rhinovirus, and
Epstein Barr virus sleep more, as reviewed by Pollmacher et al. (11) Other diseases appear to be associated with abnormalities in the distribution rather than
the ~m?un.t of sleep across the day, such as trypanosorruasls, III which both fragmentation of nocturnal
sleep and increases in daytime sleep have been observed (12).
Alterations in sleep patterns in response to challenges with pathogens have been reported in rabbits
(13,14). Initial increases in slow-wave sleep (SWS)
amount and delta wave amplitude occurred during the
first hours after inoculation with S. pyogenes, E. coli,
?r c. albicans, followed by more prolonged decreases
III these parameters. The time course of the observed
changes varied somewhat, depending on the microorganism (13). For example, in rabbits infected with
Trypanosoma brucei, increases in temperature, SWS,
a~d ~elta wave amplitude followed episodes of paraslterrua (14). Variability in sleep responses during infectious illness may be related to differences in the
structures of pathogens and/or the host responses to
them.
It has been suggested that increased sleep may have
a beneficial effect on the cause of an infectious illness.
Rabbits given intravenous inoculations of E. coli, S.
aureus, or C. albicans showed a biphasic sleep response in the 48 hours after injection; sleep was initially enhanced and then decreased (15). Animals with
the largest increases in SWS had the lowest mortality
rates. These results have been interpreted as suggesting
that a greater sleep response following infectious challenge might enhance host defense functions and thus
be protective to the organism. However, animals more
likely to die following inoculation not only had smaller
increases in SWS but also had been injected with higher doses of the infectious agents. The poorer quality
of sleep in the terminal animals might have reflected
their moribund state, and sleep may simply be a prognostic factor in recovery from infection.
BACTERIAL PRODUCTS ALTER SLEEP
Changes in sleep during infections appear to be
caused by pathogens, because bacterial and viral com-
1029
ponents have hypnotic effects when injected into a variety of mammalian species. Muramyl peptides (MPs),
components of bacterial peptidoglycans, increased
non-rapid eye movement (NREM) sleep and SWS
when injected intraperitoneally (ip) or intracerebroventricularly (icv) in rats, rabbits, and cats (16-18),
whereas rapid eye movement (REM) sleep was relatively suppressed. These effects were usually seen
when MP was administered during the normal period
of wakefulness; MP given at the beginning of the usual
sleep period resulted in smaller and/or insignificant increases in sleep (19). The bacterial membrane components lipid A and lipopolysaccharide (LPS, or endotoxin), as well as virus-derived substances such as
double-stranded RNA, have also been found to have
somnogenic properties in several species (20,21).
Several studies have documented sleep-promoting
effects of endotoxin administered to humans (11,22).
Intravenous injection of endotoxin 4 hours prior to the
onset of the normal sleep period resulted in prolonged
REM sleep latency and relative suppression of REM
sleep during the first part of the night, increased
NREM and stage 2 sleep time, and increased alpha
and beta electroencephalograph (EEG) power. In contrast to the animal studies, no enhancement of SWS or
delta power was noted. In addition to the sleep
changes, increases in tumor necrosis factor (TNF) alpha, IL-6, temperature, and cortisol were noted during
the early part of the night; growth hormone secretion
was decreased.
Administration of endotoxin to humans at 9:00 a.m.
had no significant effects on sleep, however, except for
suppression of REM sleep in the early morning (23).
The effects of endotoxin on temperature, cytokines,
and cortisol were not as great as following nocturnal
a~min~stration, suggesting that endotoxin effects vary
wIth tIme of administration. The observed differences
could be related to circadian effects and to differences
in ho~~ostatic sleep drive. In any case, the apparent
assoCIatIon between effects on sleep and temperature
supports the possibility that hypnotic effects could be
secondary to increased temperature.
Comparisons between the animal and human studies
are difficult to make because endotoxin has pleiotropic
effects that may differ somewhat across species. Furthermore, no careful dose-response studies have been
performed in humans. However, in both human and
animal studies, endotoxin effects were consistent in
suppressing REM sleep and increasing NREM sleep.
Overall, these results indicate that administration of
bacterial products tends to promote NREM sleep and
suppress REM sleep.
