Editing Immune system (section)

== Innate immune system ==
{{further|Innate immune system}}
Microorganisms or toxins that successfully enter an organism encounter the cells and mechanisms of the innate immune system. The innate response is usually triggered when microbes are identified by [[pattern recognition receptors]], which recognize components that are conserved among broad groups of microorganisms,<ref name="pmid17943118">{{cite journal | vauthors = Medzhitov R | title = Recognition of microorganisms and activation of the immune response | journal = Nature | volume = 449 | issue = 7164 | pages = 819–26 | date = Oct 2007 | pmid = 17943118 | doi = 10.1038/nature06246 | bibcode = 2007Natur.449..819M | s2cid = 4392839 | doi-access = free }}</ref> or when damaged, injured or stressed cells send out alarm signals, many of which are recognized by the same receptors as those that recognize pathogens.<ref name="pmid11951032">{{cite journal | vauthors = Matzinger P | s2cid = 13615808 | title = The danger model: a renewed sense of self | journal = Science | volume = 296 | issue = 5566 | pages = 301–05 | date = Apr 2002 | pmid = 11951032 | doi = 10.1126/science.1071059 | bibcode = 2002Sci...296..301M | url = http://www.scs.carleton.ca/~soma/biosec/readings/matzinger-science.pdf }}</ref> Innate immune defenses are non-specific, meaning these systems respond to pathogens in a generic way.{{sfn|Alberts|Johnson|Lewis|Raff|2002|loc= Chapter: [https://www.ncbi.nlm.nih.gov/books/NBK26846/ "Innate Immunity"] }} This system does not confer long-lasting [[immunity (medical)|immunity]] against a pathogen. The innate immune system is the dominant system of host defense in most organisms,<ref name="Litman" /> and the only one in plants.{{sfn | Iriti | 2019 | p=xi}}

===Immune sensing===
Cells in the innate immune system use [[pattern recognition receptor]]s to recognize molecular structures that are produced by pathogens.<ref name="Kumar_2011">{{cite journal | vauthors = Kumar H, Kawai T, Akira S | title = Pathogen recognition by the innate immune system | journal = International Reviews of Immunology | volume = 30 | issue = 1 | pages = 16–34 | date = February 2011 | pmid = 21235323 | doi = 10.3109/08830185.2010.529976 | s2cid = 42000671 }}</ref> They are [[protein]]s expressed, mainly, by cells of the [[innate immune system]], such as dendritic cells, macrophages, monocytes, neutrophils, and epithelial cells,{{sfn|Alberts|Johnson|Lewis|Raff|2002|loc= Chapter: [https://www.ncbi.nlm.nih.gov/books/NBK26846/ "Innate Immunity"] }}<ref>{{cite journal | vauthors = Schroder K, Tschopp J | s2cid = 16916572 | title = The inflammasomes | journal = Cell | volume = 140 | issue = 6 | pages = 821–32 | date = March 2010 | pmid = 20303873 | doi = 10.1016/j.cell.2010.01.040 | doi-access = free }}</ref> to identify two classes of molecules: [[pathogen-associated molecular patterns]] (PAMPs), which are associated with microbial [[pathogens]], and [[damage-associated molecular patterns]] (DAMPs), which are associated with components of host's cells that are released during cell damage or cell death.{{sfn | Sompayrac | 2019 | p=20}}

Recognition of extracellular or endosomal PAMPs is mediated by [[transmembrane protein]]s known as [[toll-like receptor]]s (TLRs).<ref name="pmid16551253">{{cite journal | vauthors = Beutler B, Jiang Z, Georgel P, Crozat K, Croker B, Rutschmann S, Du X, Hoebe K | s2cid = 20991617 | title = Genetic analysis of host resistance: Toll-like receptor signaling and immunity at large | journal = Annual Review of Immunology | volume = 24 | pages = 353–89 | year = 2006 | pmid = 16551253 | doi = 10.1146/annurev.immunol.24.021605.090552 }}</ref> TLRs share a typical structural motif, the [[Leucine-rich repeat|leucine rich repeats (LRRs)]], which give them a curved shape.<ref>{{cite journal | vauthors = Botos I, Segal DM, Davies DR | title = The structural biology of Toll-like receptors | journal = Structure | volume = 19 | issue = 4 | pages = 447–59 | date = April 2011 | pmid = 21481769 | pmc = 3075535 | doi = 10.1016/j.str.2011.02.004 }}</ref> Toll-like receptors were first discovered in ''[[Drosophila melanogaster|Drosophila]]'' and trigger the synthesis and secretion of [[cytokine]]s and activation of other host defense programs that are necessary for both innate or adaptive immune responses. Ten toll-like receptors have been described in humans.<ref>{{cite journal |vauthors=Vijay K |title=Toll-like receptors in immunity and inflammatory diseases: Past, present, and future |journal=Int Immunopharmacol |volume=59 |pages=391–412 |date=June 2018 |pmid=29730580 |pmc=7106078 |doi=10.1016/j.intimp.2018.03.002 }}</ref>

