Alcohol Dependence Sleep and Immunity

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Diagnostic criteria for alcohol dependence include at least three of seven patterns of substance use causing significant impairment over a 12-month period. Criteria can include tolerance to alcohol, presence of withdrawal symptoms, intake of larger amounts than intended, persistent desire to drink, much time spent in activities related to drinking, abandonment of occupational, social or recreational activities because of alcohol use, and continued intake despite recurrent problems related to drinking (American Psychiatric Association and American Psychiatric Association, Task Force on DSM-IV 1994).

Alcohol dependent patients have profound disturbances of sleep continuity and sleep architecture including decreases of total sleep time, declines of delta sleep, and increases of REM sleep (Irwin, Miller, Gillin, Demodena, and Ehlers 2000; Irwin, Gillin, Dang, Weissman, Phillips, and Ehlers 2002).

In addition to poor sleep, alcohol dependent patients are also more prone to infectious diseases such as pneumonia (Nelson and Kolls 2002), tuberculosis (Buskin, Gale, Weiss, and Nolan 1994), hepatitis C (Balasekaran et al. 1999) and possibly HIV infection (Crum, Galai, Cohn, Celentano, and Vlahov 1996), suggesting broad impairments in host defense.

When immune parameters are examined more specifically in alcohol dependence, studies show that these patients have decreases in NK activity, interleukin-2 (IL-2) stimulated killer cell activity (LAK activity), and ex vivo production of IL-6 (Irwin and Miller 2000). There is also a shift in cytokine expression reflecting greater T-helper 2 cytokine expression that persists after weeks of abstinence (Redwine, Dang, Hall, and Irwin 2003).

Throughout the night, alcohol dependent persons show a shift toward a Th2 cytokine expression with a predominance of this Th2 response, evidenced by a decreased IFN-y/IL-10 ratio. In contrast, healthy control subjects show an increase in Th1 cytokine expression during the later half of the nocturnal period. T helper cell differentiation into Th1 or Th2 subtypes allow for greater flexibility in coordinating cell-mediated immunity (Th1 cells) or coordinating antibody production (Th2 cells).

Th1 cytokines such as IFN, IL-2, and granulocyte colony stimulating factor can stimulate monocyte/macrophage and NK cell activity, in turn leading to heightened defense against intracellular pathogens such as Pneumocystis carinii and M. tuberculosis (Curtis 2005). The preferential nocturnal shift toward Th2 cytokines in alcoholic patients may reflect a primary defect in the coordination of T-cell differentiation into Th1 versus Th2 cell subtypes and this may underlie their greater susceptibility to pneumonia and tuberculosis.

Inflammatory cytokines are also dysregulated in alcoholic patients. Daytime circulating levels of inflammatory cytokines such as TNF and IL-6 are elevated in alcohol dependent patients, but these levels may decrease during periods of abstinence (Gonzalez-Quintela, Dominguez-Santalla, Perez, Vidal, Lojo, and Barrio 2000).

In contrast, in vitro production assays, in which whole blood is stimulated with an antigen such as liposaccharide (LPS), indicate that nocturnal production of IL-6 is reduced in alcoholic patients in the first half of the night as compared with controls, with subsequent increases in the second half of the night yielding levels that are comparable with controls (Redwine et al. 2003). Sleep macroarchitecture also appears related to IL-6 in alcohol dependence; increased REM sleep predicts morning higher stimulated IL-6 production. These data along with evidence that IL-6 is elevated during REM sleep (Redwine et al. 2000) raise the possibility that greater amounts of REM sleep during the late part of the night contribute to the nocturnal rise of IL-6 in alcohol dependent persons. Deficits in SWS in alcohol dependence may also lead to abnormal elevations of IL-6 and TNF. For example, experimental sleep deprivation typically induces a rebound increase in SWS as described above. However, alcoholics evidence a defect in SWS recovery, which is coupled with an exaggerated recovery night increase in circulating levels of IL-6 and TNF in alcoholics as compared to controls (Irwin, Rinetti, Redwine, Motivala, Dang, and Ehlers 2004) (see Fig. 10.3). Finally, given that daytime elevations of IL-6 correlate with fatigue (Vgontzas, Papanicolaou, Bixler, Kales, Tyson, and Chrousos 1997), such increases in the production or circulating levels of IL-6 may have implications for daytime fatigue in alcohol dependent persons.

Just as sleep can influence cytokine expression, cytokines can affect sleep in alcohol dependence. In clinical studies with alcoholic patients, higher levels of circulating IL-6 before sleep (11 PM) were associated with prolonged sleep latency (Irwin and Rinetti 2004) (Fig. 10.4). In addition, IL-6 is associated with increases in REM sleep during the later half of the night. In contrast, expression of the anti-inflammatory cytokine, IL-10 before sleep predicted increases in delta sleep, accounting for over 23% of the variance in delta sleep independent of age, and alcohol consumption (Redwine et al. 2003).

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Alcoholics

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Figure 10.3. Alcoholics (n = 15) have higher circulating levels of IL-6 as compared to controls (n = 16) across consecutive nights of baseline sleep, early partial sleep deprivation (4 h) and recovery sleep.

PSD-E

In alcohol dependent patients, there is evidence that the bidirectional effects between sleep parameters and cytokine expression are altered and that dysregulation persists even during periods of abstinence. Peripheral proinflammatory cytokines are capable of exerting direct effects on central nervous system function, promoting behavioral consequences that include increased fatigue, anxiety, and depressed mood. Like insomnia, alcohol dependence is associated with increased circulating levels of IL-6 during the day.

High levels of this cytokine are associated with severity of fatigue symptoms in women recovering from breast cancer (Collado-Hidalgo, Bower, Ganz, Cole, and Irwin 2006), and experimental immune activation results in increases of anxiety and depressed mood, which are coupled with declines of memory functions (Reichenberg et al. 2001).

No studies to date have examined whether disordered sleep and daytime elevations of proinflammatory cytokines contribute to fatigue or depressive symptoms in recovering alcoholics. However, in sleep apnea patients, administration of a TNF antagonist medication (etanercept) reduced IL-6 as well as daytime sleepiness (Vgontzas et al. 2004a, 2004b). Importantly, the contribution of cytokines in the regulation of sleep suggests that cytokine mechanisms are a possible target for interventions to optimize sleep initiation and sleep quality in alcoholic and other at risk populations.

Log IL-6 at 23:00

Figure 10.4. Scatterplot of IL-6 before sleep onset and sleep latency (both log transformed to normalize distributions) during a night of recovery sleep in both alcoholics and controls (r = 0.53, p < 0.01). The relationship between these variables was similar for initial baseline sleep (r = 0.37, p = 0.08) and during partial sleep deprivation (r = 0.56, p < 0.01).

Log IL-6 at 23:00

Figure 10.4. Scatterplot of IL-6 before sleep onset and sleep latency (both log transformed to normalize distributions) during a night of recovery sleep in both alcoholics and controls (r = 0.53, p < 0.01). The relationship between these variables was similar for initial baseline sleep (r = 0.37, p = 0.08) and during partial sleep deprivation (r = 0.56, p < 0.01).

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