Sleep, the Immune System, and Chronic Inflammation

Immune molecules can induce sleep in dogs and humans!

Before coronavirus took over our world, infectious diseases had been on a decades-long decline in terms of cause of death and impact in the public health sphere. Indeed, present pandemic aside, the leading cause of death for the past 100 years or so have generally been chronic diseases such as heart disease, diabetes, cancer, and stroke, which together account for ~ 75% of deaths in the developed world. The graph below is a bit dated, but you can see how in steeply the mortality curves for infectious diseases has dropped over the years.

In the blog which follows, we’ll discuss chronic inflammation and it’s bidirectional role with sleep health. We will see how poor sleep can have direct impacts on cellular and immune functioning, and understand how proper sleep can contributed to reducing inflammation and may improve risk and progression of chronic diseases, many of which shared a common pathophysiology linked to systemic inflammation.

It is important to differentiate systemic inflammation (the long term, chronic kind) from acute inflammation, which is a normal and even healthy response to trauma. As an example, when we cut ourselves, or prick our skin, we release a cascade of immune reactions meant to prevent infection. This keeps us safe and prevents sepsis.

The issue is when we don’t have any acute injury, but we put stress on our body through long-term lifestyle issues such as smoking, tobacco, excess sun exposure, obesity, and even insufficient sleep. When the body is chronically stressed, it causes a release of stress hormones (such as cortisol), as well as an immune response through increased cytokines (which we’ll cover in more detail below. All of this leads to long term oxidative stress which causes cellular damage and even DNA changes (a factor in development of cancer).

Cortisol secretion is actually tied to the circadian rhythm which drives sleep and wake rhythms. In normal patients, it starts to rise about 2 hours before awakening, with peak levels around 8-9 am. It declines thereafter with a low around midnight. Deep sleep (stage N3) suppresses cortisol secretion. So when we are sleep deprived or have frequent awakenings at night, it increases cortisol. Chronically high cortisol is known to contribute to storing belly fat and also to overall higher levels of inflammation.

An important concept related to the immune system is the term cytokine. These are signaling molecules (technically a kind of protein), which regulate many cellular processes. They are often at an increased concentration with trauma, infection, inflammation, and oxidative stress. In acute issues, they can generate lethal ‘cytokine storms’ when their production spirals out of control. This was seen in the 1918 flu pandemic, in Ebola, sepsis, graft vs host disease, and most recently COVID-19. Chronically high amounts of cytokines have been associated with dementia.

So what does sleep have to do with this? Normal sleep has a role in reducing inflammation and supports proper immune function. Indeed, each immune cell has its own circadian oscillators which signal activity. Getting insufficient sleep, or having sleep disordered breathing (apnea) can interfere with these processes and actually cause inflammation! On the flip side, inflammation carries its own circadian pacing, with diseases such as asthma, rheumatoid arthritis, and COPD having diurnal symptom severity variation. Certainly I feel this every time I have an asthma flare- it’s always worse at night.

An interesting studies was done over 100 years ago in dogs as proof of concept. The sorted dogs (god knows why) into two groups and sleep deprived one. Then they drew cerebro-spinal fluid (CSF)from the sleep deprived dogs and injected it into the normal sleepers. The CFS fluid actually made the normal dogs much sleepier! The thought was that both hormones and cytokines played a role. (Ishimori 1909, Legendre &Pieron 1913)

Fast forward about a hundred years, and now we know much more about these substances and their role in sleep deprivation. Two of the big ones are tumor necrosis factor (TNF) and Interleukin 1). A PubMed search with TNF and sleep will yield over 500 hits and Interleukin and sleep will give over 1600 hirs. Both of these cytokines also happen to play a role in neural plasticity. This makes good sense. Sleep is although though to improve neural contentedness, and TNF has specifically been linked to synaptic pruning. Interestingly, TNF also has a role in clock gene regulation. Indeed, it can be injected into patients to induce dose-dependent changes to NREM sleep, increasing delta power or the voltage of certain brain waves (it doesn’t seem to impact REM sleep as much). So it seems TNF-alpha actually induces sleep within one hour and sustaining for 8-12 hours! (Davis and Krueger SMC 2012).

The above explains how normal immune cells can alter your sleep patterns. What happens when you’re sick with an infection? We see changes to sleep in both bacterial and viral infections. A bacterial challenge in general promotes sleep, with more sleep drive the first day of infection generally. The specific impact to sleep drive can vary by species, level of exposure, and site of infection. There are different patterns in gram positive versus negative bacteria. For viruses such as the flu, we sleep more in general and also lose some circadian timing. We also see changes in architecture, with more NREM and less REM sleep. Given that NREM sleep is thought to be more for the body and tissues, this makes sense.