MP and other bacterial/viral components may influence sleep in various ways. It is possible that bacterial
products could directly stimulate hypnogenic centers
Sleep, Vol. 20, No. II, 1997
R. M. BENCA AND J. QUINTANS
1030
without acting via host defense mechanisms, although
specific pathways have not yet been identified. MP,
endotoxin (LPS), and other bacterial components are
also potent inducers of cytokine and hormone release
and could thus regulate sleep through activation of
host defense systems. Ii has even been suggested that
sleep is rooted in a symbiotic relationship between
bacteria and mammals, and that bacterial components
are "vitaminlike" in that they are not synthesized by
the host but required for normal sleep induction (2).
A related hypothesis is that sleep is a host defense that
evolved to protect the brain from gut-derived bacterial
components (24). To our knowledge, there is no experimental data to support these hypotheses.
CYTOKINES AFFECT SLEEP
The likely mediator for the sleep-inducing effects of
MP is the cytokine interleukin-l (IL-l), which itself
has pleiotropic effects, including sleep induction, fever, anorexia, hypotension, immunomodulation, and
release of pituitary hormones (25). IL-l administered
intravenously, intracerebroventricularly, or locally to
brain stem sites resulted in an increase in SWS and
suppression of REM sleep in rabbits, cats, rats, and
monkeys (18,21). Rats showed more pronounced circadian sensitivity to the effects of IL-l (26).
The possible involvement of IL-I in physiological
sleep regulation is further suggested by the findings
that anti-IL-l-beta antibodies given icv reduced SWS
in rats when given prior to light onset or following 3
hours of sleep deprivation (27,28). IL-l receptor antagonist caused a transient decrease in NREM sleep in
rabbits and prevented sleep and febrile responses to
IL-l (29).
Other cytokines shown to have sleep-inducing properties include TNF-alpha and IFN-alpha (30,31). Cytokines with somnogenic properties also tend to induce
fever along with sleep, which has raised the possibility
that the somnogenic properties of these agents are related to their hyperthermic effects. Both increased
brain temperature and cytokine administration lead to
increases in total sleep and NREM sleep (32,33). Cytokines may regulate sleep indirectly through hyperthermic effects, but it is also possible that the sleepand fever-inducing effects of cytokines and MPs are
mediated by independent mechanisms. A study of various MPs found that although somnogenic compounds
were always pyrogenic, not all pyrogenic compounds
were somnogenic, suggesting that increasing temperature alone was not necessary to induce sleep (34).
Similarly, analysis of human TNF-alpha fragments
demonstrated induction of a slight fever without a significant increase in sleep (35). Microinjection of IL-l
into various brain sites suggested that fever and sleep
Sleep. Vol. 20. No. 11. 1997
responses could be localized to different areas (36).
Blockade of the febrile but not sleep response to IL-I
was reported following administration of a protein
synthesis inhibitor or antiprostaglandin (37,38). Although febrile and somnogenic effects may be separable under certain circumstances, in most situations
they occur together, and it is possible that at least some
of the observed effects on sleep may be due to thermoregulatory actions of cytokines.
Other correlations suggesting involvement of cytokines in sleep come from the observation of physiological fluctuations of cytokine activity during normal
periods of sleep and wakefulness. IL-I activity and ILl-beta were found to increase during normal sleep in
the cerebrospinal fluid of cats (39). A study of normal
men found that during sleep, serum levels of IL-l and
IL-2 activity increased in comparison to wakefulness
(40). IL-l measured during daytime napping increased
significantly in comparison to wakefulness, but only
during SWS (41). Changes in serum cytokine activity,
however, could be related to changes in production or
clearance.
A more recent study assessing cytokine production
by stimulated lymphocytes in vitro obtained different
results: IL-l-beta and TNF-alpha secretion were reduced in blood samples obtained during sleep, whereas
IL-2 levels were increased in samples obtained during
sleep during the second half of the night only (42).
Conversely, sleep deprivation was associated with increased production of TNF-alpha and IL-l-beta production by PBLs (42). These findings have been interpreted as suggesting that IL-l-beta and TNF-alpha
may increase during wakefulness and act as sleep-promoting factors.
