The Immune System Shows Circadian Organization

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Light and daily rhythms have a profound influence on immune function. Many studies have described circadian variations of different immune parameters such as lymphocyte proliferation, antigen presentation, and cytokine gene expression. The number of lymphocytes and monocytes in the human blood reach maximal values during the night and are lowest after waking. Natural killer (NK) cells, by contrast, reach their highest level in the afternoon, with a normal decrease in number and activity around midnight.

Immune cells have been checked for the presence of clock genes. In a study aimed to investigate whether circadian clock genes function in human peripheral blood mononuclear cells, circadian clock genes human Per1, Per2, Per3 and Dec1 were found to be expressed in a circadian manner in human peripheral blood mononuclear cells, with the a peak level occurring during the second part of the active phase (Boivin et al. 2004). Studies on clock gene oscillations in splenic-enriched NK cells have also been reported. In addition, the circadian expression of granzyme B, perforin, interferon (IFN)-y, and tumor necrosis factor (TNF)-a found in NK cells underlines the circadian nature of NK cell function (Arjona and Sarkar 2005). Thus, the existence of molecular clock machinery may be conserved across different lymphocyte subsets and peripheral blood cells. Moreover, they may share common entrainment signals. Emerging data in the human and animal literature suggest that circadian regulation may be crucial for the host defenses against cancer. Virtually all immunological variables investigated to date in animals and humans have been shown to display biological periodicity. In most of its components, the immune system shows regularly recurring, rhythmic variations in numerous frequencies, the circadian being the best known (Haus and Smolensky 1999; Pelegri, Vilaplana, Castellote, Rabanal, Franch, and Castell 2003; Petrovsky and Harrison 1998).

Both the humoral arm and the delayed (cellular) arm of the immune system function in a rhythmic manner. Indeed, circadian variations in immunocompetent cells in peripheral blood are of a magnitude to require attention in medical diagnostics (Mazzoccoli et al. 1999; Niehaus, Ervin, Patel, Khanna, Vanek, and Fagan 2002; Undar, Ertugrul, Altunbas, and Akca 1999). Circadian changes in the circulation of T, B, or natural killer NK lymphocyte subsets in peripheral blood and in the density of epitope molecules at their surface, which may be related to cell reactivity to antigen exposure, have been reported (Cardinali, Brusco, Garcia, and Esquifino 1998b). Changes in lymphocyte subset populations can depend on time of day-associated changes in cell proliferation in immunocompetent organs and/or on diurnal modifications in lymphocyte release and traffic among lymphoid organs. Circadian rhythmicity is revealed in circulating cells, lymphocyte metabolism and transformability, circulating hormones and other substances that may exert various actions on different targets of the immune system, cytokines, receptors, and adhesion molecules, cell cycle events in health and cancer, reactions to antigen challenge, and disease etiology and symptoms. It must be noted that the role of the SCN, the central circadian pacemaker, in entrainment of lymphocyte function and in coordinating signals by which circadian information is conveyed to the immune cells remains unsettled. Rhythms in the number of circulating T cells persisted in rats with disrupted circadian outputs (Kobayashi, Oishi, Hanai, and Ishida 2004). Similarly, SCN ablation did not affect the 24-h rhythms in cell cycle phase distribution in bone marrow cells (Filipski et al. 2004), suggesting that some rhythms in the immune system may be SCN-independent. It is known that circadian gene expression can be maintained in vitro (Yoo et al. 2004). Thus, some peripheral clocks may be able to independently generate circadian oscillations and this could be also the case for lymphocytes. Rather than a mere rhythm generator for the periphery, the SCN should be envisioned as a transducer for light entrainment. However, there are entrainment signals other than light that may be coordinating the rhythm in NK cell function and other immunological parameters. For example, feeding is an important zeitgeber for peripheral clock gene expression (Kobayashi et al. 2004), and interestingly enough, internal desynchronization produced by restricted feeding during the light period slowed down tumor progression in mice (Wu, Li, Xian, and Levi 2004). Daily activity rhythms are also considered to act as entrainment cues for peripheral tissues (Schibler, Ripperger, and Brown 2003) and may as well influence the molecular clock in lymphocyte cells. In addition, intrinsic immunological outputs such a cytokine secretion could function as entrainment factors for immune cells. Indeed, interleukin (IL)-6 has been shown to induce Perl expression in vitro (Motzkus, Albrecht, and Maronde 2002).

Several studies have investigated the changes in cytokine levels that occur during the sleep-wake cycle; however, it is difficult to measure these changes because endogenous cytokine levels are low. Plasma TNF levels peak during sleep, and the circadian rhythm of TNF release is disrupted by obstructive sleep apnea. Plasma IL-1P levels also have a diurnal variation, being highest at the onset of non-REM sleep (Obal and Krueger 2005). The levels of other cytokines (including IL-2, IL-6, IL-10, and IL-12) and the proliferation of T cells in response to mitogens also change during the sleep-wake cycle. Although the production of macrophage-related cytokines (such as TNF) increases during sleep (in response to in vitro stimulation), this occurs in parallel with the rise in monocyte numbers in the blood. The production of T-cell-related cytokines (such as IL-2) increases during sleep, independent of migratory changes in T-cell distribution (Obal and Krueger 2005).

All of these observed diurnal changes could be specific to the effects of sleep or associated with the circadian oscillator. To dissociate the effects that result from the sleep-wake cycle from those due to the endogenous circadian oscillator, experimental procedures such as constant routine or forced desynchrony need to be used. At present, there are no reports of studies using these methods to elucidate the effects of sleep on immunity.

Sleep and the immune system share regulatory molecules. These are involved in both physiological sleep and sleep in the acute-phase response to infection. This supports the view that sleep and the immune system are closely interconnected (Obal and Krueger 2005). It is probable that sleep influences the immune system through the action of centrally produced cytokines that are regulated during sleep. These endogenous cytokines are known to function through the autonomic nervous system and the neuroendocrine axis, although other pathways might be involved.

During the last years, we have examined the regulation of circadian rhythmicity of lymph cell proliferation in a number of experimental models in rat submaxillary lymph nodes. The bilateral anatomical location of submaxillary lymph nodes and their easily manipulable autonomic innervation allowed us to dissect some of humoral and neural mechanisms regulating the lymphoid organs and their interaction. A significant diurnal variation of rat submaxillary lymph node ornithine decarboxylase activity (ODC), an index of cell proliferation in immunocompetent organs (Neidhart and Larson 1990) and endocrine glands (Scalabrino, Ferioli, Modena, and Fraschini 1982), was uncovered, displaying maximal activity at early afternoon (Cardinali, Della Maggiore, Selgas, and Esquifino 1996a). Such a maximum coincided with peak mitotic responses to lipopolysaccharide (LPS) and concanavalin A (Con A) in incubated lymph node cells (Esquifino, Selgas, Arce, Della Maggiore, and Cardinali 1996). A purely neural pathway including as a motor leg the autonomic nervous system innervating the lymph nodes was identified (Cardinali and Esquifino 1998). The combined sympathetic-parasympathetic denervation of the lymph node suppressed circadian variation in lymph cell proliferation. In addition, a hormonal pathway involving the circadian secretion of melatonin also plays a role to induce rhythmicity (Cardinali, Brusco, Cutrera, Castrillon, and Esquifino 1999; Cardinali et al. 1998b).

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