Effects of poor sleep on the immune cell landscape as assessed by single-cell analysis.

Poor sleep has become an important public health issue. With loss of sleep durations, poor sleep has been linked to the increased risks for diseases. Here we employed mass cytometry and single-cell RNA sequencing to obtain a comprehensive human immune cells landscape in the context of poor sleep, which was analyzed in the context of subset composition, gene signatures, enriched pathways, transcriptional regulatory networks, and intercellular interactions. Participants subjected to staying up had increased T and plasma cell frequency, along with upregulated autoimmune-related markers and pathways in CD4+ T and B cells. Additionally, staying up reduced the differentiation and immune activity of cytotoxic cells, indicative of a predisposition to infection and tumor development. Finally, staying up influenced myeloid subsets distribution and induced inflammation development and cellular senescence. These findings could potentially give high-dimensional and advanced insights for understanding the cellular and molecular mechanisms of pathologic conditions related to poor sleep.

The Exposome and Immune Health in Times of the COVID-19 Pandemic.

Growing evidence supports the importance of lifestyle and environmental exposures-collectively referred to as the 'exposome'-for ensuring immune health. In this narrative review, we summarize and discuss the effects of the different exposome components (physical activity, body weight management, diet, sun exposure, stress, sleep and circadian rhythms, pollution, smoking, and gut microbiome) on immune function and inflammation, particularly in the context of the current coronavirus disease 2019 (COVID-19) pandemic. We highlight the potential role of 'exposome improvements' in the prevention-or amelioration, once established-of this disease as well as their effect on the response to vaccination. In light of the existing evidence, the promotion of a healthy exposome should be a cornerstone in the prevention and management of the COVID-19 pandemic and other eventual pandemics.

Subjective Sleep Quality and Trajectories of Interleukin-6 in Older Adults.

BACKGROUND: We aimed to identify trajectories of inflammation in older adults at elevated risk for syndromal depression and anxiety and to determine whether baseline physical, cognitive, and psychosocial factors could distinguish 15-month longitudinal trajectories. METHODS: Older adults (N = 195, mean age (±SD) = 74.4 years (9.0) participating in three depression and anxiety prevention protocols completed a comprehensive battery of psychosocial assessments and provided blood samples for analysis of interleukin-6 (IL-6) every 3 months over a maximum of 15 months. Group-based trajectory modeling identified trajectories. Adjusted logistic regression examined associations between baseline factors and trajectory groups. RESULTS: Two 15-month trajectories were identified: stable lower IL-6 levels (84%; mean (±SD) = 3.2 (2.1) pg/mL); and consistently higher IL-6 levels (16%; mean = 9.5 (7.4) pg/mL). Poor sleep quality predicted consistently higher levels of IL-6 (OR = 1.9, 95% CI = 1.03-3.55). CONCLUSION: Poor sleep quality may represent a therapeutic target to reduce inflammation.

Human sleep consolidates allergic responses conditioned to the environmental context of an allergen exposure.

Allergies are highly prevalent, and allergic responses can be triggered even in the absence of allergens due to Pavlovian conditioning to a specific cue. Here we show in humans suffering from allergic rhinitis that merely reencountering the environmental context in which an allergen was administered a week earlier is sufficient to trigger an allergic response-but only if participants had slept after allergen exposure. This context-conditioning effect was entirely absent when participants stayed awake the night after allergen exposure or were tested in a different context. Unlike in context conditioning, cue conditioning (to an odor stimulus) occurred independently of sleep, a differential pattern that is likewise observed for conditioning in the behavioral domain. Our findings provide evidence that allergic responses can be conditioned to contextual information alone, even after only a single-trial conditioning procedure, and that sleep is necessary to consolidate this rapidly acquired maladaptive response. The results unravel a mechanism that could explain part of the strong psychological impact on allergic responses.

Perfect timing: circadian rhythms, sleep, and immunity - an NIH workshop summary.

Recent discoveries demonstrate a critical role for circadian rhythms and sleep in immune system homeostasis. Both innate and adaptive immune responses - ranging from leukocyte mobilization, trafficking, and chemotaxis to cytokine release and T cell differentiation -are mediated in a time of day-dependent manner. The National Institutes of Health (NIH) recently sponsored an interdisciplinary workshop, "Sleep Insufficiency, Circadian Misalignment, and the Immune Response," to highlight new research linking sleep and circadian biology to immune function and to identify areas of high translational potential. This Review summarizes topics discussed and highlights immediate opportunities for delineating clinically relevant connections among biological rhythms, sleep, and immune regulation.