Pulsatile increases in cytokine levels may be related
to NREM sleep, as indicated by correlations between
plasma TNF-alpha and IL-I-beta levels and delta amplitude found in normal control subjects and patients
with human immunodeficiency virus (HIV) during the
early phases of infection (43,44). However, during
more advanced stages of HIV infection, cytokine levels and delta amplitude were less highly correlated.
The reasons for the breakdown in coupling are unclear,
but this is hardly surprising given that HIV-induced
damage to the central nervous system could also affect
sleep induction and maintenance. Alternatively, the
uncoupling of cytokines and delta amplitude may relate to abnormal elevation in brain levels of TNF-alpha
or increased peripheral TNF-alpha and IL-l-beta production, as suggested by Darko and colleagues (44).
A study comparing sleep, cytokines, and lymphocyte subsets in young vs. aged subjects suggests that
the relationships between sleep and cytokine production may not be straightforward (45). In comparison
to young adults, elderly subjects had decreased
SLEEP AND HOST DEFENSES
amounts of SWS and REM sleep and increased wake
time during sleep. They also showed decreased numbers of T cells in peripheral blood but had increased
levels of production of TNF-alpha, IL-I-beta, and
IFN-gamma. NK cells and activated T cells were increased in peripheral blood. Thus, elderly subjects appeared to have greater activation of host defenses during sleep accompanied by the predicted decrement in
REM sleep, but they had no increases in NREM sleep
or SWS. As in the case of patients with advanced HIV,
the apparent failure of somnogenic cytokines to increase sleep in the elderly may relate to central nervous system degeneration, decreased responsivity to
cytokines, or both. Alternatively, the apparent relationships between sleep and cytokines may not be due to
primary relationships between sleep-wake behavior
and host defense systems but may instead represent
effects of perturbations of circadian rhythms, thermoregulatory systems, and/or neuroendocrine systems.
A recent study by Born et al. (46) assessed the differential effects of sleep and circadian rhythms on circulating white blood cell subpopulations and cytokine
production. Sleep caused reductions in monocytes, NK
cells, and lymphocytes in peripheral blood during the
night in comparison to a night of wakefulness. A night
of sleep deprivation, however, led to decreases in NK
cells and lymphocytes during the following day in
comparison to daytime levels follow~ng normal sleep.
Production of the cytokines IL-l-beta and TNF-alpha
was decreased in whole blood samples obtained during
a night of normal sleep vs. sleep deprivation, but these
effects were likely due to the changes in cell populations in peripheral blood, because cytokine production
per peripheral blood monocyte did not change with
sleep or sleep deprivation. IL-6 did not change in relation to sleep vs. sleep deprivation; IFN-gamma production also appeared to be largely unaffected by sleep
or sleep deprivation, except for an increase at the end
of recovery sleep. The only notable change in cytokine
production was an increase in IL-2 by peripheral blood
T cells during a night of sleep vs. a night of sleep
deprivation, which was interpreted as suggesting a
stimulatory effect of sleep on IL-2 production. Circadian rhythms of circulating levels of peripheral blood
lymphocytes and monocytes were observed. The combination of sleep-related and circadian fluctuations in
peripheral blood cells may thus account for the observed differences in IL-I-beta and TNF-alpha levels
during the night observed in this and other studies.
In addition to the effects of circadian rhythms,
changes in neuroendocrine parameters may mediate alterations observed in cytokine production during sleep
deprivation. Hohagen et al. (47) found that production
of IL-I-beta and IFN-gamma was greatest about the
time of sleep onset and decreased during the night in
1031
healthy control subjects. However, decreased cytokine
production was associated with increased serum cortisollevels, suggesting the possibility that cortisol may
have suppressed cytokine production. Cytokine effects
on sleep may be in part mediated by the endocrine
system, because IL-I can activate the hypothalamicpituitary-adrenal (HPA) axis, which in tum inhibits
sleep. However, IL-I can also increase growth hormone (GH) secretion, which appears to have sleeppromoting effects. Thus, regulation of sleep by cytokines could be mediated by a variety of endocrine
mechanisms with potentially opposite results, which
may explain some of the discrepancies among various
studies.
