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Indeed, temporal organization is an important feature of the biological systems,
and its main function is to facilitate adaptation of the organism to the environment.
The light-dark cycle, food, ambient temperature, scents, and social cues have all
been identified as Zeitgebers in rats [9] . Stress is also capable of perturbing temporal
organization by affecting the shape and amplitude of a rhythm or by modifying the
intrinsic oscillatory mechanism itself. In particular, social stress in rodents has been
found to cause disruptions of the body temperature, heart rate, and locomotor activity
rhythms (see, e.g., Refs [14-16] ).
An entraining agent can actually reset, or phase-shift, the internal clock. Depending
on when an organism is exposed to such an entraining agent, circadian rhythms can
be advanced, delayed, or not shifted at all. Therefore, one factor involved in adjusting
the daily activity pattern to the appropriate time of day is a rhythmic variation in the
influence of the Zeitgeber as a resetting factor [13] . In humans, light exposure dur-
ing the first part of the night delays the phase of the cycle; a comparable light change
near the end of the night advances it. At other times during the day, light exposure has
no phase-shifting influence [17,18] .
In the case of the immune system, our work concentrated on the role of the auto-
nomic nervous system (parasympathetic and sympathetic) in providing the anatomi-
cal basis for the circadian control of lymph node function [19,20] . These studies
continued our former studies on the role of sympathetic and parasympathetic nerve
terminals in thyroid follicular and C cell and parathyroid cell regulation [21,22] . The
concept that autonomic nerves are a very efficient avenue for conveying time-of-day
information to the periphery has since been generalized to tissues like the adrenal
glands, pancreas, liver, ovaries, and many other organs [2,23] .
6.2 The Immune System Shows a Circadian Organization
Light and daily rhythms have a profound influence on immune function. Many stud-
ies have described circadian variations of immune parameters such as lymphocyte
proliferation, antigen presentation, and cytokine gene expression. The number of
lymphocytes and monocytes in the human blood reaches maximal values during the
night and is 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 [24-28] .
Immune cells have been checked for the presence of clock genes [29-33] . In a
study intended to determine whether circadian clock genes function in human periph-
eral blood mononuclear cells, the circadian clock genes human Per1, Per2, and Per3
were found to be expressed in a circadian manner in human peripheral blood mono-
nuclear cells, with a peak level occurring during the second part of the active phase
[34,35] . To investigate the presence of molecular clock mechanisms in NK cells,
as well as the circadian expression of critical factors involved in NK cell function,
Arjona and Sarkar [36] measured the circadian changes in the expression of clock
genes (Per1, Per2, Bmal1, Clock), Dbp (a clock-controlled output gene), cAMP
(response element-binding) CREB (involved in clock signaling), cytolytic factors
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