Does Weekend Catch-up Sleep Affect High-Sensitivity C-Reactive Protein Levels Among Korean Workers?: A Cross-Sectional Study Using KNHANES.

OBJECTIVE: We sought to determine whether weekend catch-up sleep (CUS) influenced serum high-sensitivity C-reactive protein (hs-CRP) levels in workers. METHODS: We analyzed the Korean National Health and Nutrition Examination Survey (2016) data from 3304 workers. Univariate and multivariate logistic regression analyses were used to calculate odds ratios and 95% confidence intervals based on serum hs-CRP cut-off values of 1.0 and 3.0 mg/L, respectively. RESULTS: We found that at least 1-hour and less than 2 hours of weekend CUS reduced the risk of elevated hs-CRP levels (odds ratio 0.80, 95% confidence interval 0.64 to 0.99) in multivariate logistic regression analysis. CONCLUSION: CUS may reduce serum hs-CRP levels in workers, thereby reducing the risk of cardiovascular disease.

Sleep and inflammation: partners in sickness and in health.

The discovery of reciprocal connections between the central nervous system, sleep and the immune system has shown that sleep enhances immune defences and that afferent signals from immune cells promote sleep. One mechanism by which sleep is proposed to provide a survival advantage is in terms of supporting a neurally integrated immune system that might anticipate injury and infectious threats. However, in modern times, chronic social threats can drive the development of sleep disturbances in humans, which can contribute to the dysregulation of inflammatory and antiviral responses. In this Review, I describe our current understanding of the relationship between sleep dynamics and host defence mechanisms, with a focus on cytokine responses, the neuroendocrine and autonomic pathways that connect sleep with the immune system and the role of inflammatory peptides in the homeostatic regulation of sleep. Furthermore, I discuss the therapeutic potential of harnessing these reciprocal mechanisms of sleep-immune regulation to mitigate the risk of inflammatory and infectious diseases.

Febrile and sleep responses to an immune challenge are affected by trait aggressiveness in rats.

Sleep is altered in response to an immune challenge: non-rapid eye movement (NREM) sleep is increased and fragmented, REM sleep is inhibited. Sleep and immune response are affected by stress: several stressors inhibit sleep and increase waking time; stress-induced cortisol secretion affects the immune response, with immunosuppressive effects. Different levels of trait aggressiveness are associated with specific patterns of neuroendocrine and autonomic stress responsiveness. Aim of this study was to test the hypothesis that trait aggressiveness, by affecting response to stressors, modifies sleep alterations induced by the activation of the immune response. To this aim, rats were selected on the basis of their latency time to attack a male intruder in the resident-intruder test. Animals were instrumented for chronic recordings of sleep-wake activity and injected, intraperitoneally, with an immune challenge (250 µg/kg lipopolysaccharide - LPS, a component of gram-negative bacterial cell wall). Here we report that high aggressive (HA) rats responded to an immune challenge with a 24-h long increase in cortical brain temperature. During the first 12 post-injection hours, HA rats also responded with a prolonged increase in NREM sleep amount, and a 5-h long and continuous inhibition of REM sleep. In HA rats, the LPS-induced increase in the amount of time spent in NREM sleep was due to an increase in the number of episodes of this sleep phase, without any change in the bout duration. The LPS-induced REM sleep inhibition observed in HA rats was due to a decrease in both the number and duration of REM sleep bouts. In HA rats, during REM sleep, LPS administration significantly reduced the power of the EEG theta band. In non-aggressive (NA) rats, in response to LPS administration, cortical brain temperature was increased only for two hours, NREM sleep was unaffected, and REM sleep inhibition was scattered along the first 8 post-injection hours. The LPS-induced changes in the number of NREM sleep bouts of NA rats were limited to few and scattered hours, with a change in bout duration only in a single hour. A combination of decreases, in few hours, in both REM sleep bouts and their duration contributed to the REM sleep inhibition observed in NA rats. In NA rats, the power of EEG theta band was not modified, during REM sleep, by LPS administration. Gross motor activity was inhibited in both HA and NA rats. Results of this study show that trait aggressiveness affects febrile and sleep responses to an immune challenge.

The Sleep-Immune Crosstalk in Health and Disease.

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.

Circulating Interleukin-6 concentration covaries inversely with self-reported sleep duration as a function of polymorphic variation in the glucocorticoid receptor.