The studies summarized above demonstrate that
changes in sleep patterns occur in mammals fighting
infections, although the mechanisms for these effects
are not fully understood. It has been suggested that
sleep may be a part of the acute-phase response, a
systemic reaction to infection mediated by cytokines
(particularly IL-l, TNF, and IL-6) resulting in fever,
activation of the immune system, hormone secretion,
norepinephrine release, increased metabolic rate, and
increased hepatic synthesis of proteins (48). Implicit
in this theory is the idea that sleep is somehow helpful
or necessary to combat infectious illness; this is not
necessarily the case, as increased sleep could simply
be a side effect of cytokine release without clinically
significant regulatory effects on host defenses. To conclude that sleep is an adaptive organismal response to
infection, it would be necessary to demonstrate that
host defenses are enhanced by sleep and/or that sleep
deprivation impairs host defenses.
EFFECTS OF SLEEP DEPRIVATION ON
HOST DEFENSES
The hypothesis that sleep might influence host defenses in clinically significant ways has been suggested
by the association between decreased sleep amounts
and increased morbidity and mortality in humans (49)
and by the finding that chronic sleep deprivation is
fatal in an animal model (50). The effects of some
stressors on host defenses are similar to those observed
in response to sleep deprivation (4,51), which makes
it difficult to be certain that the effects observed on
host defenses in sleep deprivation paradigms are due
to sleep loss per se. In both the animal and human
studies reviewed below, some paradigms used to
achieve sleep deprivation are clearly more stressful
than others. As reviewed recently by Dinges et al. (52),
there is no compelling evidence to suggest that sleep
deprivation in humans is invariably associated with
stress reactions (e.g. elevated plasma glucocorticoids
and urinary catecholamines). Similarly, sleep-deprived
Sleep, Vol. 20, No. II, 1997
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R. M. BENCA AND J. QUINTANS
rats do not show signs of typical stress responses in a
controlled paradigm (50). From an immunological
standpoint, however, it does not really matter whether
consequences to host defenses are specific to sleep loss
or stress; therefore, the issue as to whether sleep-deprivation effects on host defenses are related to sleep
loss vs. stress will not be addressed further in this review.
Several studies have assessed the effects of shortterm sleep deprivation on host defenses in humans,
although these studies have been limited to the assessment of peripheral blood samples. In one of the
earliest studies (53), normal female subjects were kept
awake for 77 hours shooting rifles at small targets almost continuously. Peripheral venous blood samples
were collected daily on the day prior to beginning the
77-hour vigil, the second and third days of sleep deprivation, and the fifth day of recovery after completing the deprivation. Interferon levels increased progressively on the 4 days sampled and were highest on
the recovery sleep day. Phagocytosis of bacteria by
white blood cells was somewhat decreased on the two
sleep-deprivation days and highest on the recovery
day. Numbers of circulating polymorphonuclear cells
and monocytes did not change significantly throughout
the study.
In another study, multiple performance tasks were
used to maintain wakefulness for 48 hours (54). Mitogen responses of PBLs to phytohemagglutinin
(PHA) were decreased during sleep deprivation, but
no changes were seen in granulocyte function, which
was the only other parameter tested.
The effects of 40 hours of sleep deprivation on various host defenses were assessed in a group of male
subjects (55). Venous blood samples were obtained
frequently during a baseline day and night (with normal sleep), a 40-hour period of sleep deprivation, and
a night of recovery sleep. Responses to pokeweed mitogen (PWM) increased during sleep deprivation in
comparison to baseline and increased further during
recovery sleep; the increase in nocturnal PWM responses was also delayed by sleep deprivation in comparison to baseline or recovery sleep. PHA responses
were unaffected. Natural killer cell (NK) activity decreased progressively over the study. In general, NK
activity was greater in the 4-hour period just prior to
the normal nocturnal sleep period, but the largest decrement occurred on the night of recovery sleep; decreases in NK activity thus occurred both following
sleep deprivation and during sleep. IL-I activity did
not show significant relationships with sleep or wake
during baseline but was significantly higher during the
nights of sleep deprivation and recovery days than during baseline. IL-2 activity also peaked during the night
in all conditions but was higher during the night of
Sleep, Vol. 20, No. 11, 1997
sleep deprivation than during baseline or recovery
nights.