Cells in the innate immune system have pattern recognition receptors, which detect infection or cell damage, inside. Three major classes of these "cytosolic" receptors are [[NOD-like receptor|NOD–like receptors]], [[RIG-I-like receptor|RIG (retinoic acid-inducible gene)-like receptors]], and cytosolic DNA sensors.<ref>{{cite journal | vauthors = Thompson MR, Kaminski JJ, Kurt-Jones EA, Fitzgerald KA | title = Pattern recognition receptors and the innate immune response to viral infection | journal = Viruses | volume = 3 | issue = 6 | pages = 920–40 | date = June 2011 | pmid = 21994762 | pmc = 3186011 | doi = 10.3390/v3060920 | doi-access = free }}</ref>

=== Innate immune cells ===
[[File:SEM blood cells.jpg|thumb|right |alt=See caption |A [[scanning electron microscope]] image of normal circulating human [[blood]]. One can see [[red blood cell]]s, several knobby [[white blood cell]]s, including [[lymphocyte]]s, a [[monocyte]], and a [[neutrophil]], and many small disc-shaped [[platelet]]s.]]
Some [[leukocytes]] (white blood cells) act like independent, single-celled organisms and are the second arm of the innate immune system. The innate leukocytes include the [[phagocyte#Professional phagocytes|"professional" phagocytes]] ([[macrophage]]s, [[neutrophil]]s, and [[dendritic cell]]s). These cells identify and eliminate pathogens, either by attacking larger pathogens through contact or by engulfing and then killing microorganisms. The other cells involved in the innate response include [[innate lymphoid cell]]s, [[mast cell]]s, [[eosinophil granulocyte|eosinophils]], [[basophil granulocyte|basophils]], and [[natural killer cell]]s.{{sfn| Sompayrac |2019 |pp= 1–4}}

[[Phagocytosis]] is an important feature of cellular innate immunity performed by cells called phagocytes that engulf pathogens or particles. Phagocytes generally patrol the body searching for pathogens, but can be called to specific locations by cytokines.{{sfn|Alberts|Johnson|Lewis|Raff|2002|loc=sec. [https://www.ncbi.nlm.nih.gov/books/NBK26846/#A4686 "Phagocytic Cells Seek, Engulf, and Destroy Pathogens"]}} Once a pathogen has been engulfed by a phagocyte, it becomes trapped in an intracellular [[vesicle (biology)|vesicle]] called a [[phagosome]], which subsequently fuses with another vesicle called a [[lysosome]] to form a [[phagolysosome]]. The pathogen is killed by the activity of digestive enzymes or following a [[respiratory burst]] that releases [[radical (chemistry)|free radicals]] into the phagolysosome.<ref>{{cite journal | vauthors = Ryter A | title = Relationship between ultrastructure and specific functions of macrophages | journal = Comparative Immunology, Microbiology and Infectious Diseases | volume = 8 | issue = 2 | pages = 119–33 | year = 1985 | pmid = 3910340 | doi = 10.1016/0147-9571(85)90039-6 }}</ref><ref>{{cite journal | vauthors = Langermans JA, Hazenbos WL, van Furth R | title = Antimicrobial functions of mononuclear phagocytes | journal = Journal of Immunological Methods | volume = 174 | issue = 1–2 | pages = 185–94 | date = Sep 1994 | pmid = 8083520 | doi = 10.1016/0022-1759(94)90021-3 }}</ref> Phagocytosis evolved as a means of acquiring [[nutrient]]s, but this role was extended in phagocytes to include engulfment of pathogens as a defense mechanism.<ref>{{cite journal | vauthors = May RC, Machesky LM | title = Phagocytosis and the actin cytoskeleton | journal = Journal of Cell Science | volume = 114 | issue = Pt 6 | pages = 1061–77 | date = Mar 2001 | doi = 10.1242/jcs.114.6.1061 | pmid = 11228151 | url = http://jcs.biologists.org/cgi/pmidlookup?view=long&pmid=11228151 | access-date = 6 November 2009 | archive-date = 31 March 2020 | archive-url = https://web.archive.org/web/20200331165444/https://jcs.biologists.org/content/114/6/1061.long | url-status = dead | url-access = subscription }}</ref> Phagocytosis probably represents the oldest form of host defense, as phagocytes have been identified in both vertebrate and invertebrate animals.<ref>{{cite journal | vauthors = Salzet M, Tasiemski A, Cooper E | s2cid = 28520695 | title = Innate immunity in lophotrochozoans: the annelids | journal = Current Pharmaceutical Design | volume = 12 | issue = 24 | pages = 3043–50 | year = 2006 | pmid = 16918433 | doi = 10.2174/138161206777947551 | url = https://pdfs.semanticscholar.org/da11/601b7ba0121f210136e0317729e3f367dd8c.pdf | archive-url = https://web.archive.org/web/20200331165454/https://pdfs.semanticscholar.org/da11/601b7ba0121f210136e0317729e3f367dd8c.pdf | url-status = dead | archive-date = 2020-03-31 }}</ref>