Growing evidence links extremes of self-reported sleep duration with higher circulating markers of inflammatory disease risk, although not all findings are consistent. Extremes of sleep duration also associate with activation of the hypothalamic-pituitary-adrenocortical (HPA) system and the peripheral release of cortisol, a glucocorticoid (GC) important in downregulating transcription of pro-inflammatory molecules. Polymorphic variation in the gene encoding the GC receptor (GR; NR3C1) modulates cellular sensitivity to GC-mediated anti-inflammatory signaling, thereby affecting levels of pro-inflammatory molecules. Thus, we hypothesized that extremes of self-reported sleep duration may covary with circulating levels of inflammatory markers as a function of allelic variation in NR3C1. Specifically, we examine the possibility that a single nucleotide polymorphism of the GR gene-(rs6198), the minor (G) allele of which confers reduced GR sensitivity-moderates an association of sleep duration with interleukin (IL)-6 and C-reactive protein (CRP) among a large sample (IL-6: N = 857; CRP: N = 929) of midlife community volunteers of European ancestry. Findings showed that sleep duration varied inversely with IL-6 (ß = -0.087, p = .012), and this association was stronger among individuals homozygous for the rs6198 G-allele compared to alternate genotypes (ß = -0.071, p = .039). We also found that sleep duration showed a U-shaped association with CRP (polynomial term: ß = 0.093, p = .006), which was not moderated by rs6198 genotype. In conclusion, we show that a common genetic variant in the GR moderates an inverse association of self-reported sleep duration with circulating IL-6, possibly contributing to the increased disease risk observed among some short sleepers.

Low-grade inflammation in the relationship between sleep disruption, dysfunctional adiposity, and cognitive decline in aging.

Aging is characterized by a progressive increase in proinflammatory status. This state, known as inflammaging, has been associated with cognitive decline in normal and pathological aging. However, this relationship has been inconsistently reported, likely because it is conditioned by other factors also affected by the aging process. Sleep and adiposity are two factors in particular that show significant alterations with aging and have been related to both cognitive decline and inflammaging. Given the consequences this state also has for brain integrity and cognition, we discuss here evidence supporting the potential mediating role of chronic low-grade systemic inflammation in the complex relationship between impaired sleep, dysfunctional adiposity, and cognitive decline through the common pathway of neuroinflammation. This review proposes a multi-factor model of aging-related cognitive decline that highlights the reciprocal interactions between sleep, the circadian system, and inflammation on the one hand, and between sleep, adiposity, and hormone resistance on the other. The model identifies sleep and adiposity as modifiable lifestyle factors that can be targeted to maximize cognitive function and quality of life in the elderly.

[Sleep and immune system]. / Sueño y sistema immune.

Sleep is a process that occupies one third part of the life of the human being, and it is essential in order for the individual to be able to maintain body homeostasis. It emerges as an important regulator of the immune system since, during sleep, the necessary functions to maintain its balance are carried out. On the other hand, decreased sleep has deleterious effects that alter the metabolism and produce an increase in the secretion of C-reactive protein, interleukin (IL)-6 and tumor necrosis factor (TNF). These cytokines activate NF-κB; therefore, sleep disturbance can be a risk factor for the development of chronic inflammatory and metabolic diseases. Pro-inflammatory cytokines IL-1, IL-6 and TNF increase non-rapid eye movement sleep, whereas anti-inflammatory cytokines such as IL-4 and IL-10 decrease it. Sleep can modify the immune system function by inducing changes in the hypothalamus-pituitary-adrenal axis and the sympathetic nervous system. In turn, the circadian rhythm of hormones such as cortisol and adrenaline, which have a nocturnal decrease, favors different activities of the immune system. The purpose of the present review is to address different aspects of sleep and their relationship with the immune system.

El sueño es un proceso que ocupa la tercera parte de la vida del ser humano y resulta imprescindible para que el individuo mantenga la homeostasis del organismo. Emerge como un regulador importante del sistema inmune, ya que durante el sueño se llevan a cabo las funciones necesarias para mantener su equilibrio. Por otro lado, la reducción de sueño tiene efectos adversos que alteran el metabolismo y produce incremento en la secreción de la proteína C reactiva, interleucina (IL)-6 y factor de necrosis tumoral (TNF). Estas citocinas activan a NF-κB, por lo que la alteración en el sueño puede ser un factor de riesgo para desarrollar enfermedades inflamatorias crónicas y metabólicas. Las citocinas proinflamatorias IL-1, IL-6 y TNF aumentan el sueño de movimientos oculares no rápidos y las antiinflamatorias como IL-4 e IL-10 lo disminuyen. El sueño puede modificar la función del sistema inmune induciendo cambios en el eje hipotálamo-pituitaria-adrenal y el sistema nervioso simpático. A su vez, el ritmo circadiano de hormonas como el cortisol y la adrenalina, que descienden en la noche, favorece diferentes actividades del sistema inmune. El objetivo de la presente revisión es abordar diversos aspectos del sueño y su relación con el sistema inmune.

