View source for Immune system

{{Short description|Biological system protecting an organism against disease}}
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{{Use dmy dates|date=November 2020}}
{{Infobox anatomy|
| Name          = Immune system
| Image         = Neutrophil with anthrax copy.jpg
| Caption       = A [[scanning electron microscope]] image of a single [[neutrophil]] (yellow/right), engulfing [[Bacillus anthracis|anthrax bacteria]] (orange/left) – scale bar is 5 μm (false color)
}}
The '''immune system''' is a network of [[biological systems]] that protects an [[organism]] from [[diseases]]. It detects and responds to a wide variety of [[pathogen]]s, such as [[virus]]es, [[bacteria]], and [[Parasitism|parasites]], as well as [[Tumor immunology|cancer cells]] and objects, such as wood [[splinter]]s—distinguishing them from the organism's own healthy [[biological tissue|tissue]]. Many species have two major subsystems of the immune system. The [[innate immune system]] provides a preconfigured response to broad groups of situations and stimuli. The [[adaptive immune system]] provides a tailored response to each stimulus by learning to recognize molecules it has previously encountered. Both use [[humoral immunity|molecules]] and [[cell-mediated immunity|cells]] to perform their functions.

Nearly all organisms have some kind of immune system. [[Bacteria]] have a rudimentary immune system in the form of [[enzyme]]s that protect against [[bacteriophage|viral]] infections. Other basic immune mechanisms evolved in ancient [[eukaryote|plants and animals]] and remain in their modern descendants. These mechanisms include [[phagocytosis]], [[antimicrobial peptides]] called [[defensin]]s, and the [[complement system]]. [[Jawed vertebrate]]s, including humans, have even more sophisticated defense mechanisms, including the ability to adapt to recognize pathogens more efficiently. Adaptive (or acquired) immunity creates an [[immunological memory]] leading to an enhanced response to subsequent encounters with that same pathogen. This process of acquired immunity is the basis of [[vaccination]].

Dysfunction of the immune system can cause [[autoimmune disease]]s, [[Inflammation|inflammatory diseases]] and [[Carcinogenesis|cancer]]. [[Immunodeficiency]] occurs when the immune system is less active than normal, resulting in recurring and life-threatening infections. In humans, immunodeficiency can be the result of a [[genetic disease]] such as [[severe combined immunodeficiency]], acquired conditions such as [[HIV]]/[[AIDS]], or the use of [[immunosuppressive drugs|immunosuppressive medication]]. [[Autoimmunity]] results from a hyperactive immune system attacking normal tissues as if they were foreign organisms. Common autoimmune diseases include [[Hashimoto's thyroiditis]], [[rheumatoid arthritis]], [[diabetes mellitus type 1]], and [[systemic lupus erythematosus]]. [[Immunology]] covers the study of all aspects of the immune system.

== Layered defense ==
The immune system protects its host from [[infection]] with layered defenses of increasing specificity. Physical barriers prevent pathogens such as [[bacteria]] and [[virus]]es from entering the organism.{{sfn | Sompayrac | 2019 | p=1}} If a pathogen breaches these barriers, the [[innate immune system]] provides an immediate, but non-specific response. Innate immune systems are found in all [[animal]]s.<ref name=Litman>{{cite journal | vauthors = Litman GW, Cannon JP, Dishaw LJ | title = Reconstructing immune phylogeny: new perspectives | journal = Nature Reviews. Immunology | volume = 5 | issue = 11 | pages = 866–79 | date = Nov 2005 | pmid = 16261174 | pmc = 3683834 | doi = 10.1038/nri1712 }}</ref> If pathogens successfully evade the innate response, vertebrates possess a second layer of protection, the [[adaptive immune system]], which is activated by the innate response.{{sfn | Sompayrac | 2019 | p=4}} Here, the immune system adapts its response during an infection to improve its recognition of the pathogen. This improved response is then retained after the pathogen has been eliminated, in the form of an [[immunological memory]], and allows the adaptive immune system to mount faster and stronger attacks each time this pathogen is encountered.<ref name="Restifo_2013">{{cite journal | vauthors = Restifo NP, Gattinoni L | title = Lineage relationship of effector and memory T cells | journal = Current Opinion in Immunology | volume = 25 | issue = 5 | pages = 556–63 | date = October 2013 | pmid = 24148236 | doi = 10.1016/j.coi.2013.09.003 | pmc=3858177}}</ref><ref name="Kurosaki_2015">{{cite journal | vauthors = Kurosaki T, Kometani K, Ise W | title = Memory B cells | journal = Nature Reviews. Immunology | volume = 15 | issue = 3 | pages = 149–59 | date = March 2015 | pmid = 25677494 | doi = 10.1038/nri3802 | s2cid = 20825732 }}</ref>

{| class="wikitable center" style="margin: 1em auto;"
|+ '''Components of the immune system'''
! scope="col" style="background:#ccccff;" | [[#Innate immune system|Innate immune system]]
! scope="col" style="background:#ccccff;" | [[#Adaptive immune system|Adaptive immune system]]
|-
| Response is non-specific || Pathogen and [[antigen]] specific response
|-
| Exposure leads to immediate maximal response|| Lag time between exposure and maximal response
|-
| [[Cell-mediated immunity|Cell-mediated]] and [[Humoral immune response|humoral]] components|| [[Cell-mediated immunity|Cell-mediated]] and [[Humoral immune response|humoral]] components
|-
| No immunological memory || Exposure leads to immunological memory
|-
| Found in nearly all forms of life||Found only in [[Gnathostomata|jawed vertebrates]]
|}

