Insomnia and obstructive sleep apnea are the most prevalent sleep disorders in the general population (Ancoli-Israel 1993). Such disturbances result in major alterations in the immune system and may be mediated by the augmented activity of the HPA axis and/or sympathetic nervous system, as we will soon describe.
There is evidence of the association of insomnia and elevated HPA axis activity. Primary insomnia patients connect the onset of the disorder to some stressful event. Chronic internalization of feelings may cause a psychological and physiological arousal, leading, ultimately to insomnia. Perlis, Giles, Mendelson, Bootzin, and Wyatt (1997), for instance, propose the existence of a mechanism of cortical hyperarousal in insomniac patients triggered by emotional, cognitive, and physiological components. Therefore, the hyperactivity exacerbates vigilance and impact negatively on sleep, thus forming a vicious circle in which difficulty to sleep becomes the stressful factor itself. This phenomenon had been proposed by Spath-Schwalbe and co-workers, in 1991, who demonstrated that increased HPA axis activity produces sleep fragmentation, which in turn elevates cortisol-circulating levels. One of the first studies on the relationship between the HPA axis activity and sleep showed that poor sleepers exhibited augmented 24 h urinary cortisol levels (Johns, Gay, Masterton, and Bruce 1971). This association was later confirmed by Vgontzas et al. (1998) who showed a positive correlation between elevated levels of cortisol, increased activity of the sympathetic system and time of waking in chronic insomniacs. In addition, plasma levels of ACTH and cortisol measured throughout a 24-h period are elevated in chronic insomniacs exactly during the nadir of the circadian rhythm, i.e., between approximately 22:00 and 02:00 h, although no change in the circadian pattern of secretion has been observed besides a flattening of the amplitude (Vgontzas et al. 2001). Similar results were reported by Rodenbeck, Huether, Ruther, and Hajak (2002) who showed that patients with severe primary insomnia exhibit high cortisol levels at the beginning of the night.
Convincing evidence confirm the correlation between immune alterations and insomnia, as, for instance, is shown in chronic insomnia patients, whose CD3+, CD4+, and CD8+ cells are reduced (Savard, Laroche, Simard, Ivers, and Morin 2003). Moreover, a decrease in the number of natural killer (NK) cells is also associated with augmented sympathetic tonus (Irwin, Clark, Kennedy, Christian Gillin, and Ziegler 2003), and the balance between Th1 and Th2 response is impaired in these patients with predominance of the Th2 response (Sakami et al. 2002). Th2-type cytokines enhance the humoral immune response. In addition, alterations in Th1/Th2 balance are characteristic of autoimmune diseases. It is known that the major effects of glucocorticoids on the immune system are suppression of cellular immunity and enhancement of humoral immunity, a process that also is driven by the Th1 to Th2 shift in cytokine profile production. Thus, these results indicate that the relationship between sleep and the etiology of immune-related diseases should be considered.
Recurrent nocturnal hypoxia and sleep fragmentation are related to obstructive sleep apnea, and these are also associated with increased activation of the HPA and the sympathetic systems. Ultimately, the latter alteration is regarded as one of the mechanisms responsible for hypertension that are commonly associated with to obstructive sleep apnea (Waradekar, Sinoway, Zwillich, and Leuenberger 1996). Patients with sleep apnea show higher nocturnal urinary and plasma catecholamine levels than healthy individuals (Fletcher, Miller, Schaaf, and Fletcher 1987). Although the assessment of the HPA axis activity in these patients is scarce, there is a study that shows a greater tryptophan-induced cortisol response, indicating augmented sensitivity of the axis (Hudgel and Gordon 1997). Despite this scarcity, increased sympathetic tonus and especially, augmented sleep fragmentation are connected to increased stress response and it seems unquestionable that such poor sleep quality leads to higher HPA axis activity. In a recent review, the HPA axis hyperactivity was attributed as being responsible for some morbid conditions frequently associated to sleep apnea, such as metabolic syndrome and increased aldosterone plasma levels (Buckley and Schatzberg 2005). In this pathological condition, high levels of proinflammatory cytokines, including TNF and IL-6 (Alberti et al. 2003) and of C-reactive protein (CRP) are observed (Shamsuzzaman, Winnicki, Lanfranchi, Wolk, Kara, and Accurso 2002). This myriad of altered inflammatory mediators, together with apnea pathophysiology is extremely harmful due to their contribution to the development of severe complications, which include increased risk to cardiovascular problems, metabolic syndrome and neurocognitive impairment. The regular use of CPAP results in restoration of adequate sleep and reduction of inflammatory markers (Yokoe et al. 2003), as well as of catecholamines and of the sympathetic tonus (Hedner, Darpo, Ejnell, Carlson, and Caidahl 1995; Ziegler, Mills, Loredo, Ancoli-Israel, and Dimsdale 2001).
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