Two recent studies have focused on the effects of
sleep deprivation on NK activity, yielding seemingly
opposite findings. Irwin et a1. (56) measured NK activity in the early morning following a night of normal
sleep after a single night of partial sleep deprivation
(3:00 to 7:00 a.m.) and following. a recovery night of
sleep. NK activity was significantly reduced on the
morning following deprivation in comparison to the
values obtained during baseline or after recovery
sleep. In contrast, Dinges et al. (57) failed to find significant decrements in NK activity after 64 hours of
total sleep deprivation; in fact, NK activity increased
significantly by the end of the sleep-deprivation period. In the latter study, NK activity was measured at
10:00 a.m., coinciding with the normal daily peak in
NK activity, rather than in the early morning; several
other parameters tested also failed to show significant
changes during sleep deprivation, including mitogen
stimulation responses and counts of lymphocytes, eosinophils, and Band T cells in peripheral blood samples. Total white blood cell counts, granulocytes, and
monocytes increased, whereas red blood cells and CD4
T cells were found to decrease with sleep deprivation.
Overall, the human studies summarized above failed
to show consistent effects of sleep loss on cytokine
activity, mitogen 'responses, or NK activity, although
fluctuations in several parameters occurred in association with sleep loss in all studies. One possible explanation for the seemingly inconsistent results of
these studies is that white cell populations, their activities, andcytokine levels from peripheral blood may
vary depending on the circadian time of testing. Alternatively, changes in these parameters may vary depending on the length of deprivation. As discussed
above, varying amounts of stress in the different paradigms could also contribute to variability in the results.
To interpret the findings, it is useful to keep in mind
that the parameters tested may not be meaningful reflections of host defense function. For example, NK
activity in the blood might be a functionally irrelevant
marker. NK cells probably carry out their protective
effects in tissues, not in circulation, and a decrease in
NK activity in blood could actually reflect an enhancement in host defenses. This was recently shown to be
the case in a stress paradigm in rodents (8), in which
decreased NK activity in the blood was accompanied
by redistribution of NK cells to tissues and an increase
in NK function.
More extensive investigations of the effects of sleep
deprivation on host defenses have been performed in
animals, where it is possible to assess host defenses
systemically. Some studies have suggested that sleep
SLEEP AND HOST DEFENSES
deprivation may have detrimental effects on certain
host defenses. An often-cited study in support of immunosuppressive effects of sleep deprivation is that of
Brown et al. (58), which assessed the effects of sleep
deprivation on mice challenged with influenza virus.
Immunized mice were given three intranasal inoculations spaced 1 week apart; sham-immunized mice received live virus only in the last inoculation. Following the final administration of virus, groups of immunized and sham-immunized mice were either allowed to sleep ad-lib or sleep deprived for 7 hours by
cage tapping, handling, or both. Three days later, mice
were sacrificed and lung homogenates were assayed
for virus and antibody titer. Virus was recovered from
all mice except the immunized, nonsleep-deprived
group, which also showed significantly higher antibody titers. Virus recovery and antibody titer were not
significantly different in immunized, sleep-deprived
mice vs. sham-immunized animals. The authors state
that their findings support the concept that sleep is a
behavioral state that is essential for optimal immune
function in the presence of a respiratory pathogen.
Although this study suggests that sleep-deprived rats
showed impaired ability to clear a viral challenge, it
is not possible to conclude from the data provided that
this was due to impairment of immune function per
se. Antibody titers in lung homogenates were measured only 3 days postimmunization, which is too
short a period of time to boost antibody responses optimally, and the study did not include measurements
of serum antibody titers for different immunoglobulin
classes to ascertain whether the effects were site specific or systemic. The lowered antibody concentrations
in lung homogenates of sleep-deprived mice could
have been caused by increased catabolism rather than
decreased antibody production; i.e. the experimental
procedure could have had secondary effects on viral
clearance via primary effects on mucosal physiology,
resulting in increased proteolytic activity in lung fluids.
