If sleep is indeed a restorative process that is important for the appropriate functioning of the immune system, it should come as no surprise that a number of researchers have attempted to investigate possible correlations between disordered sleep and disease, both incidence and/or progression, particularly those diseases for which there is already evidence for an immunological component. This explains the interest in infectious disease (see above). In one study attempting to dissect the immune changes which might accompany sleep disruption, immune functioning between patients with chronic insomnia (17 adults meeting criteria for a chronic primary insomnia disorder) and good sleepers (19 adults with a regular sleep schedule and no complaint of sleep disturbances) was compared (Savard, Laroche, Simard, Ivers, and Morin 2003). In this study a detailed analysis of PBL samples at baseline and before a second night of polysomnographic assessment included enumeration of blood cell counts (i.e., white blood cells, monocytes, lymphocytes, and different cell subsets, including CD3+, CD4+, CD8+, CD16+, and CD56+ cells), natural killer cell activity, and cytokine production, i.e., IL-1P, IL-2, and interferon (IFN)y. Perhaps not surprisingly few differences were found, with some evidence for higher levels of CD3+, CD4+, and CD8+ cells in good sleepers.
However, more subtle interactions have also been reported. Thus, the severity of disordered sleep in depressed and/or alcoholic subjects also shows a correlation with altered innate and cellular immune functions, and furthermore may be related to changes in cytokines/chemokines (Irwin 2002). Alcoholics are recognized to be at increased risk for infectious disease, along with the profound disturbances of sleep and cellular immunity. Accordingly, one study attempted to investigate the possible interrelationships between sleep, nocturnal expression of immunoregulatory cytokines, and natural killer (NK) cell activity in alcoholic patients in comparison to control subjects (Redwine, Dang, Hall, and Irwin 2003). Along with losses of delta sleep and increases of rapid eye movement sleep in comparison to control subjects, the alcoholic patients showed lower levels of IL-6 production, suppression of the IL-6/IL-10 ratio, and a reduction of NK cell activity. In addition, they showed a persistently low ratio of IFNy:IL-10 with decreased NK cell activity throughout the night, which the authors concluded as implicating sleep in the regulation of immune function, and further that disordered sleep might contribute to immune alterations in patients with chronic alcoholism. Partial night sleep deprivation studies in humans, aimed to replicate the pattern of sleep loss found in clinical samples, was indeed found to produce a pattern of immune alterations similar to that found in depressed and alcoholic patients (Irwin 2002).
Depression itself is well-recognized to be associated with sleep disruption, and with immune impairment (Anisman and Merali 2002) but the nature of the relationship, and indeed any causality, remains obscure. Immune activation, and increases in the activity of several cytokines, including IL-1, IL-2, IL-6, TNF-a, and their receptors, have all been recorded during depressive illness. However, despite successful treatment of depression, altered cytokine patterns apparently remain, suggesting that cytokines may be trait markers of depression, or epigenetic effects of the illness (Anisman et al. 2002). Interestingly, it has been recognized for some time that patients receiving cytokine immunotherapy frequently show depressive symptoms, which may be attenuated by antidepressant medication, supporting a causal role for cytokines in depressive disorders, including in the sleep disruption seen. The mechanisms implicated in these processes (cytokine-induced depression) are extensive, however, with the affective changes potentially stemming from both the neuroendocrine and central neurochemical changes elicited by cytokines. Animal studies also support the view that therapeutic administration of inflammatory cytokines can induce typical major depression, with further support coming from evidence that stimulated cytokine-release during experimental endotoxemia provokes transient deterioration in mood and memory (Pollmacher, Haack, Schuld, Reichenberg, and Yirmiya 2002). However, in most of these studies of animal models of acute infections it is only in the presence of very high amounts of cytokines produced in the periphery that actions within the CNS are observed, while in cases of (arguably) greater interest clinically, such as chronic infection and inflammation, the levels of circulating cytokines is actually quite low. Studies from Pollmacher's group showed that while low levels (and high levels) of circulating cytokines can impinge on CNS responses in general, and sleep in particular, the qualitative effects were quite different. Non-REM sleep was promoted by a slight increase in cytokine levels, but suppressed by greater increases (Pollmacher et al. 2002). These results should be taken into account in building any generalized theory of an effect of cytokines on mood, sleep, and depression. Fatigue and sleep disturbances are also common in cancer patients as well as in those receiving cytokine therapy, but the role of sleep in cancer is still relatively uninvestigated (Krueger et al. 2003).
As has commonly been the case in the research field, analysis of inbred strains of mice has been used to attempt to uncover possible genetic variations in the expression of sleep patterns. It is of interest in this regard that while the genetic influence on many behaviors has been shown to be gender specific, to date, there has been no evidence to suggest variations in sleep patterns in different strains of female mice. Koehl et al. have recently addressed this issue, taking into account a possible confounder of the estrous cycle to eliminate effects solely due to reproductive hormones on sleep (Koehl, Battle, and Turek 2003). These data showed that there was in fact an important impact of the genetic background on the regulation of nonrapid eye movement sleep over a 24-h period, with clear strain differences in rapid eye movement sleep distribution over the light-dark cycle. In contrast, and as had been reported by our group earlier in a human study (Moldofsky, Lue, Davidson, and Gorczynski 1989), the estrous cycle had much less influence on non-rapid eye movement sleep and rapid eye movement sleep. These data, if extrapolated to humans, clearly imply that genetic factors must be accounted for in comparisons of human populations studied in regards to altered sleep behavior, particularly given what we already know about the effects of variations in genetic background on immune function.
Was this article helpful?