Editing Immune system (section)

== Physiological regulation ==
[[File:Immune response2.svg|thumb|right|upright=1.65 |alt=The initial response involves antibody and effector T-cells. The resulting protective immunity lasts for weeks. Immunological memory often lasts for years. |The time-course of an immune response begins with the initial pathogen encounter, (or initial vaccination) and leads to the formation and maintenance of active immunological memory.]]
The immune system is involved in many aspects of physiological regulation in the body. The immune system interacts intimately with other systems, such as the [[Endocrine system|endocrine]]<ref>{{cite journal | vauthors = Wick G, Hu Y, Schwarz S, Kroemer G | title = Immunoendocrine communication via the hypothalamo-pituitary-adrenal axis in autoimmune diseases | journal = Endocrine Reviews | volume = 14 | issue = 5 | pages = 539–63 | date = October 1993 | pmid = 8262005 | doi = 10.1210/edrv-14-5-539 }}</ref><ref>{{cite journal | vauthors = Kroemer G, Brezinschek HP, Faessler R, Schauenstein K, Wick G | title = Physiology and pathology of an immunoendocrine feedback loop | journal = Immunology Today | volume = 9 | issue = 6 | pages = 163–5 | date = June 1988 | pmid = 3256322 | doi = 10.1016/0167-5699(88)91289-3 }}</ref> and the [[Nervous system|nervous]]<ref>{{cite journal | vauthors = Trakhtenberg EF, Goldberg JL | title = Immunology. Neuroimmune communication | journal = Science | volume = 334 | issue = 6052 | pages = 47–8 | date = October 2011 | pmid = 21980100 | doi = 10.1126/science.1213099 | bibcode = 2011Sci...334...47T | s2cid = 36504684 }}</ref><ref>{{cite journal | vauthors = Veiga-Fernandes H, Mucida D | title = Neuro-Immune Interactions at Barrier Surfaces | journal = Cell | volume = 165 | issue = 4 | pages = 801–11 | date = May 2016 | pmid = 27153494 | pmc = 4871617 | doi = 10.1016/j.cell.2016.04.041 }}</ref><ref>{{cite journal | title = Neuroimmune communication | journal = Nature Neuroscience | volume = 20 | issue = 2 | pages = 127 | date = February 2017 | pmid = 28092662 | doi = 10.1038/nn.4496 | doi-access = free }}</ref> systems. The immune system also plays a crucial role in [[embryogenesis]] (development of the embryo), as well as in [[Tissue (biology)|tissue]] repair and [[Regeneration (biology)|regeneration]].<ref name="pmid28542262">{{cite journal |vauthors=Wilcox SM, Arora H, Munro L, Xin J, Fenninger F, Johnson LA, Pfeifer CG, Choi KB, Hou J, Hoodless PA, Jefferies WA |title=The role of the innate immune response regulatory gene ABCF1 in mammalian embryogenesis and development |journal=PLOS ONE |volume=12 |issue=5 |pages=e0175918 |date=2017 |pmid=28542262 |pmc=5438103 |doi=10.1371/journal.pone.0175918 |bibcode=2017PLoSO..1275918W |doi-access=free }}</ref>