Furthermore, it is not clear whether the observed
effects were due to sleep loss or the procedure used to
effect sleep deprivation, because deprivation was
achieved using stressors (cage tapping and handling)
for which there was no control. A recent study assessing the effects of stress on cytokine production during
experimental influenza virus infection in mice has
demonstrated that restraint stress led to alterations in
the production of cytokines important for the regulation of Thl and Th2 immune responses (59). Decreases were reported in the production of several Thl and
Th2 cytokines from regional lymph node and spleen
cells, but IL-6 production from spleen cells was increased. A previous study by the same group had demonstrated that stress-induced sympathetic nervous sys-
1033
tem activation also contributed to decrements in cytotoxic T-cell activation (60). Thus, no firm conclusions can be made regarding the mechanisms for the
reduced viral clearance in the Brown et al. (58) study
(i.e. relatively specific effects on antibody production
vs. nonspecific effects on lung mucosa), or whether
the effects were due to sleep loss or stress. The findings do suggest impairment of as yet unidentified aspects of host defense, however.
In a subsequent study, Brown and coworkers (61)
assessed the effects of sleep deprivation and administration of IL-l and muramyl dipeptide (MDP) on secondary antibody responses in rats. Rats were immunized intraperitoneally with sheep red blood cells and
then rechallenged with the same antigen 14 days later.
Following the second immunization, rats were given
injections of saline, IL-l, or MDP and then either allowed to sleep ad-lib or sleep deprived for 8 hours by
cage tapping or handling. The rats were sacrificed 3
days later, and serum antibody titers were found to be
significantly lower in sleep-deprived rats given saline
and in normally sleeping rats injected with either MDP
or high-dose IL-l. All other groups (saline and normal
sleep; low-dose IL-l whether normal sleep or sleep
deprived; high-dose IL-l and sleep deprived; or MDP
and sleep deprived) had similarly high antibody titers
to sheep red blood cells. One of the conclusions of this
study was that combinations of two manipulations
shown to be immunosuppressive (e.g. sleep deprivation, MDP, or high-dose IL-l) are immunoenhancing.
From an immunological standpoint, these studies are
difficult to interpret. Clinicians administering immunosuppressant drugs to transplant recipients or patients
with autoimmune disorders know that, in general, the
combination of two drugs enhances immune suppression. Measurement of antibody titers 3 days postimmunization may be too early to determine the response
to the last immunization. Furthermore, to focus on humoral parameters alone might distort the picture, because responses to sheep red blood cells can include
Thl responses (as measured by delayed type hypersensitivity) as well as humoral Th2 responses.
One of the more compelling findings suggesting a
breakdown in host defenses with sleep deprivation is
the report by Everson (62) of an increased rate of bacteremia in rats chronically deprived of sleep. Rats deprived of sleep by the disk-over-water method for prolonged periods of time evidence a series of physiological abnormalities, including increased metabolism,
hyperphagia, weight loss, hypothermia, and eventual
death (50). The mechanisms by which sleep deprivation causes death are unknown, and the possibility of
a breakdown in host defenses, including the immune
system, must be considered. Everson found bacteria in
blood cultures from five of six rats deprived to nearSleep, Vol. 20, No. 11, 1997
1034
R. M. BENCA AND J. QUINTANS
terminal conditions. Although the data are highly sug- creased rate of tumor regression following injection of
gestive of a breakdown in host defenses in terminally Walker carcinoma cells in comparison with nondesleep-deprived rats, it is impossible to know from this prived control rats (65). The experimental design used
study whether impairment in host defenses was an ear- by Bergmann et al. (65) is particularly attractive bely, primary effect of sleep deprivation or a late-devel- cause it measures total contributions of defense reacoping complication in a debilitated animal with mul- tions to rid the body of an allogeneic tumor load. (In
tiorgan system failure. Nevertheless, an important this model, the tumor is an allograft, and complete
strength of the Everson study was the control for the tumor regression is the end point). However, it is not
stimulus used to achieve sleep deprivation.
clear which aspects of host defense are affected in this
A subsequent study by Bergmann et al. (63) used particular paradigm; future studies may help delineate
the same paradigm to address the temporal relationship which components of the allograft response are afbetween sleep loss and host defense breakdown by fected by the sleep-deprivation protocol.
looking for signs of ;bacterial invasion earlier in the
course of sleep deprivation. Rats subjected to chronic
CONCLUDING REMARKS
sleep deprivation for 4 days and their yoked controls
were sacrificed and examined for bacterial infection.