TNF elevation shows up in a host of acute and chronic diseases, including HIV, flu, heart attack, alcoholism, chronic fatigue syndrome, and Alzheimer’s (among many more). But it’s also present in sleep disorders including insomnia, hypersomnia (wanting to sleep too much), and obstructive sleep apnea. TNF changes are also common in a category of diseases called NAIDs (chronic inflammatory neurological auto-immune diseases). This includes MS, Guillane-Barre, Rheumatoid Arthritis, and even Narcolepsy! Interestingly, sleepiness is a shared feature of all of these. One study found that inhibiting TNA-alpha improved fatigue associated with rheumatoid arthritis (Khatami 2008).

Inflammation also plays a role in metabolic syndrome and sleep. The features of metabolic syndrome include visceral adiposity, hypertension, insulin resistance, high cholesterol, clotting risk, and excess urination. All of these are not only associated with chronic systemic inflammation, but also sleep loss and risk for obstructive apnea. We know that around 70% of apnea patients are overweight/obese, but sleep restriction even without apnea is an independent predictor of metabolic syndrome. Sleep deprivation for any reason causes multiple immune responses including the release of monocyte and natural killer cells, TNF-alpha, interleukin 6, c-reactive proteins, and reduced antibody production. It also causes cellular change through a process of methylation. (Conwell and Lee-Chiong Jr 2013).

So what the heck is methylation? A methyl group is a type of molecule which can glom onto the DNA base cytosine). When a methyl group is added to a gene, it can switch it off. Researchers looked at sleep in depressed college students and found 87 different site changes with short versus long sleepers. 59 of these were hyper-methylation and the rest were hypo-methylation changes. Among these were a circadian gene, and oncogene, and a DNA repaid gene. This is concerning because oncogenes and DNA repair genes are key factors in cancer, immunologic disease, and connective tissue disorders. These changes were all noted more frequently in the shorter sleepers, and sleeping an average of less than 5 hours per night seemed to carry the greatest risk (Carskadon 2014).

Since that groundbreaking study, there have been many others into the role of sleep loss and DNA damage and repair. It seems DNA is the main place damage occurs systemically. Early findings are the damage can be worse in the liver and lungs, and even full cell death has been noted in the small intestine. Essentially, this is caused by an imbalance of damage and repair within DNA. Asking DNA to repair itself expends metabolic energy and increases cell turnover- in a vicious cycle, this in turn can cause more replication errors.

This begs the question, does poor or inadequate sleep increase the risk for cancer? We know so far that a lack of good sleep alone doesn’t cause cancer, but that good quality sleep can help your body fight cancer. One study of active young women who slept for less than 7 hours per night had a 47% higher risk of cancer than those who got more sleep. Short sleep has also been linked to increased risk of colo-rectal cancer and liver cancer. Sleep disorders can also alter two hormones which impact cancer- cortisol and melatonin. Research in patients with cancer shows that sleep may be a possible factor in recovery and remission, and that more and better sleep can help improve pain tolerance associated with cancer.

Obstructive Sleep Apnea (OSA) poses its own unique set of risks, not just from reducing sleep, but from the drops in oxygen which occur with pauses in breathing. OSA causes increased production of adhesion molecules which cause clotting, a rise in the aggregation of platelets, and DNA methylation. The pathologic causes are twofold. There are frequent arousals causing an increase in sympathetic tone, as well as a range of issues with intermittent hypoxia (drops in oxygen). Indeed, hypoxia has a linear relationship to TNF-alpha levels! This conditions plays a key role in inflammation by generating reactive oxygen species, releasing pro-inflammatory cytokines, causing endothelial dysfunction, altering glucose metabolism, causing pancreatic beta cell injury, distorting lipid profiles, and perhaps even promoting neoplasms! (Conwell 2013). It’s the intermittent part of hypoxia that’s so problematic. Sustained hypoxia (say at altitude causes) adaptive mechanisms to kick in.

Endothelial dysfunction is worth spending a bit more time on. The endothelium is a thin layer of cells that lined the blood vessels and maintain a balance between vascular constriction and dilation. Too much constriction causes injury to arterial walls. Intermittent hypoxia causes an increase in various cytokines including TNF-alpha and IL 6,8. This in turn stimulates activation of endothelial cells such as leukocytes and platelets, all of which further drives endothelial dysfunction.(Conwell 2013).

