Editing Immune system (section)

=== Sleep and rest ===
The immune system is affected by sleep and rest, and [[sleep deprivation]] is detrimental to immune function.<ref>{{cite journal | vauthors = Bryant PA, Trinder J, Curtis N | title = Sick and tired: Does sleep have a vital role in the immune system? | journal = Nature Reviews. Immunology | volume = 4 | issue = 6 | pages = 457–67 | date = Jun 2004 | pmid = 15173834 | doi = 10.1038/nri1369 | s2cid = 29318345 }}</ref> Complex feedback loops involving [[cytokines]], such as [[interleukin-1]] and [[tumor necrosis factor-α]] produced in response to infection, appear to also play a role in the regulation of non-rapid eye movement ([[Non-rapid eye movement sleep|NREM]]) sleep.<ref>{{cite journal | vauthors = Krueger JM, Majde JA | title = Humoral links between sleep and the immune system: research issues | journal = Annals of the New York Academy of Sciences | volume = 992 | issue = 1 | pages = 9–20 | date = May 2003 | pmid = 12794042 | doi = 10.1111/j.1749-6632.2003.tb03133.x | bibcode = 2003NYASA.992....9K | s2cid = 24508121 }}</ref> Thus the immune response to infection may result in changes to the sleep cycle, including an increase in [[slow-wave sleep]] relative to rapid eye movement ([[Rapid eye movement sleep|REM]]) sleep.<ref>{{cite journal | vauthors = Majde JA, Krueger JM | title = Links between the innate immune system and sleep | journal = The Journal of Allergy and Clinical Immunology | volume = 116 | issue = 6 | pages = 1188–98 | date = Dec 2005 | pmid = 16337444 | doi = 10.1016/j.jaci.2005.08.005 | doi-access = free }}</ref>

In people with sleep deprivation, [[active immunization]]s may have a diminished effect and may result in lower antibody production, and a lower immune response, than would be noted in a well-rested individual.<ref name="pmid27077395">{{cite journal |vauthors=Taylor DJ, Kelly K, Kohut ML, Song KS |title=Is Insomnia a Risk Factor for Decreased Influenza Vaccine Response? |journal=Behavioral Sleep Medicine |volume=15 |issue=4 |pages=270–287 |date=2017 |pmid=27077395 |pmc=5554442 |doi=10.1080/15402002.2015.1126596}}</ref><ref>{{Cite journal |last1=Rayatdoost |first1=Esmail |last2=Rahmanian |first2=Mohammad |last3=Sanie |first3=Mohammad Sadegh |last4=Rahmanian |first4=Jila |last5=Matin |first5=Sara |last6=Kalani |first6=Navid |last7=Kenarkoohi |first7=Azra |last8=Falahi |first8=Shahab |last9=Abdoli |first9=Amir |date=June 2022 |title=Sufficient Sleep, Time of Vaccination, and Vaccine Efficacy: A Systematic Review of the Current Evidence and a Proposal for COVID-19 Vaccination |journal=The Yale Journal of Biology and Medicine |volume=95 |issue=2 |pages=221–235 |issn=1551-4056 |pmc=9235253 |pmid=35782481}}</ref> Additionally, proteins such as [[NFIL3]], which have been shown to be closely intertwined with both T-cell differentiation and [[circadian rhythm]]s, can be affected through the disturbance of natural light and dark cycles through instances of sleep deprivation. These disruptions can lead to an increase in chronic conditions such as heart disease, chronic pain, and asthma.<ref name="pmid19075717">{{cite journal |vauthors=Krueger JM |title=The role of cytokines in sleep regulation |journal=Current Pharmaceutical Design |volume=14 |issue=32 |pages=3408–16 |date=2008 |pmid=19075717 |pmc=2692603 |doi=10.2174/138161208786549281}}</ref>

In addition to the negative consequences of sleep deprivation, sleep and the intertwined circadian system have been shown to have strong regulatory effects on immunological functions affecting both innate and adaptive immunity. First, during the early slow-wave-sleep stage, a sudden drop in blood levels of [[cortisol]], [[epinephrine]], and [[norepinephrine]] causes increased blood levels of the hormones [[leptin]], [[Growth hormone 1|pituitary growth hormone]], and [[prolactin]]. These signals induce a pro-inflammatory state through the production of the pro-inflammatory cytokines interleukin-1, [[interleukin-12]], [[TNF-alpha]] and [[IFN-gamma]]. These cytokines then stimulate immune functions such as immune cell activation, proliferation, and [[Cell differentiation|differentiation]]. During this time of a slowly evolving adaptive immune response, there is a peak in undifferentiated or less differentiated cells, like naïve and central memory T cells. In addition to these effects, the milieu of hormones produced at this time (leptin, pituitary growth hormone, and prolactin) supports the interactions between APCs and T-cells, a shift of the [[Th1 cell|T<sub>h</sub>1/T<sub>h</sub>2]] cytokine balance towards one that supports T<sub>h</sub>1, an increase in overall T<sub>h</sub> cell proliferation, and naïve T cell migration to lymph nodes. This is also thought to support the formation of long-lasting immune memory through the initiation of Th1 immune responses.<ref name="Sleep and immune function">{{cite journal | vauthors = Besedovsky L, Lange T, Born J | title = Sleep and immune function | journal = Pflügers Archiv | volume = 463 | issue = 1 | pages = 121–37 | date = Jan 2012 | pmid = 22071480 | doi = 10.1007/s00424-011-1044-0 | pmc=3256323}}</ref>

During wake periods, differentiated effector cells, such as cytotoxic natural killer cells and CD45RA+ cytotoxic T lymphocytes, peak in numbers. Anti-inflammatory molecules, such as cortisol and [[catecholamine]]s, also peak during awake active times. Inflammation can cause [[oxidative stress]] and the presence of melatonin during sleep times could counteract free radical production during this time.<ref name="Sleep and immune function"/><ref>{{cite web|url=http://www.webmd.com/sleep-disorders/excessive-sleepiness-10/immune-system-lack-of-sleep/ |title=Can Better Sleep Mean Catching fewer Colds? |access-date=28 April 2014 |url-status=dead |archive-url=https://web.archive.org/web/20140509003219/http://www.webmd.com/sleep-disorders/excessive-sleepiness-10/immune-system-lack-of-sleep |archive-date=9 May 2014 }}</ref>