Both innate and adaptive immunity depend on the ability of the immune system to distinguish between self and non-self [[molecule]]s. In immunology, ''self'' molecules are components of an organism's body that can be distinguished from foreign substances by the immune system.{{sfn | Sompayrac | 2019 | p=11}} Conversely, ''non-self'' molecules are those recognized as foreign molecules. One class of non-self molecules are called antigens (originally named for being ''anti''body ''gen''erators) and are defined as substances that bind to specific [[immune receptor]]s and elicit an immune response.{{sfn | Sompayrac | 2019 | p=146}}

== Surface barriers ==
Several barriers protect organisms from infection, including mechanical, chemical, and biological barriers. The waxy [[plant cuticle|cuticle]] of most leaves, the [[exoskeleton]] of insects, the [[eggshell|shells]] and membranes of externally deposited eggs, and [[skin]] are examples of mechanical barriers that are the first line of defense against infection.{{sfn|Alberts|Johnson|Lewis|Raff|2002|loc= sec. [https://www.ncbi.nlm.nih.gov/books/NBK26833/#A4639 "Pathogens Cross Protective Barriers to Colonize the Host"]}} Organisms cannot be completely sealed from their environments, so systems act to protect body openings such as the [[lung]]s, [[intestine]]s, and the [[genitourinary system|genitourinary tract]]. In the lungs, coughing and sneezing mechanically eject pathogens and other [[irritation|irritants]] from the [[respiratory tract]]. The flushing action of [[tears]] and [[urine]] also mechanically expels pathogens, while [[mucus]] secreted by the respiratory and [[gastrointestinal tract]] serves to trap and entangle [[microorganism]]s.<ref>{{cite journal | vauthors = Boyton RJ, Openshaw PJ | title = Pulmonary defences to acute respiratory infection | journal = British Medical Bulletin | volume = 61 | issue = 1 | pages = 1–12 | year = 2002 | pmid = 11997295 | doi = 10.1093/bmb/61.1.1 | doi-access = free }}</ref>

Chemical barriers also protect against infection. The skin and respiratory tract secrete [[antimicrobial peptides]] such as the β-[[defensin]]s.<ref>{{cite book | vauthors = Agerberth B, Gudmundsson GH | title = Antimicrobial Peptides and Human Disease | chapter = Host antimicrobial defence peptides in human disease | volume = 306 | pages = 67–90 | year = 2006 | pmid = 16909918 | doi = 10.1007/3-540-29916-5_3 | isbn = 978-3-540-29915-8 | series = Current Topics in Microbiology and Immunology }}</ref> [[Enzyme]]s such as [[lysozyme]] and [[phospholipase A2]] in [[saliva]], tears, and [[breast milk]] are also [[antiseptic|antibacterials]].<ref>{{cite journal|vauthors=Moreau JM, Girgis DO, Hume EB, Dajcs JJ, Austin MS, O'Callaghan RJ |title=Phospholipase A(2) in rabbit tears: a host defense against Staphylococcus aureus |journal=Investigative Ophthalmology & Visual Science |volume=42 |issue=10 |pages=2347–54 |date=Sep 2001 |pmid=11527949 |url=http://iovs.arvojournals.org/article.aspx?articleid=2200058}}</ref><ref>{{cite journal | vauthors = Hankiewicz J, Swierczek E | title = Lysozyme in human body fluids | journal = Clinica Chimica Acta; International Journal of Clinical Chemistry | volume = 57 | issue = 3 | pages = 205–09 | date = Dec 1974 | pmid = 4434640 | doi = 10.1016/0009-8981(74)90398-2 }}</ref> [[Vagina]]l secretions serve as a chemical barrier following [[menarche]], when they become slightly [[acid]]ic, while [[semen]] contains defensins and [[zinc]] to kill pathogens.<ref>{{cite journal | vauthors = Fair WR, Couch J, Wehner N | title = Prostatic antibacterial factor. Identity and significance | journal = Urology | volume = 7 | issue = 2 | pages = 169–77 | date = Feb 1976 | pmid = 54972 | doi = 10.1016/0090-4295(76)90305-8 }}</ref><ref>{{cite journal | vauthors = Yenugu S, Hamil KG, Birse CE, Ruben SM, French FS, Hall SH | title = Antibacterial properties of the sperm-binding proteins and peptides of human epididymis 2 (HE2) family; salt sensitivity, structural dependence and their interaction with outer and cytoplasmic membranes of Escherichia coli | journal = The Biochemical Journal | volume = 372 | issue = Pt 2 | pages = 473–83 | date = Jun 2003 | pmid = 12628001 | pmc = 1223422 | doi = 10.1042/BJ20030225 }}</ref> In the [[stomach]], [[gastric acid]] serves as a chemical defense against ingested pathogens.<ref>{{cite journal|vauthors=Smith JL|year=2003|title=The role of gastric acid in preventing foodborne disease and how bacteria overcome acid conditions|journal=J Food Prot|volume=66|issue=7|pages=1292–1303|pmid=12870767|doi=10.4315/0362-028X-66.7.1292|doi-access=free}}</ref>

Within the genitourinary and gastrointestinal tracts, [[commensalism|commensal]] [[gut flora|flora]] serve as biological barriers by competing with pathogenic bacteria for food and space and, in some cases, changing the conditions in their environment, such as [[pH]] or available iron. As a result, the probability that pathogens will reach sufficient numbers to cause illness is reduced.<ref>{{cite journal | vauthors = [[Sherwood Gorbach|Gorbach SL]] | title = Lactic acid bacteria and human health | journal = Annals of Medicine | volume = 22 | issue = 1 | pages = 37–41 | date = Feb 1990 | pmid = 2109988 | doi = 10.3109/07853899009147239 }}</ref>

== 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 hosts' cells that are released during cell damage or cell death.{{sfn | Sompayrac | 2019 | p=20}} Cells in the innate immune system have pattern recognition receptors that detect internal infection or cell damage. 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 |date=June 2011 |title=Pattern recognition receptors and the innate immune response to viral infection |journal=Viruses |volume=3 |issue=6 |pages=920–40 |doi=10.3390/v3060920 |pmc=3186011 |pmid=21994762 |doi-access=free}}</ref>

