Sleep and Immune Function

by Emerson Ecologics

Can Better Sleep Strengthen Defenses?

“A good laugh and a long sleep are the best cures in the doctor’s book.” —Irish Proverb

Sleep is an undeniable biological need and is essential for immune function. Many studies suggest that a lack of sleep or disrupted sleep can increase susceptibility to immune-related illnesses. Specifically:

  • Short sleep duration may increase the risk of infectious disease. Among 164 healthy men and women in Pittsburgh, those who slept less than six hours per night were more susceptible to the common cold than those who slept more than seven hours.
  • Sleep deprivation may increase the risk of allergic reactions. A study of 126 patients with peanut allergies in the United Kingdom found that sleep deprivation lowered the threshold of peanut exposure required to trigger an allergy attack by 45 percent.
  • Short or long sleep duration may increase the risk of autoimmune disease. Prospective data from the Nurse’s Health Survey suggested that sleeping less than six hours or more than nine hours per night increased the risk of autoimmune ulcerative colitis.

Sleep problems are also common in many chronic illnesses, such as diabetes and heart disease. But whether sleep disturbances are a cause or consequence of these diseases isn’t clear, because the relationship appears to be bidirectional. 

However, studies do reveal a variety of proposed mechanisms that explain the connection between sleep and immune function. Here are six of the most-researched connections.

Connection #1: The Circadian Clock

It’s well understood that the circadian rhythm is a 24-hour biological clock that regulates the sleep-wake cycle. Guided by a master clock in the suprachiasmatic nuclei of the hypothalamus, the circadian rhythm coordinates a hormonal constellation that promotes sleep at night and wakefulness during the day. 

But the effects of the circadian rhythm extend beyond the sleep-wake cycle. The master clock in the hypothalamus synchronizes cellular clocks within immune cells (including macrophages, monocytes, B cells, and T cells), leading to rhythmic variations in immune function. 

When healthy, the circadian immune rhythm is characterized by peak levels of proinflammatory cytokines (such as interleukin-1 [IL-1] and tumor necrosis factor [TNF]-alpha) during sleep, along with peak levels of natural killer (NK) cells during the day.  

 

Not only does the master clock regulate a circadian immune rhythm, but immune chemicals also regulate sleep. Cytokines IL-1 and TNF-alpha are considered sleep-regulatory substances that contribute to the deepest form of sleep—stage 3 non-REM slow-wave sleep. While these cytokines don’t appear to regulate REM sleep, there’s ample evidence that they contribute to non-REM sleep in animals and probably humans.

Connection #2: Gut-Derived Muramyl Peptides

If you hold to the belief that all health and disease begins in the gut, you’re going to love this connection. 

In 1975, scientists extracted a substance from the cerebrospinal fluid of sleep-deprived animals. They named it substance S (for sleep). Substance S was eventually identified as muramyl peptide, a type of pathogen-associated molecular pattern (PAMP) that’s released from the cell walls of bacteria in the gut. 

Muramyl peptides and other PAMPs can be released from commensal gut bacteria whenever there’s interaction with the environment, which of course happens during waking hours. The release of muramyl peptide triggers subtle increases in systemic cytokine and prostaglandin levels, including sleep-regulatory substances like IL-1 and TNF. 

Scientists think muramyl peptides act as a sort of activity tracking system. During sleep deprivation, when activity and environmental interactions persist, the peptides cause a gradual increase of cytokines. When they reach a certain threshold, those cytokines contribute to the induction of sleep, and eventually non-REM sleep. 

Connection #3: Integrins

The immune response requires that T cells adhere to these target cells. They do this through sticky types of protein called integrins. Consequently, the ability of the immune system to eliminate cells depends on integrins. 

In a study conducted in Germany and published in 2019, researchers compared T cells from healthy people who either slept all night or stayed awake all night. In the people who slept, T cells showed a higher level of integrin activation than in the people who stayed awake. 