Neutrophils and macrophages are phagocytes that travel throughout the body in pursuit of invading pathogens.<ref>{{cite journal | vauthors = Zen K, Parkos CA | title = Leukocyte-epithelial interactions | journal = Current Opinion in Cell Biology | volume = 15 | issue = 5 | pages = 557–64 | date = Oct 2003 | pmid = 14519390 | doi = 10.1016/S0955-0674(03)00103-0 }}</ref> Neutrophils are normally found in the [[circulatory system|bloodstream]] and are the most abundant type of phagocyte, representing 50% to 60% of total circulating leukocytes.{{sfn|Stvrtinová | Jakubovský | Hulín |1995 |loc= Chapter: [https://web.archive.org/web/20010711220523/http://nic.savba.sk/logos/books/scientific/Inffever.html Inflammation and Fever]}} During the acute phase of [[inflammation]], neutrophils migrate toward the site of inflammation in a process called [[chemotaxis]] and are usually the first cells to arrive at the scene of infection. Macrophages are versatile cells that reside within tissues and produce an array of chemicals including enzymes, [[complement system|complement proteins]], and cytokines. They can also act as scavengers that rid the body of worn-out cells and other debris and as [[antigen-presenting cell]]s (APCs) that activate the adaptive immune system.<ref name="Rua_2015">{{cite journal | vauthors = Rua R, McGavern DB | title = Elucidation of monocyte/macrophage dynamics and function by intravital imaging | journal = Journal of Leukocyte Biology | volume = 98 | issue = 3 | pages = 319–32 | date = September 2015 | pmid = 26162402 | doi = 10.1189/jlb.4RI0115-006RR | pmc=4763596}}</ref>

Dendritic cells are phagocytes in tissues that are in contact with the external environment; therefore, they are located mainly in the skin, nose, lungs, stomach, and intestines.<ref name=Guermonprez>{{cite journal | vauthors = Guermonprez P, Valladeau J, Zitvogel L, Théry C, Amigorena S | title = Antigen presentation and T cell stimulation by dendritic cells | journal = Annual Review of Immunology | volume = 20 | issue = 1 | pages = 621–67 | year = 2002 | pmid = 11861614 | doi = 10.1146/annurev.immunol.20.100301.064828 }}</ref> They are named for their resemblance to [[neuron]]al [[dendrite]]s, as both have many spine-like projections. Dendritic cells serve as a link between the bodily tissues and the innate and adaptive immune systems, as they [[antigen presentation|present antigens]] to [[T cell]]s, one of the key cell types of the adaptive immune system.<ref name=Guermonprez />

[[Granulocyte]]s are leukocytes that have granules in their cytoplasm. In this category are neutrophils, mast cells, basophils, and eosinophils. Mast cells reside in [[connective tissue]]s and [[mucous membrane]]s and regulate the inflammatory response.{{sfn| Krishnaswamy | Ajitawi | Chi | 2006 | pp = 13–34}} They are most often associated with [[allergy]] and [[anaphylaxis]].{{sfn|Stvrtinová | Jakubovský | Hulín |1995 |loc= Chapter: [https://web.archive.org/web/20010711220523/http://nic.savba.sk/logos/books/scientific/Inffever.html   Inflammation and Fever]}} [[Basophil]]s and [[eosinophil]]s are related to neutrophils. They secrete chemical mediators that are involved in defending against [[parasitism|parasites]] and play a role in allergic reactions, such as [[asthma]].<ref>{{cite journal | vauthors = Kariyawasam HH, Robinson DS | title = The eosinophil: the cell and its weapons, the cytokines, its locations | journal = Seminars in Respiratory and Critical Care Medicine | volume = 27 | issue = 2 | pages = 117–27 | date = Apr 2006 | pmid = 16612762 | doi = 10.1055/s-2006-939514 | s2cid = 260317790 }}</ref>