Sleep occurs in all animal species, and although it
Cultures of blood showed bacteremia in 3 of 11 sleepdeprived rats and 1 of 10 yoked controls, whereas cul- is necessary for survival, the specific functions of
tures of organs of filtration (kidney, liver, and mes- sleep are unknown. Although host defenses are also
enteric lymph nodes) were either free of bacterial found throughout the animal kingdom, clonal immune
growth or had only low numbers of colonies present. responses are found only in vertebrates, whereas nonOverall, no significant differences in bacterial growth specific defenses have a longer evolutionary history.
were seen between the deprived and control groups. At the risk of oversimplification, host defense reMore important, other symptoms of sleep deprivation sponses to pathogens can be thought of in terms of
(increased energy expenditure, increased temperature, antigen-driven clonal events and supporting nonspeand weight loss) were unrelated to the presence of bac- cific effects (homing, cellular interactions in secondary
teria, suggesting that the physiological syndrome that lymphoid organs, cytokine release, etc.) that make
accompanies sleep deprivation is not necessarily relat- clonal events possible and maximize their efficacy. It
is difficult to envision a direct link between sleep and
ed to infection.
An earlier study by Benca et al. (64) using the disk- clonal events in lymphocytes. From an evolutionary
over-water sleep-deprivation method failed to docu- standpoint, one would predict that the connections bement abnormalities in mitogen responses or in vitro or tween sleep and host defenses were established early,
in vivo antibody responses in near-terminal rats de- prior to the emergence of specific immunity. Perhaps
prived of total sleep or paradoxical sleep. These results the earliest links involved low molecular weight pepsuggest that specific components of the immune sys- tides, because the involvement of neuropeptides in the
tem (e.g. lymphocytes and antigen-processing cells) adherence and migration of invertebrate hemocytes has
are not specifically impaired as a consequence of pro- been demonstrated (66). In this context, it is not surprising that the interactions between sleep and host
longed sleep deprivation.
Although the three studies discussed above [Everson defenses that appear to be robust involve the more
(62), Bergmann et al. (63), and Benca et al. (64)] used primitive components of host defenses such as IL-l
a similar experimental procedure, their seemingly dis- and TNF.
It is more likely that the effects of sleep or sleep
parate findings may be related to the fact that different
aspects of host defenses were assessed after differing loss impact on host defenses indirectly, as a conseamounts of sleep deprivation. However, the results of quence of significant impairment of the central nerthese three studies are not necessarily inconsistent with vous system and the subsequent cascade of effects on
each other; one possible interpretation is that bactere- various physiological systems. Instead of having direct
mia resulting from sleep deprivation may be related to effects on the immune system, sleep probably affects
breakdown in barriers and/or alterations in nonspecific the supporting events that regulate the quality and
defenses rather that primary effects on the immune quantity of immune responses. This could occur as
system.
part of the systemic changes characteristic of circadian
Although the generally held view is that sleep loss rhythms, as a result of stress, or more directly by
is harmful to host defense mechanisms, there is also sleep-related regulation of the autonomic nervous sysevidence that sleep deprivation may actually enhance tem. It is well known that both primary and secondary
certain aspects of host defenses. Rats deprived of sleep lymphoid organs are hard wired to the sympathetic and
for 10 days showed less tumor growth and an in- parasympathetic systems (67), and, not surprisingly,
Sleep, Vol. 20, No. 11, 1997
1035
SLEEP AND HOST DEFENSES
numerous studies document effects of the autonomic
system and HPA axis on immune responses (3).