Whereas epinephrine and norepinephrine inhibit integrin activation when people are awake, sleep has the opposite effect. Activating integrins may be one mechanism to connect sleep with a stronger defense against viral infections.   

Connection #4: Immune Memory

Studies tracking the immune responses to vaccinations have given us insight into the role of sleep in creating immunologic memory. Just as sleep is important to consolidate emotional and psychological memories of the day, it also appears to be key in consolidating immune memories. 

The first human study to observe the effects of sleep deprivation on the immune response to vaccination measured influenza-specific antibody titers 10 days after administration of a flu vaccine. 

Participants either slept a typical seven to eight hours per night, or restricted their sleep to only four hours per night for four days before and two days after vaccination. Results showed that the antibody response to vaccination was more than double in people who received adequate sleep. 

Connection #5: Fevers 

Acute infections tend to make people feel tired and sleep more, but they also change the nature of sleep. 

The cytokines released in response to an acute infection induce more time in stage 3 non-REM sleep. Not only is this the deepest stage of sleep, but it’s also the period when the metabolism is at its lowest, freeing up energy to boost immune activity and mount a high fever. 

 REM sleep also becomes nearly nonexistent during acute infection. This may be because shivering is an important mechanism to release heat and maintain a fever, and the body can’t shiver during REM sleep. 

REM is the dreaming phase, and muscles become immobilized to prevent people from acting out their dreams. The disruption of REM during acute infections may contribute to what people experience as bizarre or intense “fever dreams.”

Connection #6: Inflammation

In our final connection between sleep and immune function, we come full circle to the concept of the circadian release of inflammatory cytokines. Experts don’t know for sure, but they think the reason inflammatory markers increase during sleep is because it’s a safe and beneficial time for the immune system to be active. If inflammation were to increase during the day, it could harm physical or mental performance. 

The natural increase of inflammatory cytokines during sleep is beneficial, but also self-regulating. In a healthy state, the nighttime peak of inflammation returns to baseline before waking. If a person doesn’t get enough sleep, however, this self-regulating system may fail, allowing inflammation to continue without constraint. 

Studies have found that sleep deficiency can be a behavioral trigger of low-grade inflammation. For example, sleeping less than five hours per night was related to an elevated inflammatory burden in older men, measured by levels of c-reactive protein (CRP), interleukin-6 (IL-6), TNF, and other inflammatory markers. And data from more than 5,000 middle-aged men and women enrolled in the London-based Whitehall II study showed that shorter sleep was associated with an increase in inflammatory CRP and IL-6.

Research also shows that too much sleep may be even more problematic than too little. A study of more than 8,000 Chinese adults found that sleeping longer than nine hours per night (but not shorter than six hours) correlated with elevated levels of high-sensitivity CRP. Meanwhile, a meta-analysis found that sleep disturbances and long sleep duration (but not short sleep duration) were associated with increases in markers of systemic inflammation.

Practical Perspectives

The observed association between sleep disturbances and inflammation is intriguing, but still leaves unanswered questions. 

For instance, we know that chronic and low-grade inflammation is a driving force behind many common chronic illnesses. Inflammation drives insulin resistance, endothelial dysfunction, and neuroinflammation—which can contribute to conditions like obesity, type 2 diabetes, cardiovascular disease, and other chronic diseases. But although it is tempting to conclude that inflammation mediates the link between sleep disturbances and vulnerability to disease, studies have yet to confirm this. Further research is needed to fully understand the mechanistic underpinnings. 

Another key question is if we improve sleep, can we support healthier immune function? One of the largest studies of cognitive behavioral therapy (CBT) for insomnia tracked more than 100 older adults for 16 months. People receiving CBT experienced improvements in sleep, decreases in levels of inflammatory CRP, and downregulation of genes involved in inflammation. Researchers concluded that CBT simultaneously helped insomnia and lowered inflammatory risk.

Given all of these sleep-immune connections, it may indeed be true that a good night’s sleep is the best medicine, as sleep fine-tunes our immune defenses.