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The FASEB Journal, Vol 10, 643-653, Copyright © 1996 by The Federation of American Societies for Experimental Biology

RESEARCH COMMUNICATIONS

Partial night sleep deprivation reduces natural killer and cellular immune responses in humans

M Irwin, J McClintick, C Costlow, M Fortner, J White and JC Gillin
Department of Psychiatry, University of California, San Diego, USA.

Prolonged and severe sleep deprivation is associated with alterations of natural and cellular immune function. To determine whether alterations of immune function also occur after even a modest loss of sleep, the effects of early-night partial sleep deprivation on circulating numbers of white blood cells, natural killer (NK) cell number and cytotoxicity, lymphokine-activated killer (LAK) cell number and activity, and stimulated interleukin-2 (IL-2) production were studied in 42 medically and psychiatrically healthy male volunteers. After a night of sleep deprivation between 10 P.M. and 3 A.M., a reduction of natural immune responses as measured by NK cell activity, NK activity per number of NK cells, LAK activity, and LAK activity per number of LAK precursors (CD16,56, CD25) was found. In addition, concanavalin A-stimulated IL-2 production was suppressed after sleep deprivation due to changes in both adherent and nonadherent cell populations. After a night of recovery sleep, NK activity returned to baseline levels and IL-2 production remained suppressed. These data implicate sleep in the modulation of immunity and demonstrate that even a modest disturbance of sleep produces a reduction of natural immune responses and T cell cytokine production.

Semin Clin Neuropsychiatry. 2001 Oct;6(4):295-307. Links

Neuroimmunologic aspects of sleep and sleep loss.

• Rogers NL,

• Szuba MP,

• Staab JP,

• Evans DL,

• Dinges DF.

Department of Psychiatry, University of Pennsylvania, School of Medicine, Philadelphia, PA 19104, USA.

The complex and intimate interactions between the sleep and immune systems have been the focus of study for several years. Immune factors, particularly the interleukins, regulate sleep and in turn are altered by sleep and sleep deprivation. The sleep-wake cycle likewise regulates normal functioning of the immune system. Although a large number of studies have focused on the relationship between the immune system and sleep, relatively few studies have examined the effects of sleep deprivation on immune parameters. Studies of sleep deprivation's effects are important for several reasons. First, in the 21st century, various societal pressures require humans to work longer and sleep less. Sleep deprivation is becoming an occupational hazard in many industries. Second, to garner a greater understanding of the regulatory effects of sleep on the immune system, one must understand the consequences of sleep deprivation on the immune system. Significant detrimental effects on immune functioning can be seen after a few days of total sleep deprivation or even several days of partial sleep deprivation. Interestingly, not all of the changes in immune physiology that occur as a result of sleep deprivation appear to be negative. Numerous medical disorders involving the immune system are associated with changes in the sleep-wake physiology--either being caused by sleep dysfunction or being exacerbated by sleep disruption. These disorders include infectious diseases, fibromyalgia, cancers, and major depressive disorder. In this article, we will describe the relationships between sleep physiology and the immune system, in states of health and disease. Interspersed will be proposals for future research that may illuminate the clinical relevance of the relationships between sleeping, sleep loss and immune function in humans. Copyright 2001 by W.B. Saunders Company

PMID: 11607924 [PubMed - indexed for MEDLINE]

Brain Behav Immun. 2002 Oct;16(5):503-12.  Links

Effects of sleep and sleep loss on immunity and cytokines.

• Irwin M.

Cousins Center for Psychoneuroimmunology, UCLA Neuropsychiatric Institute and Department of Psychiatry and Biobehavioral Sciences, University of California, David Geffen School of Medicine at UCLA, Los Angeles, CA 90095-7057, USA. mirwin1@ucla.edu

Sleep is hypothesized to be a restorative process that is important for the proper functioning of the immune system. Severity of disordered sleep in depressed- and alcoholic subjects correlates with declines in natural- and cellular immunity and is associated with alterations in the complex cytokine network. Sleep loss has a role in mediating these immune changes as experimentally induced partial night sleep deprivation replicates the kind of sleep loss found in clinical samples and induces a pattern of immune alterations similar to that found in depressed- and alcoholic patients. Despite evidence that sleep and sleep loss have effects on immune processes and nocturnal secretion of cytokines, the clinical significance of these immune changes is not known. Moreover, in view of basic evidence of a reciprocal interaction between sleep and cytokines, further research is needed to understand whether alterations in cytokines contribute to disordered sleep in patient populations. Copyright 2002 Elsevier Science (USA)

Neuropsychopharmacology. 2001 Nov;25(5 Suppl):S45-9.  Links

Neuroimmunology of disordered sleep in depression and alcoholism.