=== Hormones ===
[[Hormone]]s can act as [[immunomodulators]], altering the sensitivity of the immune system. For example, [[female sex hormones]] are known [[immunostimulator]]s of both adaptive{{sfn| Wira |Crane-Godreau |Grant |2004 |loc= Chapter: Endocrine regulation of the mucosal immune system in the female reproductive tract}} and innate immune responses.<ref>{{cite journal | vauthors = Lang TJ | title = Estrogen as an immunomodulator | journal = Clinical Immunology | volume = 113 | issue = 3 | pages = 224–30 | date = Dec 2004 | pmid = 15507385 | doi = 10.1016/j.clim.2004.05.011 }}<br />{{cite journal | vauthors = Moriyama A, Shimoya K, Ogata I, Kimura T, Nakamura T, Wada H, Ohashi K, Azuma C, Saji F, Murata Y | title = Secretory leukocyte protease inhibitor (SLPI) concentrations in cervical mucus of women with normal menstrual cycle | journal = Molecular Human Reproduction | volume = 5 | issue = 7 | pages = 656–61 | date = Jul 1999 | pmid = 10381821 | doi = 10.1093/molehr/5.7.656 | doi-access = free }}<br />{{cite journal | vauthors = Cutolo M, Sulli A, Capellino S, Villaggio B, Montagna P, Seriolo B, Straub RH | title = Sex hormones influence on the immune system: basic and clinical aspects in autoimmunity | journal = Lupus | volume = 13 | issue = 9 | pages = 635–38 | year = 2004 | pmid = 15485092 | doi = 10.1191/0961203304lu1094oa | s2cid = 23941507 }}<br />{{cite journal | vauthors = King AE, Critchley HO, Kelly RW | title = Presence of secretory leukocyte protease inhibitor in human endometrium and first trimester decidua suggests an antibacterial protective role | journal = Molecular Human Reproduction | volume = 6 | issue = 2 | pages = 191–96 | date = Feb 2000 | pmid = 10655462 | doi = 10.1093/molehr/6.2.191 | doi-access = free }}</ref> Some autoimmune diseases such as [[lupus erythematosus]] strike women preferentially, and their onset often coincides with [[puberty]]. By contrast, [[androgen|male sex hormones]] such as [[testosterone]] seem to be [[immunosuppressive]].<ref>{{cite journal | vauthors = Fimmel S, Zouboulis CC | title = Influence of physiological androgen levels on wound healing and immune status in men | journal = The Aging Male | volume = 8 | issue = 3–4 | pages = 166–74 | year = 2005 | pmid = 16390741 | doi = 10.1080/13685530500233847 | s2cid = 1021367 }}</ref> Other hormones appear to regulate the immune system as well, most notably [[prolactin]], [[growth hormone]] and [[vitamin D]].<ref>{{cite journal | vauthors = Dorshkind K, Horseman ND | title = The roles of prolactin, growth hormone, insulin-like growth factor-I, and thyroid hormones in lymphocyte development and function: insights from genetic models of hormone and hormone receptor deficiency | journal = Endocrine Reviews | volume = 21 | issue = 3 | pages = 292–312 | date = Jun 2000 | doi = 10.1210/edrv.21.3.0397 | pmid = 10857555 | doi-access = free }}</ref><ref>{{cite journal | vauthors = Nagpal S, Na S, Rathnachalam R | title = Noncalcemic actions of vitamin D receptor ligands | journal = Endocrine Reviews | volume = 26 | issue = 5 | pages = 662–87 | date = Aug 2005 | pmid = 15798098 | doi = 10.1210/er.2004-0002 | doi-access = free }}</ref>

===Vitamin D===
Although cellular studies indicate that vitamin D has receptors and probable functions in the immune system, there is no [[evidence-based medicine|clinical evidence]] to prove that [[vitamin D deficiency]] increases the risk for immune diseases or vitamin D [[dietary supplement|supplementation]] lowers immune disease risk.<ref name="ods">{{cite web |title=Vitamin D - Fact Sheet for Health Professionals |url=https://ods.od.nih.gov/factsheets/VitaminD-HealthProfessional/ |publisher=Office of Dietary Supplements, US National Institutes of Health |access-date=31 March 2022 |date=17 August 2021}}</ref> A 2011 United States [[Institute of Medicine]] report stated that "outcomes related to ... immune functioning and [[autoimmune disorder]]s, and infections ... could not be linked reliably with calcium or vitamin D intake and were often conflicting."<ref name="Ross_2011">{{cite book |author=Institute of Medicine |chapter=8, Implications and Special Concerns |chapter-url=https://www.ncbi.nlm.nih.gov/books/NBK56078/ |veditors=Ross AC, Taylor CL, Yaktine AL, Del Valle HB |title=Dietary Reference Intakes for Calcium and Vitamin D |publisher=National Academies Press |year=2011 |isbn=978-0-309-16394-1 |pmid=21796828 |doi=10.17226/13050 |url=https://www.ncbi.nlm.nih.gov/books/NBK56070/ |series=The National Academies Collection: Reports funded by the National Institutes of Health|s2cid=58721779 }}</ref>{{rp|5}}

