What
does sleep have to do with the immune system?
First a brief review of sleep architecture. Sleep can be divided into two
categories: rapid eye movement (REM) and
non-rapid eye movement (NREM). In REM
sleep electroencephalogram (EEG) patterns resemble awake brain activity. Voluntary muscles are inactive, essentially
putting us in a paralytic state. It is
during this state, typically 20- 25% of our sleep time, that we dream. NREM sleep consists of four sleep stages, in
which we transition from wakefulness to slow wave sleep. The normal adult cycles through these stages and
into REM sleep 4-5 times per night (Pressman, 2011).
(Lundbeck, 2011)
Our ability to mount an immune response can be
compromised with sleep deprivation. While we are awake or in REM sleep our
bodies are less able to combat infection than when we are in NREM sleep. Dr. Cohen touched on one cause for this in
the notes on T-cells when he identified IL-1 (released by M1 macrophages) as a
stimulator of PGE2 in the preoptic anterior hypothalamus which activates the
heat generation response. Simply put, we
can spike a fever to fight infection while in NREM sleep, but cannot do the
same when we are in REM sleep.
There is a some evidence to support the idea that
IL-1 and TNF are associated with increased NREM sleep. In animal studies when bacterial cell wall
components were injected into subjects IL-1 and TNF increased. Subsequently, NREM sleep increased while REM
sleep decreased (Imeri & Opp, 2009). In another animal study, an association was
found between disrupted sleep and poor sleep quality and survival rates in
infected rabbits (Imeri & Opp, 2009).
The diagram below shows the changes in sleep architecture during fever.
(Imeri & Opp, 2009)
This
shift to increased NREM sleep and suppressed REM sleep allows our bodies to
mount an adaptive response to a pathogen by increasing our core temperature. This creates a less optimal environment and inhibits
pathogen growth. Further studies need to
be done in human populations, but this could help to explain one function of a
good night's rest.
Gamaldo, C. E., Shaikh, A. K., & McArthur, J. C.
(2012). The sleep-immunity
relationship. Neurologic Clinics, 30,
1313-1343. doi:
10.1016/j.ncl.2012.08.007
Imeri, L. & Opp, M. R. (2009). How (and why) the immune system makes us
sleep. Nature Reviews: Neuroscience, 10, 199-210.
Lundbeck, H. (2011).
Insomnia knowledge center. EPG
Online. Retrieved on 12/5/2012 at http://www.epgonline.org/sleep-medicine/
Pressman, M. R. (2011). Stages and architecture of normal sleep. Up To
Date. Retrieved on 12/5/2012 from http://www.uptodate.com.hsl-ezproxy.ucdenver.edu/contents/stages-and- architecture-of-normal-sleep?source=search_ result&search=sleep+architecture&selected
Title=1%7E44#H20
Another interesting research finding linking sleep and the immune system is TLR9 (see article below). TLR9 is an immune system protein that can sense bacterial and viral DNA. The circadian clock appears to be linked to TLR9 expression and function. Apparently, patients suffering from sepsis are at increased risk of death between 2 and 6am (perhaps their sleep is disturbed from ICU activity). And a mouse model of sepsis showed the disease severity correlated with cyclical changes in TLR9; I am unsure if this has been observed in humans. Pretty interesting, right?!
ReplyDeleteI wonder if as more comes out about the link between circadian rhythms and the immune system if current therapeutic strategies will be altered?
Adam C. Silver, Alvaro Arjona, Wendy E. Walker, Erol Fikrig. The Circadian Clock Controls Toll-like Receptor 9-Mediated Innate and Adaptive Immunity. Immunity, 2012
I recently read an article in nature about how many genes are regulated based on the circadian rhythm, which goes along with the above comment. The finding suggested similarly that genes expressing molecules that would fight infection were highest during the middle of the day, most likely when an organism like us is up and about in the world and will need to the most protection. Pretty cool when you think about our evolution this way! This article especially talks about TLR9
ReplyDeletehttp://www.nature.com/nri/journal/v12/n4/full/nri3194.html?WT.ec_id=NRI-201204
The other really interesting idea is that of clock gene variation and its role in immune function. I did a quick search of PubMed but couldn't find any studies as to whether individual's who identify as "night owls" and have the short clock gene allele, also manifest alternative circadian rhythm of their immune function.
DeleteBeing a "night owl" myself, I have to wonder as my immunity and other biological functions seem to not be disrupted by my night shift work and higher productivity at off-circadian hours :)
The two comments concerning TLR9 are very interesting. During the development of the brain, many cell surface receptors can be vital for the morphogenesis and differentiation of many classes of neurons. These include receptor types that in the mature brain have very different roles, and one of these proteins happens to be TLR9. In one paper studying if TLRs had any influence on the development of the mouse brain, the authors showed that TLR7 and TLR9 were widely expressed in neurons throughout the developing brain. None of the other TLRs had any significant expression during these developmental phases. I wonder that if the widespread distribution of TLR9 in the brain, possibly due to its apparently beneficial role in development, might lead to its role in diurnal variation of CNS immune responses.
ReplyDeleteNice post. I have noticed in myself that I generally only get sick when I don't get enough sleep and that I get healthy faster when I sleep a lot! Another weird thing that I hadn't considered until reading this is the link between temperature and sleep, another aspect I have experienced.
ReplyDeleteA lot of your post focused on NREM sleep. I am forgetting right now which stage of sleep is affected by medications like Ambien, but I wonder if the use of those types of drugs for sleep aid also effects the immune system in a similar way? I also wonder whether researchers have looked at the immune systems of narcoleptics?
Nice post, and very familiar to anyone who has been sleep deprived for an extended work week. I have never thought of this from the perspective of temperature regulation before. I did some further research, and found an interesting article from a German research group which indicated that the response to vaccines was greatly affected by sleep patterns. They vaccinated some people, then deprived half of them of sleep post-vaccination for a period of time. they found the sleep group maintained double the amount of t helper memory cells as the non-sleep group, and increased antibody production as well. Another review article I read indicated that IL-6 and TNF secretion follows a circadian sleep cycle, but in insomniacs, the secretions are switched to higher production during daytime hours.
ReplyDeleteJ Immunol. 2011 Jul 1;187(1):283-90. doi: 10.4049/jimmunol.1100015. Epub 2011 Jun 1.
Sleep after vaccination boosts immunological memory.
Lange T, Dimitrov S, Bollinger T, Diekelmann S, Born J.
“Metabolic, Endocrine, and Immune Consequences of Sleep Deprivation.” The Open Respiratory Medicine Journal 5, no. 1 (June 23, 2011): 31–43.