Circadian rhythms are daily changes in behavior and biological activity consistent with the 24-hour cycle of day and night. Circadian rhythms are controlled by the internal biological clock, which determines the sleep-wake cycle, daily fluctuations in blood pressure, body temperature, and cortisol.
Shift work or frequent jet lag disrupts circadian rhythms and increases the risk of cardiovascular disease, metabolic syndrome, and cancer. Circadian rhythms affect the clinical manifestations of diseases: pain syndrome, exacerbations of asthma, and myocardial infarction are more common at certain times of the day or night.
In the 1980s and 1990s, scientists discovered that circadian rhythms depend on clock genes. The expression of clock genes and the synthesis of clock proteins cyclically change every 24 hours. A study in fruit flies has shown that mutations in clock genes disrupt the sleep-wake cycle. Clock proteins influence metabolism, signaling, cellular physiology, and immune response.
In 2019, the U.S. National Institutes of Health hosted a seminar on Sleep Deprivation, Circadian Rhythm Disruption, and the Immune Response. The workshop aims to combine knowledge about circadian rhythms, sleep and immune dysfunctions to treat patients based on biological rhythms more effectively.
The Biological Clock Needs Synchronization
Circadian rhythms are essential for survival. They allow plants and animals to adapt their behavior to daily fluctuations in light and temperature. The basis of circadian rhythms is the clock gene. The expression of clock genes fluctuates on a 24-hour basis, allowing cells to consider information about the time of day to control metabolism and other vital processes. Typically, the cells of the body are synchronized.
The hypothalamus is responsible for circadian rhythms. The hypothalamus receives light information from the retina and then projects it to other areas of the central nervous system that regulate arousal, autonomic tone, temperature, and hormone secretion.
Light has the most significant influence on the rhythms of rest and activity. However, the hypothalamus synchronizes with changes in light cycles faster than peripheral tissues. Therefore, such a biochemical signal as an untimely meal can compete with the hypothalamus and cause the body’s cells to stop working synchronously. Internal desynchronization explains the consequences of jet lag and shift work, such as sleep disturbance, constant fatigue, dependence on sleeping pills, mood swings, and depression. In contrast, the synchronous operation of cells allows the body to solve complex problems – for example, to launch an optimal immune response.
Circadian Rhythms Affect Immunity
More than 50 years ago, scientists discovered that in healthy people, the number of circulating lymphocytes fluctuates daily, and in rodents, depending on the time of day, susceptibility to endotoxin changes.
Later studies showed that lymphoid organs and all types of immune cells have a biological clock, and shift work leads to disruption of circadian rhythms and increases the level of markers of systemic inflammation.
Circadian Rhythms-Related Immunological Processes
1. Secretion of pro-inflammatory cytokines
Cytokines are signaling molecules that regulate the immune response to infection or injury. Circadian rhythms influence cytokine expression because clock proteins regulate genes’ expression for critical cytokines and chemokines.
In laboratory studies, endotoxin is used to stimulate inflammation. In a mouse study, the secretion of the pro-inflammatory cytokine TNF-α was dependent on the timing of endotoxin administration.
Disruption of circadian rhythms causes inflammation. Acute infection often disrupts the expression of clock genes and increases the expression of pro-inflammatory genes. In addition, stressors such as shift work disrupt circadian rhythms and increase inflammation. Excessive inflammation suppresses the immune system and increases the risk of infections and stroke.
2. Migration of leukocytes
Leukocytes are white blood cells whose primary function is to protect the body from infections.
Leukocyte migration includes:
- release of leukocytes from the bone marrow;
- the return of leukocytes from the bloodstream to the internal organs;
- removal of leukocytes from organs by phagocytosis or movement to the lymph nodes.
The migration of leukocytes is controlled by signaling chemokine proteins. With the help of special receptors, leukocytes capture chemokines and move towards increasing the concentration of chemokines. Circadian rhythms are critical to the movement of leukocytes as they regulate both chemokine expression and the expression of chemokine receptors on the surface of leukocytes.
3. Differentiation and maturation of leukocytes
White blood cells play an essential role in inflammation, allergies, parasite defense, and autoimmune disease. Clock genes are required for the differentiation and development of leukocytes.
In mouse studies, disruption of the circadian rhythm resulted in abnormal development of Th17 cells and predisposed to autoimmune encephalomyelitis, multiple sclerosis, and colitis.
Circadian rhythms regulate the maturation of neutrophils. As we age, neutrophils undergo changes that enhance their migration to the internal organs following the circadian rhythm. The deficiency of the clock gene Bmal1 blocks the movement of neutrophils to the internal organs. In a mouse study, Bmal1 lack weakened innate immunity and increased disease severity.
Sleep Disturbance Suppresses Immune
There is no consensus on what defines perfect sleep, but total sleep deprivation in rodents is deadly. Studies have shown that chronically sleep-deprived animals develop splenic atrophy and polymicrobial bacteremia, suggesting that immune dysfunction may be part of the process of dying.
In humans, habitual sleep of fewer than 6 hours per night is statistically associated with reduced life expectancy, increased vulnerability to viral infections, and reduced antibody titers after vaccination. Short-term sleep deprivation before vaccination negatively affects antibody titers and reduces the flu vaccine’s effectiveness.
How are circadian rhythms and sleep related?
Circadian rhythms and sleep are biologically distinct phenomena, but it is hard to disrupt one without affecting the other. Circadian rhythms generate daily neurological arousal fluctuations that promote wakefulness and counter sleepiness. Disturbance of circadian rhythms leads to sleep disturbance.
A study in mice showed that deficiency of the Bmal1 clock gene leads to more fragmented sleep, longer stays awake at night, less depth of sleep, difficulty recovering from sleep deprivation, and impaired memory.
Short-term sleep disruption can affect circadian regulation in peripheral tissues such as the blood and lungs, either downregulating the expression of clock genes or altering its rhythm.
Sleep disturbance exacerbates inflammation
Sleep deprivation and habitual sleep of fewer than 6 hours per night increase the secretion of pro-inflammatory cytokines, especially in men. The number of circulating neutrophils, NK cells, monocytes, and B cells increases with prolonged wakefulness and decreases with restorative sleep, highlighting the role of sleep in leukocyte migration.
In mice, deficiency of the Bmal1 clock gene increased sleep fragmentation. In turn, fragmented sleep increased the production of inflammatory monocytes by the bone marrow and led to atherosclerosis and inflammatory pathology. In addition, insufficient sleep impairs NK cell function.
Output
Shift work, exposure to nighttime lighting, jet lag, and gaps between weekday and weekend sleep-wake schedules disrupt circadian rhythms daily. Disruption of circadian rhythms or sleep can cause inflammation and functional immunodeficiency, making the body vulnerable to infections.
The relationship of circadian rhythms with the immune system is essential for clinical practice. If you determine in advance which circadian phase the patient is in, it is possible to carry out treatment at the optimal time for each patient. This approach will increase the effectiveness of drugs and vaccines, help fight infections, and optimize the timing of organ transplants to minimize rejection.
Useful article, necessary information? Share it!
Someone will also find it useful and necessary:
Reference
Perfect timing: circadian rhythms, sleep, and immunity – an NIH workshop summary
