Study shows how lack of sleep affects immunity | AGÊNCIA FAPESP

Experiments carried out at the Sleep Institute detail changes in the production of defense cells and the loss of the immune defense response

Study shows how lack of sleep affects immunity

November 07, 2012

By Karina Toledo

Agência FAPESP – Although it is well established that sleep is important for a well-functioning immune system, little is known about the mechanisms involved. In recent years, a study funded by FAPESP has shown how different types of sleep deprivation interfere with the human defense system. 
In the first phase of the study, to mimic situations common in society, the researchers subjected volunteers to complete sleep deprivation for a 48-hour period (similar to the sleep deprivation that people experience when working night shifts) as well as to selective rapid eye movement (REM) sleep deprivation for four consecutive nights. 
“In recent decades, there has been a progressive and significant reduction in the average duration of sleep time, especially in the second half of the night, when REM sleep prevails,” said Francieli Ruiz da Silva, the main author of the study, which was carried out during her doctoral studies at the Universidade Federal de São Paulo (Unifesp) under a FAPESP fellowship.
The study, oriented by Professor Sergio Tufik, was directed at the Sleep Institute, one of the FAPESP-funded Research, Innovation and Dissemination Centers (CEPID). The results of the study were published in the journal Innate Immunity and presented at the 23rd Annual Meeting of the Associated Professional Sleep Societies, held in the United States in 2009. The authors also received an award from the European Federation of Immunological Societies during the 2nd European Congress of Immunology, held in Germany in 2009. 
In the second phase of the study, the researchers investigated the effects of sleep deprivation on the development in mice of a specific response to an immunological challenge. The results of the experiments were presented at the 27th Annual Meeting of the Federation of Societies of Experimental Biology (FeSBE), held in August 2012.
The objective of the first phase, Ruiz explained, was to “evaluate the change in the immune profile of the volunteers caused by the lack of sleep. To do this, we did a white blood cell count—to measure the number of leukocytes in the blood—before and after the experiment.” 
Over a week, 30 healthy volunteers between the ages of 18 and 30 were subdivided into three groups and remained in the laboratory for the duration of the experiment. Volunteers in the control group slept normally, and their sleep was monitored with a polysomnograph.
The sleep of the second group, which underwent selective sleep deprivation, was monitored as well. These subjects were awakened by a bell every time the equipment  indicated that a REM phase was approaching.
According to Ruiz, “The first night was easy, but as the  [participants’] need for REM sleep increased, it got more difficult. This stage appeared earlier and earlier on, an effect known as REM rebound. On the fourth night, the subjects were entering into REM sleep as soon as they dozed off.”
The third group, which was completely  deprived of sleep, remained awake for 48 hours with the help of video games, card games, Internet access and an occasional shake. On the subsequent three nights, they were allowed to sleep normally and were monitored via a polysomnograph to record the sleep rebound effect. 
Whereas the control group showed no change in the immune profile, as expected, the volunteers in the group completely deprived of sleep exhibited an increase in the number of circulating leukocytes, specifically neutrophils—the type of cell that is the first to respond to most infections. An increase in the number of T helper cells, which are responsible for adaptive immunity specific for each illness, was also observed.
“Leukocytes perform the function of defense at the first sign of a pathogen invasion, we observed that total sleep deprivation sets off an alarm in the organism. It was interpreted as an aggression and [triggered] a response as if it were something real,” Ruiz said. 
This change was reversed after the first 24 hours of sleep recuperation. “But to our surprise, the number of lymphocytes didn’t return to normal after three nights of recuperation,” she added. 
In the REM sleep-deprived group, a reduction in circulating immunoglobulin A (IgA) was observed throughout the experiment. This effect was maintained after the three nights of sleep recuperation. 
Ruiz explained, “This immunoglobulin, which is found in mucous secretions, is directly related to protection against pathogen invasion. This could explain why REM sleep deprivation could be related to a greater susceptibility to illnesses like colds and flu, as described in the literature.” 

Immunological challenge
In the second phase of the study, the researchers investigated the effects of sleep deprivation on a specific response to an immunological challenge in mice. “We needed a stimulus that would set off a vigorous response and opted for a skin transplant model between two different and genetically incompatible lineages of mice,” Ruiz said. 
According to Ruiz, the rejection of the grafted skin by the recipient is normal in this model. But whereas the animals in the control group rejected the foreign skin in 8 to 10 days, the animals subjected to sleep deprivation (either complete or REM only) required 15 to 18 days. “This is an 80% increase in tissue survival time, the equivalent of the effect of immunosuppressant drugs like cyclosporin,” she pointed out.
In order to determine the cause of the weakened immune response, the researchers analyzed the lymphatic organs in the animals and found a 76.4% decrease in the number of T helper cells in the group subjected to REM-sleep deprivation. In the group that underwent complete sleep deprivation, the reduction was 34% as compared to the control group. 
Ruiz explained, “T lymphocytes are essential to the rejection process. They are activated by the antigen-presenting cells (APCs) and then migrate from the lymphatic organs to the affected region, where they set off an inflammatory response that culminates in rejection.”
The analyses showed that both sleep-deprived groups exhibited an approximately 40% reduction of T lymphocytes in the inflammatory infiltrate of the skin graft, indicating that there were fewer defense cells in the region. 
This decrease could be accounted for by a reduced expression of the class 2 MHC molecules, which are essential for communication between the APCs and lymphocytes. In addition, a 40% decrease in the number of interleukin-2 (IL-2) receptors was observed in the bloodstream. 
“When the lymphocyte moves to the affected area,” Ruiz explained, “it needs to proliferate in order to attack the tissue. That’s why it releases IL-2, the main mediator for this proliferation. However, a smaller quantity of these receptors in the blood indicates less lymphocyte proliferation and a weakening of the rejection process.” 
To ensure that the possible stress caused by the sleep deprivation was not the cause of the immunosuppression, the researchers evaluated the levels of circulating corticosterone in the animals. 
“This hormone in mice is equivalent to cortisol in humans. As the levels weren’t higher in the sleep-deprived rodents than in the control group, we believe that the stress didn’t interfere with the results,” Ruiz noted. 
The next step in the research will be to investigate why sleep deprivation reduces the expression of class 2 MHC and lymphocyte proliferation. In addition, in her FAPESP-funded post-doctoral research, Ruiz intends to examine the effect of sleep deprivation on people who work night shifts and trade days for nights. “The literature indicates that daytime sleep isn’t as reparative as night sleep,” she said. “Our intention is to vaccinate these volunteers and see how inverting sleep schedules interferes with immunity.”


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