• Irwin M.

Department of Psychiatry and Biobehavioral Sciences, University of California, Los Angeles, CA, USA. mirwin1@ucla.edu

The specific functions of sleep are not known, although sleep is commonly considered a restorative process that is important for the proper functioning of the immune system. Severity of disordered sleep in depressed and alcoholic subjects correlates with declines in natural and cellular immunity and is associated with alterations in the complex cytokine network. Despite evidence that sleep and sleep loss have effects on immune processes and nocturnal secretion of cytokines, the physiological significance of these immune changes is not known. Moreover, in view of basic evidence of a reciprocal interaction between sleep and cytokines, further research is needed to understand whether alterations in cytokines contribute to disordered sleep.

PMID: 11682273 [PubMed - indexed for MEDLINE]

Adv Exp Med Biol. 1999;461:1-24. Links

Immune correlates of depression.

• Irwin M.

Department of Psychiatry San Diego VA Medical Center, CA, USA.

The relation of depression to immunological assays is complex and variable. However, meta-analyses have demonstrated that depressed subjects are likely to show changes in several immune assays. Depressed subjects are likely to have changes in major immune cell classes with an increase in total white blood cell counts and a relative increase in numbers of neutrophils. However, the relative number of lymphocytes is likely to be reduced in depressed subjects. Depression also appears to be associated with increases in at least one measure of immune activation, although further investigations are clearly needed to replicate these interesting observations. Finally, depression is reliably associated with a suppression of mitogen-induced lymphocyte proliferation and with a reduction of NK activity. Despite the heterogeneity of findings, the effect sizes in the relationship between depression and lymphocyte proliferation and NK activity are large as compared to those observed in other areas of psychological and medical research. Several moderating factors may explain and account for the heterogeneity that has been found in the depression-immune results. Future immunologic studies in depressed subjects are needed to clarify the effects of gender and reproductive hormones on the relation between depression and immunity. Severity of melancholic symptoms and sleep disturbance appear to moderate the immune changes in depression but the biological mechanisms that account for the link between these neurovegetative symptoms and depression are not yet known. Finally, assessment of co-morbidity in depressed subjects deserves an increased focus. Data generated from our laboratory clearly show that assessment of alcohol- and tobacco dependence is critical in the interpretation of immune changes in depressed subjects. The clinical significance of changes in immune responses in depressed subjects remains an unanswered question. Studies that use immune measures with disease specific endpoints, as has been recently conducted in the study of VZV immune responses, would help identify the possible link between depression, immune system alterations, and health outcomes.

PMID: 10442164 [PubMed - indexed for MEDLINE]

Psychosom Med. 1999 May-Jun;61(3):263-70.  Links

Comment in:

Psychosom Med. 1999 May-Jun;61(3):271-2.

Reduction of natural killer cytotoxic activity in major depression: interaction between depression and cigarette smoking.

• Jung W,

• Irwin M.

Department of Psychiatry, University of California, San Diego VA Medical Center, 92161, USA.

OBJECTIVE: Epidemiological data suggest that the presence of a depressed mood combined with cigarette smoking increases the risk of cancer at sites associated with smoking and at sites not associated with smoking. This study tested the hypothesis that major depression and smoking together contribute to a decline of natural killer cell (NK) activity, an immune parameter thought to be important in immune surveillance. METHODS: A sample of 245 men were stratified into four groups: control subjects who were not smokers, control subjects who were smokers, subjects with major depression who were not smokers, and subjects with major depression who were smokers. Blood samples were obtained for measurement of total white blood cell (WBC) counts, differential cell counts, and assay of NK activity. RESULTS: Major depression and cigarette smoking interact and were together associated with changes in WBC counts and NK activity. Depressed subjects who were smokers had higher WBC counts (p < .001) and lower NK activity (p < .01) than depressed nonsmoking subjects. However, WBC counts and NK activity were similar in control smokers and nonsmokers. Backward elimination regression analyses showed that the interaction of depression and smoking significantly (p < .001) predicted WBC counts and NK activity. CONCLUSIONS: This study extends previous findings of immune alterations in patients with major depression. Major depression and smoking interact and together contribute to an elevation of total WBC count and a decline of NK activity.

