br Methods br Sleep and immunity For over

Methods
Sleep and immunity For over 2000 years the relationship between sleep and immunity has been the subject of discussion. Hippocrates, for example, mentioned the presence of sleepiness during the course of an acute infection [18,20]. Today we know that the interaction between sleep and immunity is established by anatomical and physiological bases [20]. Neurons, glial cells, and immune cells share common intercellular signals, such as hormones, neurotransmitters, cytokines and chemokines [21,22]. We know, for instance, that all lymphoid tissue receives innervation [23,24] and pro-inflammatory cytokines, such as IL-1β, TNF-α, and their receptors are expressed in specific H 89 regions and act in the regulation of many physiological and behavioral processes (17), such as the sleep-wake status [25–27]. At an experimental level, research regarding TNF-α and IL-1 indicates that these cytokines are also sleep regulators and exert this effect regardless of their pyrogenic effect [28]. For example, administration of IL-1 and TNF-α in vitro produces slow oscillations that resemble NREM sleep in humans [28–30]. The perfusion of IL-1 reduces excitatory synaptic potentials in rat hippocampus, and the application of TNF in the sensory cortex induces the increase in slow-wave sleep in these animals [31,32]. IL-1 and serotonergic pathways also interact with each other. 5-HT alters the expression of IL-1 mRNA in brain regions, while IL-1 increases the secretion of 5-HT in the hypothalamus, and a micro-injection of IL-1 in the dorsal raphe nuclei induces sleep NREM [33,34]. So, it seems obvious that sleep can also influence the immune response. The role of sleep in modulating the human immune function has been previously tested by observing the prolonged effects of sleep deprivation on various immune parameters or their behavior in diseases that naturally fragment sleep, such as insomnia, disorders of the circadian rhythm and shift work [35–48]. These studies have produced interesting results [36–41]. Some studies have shown that acute deprivation (50–64h) is associated with a temporary increase in the activity of natural killer cells (NK), an increasing count of T-CD4+ lymphocytes, CD8+, monocytes, granulocytes and NK [36–38,41]. Other studies regarding partial sleep (early night or late night) and chronic deprivation, which are more common in clinical practice, have, however, shown different results with a decrease in the activity of NK cells and the counts of CD 16 +, CD 56+, CD 57+ and IL-2 levels [35,39,40,45]. We know that these lymphocytes, which participate in innate immunity, are important in the defense against viruses, intracellular bacteria, as well as in response to tumor cells [42–44]. In one study, Axelsson et al. [35], aiming to investigate partial sleep deprivation for five days and the production of inflammatory cytokines and the Th1/ Th2 balance among healthy subjects, noticed a transient decrease of IL-2 and IL-2/ IL-4 ratio until the fifth day of sleep deprivation. Fondel et al. [45] conducted a study to evaluate the immune activity in healthy subjects who slept fewer than seven hours (short sleepers), compared to healthy subjects who slept seven to nine hours (normal sleepers). They observed a 30% decrease in the activity of NK cells (p 0.01) and a 49% increase in the activity of T-lymphocytes stimulated by PHA (phytohemagglutinin), independent of plasma cortisol levels. Sakami et al. [46], in a study that evaluated the immune response in insomniacs and the balance of effector response, observed a change in the Th1/ Th2 immune response in favor of the Th2 response, with a decrease in the secretion of IFN-γ and IFN-γ/IL-4 ratio in insomniacs. They concluded that insomnia causes an alteration of the immune function with a predominance of suppressive Th2 response. Savarde et al. [48] compared a group of individuals with insomnia to individuals considered to be good sleepers. They observed a significant difference: a greater amount of TCD3+, TCD4+, and TCD8+ lymphocytes and total lymphocytes in the group of good sleepers compared with insomniacs.