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>

=== 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-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 | 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 |article-number=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 | 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 />

== Adaptive immune system ==
{{further|Adaptive immune system}}
[[File:Primary immune response 1.png|thumb|upright=1.5 |alt=diagram showing the processes of activation, cell destruction and digestion, antibody production and proliferation, and response memory |Overview of the processes involved in the primary immune response]]
The adaptive immune system evolved in early vertebrates and allows for a stronger immune response as well as [[immunological memory]], where each pathogen is "remembered" by a signature antigen.<ref>{{cite journal | vauthors = Pancer Z, Cooper MD | title = The evolution of adaptive immunity | journal = Annual Review of Immunology | volume = 24 | issue = 1 | pages = 497–518 | year = 2006 | pmid = 16551257 | doi = 10.1146/annurev.immunol.24.021605.090542 }}</ref> The adaptive immune response is antigen-specific and requires the recognition of specific "non-self" antigens during a process called [[antigen presentation]]. Antigen specificity allows for the generation of responses that are tailored to specific pathogens or pathogen-infected cells. The ability to mount these tailored responses is maintained in the body by "memory cells". Should a pathogen infect the body more than once, these specific memory cells are used to quickly eliminate it.{{sfn | Sompayrac | 2019 | p=38}}

===Recognition of antigen===
The cells of the adaptive immune system are special types of leukocytes, called lymphocytes. [[B cell]]s and T cells are the major types of lymphocytes and are derived from [[hematopoietic stem cell]]s in the [[bone marrow]].{{sfn| Janeway |2005 |p=}} B cells are involved in the [[humoral immunity|humoral immune response]], whereas T cells are involved in [[cell-mediated immunity|cell-mediated immune response]]. Killer T cells only recognize antigens coupled to [[Major histocompatibility complex#MHC class I|Class I MHC]] molecules, while helper T cells and regulatory T cells only recognize antigens coupled to [[Major histocompatibility complex#MHC class II|Class II MHC]] molecules. These two mechanisms of antigen presentation reflect the different roles of the two types of T cell. A third, minor subtype are the [[gamma/delta T cells|γδ T cells]] that recognize intact antigens that are not bound to MHC receptors.<ref name="Holtmeier W, Kabelitz D 2005 151–83">{{cite journal | vauthors = Holtmeier W, Kabelitz D | title = gammadelta T cells link innate and adaptive immune responses | volume = 86 | pages = 151–83 | year = 2005 | pmid = 15976493 | doi = 10.1159/000086659 | isbn = 3-8055-7862-8 | journal = Chemical Immunology and Allergy }}</ref> The double-positive T cells are exposed to a wide variety of [[Self-protein|self-antigens]] in the [[thymus]], in which [[iodine]] is necessary for its thymus development and activity.<ref name="pmid19647627">{{cite journal | vauthors = Venturi S, Venturi M | title = Iodine, thymus, and immunity | journal = Nutrition | volume = 25 | issue = 9 | pages = 977–79 | date = September 2009 | pmid = 19647627 | doi = 10.1016/j.nut.2009.06.002 }}</ref> In contrast, the B cell antigen-specific receptor is an antibody molecule on the B cell surface and recognizes native (unprocessed) antigen without any need for [[antigen processing]]. Such antigens may be large molecules found on the surfaces of pathogens, but can also be small [[hapten]]s (such as penicillin) attached to carrier molecule.{{sfn|Janeway|Travers|Walport|2001|loc= sec. [https://www.ncbi.nlm.nih.gov/books/NBK27112/#A1746 12-10]}} Each lineage of B cell expresses a different antibody, so the complete set of B cell antigen receptors represent all the antibodies that the body can manufacture.{{sfn| Janeway |2005 |p=}} When B or T cells encounter their related antigens they multiply and many "clones" of the cells are produced that target the same antigen. This is called [[clonal selection]].{{sfn | Sompayrac | 2019 | pp= 5–6}}

===Antigen presentation to T lymphocytes===
Both B cells and T cells carry receptor molecules that recognize specific targets. T cells recognize a "non-self" target, such as a pathogen, only after antigens (small fragments of the pathogen) have been processed and presented in combination with a "self" receptor called a major histocompatibility complex (MHC) molecule.{{sfn | Sompayrac | 2019 | pp=51–53}}

===Cell mediated immunity===
{{Further|Cell-mediated immunity}}
There are two major subtypes of T cells: the [[cytotoxic T cell|killer T cell]] and the [[T helper cell|helper T cell]]. In addition there are [[regulatory T cells]] which have a role in modulating immune response.{{sfn | Sompayrac | 2019 | pp=7–8}}

==== Killer T cells ====
[[Killer T cells]] are a sub-group of T cells that kill cells that are infected with viruses (and other pathogens), or are otherwise damaged or dysfunctional.<ref>{{cite journal | vauthors = Harty JT, Tvinnereim AR, White DW | title = CD8+ T cell effector mechanisms in resistance to infection | journal = Annual Review of Immunology | volume = 18 | issue = 1 | pages = 275–308 | year = 2000 | pmid = 10837060 | doi = 10.1146/annurev.immunol.18.1.275 }}</ref> As with B cells, each type of T cell recognizes a different antigen. Killer T cells are activated when their [[T-cell receptor]] binds to this specific antigen in a complex with the MHC Class I receptor of another cell. Recognition of this MHC:antigen complex is aided by a [[co-receptor]] on the T cell, called [[CD8]]. The T cell then travels throughout the body in search of cells where the MHC I receptors bear this antigen. When an activated T cell contacts such cells, it releases [[cytotoxicity|cytotoxins]], such as [[perforin]], which form pores in the target cell's [[cell membrane|plasma membrane]], allowing [[ion]]s, water and toxins to enter. The entry of another toxin called [[granulysin]] (a protease) induces the target cell to undergo [[apoptosis]].<ref name=Radoja>{{cite journal | vauthors = Radoja S, Frey AB, Vukmanovic S | title = T-cell receptor signaling events triggering granule exocytosis | journal = [[Critical Reviews in Immunology]] | volume = 26 | issue = 3 | pages = 265–90 | year = 2006 | pmid = 16928189 | doi = 10.1615/CritRevImmunol.v26.i3.40 }}</ref> T cell killing of host cells is particularly important in preventing the replication of viruses. T cell activation is tightly controlled and generally requires a very strong MHC/antigen activation signal, or additional activation signals provided by "helper" T cells (see below).<ref name=Radoja />