Innate lymphoid cells (ILCs) are a group of [[Innate immune system|innate immune]] cells that are derived from [[common lymphoid progenitor]] and belong to the [[Lymphopoiesis|lymphoid lineage]]. These cells are defined by the absence of antigen-specific [[B-cell receptor|B-]] or [[T-cell receptor]] (TCR) because of the lack of [[recombination activating gene]]. ILCs do not express myeloid or dendritic cell markers.<ref>{{cite journal | vauthors = Spits H, Cupedo T | title = Innate lymphoid cells: emerging insights in development, lineage relationships, and function | journal = Annual Review of Immunology | volume = 30 | pages = 647–75 | year = 2012 | pmid = 22224763 | doi = 10.1146/annurev-immunol-020711-075053 }}</ref>

[[Natural killer cells]] (NK cells) are lymphocytes and a component of the innate immune system that does not directly attack invading microbes.<ref name="pmid28078307">{{cite journal |vauthors=Gabrielli S, Ortolani C, Del Zotto G, Luchetti F, Canonico B, Buccella F, Artico M, Papa S, Zamai L |title=The Memories of NK Cells: Innate-Adaptive Immune Intrinsic Crosstalk |journal=Journal of Immunology Research |volume=2016 |pages=1376595 |year=2016 |pmid=28078307 |pmc=5204097 |doi=10.1155/2016/1376595 |doi-access=free }}</ref> Rather, NK cells destroy compromised host cells, such as tumor cells or virus-infected cells, recognizing such cells by a condition known as "missing self". This term describes cells with low levels of a cell-surface marker called MHC I ([[major histocompatibility complex]])—a situation that can arise in viral infections of host cells.{{sfn|Bertok|Chow|2005|p= [https://books.google.com/books?id=DW3V2Uc-m8EC&q=%22missing+self%22+immunity+immune&pg=PA17 17]}} Normal body cells are not recognized and attacked by NK cells because they express intact self MHC antigens. Those MHC antigens are recognized by killer cell immunoglobulin receptors, which essentially put the brakes on NK cells.{{sfn| Rajalingam |2012|loc= Chapter: Overview of the killer cell immunoglobulin-like receptor system}}

=== Inflammation ===
{{further|Inflammation}}
Inflammation is one of the first responses of the immune system to infection.<ref name=autogenerated2>{{cite journal | vauthors = Kawai T, Akira S | title = Innate immune recognition of viral infection | journal = Nature Immunology | volume = 7 | issue = 2 | pages = 131–37 | date = Feb 2006 | pmid = 16424890 | doi = 10.1038/ni1303 | s2cid = 9567407 | doi-access = free }}</ref> The symptoms of inflammation are redness, swelling, heat, and pain, which are caused by increased blood flow into tissue. Inflammation is produced by [[eicosanoid]]s and [[cytokine]]s, which are released by injured or infected cells. Eicosanoids include [[prostaglandin]]s that produce [[fever]] and the [[vasodilator|dilation]] of [[blood vessel]]s associated with inflammation and [[leukotriene]]s that attract certain [[white blood cell]]s (leukocytes).<ref name=autogenerated4>{{cite journal | vauthors = Miller SB | title = Prostaglandins in health and disease: an overview | journal = Seminars in Arthritis and Rheumatism | volume = 36 | issue = 1 | pages = 37–49 | date = Aug 2006 | pmid = 16887467 | doi = 10.1016/j.semarthrit.2006.03.005 }}</ref><ref name=autogenerated1>{{cite journal | vauthors = Ogawa Y, Calhoun WJ | title = The role of leukotrienes in airway inflammation | journal = The Journal of Allergy and Clinical Immunology | volume = 118 | issue = 4 | pages = 789–98; quiz 799–800 | date = Oct 2006 | pmid = 17030228 | doi = 10.1016/j.jaci.2006.08.009 | doi-access = free }}</ref> Common cytokines include [[interleukin]]s that are responsible for communication between white blood cells; [[chemokine]]s that promote [[chemotaxis]]; and [[interferon]]s that have [[Antiviral drug|antiviral]] effects, such as shutting down [[protein biosynthesis|protein synthesis]] in the host cell.<ref name=autogenerated3>{{cite journal | vauthors = Le Y, Zhou Y, Iribarren P, Wang J | title = Chemokines and chemokine receptors: their manifold roles in homeostasis and disease | journal = Cellular & Molecular Immunology | volume = 1 | issue = 2 | pages = 95–104 | date = Apr 2004 | pmid = 16212895 | url = http://www.cmi.ustc.edu.cn/1/2/95.pdf }}</ref> [[Growth factor]]s and cytotoxic factors may also be released. These cytokines and other chemicals recruit immune cells to the site of infection and promote the healing of any damaged tissue following the removal of pathogens.<ref name=autogenerated5>{{cite journal | vauthors = Martin P, Leibovich SJ | title = Inflammatory cells during wound repair: the good, the bad and the ugly | journal = Trends in Cell Biology | volume = 15 | issue = 11 | pages = 599–607 | date = Nov 2005 | pmid = 16202600 | doi = 10.1016/j.tcb.2005.09.002 }}</ref> The pattern-recognition receptors called [[inflammasome]]s are multiprotein complexes (consisting of an NLR, the adaptor protein ASC, and the effector molecule pro-caspase-1) that form in response to cytosolic PAMPs and DAMPs, whose function is to generate active forms of the inflammatory cytokines IL-1β and IL-18.<ref>{{cite journal | vauthors = Platnich JM, Muruve DA | title = NOD-like receptors and inflammasomes: A review of their canonical and non-canonical signaling pathways | journal = Archives of Biochemistry and Biophysics | volume = 670 | pages = 4–14 | date = February 2019 | pmid = 30772258 | doi = 10.1016/j.abb.2019.02.008 | s2cid = 73464235 }}</ref>