Among defense cells, a potential target of direct autonomic effects that has been largely overlooked is the
mast cell (68). Mast cells are innervated by afferent
autonomic neurons and are capable of degranulation
in response to stimulation. Although mast cells have
not enjoyed a particularly good reputation because of
their role in allergic reactions, it is now becoming apparent that they are key modulators of both nonspecific
responses and specific immune reactions (69,70). Mast
cells are strategically located around capillary beds
throughout the connective tissue and in all mucosal
surfaces. Their local environment is rich in autonomic
innervation, neuropeptides, and cytokines. In addition
to the better known mediators such as histamine, mast
cells also contain preformed cytokines such as TNFalpha and possibly IL-4. These cytokines have potent
immunoregulatory activities on lymphocytes and
monocytes, which in tum affect the ThlITh2 balance.
Thus, mast cells are poised to act as cellular transducers of autonomic signals that modulate immune responses. Changes in sleep and wakefulness, which are
associated with alterations in sympathetic activation,
could thus influence mast cell function and, in tum,
mucosal defense reactions. For example, the necrotic
skin lesions in sleep-deprived rats could be due to abnormal cytokine secretion in response to sympathetic
nervous system stimulation of intradermal mast cells,
and sleep-induced breakdown in mucosal integrity
may be a cause of septicemia.
As a group, cytokines that affect both the immune
and nervous systems are likely to play an important
role in linking the two systems; these include the
proinflammatory cytokines such as IL-l and TNF-alph a, the neuropoietic cytokine family [IL-6, leukemia
inhibitory factor (LIF), ciliary neurotrophic factor
(CNTF), and others (71)], and the neurotrophins suctI
as nerve growth factor (NGF) (72). Clearly, cytokines
have pleiotropic and redundant effects that often make
it difficult to establish causal connections. There are
tantalizing hints of possible regulatory interactions between the two systems. For example, NGF has recently
been shown to act as an autocrine B-cell factor essential for the development of secondary antibody or
memory responses (73), whereas the cytokine IL-6,
which acts primarily on B cells, has properties similar
to those of NGF in the central nervous system. The
polypeptide growth factor leukemia inhibitory factor
(LIF) has been shown to be important in the development of a variety of systems, including stem cells
and neurons (74,75).
There are two alternative interpretations of mediator
sharing between the two systems: one suggests a deeper interdependence between the systems, and the other,
a more mundane explanation, suggests that nature displays an uncanny ability to recycle its elements for
multiple purposes. Recent findings of cytokine effects
on sleep are reminiscent of the field of immunochemistry earlier this century, with its emphasis on crossreactivity and cross-talk. Although much was learned
about antibody specificity, it was only following the
elucidation of the structure of antibodies and antibody
binding sites that the molecular framework was provided to understand the fundamental problem of immune recognition.
The challenge for future research is not only to identify the interactions between sleep and the immune
system but to determine their ultimate meanings in
molecular terms. Future research in this field should
take advantage of the growing knowledge about the
human genome. Identification of mutations in cytokine/neurotrophin genes will provide the opportunity
to begin unraveling the complexities of the cytokine
network. For example, it might be of interest to study
individuals with mutated CNTF genes (76), because
this neurotrophin is also an endogenous pyrogen. Another promising experimental model is the gene
knock-out mouse (77). Although mice pose greater
technical difficulties in the study of sleep, the growing
availability of mice with targeted gene deficits will
provide powerful tools with which to study the role of
various mediators in relation to sleep. Two recent examples of the usefulness of this approach are the studies on sleep in prion-deficient mice (78) and the use
of substance-P receptor knock-out mice to analyze
neurogenic amplification of immunologically induced
inflammation (79).
Clearly, neural systems implicated in the control of
sleep also impact on the functioning of host defenses,
but it is almost certainly an oversimplification to assume that there are unitary effects of sleep or sleep
loss on host defense systems. Both the nervous system
and host defenses are multifaceted systems with the
potential for extensive regulatory interactions. Elucidation of those interactions will be a challenging task,
but will undoubtedly be important for understanding
of the role of sleep in health and disease.
Acknowledgement: This work was supported by grants
MHOl224 and MH52226 from the National Institute of
Mental Health (R.M.B.).
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