==== Helper T cells ====
[[File:Activation of T and B cells.png|thumb|right|400px|Activation of macrophage or B cell by T helper cell]]
[[T helper cell|Helper T cells]] regulate both the innate and adaptive immune responses and help determine which immune responses the body makes to a particular pathogen.<ref>{{cite journal | vauthors = Abbas AK, Murphy KM, Sher A | title = Functional diversity of helper T lymphocytes | journal = Nature | volume = 383 | issue = 6603 | pages = 787–93 | date = Oct 1996 | pmid = 8893001 | doi = 10.1038/383787a0 | bibcode = 1996Natur.383..787A | s2cid = 4319699 }}</ref><ref>{{cite book | vauthors = McHeyzer-Williams LJ, Malherbe LP, McHeyzer-Williams MG | title = From Innate Immunity to Immunological Memory | chapter = Helper T cell-regulated B cell immunity | volume = 311 | pages = 59–83 | year = 2006 | pmid = 17048705 | doi = 10.1007/3-540-32636-7_3 | isbn = 978-3-540-32635-9 | series = Current Topics in Microbiology and Immunology }}</ref> These cells have no cytotoxic activity and do not kill infected cells or clear pathogens directly. They instead control the immune response by directing other cells to perform these tasks.{{sfn | Sompayrac | 2019 | p=8}}

Helper T cells express T cell receptors that recognize antigen bound to Class II MHC molecules. The MHC:antigen complex is also recognized by the helper cell's [[CD4]] co-receptor, which recruits molecules inside the T cell (such as [[Lck]]) that are responsible for the T cell's activation. Helper T cells have a weaker association with the MHC:antigen complex than observed for killer T cells, meaning many receptors (around 200–300) on the helper T cell must be bound by an MHC:antigen to activate the helper cell, while killer T cells can be activated by engagement of a single MHC:antigen molecule. Helper T cell activation also requires longer duration of engagement with an antigen-presenting cell.<ref>{{cite journal | vauthors = Kovacs B, Maus MV, Riley JL, Derimanov GS, Koretzky GA, June CH, Finkel TH | title = Human CD8+ T cells do not require the polarization of lipid rafts for activation and proliferation | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 99 | issue = 23 | pages = 15006–11 | date = Nov 2002 | pmid = 12419850 | pmc = 137535 | doi = 10.1073/pnas.232058599 | bibcode = 2002PNAS...9915006K | doi-access = free }}</ref> The activation of a resting helper T cell causes it to release cytokines that influence the activity of many cell types. Cytokine signals produced by helper T cells enhance the microbicidal function of macrophages and the activity of killer T cells.{{sfn|Alberts|Johnson|Lewis|Raff|2002|loc=Chapter. [https://www.ncbi.nlm.nih.gov/books/NBK26827/ "Helper T Cells and Lymphocyte Activation"]}} In addition, helper T cell activation causes an upregulation of molecules expressed on the T cell's surface, such as CD40 ligand (also called [[CD154]]), which provide extra stimulatory signals typically required to activate antibody-producing B cells.<ref>{{cite journal | vauthors = Grewal IS, Flavell RA | title = CD40 and CD154 in cell-mediated immunity | journal = Annual Review of Immunology | volume = 16 | issue = 1 | pages = 111–35 | year = 1998 | pmid = 9597126 | doi = 10.1146/annurev.immunol.16.1.111 }}</ref>

==== Gamma delta T cells ====
[[Gamma delta T cell]]s (γδ T cells) possess an alternative T-cell receptor (TCR) as opposed to CD4+ and CD8+ (αβ) T cells and share the characteristics of helper T cells, cytotoxic T cells and NK cells. The conditions that produce responses from γδ T cells are not fully understood. Like other 'unconventional' T cell subsets bearing invariant TCRs, such as [[CD1d receptor|CD1d]]-restricted [[natural killer T cell]]s, γδ T cells straddle the border between innate and adaptive immunity.<ref>{{cite journal | vauthors = Girardi M | title = Immunosurveillance and immunoregulation by gammadelta T cells | journal = The Journal of Investigative Dermatology | volume = 126 | issue = 1 | pages = 25–31 | date = Jan 2006 | pmid = 16417214 | doi = 10.1038/sj.jid.5700003 | doi-access = free }}</ref> On one hand, γδ T cells are a component of adaptive immunity as they [[V(D)J recombination|rearrange TCR genes]] to produce receptor diversity and can also develop a memory phenotype. On the other hand, the various subsets are also part of the innate immune system, as restricted TCR or NK receptors may be used as [[pattern recognition receptor]]s. For example, large numbers of human Vγ9/Vδ2 T cells respond within hours to [[non-peptidic antigen|common molecules]] produced by microbes, and highly restricted Vδ1+ T cells in [[epithelium|epithelia]] respond to stressed epithelial cells.<ref name="Holtmeier W, Kabelitz D 2005 151–83" />