Endothelial dysfunction then causes an increase in cardiovascular disease. Both interleukins named above play a role in the development of cardiovascular disease, with IL6 being a major player. TNF-alpha is associated with atherosclerosis and ischemic heart disease. Indeed, endothelial dysfunction may be a prodrome for frank cardiovascular disease in obstructive apnea patients, and the “dippers” (those whose oxygen drops the most and frequently) have it worse. A cool piece of technology to assess this is the EndoPAT which can assess endothelial damage non-invasively by looking at arterial response to increased need for blood. A poor responses is a hallmark of atherosclerosis. (Note- I have no relationship with Itamar, the manufacturer, I just think the tech is cool).

So what about sleep apnea and the risk for increased cancer mortality? A US study followed 1522 patients for 22 years and found patients with severe apnea had 4.8 times higher risk of death related to cancer. A study in Spain of 5200 patients found severe apnea led to a 65% greater risk of developing any kind of cancer, and longer times spent with lower oxygen was associated with the highest risk. Animal studies also suggest low oxygen levels related to pauses in breathing can cause angiogenesis and tumor growth. Indeed, a mouse model of intermittent hypoxia found that exposing mice to this condition causes both cancer growth and metastasis, and that hypoxia is an “oncogenic signal and modulator of tumor growth.” (Gharib et.al. 2014).

It’s clear obstructive sleep apnea causes many systemic issues, but there are also studies to show it can cause local tissue injury. Studies show trauma to the muscles and soft tissue near the throat, an increase in nasal cytokines/immune cells, increased mucous, edema, and inspiratory muscle fatigue. This includes reduced hypoglossal nerve function! (Conwell 2013/McNichols 2007). This local airway inflammation has also been shown to contribute to chronic cough and asthma, and recurrent tonsillitis in kids. (Sudar et.al 2011/Alkhalil et.al. 2009).

Beyond that, there’s some evidence that even primary snoring (without full blown apnea) isn’t so benign. Snoring itself may be a factor in local injury including “vibration induced carotid injury.” Indeed, this is found to be akin to the endothelial dysfunction associated with the use of jackhammers! In essence, the vibrations can dislodge plagues, leading to stroke/thrombosis. (Montesi 2012). Bad news for women- there’s more of a relationship between snoring and carotid artery injury for us! Early theories are perhaps it’s due to a smaller neck circumference for women, or perhaps a difference in the loudness and frequency of snoring vibrations. (Kim et.al. 2014).

For all that bad news, does wearing CPAP help? Yes! Many studies have demonstrated PAP use in improving a range of factors., and it tends to work best on those which most strongly correlated to intermittent hypoxia. A table summarizing 2 key studies is below. (Conwell 2013/Montesi 2012).

Cytokine/FactorImproves w/CPAP therapy?
IL-6Maybe
IL-8Yes
TNF-aYes
NF-kbYes
CRPMaybe
Pentraxin-3Yes (CPAP improved arterial stiffness in 1 month)
Xanthine oxidoreductaseYes (this increases levels of uric acid, but CPAP helps clear).
FibronigenYes (this causes platelet stickiness)
HomocystineYes
HbA1cMaybe (this is a key marker for diabetes)
8-isoprostaneYes (this is a free radical)
CysteineYes
Nitric OxideYes (this is a key vasodialator which helps with endothelial health)

Another studies showed “treatment of obstructive apnea alters cancer-associated transcriptional leukocytes,” which was perhaps the first indication that CPAP may help prevent cancer! In this, researchers measured peripheral blood leukocyte gene expression before and after CPAP use in severe patients, and found key oncogene nodes showed increased expression with untreated apnea! These changes were present looking at just 4+ hours of CPAP usage (the Medicare definition of compliant) for over 2 weeks. “We observed that in most subjects, there was a distinct pattern of expression suppression following exposure to CPAP, suggesting down-regulation of pathways involved in cancer upon treatment of OSA.” (Gharib et.al. 2014).

Put away the Viagra! CPAP can also prevent endothelial changes in erectile dysfunction! This condition is partially a result of endothelial dysfunction and once again, we see higher risk with more hypoxia. The Viagra class of drugs may improve endothelial function, but can also worsen apnea by increasing blood flow to the upper airway. CPAP has been shown in many studies to reduce endothelial dysfunction, and it does seem to improve sexual function independent of medications, but it can’t necessarily fix endothelial damage.

In summary, sleep is a systemic phenomenon and poor sleep causes systemic damage (as well as local at times). Good sleep helps reduce the risk of cancer, diabetes, heart disease, and many other conditions, and the shared pathway of inflammation is the main mechanism of damage when we don’t get enough sleep.

If you need help reaching your sleep goals, we offer sleep coaching virtually to help!

Related posts:

Insomnia Approaches

Sleep and Hormones

Sleep and Dementia

Sleep and Mental Health

Sleep Hygiene

The Pineal Gland and the Third Eye

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