Evaluation of the effects of sleep deprivation upon immune function has generally focused on people with disorders of excessive daytime sleepiness, healthy adult men or depressed populations. A consistent finding is that proinflammatory cytokines are elevated in these groups (Irwin, Clark, Kennedy, Christian, and Ziegler 2003; Okun, Giese, Lin, Einen, Mignot, and Coussons-Read 2004; Redwine, Dang, Hamano, and Irwin 2003; Vgontzas, Papanicolaou, Bixler, Kales, Tyson, and Chrousos 1997; Vgontzas, Zoumakis, Bixler, Lin, Follett, Kales, and Chrousos 2004). Sleep apneics and narcoleptics have higher TNF-a levels compared to controls (Vgontzas et al. 1997), while abstinent alcoholics and people partially deprived of sleep show elevations of both TNF-a and IL-6 (Irwin, Rinetti, Redwine, Motivala, Dang, and Ehlers 2004; Uthgenannt, Schoolmann, Pietrowsky, Fehm, and Born 1995; Vgontzas et al. 2004). Experimentally induced sleep deprivation has been found to alter the diurnal pattern of cellular and humoral immune functions (Dinges, Douglas, Hamarman, Zaugg, and Kapoor 1995; Heiser et al. 2000; Moldofsky, Lue, Davidson, and Gorczynski 1989) and possibly decrease overall immune function (Redwine, Hauger, Gillin, and Irwin 2000) in normal adults. More recently support for the hypothesis that sleep improves immune function comes from studies assessing the vaccination response after partial sleep deprivation (Lange, Perras, Fehm, and Born
2003; Spiegel, Sheridan, and Van Cauter 2002). It appears that sleep restriction may impair an individual to effectively respond to a vaccination.
It is suggested that immune alterations may be associated with a biological pressure for sleep (Dinges et al. 1994), and that sleep loss could produce an overall shift in immune function (Dinges et al. 1995; Irwin, Thompson, Miller, Gillin, and Ziegler 1999) that favors proinflammatory cytokine production, such as IL-1 and TNF-a (Krueger and Majde 1995). Cytokine production is different between sleep and sleep deprivation, and there exists a circadian rhythm to the production not only of cytokines, but also of the various immune cells that produce the cytokines (Born, Lange, Hansen, Molle, and Fehm 1997). This understanding guided Born and colleagues ( 1997) to assess the role of nocturnal sleep on normal immune regulation in a design to assess acute sleep loss rather than excessive sleep loss. Men, serving as their own controls, slept two consecutive regular sleep-wake cycles or remained awake for 24 h followed by recovery sleep. The researchers found no alteration in the absolute production of IL-1ß and TNF-a between the two experimental conditions; however, the expected decrease of IL-1ß and TNF-a during sleep was blocked when subjects were kept awake. Hence, there was an increase in the nocturnal production of both cytokines during the sleep deprivation period (Born et al. 1997). Other studies evaluating sleep restriction, found a delayed nocturnal release of sleep-associated cytokines, IL-1, IL-6, and TNF-a, with subsequent recuperation of normal levels on recovery nights (Moldofsky et al. 1989; Redwine et al. 2000; Vgontzas et al. 1997). This suggests that cytokines have a sleep dependent relationship. Whether experimental sleep deprivation/restriction for an acute period (Irwin et al. 2004; Vgontzas et al. 2004) or in chronic sleep disorders (Okun et al. 2004; Vgontzas et al. 1997; Vgontzas et al. 2002), proinflammatory cytokines are elevated.
Estrogen and progesterone are altered during pregnancy; they are also potential contributors to the differences in sleep patterns observed between the pregnant and nonpregnant state. Data for the influence of hormones on sleep patterns has been documented since the early 1960s. Heuser, Kales, and Jacobson found that progesterone did not decrease REM time in a pilot study of five young adult subjects (Heuser, Kales, and Jacobson 1968), and Hartmann (1966) suggested that hormonal changes in the menstrual cycle might produce an elevated need for "Dreaming Sleep" known today as REM sleep. The data that Branchey and Petre-Quadens (1968) analyzed led them to conclude that the changes in paradoxical sleep observed in their subjects could be attributed to the sexual hormones secreted during pregnancy (p. 457). Recent work intimates that estrogen enhances the total time spent in REM and reduces the latency period prior to REM sleep (Manber et al. 2001). However, the primary source for data on estrogen and its effects on sleep come from pre and postmenopausal studies. Women who experience menopause have greater sleep disruption and mood changes (Baker et al. 1997), but no studies measured estrogen levels. Women who received hormone replacement therapy in a double-blind, placebo-controlled study showed improvement in sleep parameters, but they were nonsignificant compared to the placebo group (Saletu-Zyhlarz et al. 2003). Information regarding progesterone, on the other hand, is clearer. Progesterone is secreted in high amounts by the placenta (Lee et al. 2000) and increases non-REM (NREM) sleep, shortens sleep latency, and reduces wakefulness after sleep onset (Manber et al. 2001; Santiago et al. 2001). Moldofsky et al. (1995) reported that at times of elevated progesterone in normal controls, there is a delay in onset to SWS and a decrease in Stage 4 sleep, which is associated with a reduced duration in the decline of NK activity (Moldofsky, Lue, Shahal, Jiang, and Gorczynski 1995).
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