===Humoral immune response===
{{further|Humoral immunity}}
[[File:2220 Four Chain Structure of a Generic Antibody-IgG2 Structures.jpg|thumb|upright=1.6 |alt=diagram showing the Y-shaped antibody. The variable region, including the antigen-binding site, is the top part of the two upper light chains. The remainder is the constant region. |An antibody is made up of two heavy chains and two light chains. The unique variable region allows an antibody to recognize its matching antigen.<ref name=NIAID>{{cite web|title=Understanding the Immune System: How it Works |publisher=[[National Institute of Allergy and Infectious Diseases]] (NIAID) |url=https://www.niaid.nih.gov/publications/immune/the_immune_system.pdf |access-date=1 January 2007 |archive-url=https://web.archive.org/web/20070103005411/http://www.niaid.nih.gov/Publications/immune/the_immune_system.pdf |archive-date=3 January 2007 }}</ref>]]
A [[B cell]] identifies pathogens when antibodies on its surface bind to a specific foreign antigen.<ref name=Sproul>{{cite journal | vauthors = Sproul TW, Cheng PC, Dykstra ML, Pierce SK | s2cid = 6550357 | title = A role for MHC class II antigen processing in B cell development | journal = International Reviews of Immunology | volume = 19 | issue = 2–3 | pages = 139–55 | year = 2000 | pmid = 10763706 | doi = 10.3109/08830180009088502 }}</ref> This antigen/antibody complex is taken up by the B cell and processed by [[proteolysis]] into [[peptide]]s. The B cell then displays these antigenic peptides on its surface MHC class II molecules. This combination of MHC and antigen attracts a matching helper T cell, which releases [[lymphokine]]s and activates the B cell.<ref>{{cite journal | vauthors = Parker DC | title = T cell-dependent B cell activation | journal = Annual Review of Immunology | volume = 11 | pages = 331–60 | date = 1993 | pmid = 8476565 | doi = 10.1146/annurev.iy.11.040193.001555 }}</ref> As the activated B cell then begins to [[cell division|divide]], its offspring ([[plasma cells]]) [[secretion|secrete]] millions of copies of the antibody that recognizes this antigen. These antibodies circulate in [[blood plasma]] and [[lymphatic system|lymph]], bind to pathogens expressing the antigen and mark them for destruction by [[Complement system|complement activation]] or for uptake and destruction by [[phagocyte]]s. Antibodies can also neutralize challenges directly, by binding to bacterial toxins or by interfering with the receptors that viruses and bacteria use to infect cells.{{sfn| Murphy |Weaver |2016 |loc= Chapter 10: The Humoral Immune Response}}

Newborn infants have no prior exposure to microbes and are particularly vulnerable to infection. Several layers of passive protection are provided by the mother. During pregnancy, a particular type of antibody, called [[Immunoglobulin G|IgG]], is transported from mother to baby directly through the [[placenta]], so human babies have high levels of antibodies even at birth, with the same range of antigen specificities as their mother.<ref>{{cite journal | vauthors = Saji F, Samejima Y, Kamiura S, Koyama M | title = Dynamics of immunoglobulins at the feto-maternal interface | journal = Reviews of Reproduction | volume = 4 | issue = 2 | pages = 81–89 | date = May 1999 | pmid = 10357095 | doi = 10.1530/ror.0.0040081 | s2cid = 31099552 | url = http://pdfs.semanticscholar.org/ef69/261377c9d417b646679b850fc88a19128579.pdf | archive-url = https://web.archive.org/web/20210130212930/http://pdfs.semanticscholar.org/ef69/261377c9d417b646679b850fc88a19128579.pdf | archive-date = 2021-01-30 }}</ref> Breast milk or [[colostrum]] also contains antibodies that are transferred to the gut of the infant and protect against bacterial infections until the newborn can synthesize its own antibodies.<ref>{{cite journal | vauthors = Van de Perre P | title = Transfer of antibody via mother's milk | journal = Vaccine | volume = 21 | issue = 24 | pages = 3374–76 | date = Jul 2003 | pmid = 12850343 | doi = 10.1016/S0264-410X(03)00336-0 }}</ref> This is [[passive immunization|passive immunity]] because the [[fetus]] does not actually make any memory cells or antibodies—it only borrows them. This passive immunity is usually short-term, lasting from a few days up to several months. In medicine, protective passive immunity can also be [[intravenous immunoglobulin|transferred artificially]] from one individual to another.<ref name= Keller>{{cite journal | vauthors = Keller MA, Stiehm ER | title = Passive immunity in prevention and treatment of infectious diseases | journal = Clinical Microbiology Reviews | volume = 13 | issue = 4 | pages = 602–14 | date = Oct 2000 | pmid = 11023960 | pmc = 88952 | doi = 10.1128/CMR.13.4.602-614.2000 }}</ref>

=== Immunological memory ===
{{further|Immunity (medical)}}
When B cells and T cells are activated and begin to replicate, some of their offspring become long-lived memory cells. Throughout the lifetime of an animal, these memory cells remember each specific pathogen encountered and can mount a strong response if the pathogen is detected again. T-cells recognize pathogens by small protein-based infection signals, called antigens, that bind directly to T-cell surface receptors.<ref>Sauls RS, McCausland C, Taylor BN. Histology, T-Cell Lymphocyte. In: StatPearls. StatPearls Publishing; 2023. Accessed November 15, 2023. https://www.ncbi.nlm.nih.gov/books/NBK535433/</ref> B-cells use the protein, immunoglobulin, to recognize pathogens by their antigens.<ref>	Althwaiqeb SA, Bordoni B. Histology, B Cell Lymphocyte. In: StatPearls. StatPearls Publishing; 2023. Accessed November 15, 2023. https://www.ncbi.nlm.nih.gov/books/NBK560905/</ref> This is "adaptive" because it occurs during the lifetime of an individual as an adaptation to infection with that pathogen and prepares the immune system for future challenges. Immunological memory can be in the form of either passive short-term memory or active long-term memory.{{sfn | Sompayrac | 2019 | p=98}}

