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Review
. 2019 Jul 1;99(3):1325-1380.
doi: 10.1152/physrev.00010.2018.

The Sleep-Immune Crosstalk in Health and Disease

Luciana Besedovsky  1 , Tanja Lange  1 , Monika Haack  1
Affiliations
Review

The Sleep-Immune Crosstalk in Health and Disease

Luciana Besedovsky et al. Physiol Rev. .

Abstract

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

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Conflict of interest statement

No conflicts of interest, financial or otherwise, are declared by the authors.

Figures

None
Graphical abstract
FIGURE 1.
FIGURE 1.
Research approaches for investigating sleep-immune interactions and potential influencing factors. Experimental studies investigate causal relationships between sleep and immune parameters by manipulating sleep or immunological factors, but have low ecologic validity (i.e., they cannot be easily translated into everyday situations). Field studies investigate naturally existing associations between sleep characteristics and immune parameters; however, causality cannot be inferred. Several factors (summarized in sect. VIB) influence the results of studies, including specifics of the study design, methods, and environmental factors. Orange numbers in brackets refer to the section dealing with the denoted topic. SD, sleep deprivation; LPS, lipopolysaccharide.
FIGURE 2.
FIGURE 2.
Prototypical hypnogram with EEG characteristics and sleep laboratory setting. Sleep is divided into stages N1, N2, N3 (formerly further subdivided into S3 and S4), and rapid-eye-movement (REM) sleep based on specific patterns of brain activity [measured with electroencephalography (EEG)], eye movements [measured with electroocculography (EOG)], and muscle activity [measured with electromyography (EMG)]. N1, N2, and N3 are collectively referred to as non-REM (NREM) sleep. The course of the different sleep stages across a sleep period is typically visualized in a hypnogram (bottom right). The typical sleep laboratory setting for measuring blood parameters during sleep includes a hole-through-the-wall system, allowing the blood sample to be collected from an adjacent room through a long tube without disturbing the participant’s sleep. (Adapted from Tanja Lange.)
FIGURE 3.
FIGURE 3.
Major components of the immune system, a prototypical immune response to an infectious challenge, and immunological memory. The first line of defense against an infectious challenge are physical barriers and antimicrobial peptides. If a pathogen manages to pass these barriers, the innate immune system is activated. It includes phagocytotic and cytotoxic responses of leukocytes like neutrophils and natural killer cells (NK cells). If the pathogen cannot be cleared, the adaptive immune system becomes involved. Antigen-presenting cells (APCs, such as dendritic cells) present fragments of the pathogen (consisting of peptides) together with the major histocompatibility complex II (peptide-MHCII, pMHCII) to naive T cells. Those T cells with the matching T cell receptor (TCR) for the specific antigen then differentiate into effector T cells. Together with antigen-specific memory T and B cells, antigen-specific antibodies constitute the basis of immunological memory. Whereas the primary adaptive immune response to a pathogen takes several days to develop, the secondary (memory) response develops much faster and is more efficient (bottom right). The borders between the first line of defense, the innate immune response, and the adaptive immune response are fluid.
FIGURE 4.
FIGURE 4.
Conceptual model of sleep changes in response to immune activation and underlying mechanisms. Environmental stimuli (e.g., food intake, stress), commensal bacteria, and infectious pathogens (here illustrated as viruses) are recognized by the immune system as damage- and pathogen-associated molecular patterns (DAMPs and PAMPs, green stars), which activate pattern recognition receptors (PRRs, orange polygon) on innate leukocytes. This PRR activation induces an inflammatory response with the production of sleep regulatory substances, such as interleukin (IL)-1 and tumor necrosis factor (TNF) (both represented by orange dots), which reach the brain and promote non-rapid-eye-movement (NREM) sleep (left arrow). In higher doses (e.g., during an infection; middle arrow), these sleep regulatory substances may also suppress rapid-eye-movement (REM) sleep. Prostaglandin (PG) D2 is shown as a potential further mediator of sleep changes in response to immune activation. These sleep responses to immune activation are assumed to be adaptive. Subtle immune activation may be involved in homeostatic NREM sleep regulation that in turn could serve to restore immune homeostasis. More pronounced immune activation during an infection can induce a sleep response that in turn may support host defense and immunological memory formation. However, an extreme immune activation (e.g., during severe infection; right arrow) seems to disrupt both NREM and REM sleep, often accompanied by sleep fragmentation, feelings of nonrestorative sleep, and daytime fatigue. Notably, most of our knowledge is based on animal research, and confirmation in humans is still needed.
FIGURE 5.
FIGURE 5.
Sleep supports memory consolidation in the brain and the immune system. Memory processes in the brain are usually subdivided into three phases, which may also be used to categorize memory processes in the immune system. During the Encoding phase, the information to be remembered is taken up. In the immune system, this phase refers to the uptake of the pathogen by antigen-presenting cells (APCs). In the Consolidation phase, the initially labile information is transferred from the initial store to a long-term store. For memories in the brain, the information is moved from certain brain regions to others; for memories in the immune system, the information (i.e., the antigen) is transferred from APCs to T cells. During recall, the remembered information can be retrieved, which is represented in the immune system by the activation of memory T and B cells. For both the brain and the immune system, sleep and especially slow-wave sleep seem to be most important for the consolidation phase of memory processes. (Adapted from Tanja Lange.)
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