=== Humoral defenses ===
The complement system is a [[biochemical cascade]] that attacks the surfaces of foreign cells. It contains over 20 different proteins and is named for its ability to "complement" the killing of pathogens by [[antibody|antibodies]]. Complement is the major humoral component of the innate immune response.<ref name=Rus>{{cite journal | vauthors = Rus H, Cudrici C, Niculescu F | title = The role of the complement system in innate immunity | journal = Immunologic Research | volume = 33 | issue = 2 | pages = 103–12 | year = 2005 | pmid = 16234578 | doi = 10.1385/IR:33:2:103 | s2cid = 46096567 }}</ref><ref name=Degn_2013>{{cite journal | vauthors = Degn SE, Thiel S | title = Humoral pattern recognition and the complement system | journal = Scandinavian Journal of Immunology | volume = 78 | issue = 2 | pages = 181–93 | date = August 2013 | pmid = 23672641 | doi = 10.1111/sji.12070 | doi-access = free }}</ref> Many species have complement systems, including non-[[mammal]]s like plants, fish, and some [[invertebrate]]s.{{sfn|Bertok|Chow|2005|pp= [https://books.google.com/books?id=DW3V2Uc-m8EC&q=%22complement+system%22&pg=PA17 112–113]}} In humans, this response is activated by complement binding to antibodies that have attached to these microbes or the binding of complement proteins to [[carbohydrate]]s on the surfaces of [[microbe]]s. This recognition [[cell signaling|signal]] triggers a rapid killing response.<ref>{{cite book | vauthors = Liszewski MK, Farries TC, Lublin DM, Rooney IA, Atkinson JP | title = Control of the Complement System | volume = 61 | pages = 201–283 | year = 1996 | pmid = 8834497 | doi = 10.1016/S0065-2776(08)60868-8 | isbn = 978-0-12-022461-6 | series = Advances in Immunology | url-access = registration | url = https://archive.org/details/advancesinimmuno61dixo/page/201 }}</ref> The speed of the response is a result of signal amplification that occurs after sequential [[proteolysis|proteolytic]] activation of complement molecules, which are also proteases. After complement proteins initially bind to the microbe, they activate their protease activity, which in turn activates other complement proteases, and so on. This produces a [[catalysis|catalytic]] cascade that amplifies the initial signal by controlled [[positive feedback]].<ref>{{cite journal | vauthors = Sim RB, Tsiftsoglou SA | s2cid = 24505041 | title = Proteases of the complement system | journal = Biochemical Society Transactions | volume = 32 | issue = Pt 1 | pages = 21–27 | date = Feb 2004 | pmid = 14748705 | doi = 10.1042/BST0320021 | url = http://pdfs.semanticscholar.org/9df4/e40fdcd4e1ba21a7047dca82ddf683c11d61.pdf | archive-url = https://web.archive.org/web/20190302045456/http://pdfs.semanticscholar.org/9df4/e40fdcd4e1ba21a7047dca82ddf683c11d61.pdf | url-status = dead | archive-date = 2019-03-02 }}</ref> The cascade results in the production of peptides that attract immune cells, increase [[vascular permeability]], and [[opsonin|opsonize]] (coat) the surface of a pathogen, marking it for destruction. This deposition of complement can also kill cells directly by disrupting their [[cell membrane|plasma membrane]] via the formation of a [[Complement membrane attack complex|membrane attack complex]].<ref name=Rus />