== 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 | page = 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 |article-number=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 early cellular studies suggested vitamin D might influence immune responses, more recent large-scale clinical trials and meta-analyses (2022–2024) have found that vitamin D supplementation can reduce the risk and severity of autoimmune diseases such as rheumatoid arthritis and multiple sclerosis, and may modestly reduce the incidence of acute respiratory tract infections and improve tuberculosis outcomes.<ref>{{Cite journal |last=Mercier |first=F. |title=Effect of vitamin D on inflammatory and clinical outcomes in rheumatoid arthritis: a systematic review and dose-response meta-analysis |journal=Nutrition Reviews |date=April 2024}}</ref><ref>{{Cite journal |last=Li |first=Y. |title=Vitamin D3 as an add-on treatment for multiple sclerosis: A systematic review and meta-analysis |journal=Multiple Sclerosis and Related Disorders |date=February 2024}}</ref><ref>{{Cite journal |title=Efficacy and safety of vitamin D in tuberculosis patients: a systematic review and meta-analysis |journal=Expert Review of Anti-Infective Therapy |date=July 2022}}</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 |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= |page=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>

== Disorders of human immunity ==
Failures of host defense occur and fall into three broad categories: immunodeficiencies,{{sfn | Sompayrac | 2019 | pp=120–24}} autoimmunity,{{sfn | Sompayrac | 2019 | pp=114–18}} and hypersensitivities.{{sfn | Sompayrac | 2019 | pp=111–14}}

=== Immunodeficiencies ===
{{further|Immunodeficiency}}
[[Immunodeficiency|Immunodeficiencies]] occur when one or more of the components of the immune system are inactive. The ability of the immune system to respond to pathogens is diminished in both the young and the [[old age|elderly]], with immune responses beginning to decline at around 50 years of age due to [[immunosenescence]].<ref>{{cite journal | vauthors = Aw D, Silva AB, Palmer DB | title = Immunosenescence: emerging challenges for an ageing population | journal = Immunology | volume = 120 | issue = 4 | pages = 435–46 | date = Apr 2007 | pmid = 17313487 | pmc = 2265901 | doi = 10.1111/j.1365-2567.2007.02555.x }}</ref><ref name="nutrition">{{cite journal | vauthors = Chandra RK | title = Nutrition and the immune system: an introduction | journal = The American Journal of Clinical Nutrition | volume = 66 | issue = 2 | pages = 460S–63S | date = Aug 1997 | pmid = 9250133 | doi = 10.1093/ajcn/66.2.460S | doi-access = free }}</ref> In [[developed country|developed countries]], [[obesity]], [[alcohol abuse|alcoholism]], and drug use are common causes of poor immune function, while [[malnutrition]] is the most common cause of immunodeficiency in [[developing country|developing countries]].<ref name="nutrition" /> Diets lacking sufficient protein are associated with impaired cell-mediated immunity, complement activity, phagocyte function, [[immunoglobulin A|IgA]] antibody concentrations, and cytokine production. Additionally, the loss of the [[thymus]] at an early age through [[Mutation|genetic mutation]] or surgical removal results in severe immunodeficiency and a high susceptibility to infection.<ref>{{cite journal | vauthors = Miller JF | title = The discovery of thymus function and of thymus-derived lymphocytes | journal = Immunological Reviews | volume = 185 | issue = 1 | pages = 7–14 | date = Jul 2002 | pmid = 12190917 | doi = 10.1034/j.1600-065X.2002.18502.x | s2cid = 12108587 }}</ref> Immunodeficiencies can also be inherited or '[[Immunodeficiency#Acquired immune deficiency|acquired]]'.{{sfn | Reece | 2011 | p=967}} [[Severe combined immunodeficiency]] is a rare [[genetic disorder]] characterized by the disturbed development of functional T cells and B cells caused by numerous genetic mutations.<ref name="five">{{cite journal |vauthors=Burg M, Gennery AR |title=Educational paper: The expanding clinical and immunological spectrum of severe combined immunodeficiency |journal=Eur J Pediatr |volume= 170 |issue=5 |pages=561–571 |year=2011 |doi=10.1007/s00431-011-1452-3 |pmid=21479529 |pmc=3078321 }}</ref> [[Chronic granulomatous disease]], where [[phagocyte]]s have a reduced ability to destroy pathogens, is an example of an inherited, or [[Primary immunodeficiency|congenital, immunodeficiency]]. [[AIDS]] and some types of [[cancer]] cause acquired immunodeficiency.<ref>{{cite journal | vauthors = Joos L, Tamm M | title = Breakdown of pulmonary host defense in the immunocompromised host: cancer chemotherapy | journal = Proceedings of the American Thoracic Society | volume = 2 | issue = 5 | pages = 445–48 | year = 2005 | pmid = 16322598 | doi = 10.1513/pats.200508-097JS }}</ref><ref>{{cite journal | vauthors = Copeland KF, Heeney JL | title = T helper cell activation and human retroviral pathogenesis | journal = Microbiological Reviews | volume = 60 | issue = 4 | pages = 722–42 | date = Dec 1996 | pmid = 8987361 | pmc = 239461 | doi = 10.1128/MMBR.60.4.722-742.1996 }}</ref>