=== 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>

===Physical exercise===
Physical exercise has a positive effect on the immune system and depending on the frequency and intensity, the pathogenic effects of diseases caused by bacteria and viruses are moderated.<ref name="pmid32728975">{{cite journal |vauthors=da Silveira MP, da Silva Fagundes KK, Bizuti MR, Starck É, Rossi RC, de Resende E, Silva DT |title=Physical exercise as a tool to help the immune system against COVID-19: an integrative review of the current literature |journal=Clinical and Experimental Medicine |volume=21 |issue=1 |pages=15–28 |date=February 2021 |pmid=32728975 |pmc=7387807 |doi=10.1007/s10238-020-00650-3}}</ref> Immediately after intense exercise there is a transient immunodepression, where the number of circulating lymphocytes decreases and antibody production declines. This may give rise to a window of opportunity for infection and reactivation of latent virus infections,<ref name="pmid27909225">{{cite journal |vauthors=Peake JM, Neubauer O, Walsh NP, Simpson RJ |title=Recovery of the immune system after exercise |journal=Journal of Applied Physiology |volume=122 |issue=5 |pages=1077–1087 |date=May 2017 |pmid=27909225 |doi=10.1152/japplphysiol.00622.2016|s2cid=3521624 |url=https://researchonline.ljmu.ac.uk/id/eprint/16304/3/Recovery%20of%20the%20immune%20system%20after%20exercise.pdf }}</ref> but the evidence is inconclusive.<ref name="pmid29713319">{{cite journal |vauthors=Campbell JP, Turner JE |title=Debunking the Myth of Exercise-Induced Immune Suppression: Redefining the Impact of Exercise on Immunological Health Across the Lifespan |journal=Frontiers in Immunology |volume=9 |issue= |pages=648 |date=2018 |pmid=29713319 |pmc=5911985 |doi=10.3389/fimmu.2018.00648|doi-access=free }}</ref><ref name="pmid32139352">{{cite journal |vauthors=Simpson RJ, Campbell JP, Gleeson M, Krüger K, Nieman DC, Pyne DB, Turner JE, Walsh NP |title=Can exercise affect immune function to increase susceptibility to infection? |journal=Exercise Immunology Review |volume=26 |issue= |pages=8–22 |date=2020 |pmid=32139352 |doi=}}</ref>

====Changes at the cellular level ====
[[File:Neutrophils.jpg|right|thumb|Four neutrophils in a [[Romanowsky stain|Giemsa-stained]] blood film]]

During exercise there is an increase in circulating [[leukocytes|white blood cells]] of all types. This is caused by the frictional force of blood flowing on the [[endothelial cell]] surface and [[catecholamine]]s affecting [[β-adrenergic receptor]]s (βARs).<ref name="pmid27909225"/> The number of [[neutrophils]] in the blood increases and remains raised for up to six hours and [[Left shift (medicine)|immature forms]] are present. Although the increase in neutrophils ("[[neutrophilia]]") is similar to that seen during bacterial infections, after exercise the cell population returns to normal by around 24 hours.<ref name="pmid27909225"/>

The number of circulating [[lymphocyte]]s (mainly [[natural killer cells]]) decreases during intense exercise but returns to normal after 4 to 6 hours. Although up to 2% of the cells [[apoptosis|die]] most migrate from the blood to the tissues, mainly the intestines and lungs, where [[pathogen]]s are most likely to be encountered.<ref name="pmid27909225"/>

Some [[monocyte]]s leave the blood circulation and migrate to the muscles where they differentiate and become [[macrophage]]s.<ref name="pmid27909225"/> These cells differentiate into two types: proliferative macrophages, which are responsible for increasing the number of [[Myogenesis|stem cell]]s and restorative macrophages, which are involved their maturing to muscle cells.<ref name="pmid34786967">{{cite journal |vauthors=Minari AL, Thomatieli-Santos RV |title=From skeletal muscle damage and regeneration to the hypertrophy induced by exercise: what is the role of different macrophage subsets? |journal=American Journal of Physiology. Regulatory, Integrative and Comparative Physiology |volume=322 |issue=1 |pages=R41–R54 |date=January 2022 |pmid=34786967 |doi=10.1152/ajpregu.00038.2021|s2cid=244369441 }}</ref>

=== Repair and regeneration ===
{{main|Immune system contribution to regeneration}}
The immune system, particularly the innate component, plays a decisive role in tissue repair after an [[Insult (medical)|insult]]. Key actors include [[macrophage]]s and [[neutrophil]]s, but other cellular actors, including [[Gamma delta T cell|γδ T cells]], [[innate lymphoid cell]]s (ILCs), and [[regulatory T cell]]s (Tregs), are also important. The plasticity of immune cells and the balance between pro-inflammatory and anti-inflammatory signals are crucial aspects of efficient tissue repair. Immune components and pathways are involved in regeneration as well, for example in [[amphibian]]s such as in [[Axolotl#Regeneration|axolotl limb regeneration]]. According to one hypothesis, organisms that can regenerate (''e.g.'', [[axolotl]]s) could be less immunocompetent than organisms that cannot regenerate.<ref>{{cite journal | vauthors = Godwin JW, Pinto AR, Rosenthal NA | title = Chasing the recipe for a pro-regenerative immune system | journal = Seminars in Cell & Developmental Biology | volume = 61 | pages = 71–79 | date = January 2017 | pmid = 27521522 | pmc = 5338634 | doi = 10.1016/j.semcdb.2016.08.008 | series = Innate immune pathways in wound healing/Peromyscus as a model system }}</ref>