Effects of binge alcohol consumption on sleep and inflammation in healthy volunteers.

Objective Alcohol is a hypnotic that modifies immune function, specifically the cytokines interferon gamma (IFN-γ) and interleukin 2 (IL-2). We evaluated the association between unscheduled napping and acute alcohol-induced augmentation of IFN-γ and IL-2 expression. Methods In this prospective, observational pilot study, volunteers completed questionnaires on sleep quality, alcohol use, and hangover characteristics. Actigraph recordings began three nights before and continued for four nights after study initiation. Napping was recorded by actigraphy and self-reporting. A weight-based dose of 100-proof vodka was consumed, and the blood alcohol content (BAC) and phytohemagglutinin-M stimulated cytokine level were measured before and 20 minutes, 2 hours, and 5 hours after binge consumption. Results Ten healthy volunteers participated (mean age, 34.4 ± 2.3 years; mean body mass index, 23.9 ± 4.6 kg/m2; 60% female). The mean 20-minute BAC was 137.7 ± 40.7 mg/dL. Seven participants took an unscheduled nap. The ex vivo IFN-γ and IL-2 levels significantly increased at all time points after binge consumption in the nappers, but not in the non-nappers. Conclusion Augmented IFN-γ and IL-2 levels are associated with unscheduled napping after binge alcohol consumption. Further studies are needed to clarify the associations among alcohol consumption, sleep disruption, and inflammatory mediators.

Increased Risk of Upper Respiratory Infection in Military Recruits Who Report Sleeping Less Than 6 h per night.

Introduction: Professional sleep associations recommend 7-9 h of sleep per night for young adults. Habitually sleeping less than 6 h per night has been shown to increase susceptibility to common cold in otherwise healthy, adult civilians. However, no investigations have examined the importance of sleep duration on upper respiratory tract infection (URTI) and loss of training days in military recruits. The purpose of this study was to describe self-reported sleep duration in a large cohort of military recruits and to assess the relationship between reported sleep duration and incidence of URTI's. We hypothesized that recruits who reported sleeping less than the recommended 7-9 h per night during training suffered a greater incidence of URTI and, as a consequence, lost more training days compared with recruits who met sleep recommendations. Materials and Methods: Participants included 651 British Army recruits aged 22 ± 3 yr who completed 13 wk of basic military training (67% males, 33% females). Participants were members of 21 platoons (11 male, 10 female) who commenced training across four seasons (19% winter, 20% spring, 29% summer, and 32% autumn). At the start and completion of training, participants completed a questionnaire asking the typical time they went to sleep and awoke. Incidence of physician-diagnosed URTI and lost training days due to URTI were retrieved from medical records. Results: Self-reported sleep duration decreased from before to during training (8.5 ± 1.6 vs. 7.0 ± 0.8 h; p < 0.01). Prior to training, 13% of participants reported sleeping less than the recommended 7 h sleep per night; however, this increased to 38% during training (X2 = 3.8; p = 0.05). Overall, 49 participants (8%) were diagnosed by a physician with at least one URTI and 3 participants (<1%) were diagnosed with two URTI's. After controlling for sex, body mass index, season of recruitment, smoking, and alcohol, participants who reported sleeping less than 6 h per night during training were four times more likely to be diagnosed with URTI compared with participants who slept 7-9 h per night in a logistic regression model (OR 4.4; 95% CI, 1.5-12.9, p < 0.01). On average, each URTI resulted in 2.9 ± 1.5 lost training days. Participants who were diagnosed with URTI had more overall lost training days for any illness compared with participants who did not report a URTI during basic military training (3.3 ± 1.9 vs. 0.4 ± 1.3; p < 0.01). Conclusion: In a large population of British Army recruits, these findings show that more than one third of participants failed to meet sleep duration recommendations during training. Furthermore, those who reported sleeping less than 6 h per night were four times more likely to be diagnosed with an URTI and lost more training days due to URTI. Since sleep restriction is considered a necessary element of military training, future studies should examine interventions to reduce any negative effects on immunity and host defense.

Objective measures of sleep in fibromyalgia syndrome: Relationship to clinical, psychiatric, and immunological variables.