=== Autoimmunity ===
{{further|Autoimmunity}}
[[File:Rheumatoid_Arthritis.JPG|thumb|Joints of a hand swollen and deformed by [[rheumatoid arthritis]], an autoimmune disorder|alt=See caption]]
Overactive immune responses form the other end of immune dysfunction, particularly the [[autoimmune diseases]]. Here, the immune system fails to properly distinguish between [[Self-protein|self]] and non-self, and attacks part of the body. Under normal circumstances, many T cells and antibodies react with "self" peptides.<ref>{{cite journal | vauthors = Miller JF | s2cid = 32476323 | title = Self-nonself discrimination and tolerance in T and B lymphocytes | journal = Immunologic Research | volume = 12 | issue = 2 | pages = 115–30 | year = 1993 | pmid = 8254222 | doi = 10.1007/BF02918299 }}</ref> One of the functions of specialized cells (located in the [[thymus]] and bone marrow) is to present young lymphocytes with [[Self-protein|self antigens]] produced throughout the body and to eliminate those cells that recognize [[Self-protein|self-antigens]], preventing autoimmunity.<ref name="Sproul" /> Common autoimmune diseases include [[Hashimoto's thyroiditis]],<ref name="NIH2017">{{citation-attribution|1={{cite web|title=Hashimoto's disease|url=https://www.womenshealth.gov/a-z-topics/hashimotos-disease|publisher=Office on Women's Health, U.S. Department of Health and Human Services|access-date=17 July 2017|date=12 June 2017|url-status=live|archive-url=https://web.archive.org/web/20170728031758/https://www.womenshealth.gov/a-z-topics/hashimotos-disease|archive-date=28 July 2017}}}}</ref> [[rheumatoid arthritis]],<ref name="Lancet2016">{{cite journal | vauthors = Smolen JS, Aletaha D, McInnes IB | s2cid = 37973054 | title = Rheumatoid arthritis | journal = Lancet | volume = 388 | issue = 10055 | pages = 2023–2038 | date = October 2016 | pmid = 27156434 | doi = 10.1016/S0140-6736(16)30173-8 | url = http://eprints.gla.ac.uk/131249/1/131249.pdf }}</ref> [[diabetes mellitus type 1]],<ref name="Farhy_2015">{{cite journal | vauthors = Farhy LS, McCall AL | title = Glucagon - the new 'insulin' in the pathophysiology of diabetes | journal = Current Opinion in Clinical Nutrition and Metabolic Care | volume = 18 | issue = 4 | pages = 407–14 | date = July 2015 | pmid = 26049639 | doi = 10.1097/mco.0000000000000192 | s2cid = 19872862 }}</ref> and [[systemic lupus erythematosus]].<ref name=NIH2015>{{cite web|title=Handout on Health: Systemic Lupus Erythematosus|url=https://www.niams.nih.gov/health-topics/lupus|website=www.niams.nih.gov|access-date=12 June 2016|date=February 2015|url-status=live|archive-url=https://web.archive.org/web/20160617162703/http://www.niams.nih.gov/Health_Info/Lupus/default.asp|archive-date=17 June 2016}}</ref>

=== Hypersensitivity ===
{{further|Hypersensitivity}}
[[Hypersensitivity]] is an immune response that damages the body's own tissues. It is divided into four classes (Type I&nbsp;– IV) based on the mechanisms involved and the time course of the hypersensitive reaction. Type I hypersensitivity is an immediate or [[anaphylaxis|anaphylactic]] reaction, often associated with allergy. Symptoms can range from mild discomfort to death. Type I hypersensitivity is mediated by [[immunoglobulin E|IgE]], which triggers degranulation of [[mast cell]]s and [[basophil granulocyte|basophils]] when cross-linked by antigen.<ref name="USCH">{{cite web|url=http://www.microbiologybook.org/book/immunol-sta.htm|title=Immunology&nbsp;– Chapter Seventeen: Hypersensitivity States| vauthors = Ghaffar A |year=2006|publisher=University of South Carolina School of Medicine|work=Microbiology and Immunology On-line|access-date=29 May 2016}}</ref>
Type II hypersensitivity occurs when antibodies bind to antigens on the individual's own cells, marking them for destruction. This is also called antibody-dependent (or cytotoxic) hypersensitivity, and is mediated by [[immunoglobulin G|IgG]] and [[immunoglobulin M|IgM]] antibodies.<ref name=USCH /> [[Immune complex]]es (aggregations of antigens, complement proteins, and IgG and IgM antibodies) deposited in various tissues trigger Type III hypersensitivity reactions.<ref name=USCH /> Type IV hypersensitivity (also known as cell-mediated or ''delayed type hypersensitivity'') usually takes between two and three days to develop. Type IV reactions are involved in many autoimmune and infectious diseases, but may also involve [[contact dermatitis]]. These reactions are mediated by [[T cell]]s, [[monocyte]]s, and [[macrophage]]s.<ref name=USCH />

=== Idiopathic inflammation ===
{{further|Immune-mediated inflammatory diseases}}
Inflammation is one of the first responses of the immune system to infection,<ref name=autogenerated2 /> but it can appear without known cause.

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 [[Vasodilation|dilation of blood vessels]] associated with inflammation, and [[leukotriene]]s that attract certain white blood cells (leukocytes).<ref name=autogenerated4 /><ref name=autogenerated1 /> Common cytokines include [[interleukin]]s that are responsible for communication between white blood cells; [[chemokine]]s that promote [[chemotaxis]]; and [[interferon]]s that have anti-viral effects, such as shutting down [[protein biosynthesis|protein synthesis]] in the host cell.<ref name=autogenerated3 /> [[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 healing of any damaged tissue following the removal of pathogens.<ref name=autogenerated5 />

== Manipulation in medicine ==

[[File:Dexamethasone structure.svg|thumb|right|upright=0.9 |alt=Skeletal structural formula of dexamethasone, C22 H29 F O5 |Skeletal structural formula of the [[immunosuppressive drug]] [[dexamethasone]]]]
The immune response can be manipulated to suppress unwanted responses resulting from autoimmunity, allergy, and [[transplant rejection]], and to stimulate protective responses against pathogens that largely elude the immune system (see [[#Active memory and immunization|immunization]]) or cancer.{{sfn | Sompayrac | 2019 | pp=83–85}}