PMID: 10367603 [PubMed - indexed for MEDLINE]

Journal of the American College of Nutrition, Vol. 23, No. 6, 637-646 (2004)
Published by the American College of Nutrition

Using Stress Models to Evaluate Immuno-Modulating Effects of Nutritional Intervention in Healthy Individuals

Mark Hamer, PhD, Danielle Wolvers, PhD and Ruud Albers, PhD

Unilever R & D Vlaardingen, Unilever Health Institute, The Netherlands

Address reprint requests to: Dr. R Albers, Unilever Health Institute, P O Box 114, 3130 AC Vlaardingen, The Netherlands. E-mail: Ruud.Albers@Unilever.com

There is clear evidence that nutritional supplementation helps to restore immune function and contributes to optimal resistance to infections in malnourished people. However, the literature is less clear on the suggested benefits of dietary supplementation for immune function in healthy, well nourished subjects. Such studies are hampered by large variability in immune function markers and clinical outcome measures, which are known to be affected by factors such as genotype, age, gender, history of infections and vaccinations, and various stressors associated with lifestyle. Therefore, there appears to be a need to employ experimental models that control and/or manipulate the factors that are responsible for this variability. Conceivably, such a model could experimentally apply various forms of stress to physiologically suppress the immune system and assess whether nutritional intervention can (partially) compensate the deleterious effects. Here we review effects of psychological stress, physical exertion, and sleep deprivation on various aspects of immune function and susceptibility to common infections. We focus on the usefulness of such stress models to evaluate the putative beneficial role of diets/nutrients on immune function in healthy individuals.

Key words: nutritional immunology, psychological stress, physical stress, immune markers, disease outcome, immune competence

1: J Neuroendocrinol. 2002 May;14(5):397-402.  Links

Sleep restriction alters the hypothalamic-pituitary-adrenal response to stress.

• Meerlo P,

• Koehl M,

• van der Borght K,

• Turek FW.

Department of Neurobiology and Physiology, Northwestern University, Evanston, IL, USA. p.meerlo@biol.rug.nl

Chronic sleep restriction is an increasing problem in many countries and may have many, as yet unknown, consequences for health and well being. Studies in both humans and rats suggest that sleep deprivation may activate the hypothalamic-pituitary-adrenal (HPA) axis, one of the main neuroendocrine stress systems. However, few attempts have been made to examine how sleep loss affects the HPA axis response to subsequent stressors. Furthermore, most studies applied short-lasting total sleep deprivation and not restriction of sleep over a longer period of time, as often occurs in human society. Using the rat as our model species, we investigated: (i) the HPA axis activity during and after sleep deprivation and (ii) the effect of sleep loss on the subsequent HPA response to a novel stressor. In one experiment, rats were subjected to 48 h of sleep deprivation by placing them in slowly rotating wheels. Control rats were placed in nonrotating wheels. In a second experiment, rats were subjected to an 8-day sleep restriction protocol allowing 4 h of sleep each day. To test the effects of sleep loss on subsequent stress reactivity, rats were subjected to a 30-min restraint stress. Blood samples were taken at several time points and analysed for adrenocorticotropic hormone (ACTH) and corticosterone. The results show that ACTH and corticosterone concentrations were elevated during sleep deprivation but returned to baseline within 4 h of recovery. After 1 day of sleep restriction, the ACTH and corticosterone response to restraint stress did not differ between control and sleep deprived rats. However, after 48 h of total sleep deprivation and after 8 days of restricted sleep, the ACTH response to restraint was significantly reduced whereas the corticosterone response was unaffected. These results show that sleep loss not only is a mild activator of the HPA axis itself, but also affects the subsequent response to stress. Alterations in HPA axis regulation may gradually appear under conditions of long total sleep deprivation but also after repeated sleep curtailment.

PMID: 12000545 [PubMed - indexed for MEDLINE]