We aimed to investigate the changes in the objective and subjective sleep variables during painful episodes of fibromyalgia and post-episode period, and to evaluate the impact of the sleep variables on the current clinical, psychological, and immunologic parameters. Thirty-one consecutive patients who were referred to the Erenköy Physical Therapy and Rehabilitation Polyclinic with a diagnosis of fibromyalgia were evaluated before and in the sixth week of the acute pain treatment. The sleep variables were measured by polysomnography, Pittsburgh Sleep Quality Index, and Epworth Sleepiness Scale. The clinical and psychiatric assessment of patients was performed by using Fibromyalgia Impact Questionnaire; Patient Health Questionnaire-Somatic, Anxiety, and Depressive Symptoms; and Visual Analog Scale. Serum pro-inflammatory molecules were measured to evaluate the immunological status. The pain treatment significantly affected subjective sleep variables, psychiatric variables, clinical variables, and IL-6 levels. The subjective sleep parameters, clinical and psychiatric variables, and IL-6 levels were improved with pain treatment in fibromyalgia. The objective sleep variables, IL-1 and TNF-alpha levels were not significantly improved with the pain treatment, and they were not related to clinical presentation of patients with fibromyalgia. Subjective variability of sleep contributes to the clinical presentation, suggesting that the objective structure is trait-specific with IL-1 and TNF-alpha.

Perinatal Immune Activation Produces Persistent Sleep Alterations and Epileptiform Activity in Male Mice.

Increasing evidence suggests a role for inflammation in neuropsychiatric conditions, including autism spectrum disorder (ASD). Previous work in rodents has established that immune activation during critical developmental periods can cause phenotypes that reproduce core features of ASD, including decreased social interaction, aberrant communication, and increased repetitive behavior. In humans, ASD is frequently associated with comorbid medical conditions including sleep disorders, motor hyperactivity, and seizures. Here we use a 'two-hit' immune-activation paradigm to determine whether perinatal immune activation can also produce these comorbid features in mice. In this paradigm, we treated timed-pregnant mice with polyinosinic:polycytidylic acid (Poly I:C), which simulates a viral infection, on gestational day 12.5 according to an established maternal immune activation regimen. A subset of the offspring also received a second 'hit' of lipopolysaccharide (LPS), which simulates a bacterial infection, on postnatal day 9. At 6 weeks of age, mice were implanted with wireless telemetry transmitters that enabled continuous measurements of electroencephalography (EEG), electromyography (EMG), locomotor activity, and subcutaneous temperature. Effects at 7 and 12 weeks of age were compared. Both prenatal Poly I:C and postnatal LPS produced changes in locomotor activity and temperature patterns, increases in slow-wave sleep, and shifts in EEG spectral power, several of which persisted at 12 weeks of age. Postnatal LPS also produced persistent increases in spontaneous bursts of epileptiform activity (spike-wave discharges) that occurred predominantly during sleep. Our findings demonstrate that early-life immune activation can lead to long-lasting physiologic perturbations that resemble medical comorbidities often seen in ASD and other neuropsychiatric conditions.

Inflammation Is an Important Covariate for the Crosstalk of Sleep and the HPA Axis in Rheumatoid Arthritis.

Rheumatoid arthritis (RA) patients have sleep problems, and inflammation influences sleep. We demonstrated that sleep quality improves during intensified treatment with methotrexate (MTX) or etanercept (ETA). Since the hypothalamic-pituitary-adrenal (HPA) axis is involved in sleep regulation, this study investigated the interrelation between sleep parameters, inflammation as objectified by C-reactive protein (CRP), and serum cortisol and adrenocorticotropic hormone (ACTH) levels. Thirty-one eligible patients (disease activity score, DAS28CRP ≥3.2) participated in a 16-week, open, prospective study of HPA axis outcomes. MTX was initiated in 15 patients (female-to-male ratio 9/6) and ETA in 16 patients (14/2). Clinical, laboratory (after polysomnography [PSG] between 8 and 9 a.m.), sleep (PSG), and HPA axis outcome parameters (after PSG between 8 and 9 a.m.) were recorded at baseline and week 16. Clinical characteristics of patients markedly improved throughout the study (e.g., DAS28CRP: p < 0.001; CRP: p < 0.001). Sleep efficiency and wake time after sleep onset markedly improved in the ETA group. Serum cortisol and ACTH did not change during observation. At baseline, serum cortisol levels were negatively correlated to sleep efficiency; this may depend on inflammation, because controlling for CRP eliminated this negative correlation. After ETA treatment, serum cortisol had a high positive correlation with total sleep time, sleep efficiency, and a negative correlation with wake time before and after sleep onset, which was not eliminated by controlling for CRP. In RA patients, the data indicate that inflammation is an important covariate for the crosstalk of sleep and the HPA axis.