=== Immunosuppression ===
[[Immunosuppressive drug]]s are used to control autoimmune disorders or [[inflammation]] when excessive tissue damage occurs, and to prevent rejection after an [[organ transplant]].{{sfn|Ciccone |2015 |loc = Chapter [https://books.google.com/books?id=Te1vCAAAQBAJ&q=%22immunosuppressive+drugs%22+autoimmune+tissue+damage&pg=PA625 37]}}<ref name= Taylor>{{cite journal | vauthors = Taylor AL, Watson CJ, Bradley JA | title = Immunosuppressive agents in solid organ transplantation: Mechanisms of action and therapeutic efficacy | journal = Critical Reviews in Oncology/Hematology | volume = 56 | issue = 1 | pages = 23–46 | date = Oct 2005 | pmid = 16039869 | doi = 10.1016/j.critrevonc.2005.03.012 }}</ref>

[[Anti-inflammatory]] drugs are often used to control the effects of inflammation. [[Glucocorticoid]]s are the most powerful of these drugs and can have many undesirable [[adverse effect|side effects]], such as [[central obesity]], [[hyperglycemia]], and [[osteoporosis]].<ref>{{cite journal | vauthors = Barnes PJ | title = Corticosteroids: the drugs to beat | journal = European Journal of Pharmacology | volume = 533 | issue = 1–3 | pages = 2–14 | date = Mar 2006 | pmid = 16436275 | doi = 10.1016/j.ejphar.2005.12.052 }}</ref> Their use is tightly controlled. Lower doses of anti-inflammatory drugs are often used in conjunction with cytotoxic or immunosuppressive drugs such as [[methotrexate]] or [[azathioprine]].

[[Chemotherapy|Cytotoxic drugs]] inhibit the immune response by killing dividing cells such as activated T cells. This killing is indiscriminate and other [[constantly dividing cells]] and their organs are affected, which causes toxic side effects.<ref name= Taylor /> Immunosuppressive drugs such as [[cyclosporin]] prevent T cells from responding to signals correctly by inhibiting [[signal transduction]] pathways.<ref>{{cite journal | vauthors = Masri MA | title = The mosaic of immunosuppressive drugs | journal = Molecular Immunology | volume = 39 | issue = 17–18 | pages = 1073–77 | date = Jul 2003 | pmid = 12835079 | doi = 10.1016/S0161-5890(03)00075-0 }}</ref>

=== Immunostimulation ===
{{Main|Immunostimulant|Immunotherapy|Vaccination}}
Claims made by marketers of various products and [[Alternative medicine|alternative health providers]], such as [[Chiropractic|chiropractors]], [[Homeopathy|homeopaths]], and [[Acupuncture|acupuncturists]] to be able to stimulate or "boost" the immune system generally lack meaningful explanation and evidence of effectiveness.<ref>{{cite magazine | vauthors = Hall H |author-link1 = Harriet Hall |date=July–August 2020 |title=How You Can Really Boost Your Immune System |url=https://skepticalinquirer.org/2020/06/how-you-can-really-boost-your-immune-system/ |magazine=[[Skeptical Inquirer]] |location=Amherst, New York |publisher=[[Center for Inquiry]] |archive-url=https://web.archive.org/web/20210121161902/https://skepticalinquirer.org/2020/06/how-you-can-really-boost-your-immune-system/ |archive-date=21 January 2021 |access-date=21 January 2021}}</ref>

===Vaccination===
{{Further|Vaccination}}
[[File:Polio Vaccination - Egypt (16868521330).jpg|right|thumb|Polio vaccination in Egypt|alt= A child receiving drops of polio vaccine in her mouth]]
Long-term ''active'' memory is acquired following infection by activation of B and T cells. Active immunity can also be generated artificially, through [[vaccination]]. The principle behind vaccination (also called [[immunization]]) is to introduce an [[antigen]] from a pathogen to stimulate the immune system and develop [[specific immunity]] against that particular pathogen without causing disease associated with that organism.{{sfn | Reece | 2011 | p=965}} This deliberate induction of an immune response is successful because it exploits the natural specificity of the immune system, as well as its inducibility. With infectious disease remaining one of the leading causes of death in the human population, vaccination represents the most effective manipulation of the immune system mankind has developed.{{sfn| Janeway |2005 |p=}}<ref>[https://www.who.int/healthinfo/bod/en/index.html Death and DALY estimates for 2002 by cause for WHO Member States.] {{Webarchive|url=https://web.archive.org/web/20081021133659/http://www.who.int/healthinfo/bod/en/index.html |date=21 October 2008 }} [[World Health Organization]]. Retrieved on 1 January 2007.</ref>

Many vaccines are based on [[non-cellular life|acellular]] components of micro-organisms, including harmless [[toxin]] components.{{sfn | Reece | 2011 | p=965}} Since many antigens derived from acellular vaccines do not strongly induce the adaptive response, most bacterial vaccines are provided with additional [[Immunologic adjuvant|adjuvants]] that activate the [[antigen-presenting cell]]s of the innate immune system and maximize [[immunogenicity]].<ref>{{cite journal | vauthors = Singh M, O'Hagan D | title = Advances in vaccine adjuvants | journal = Nature Biotechnology | volume = 17 | issue = 11 | pages = 1075–81 | date = Nov 1999 | pmid = 10545912 | doi = 10.1038/15058 | s2cid = 21346647 | doi-access = free }}</ref>

=== Tumor immunology ===
{{Further|Cancer immunology}}

Another important role of the immune system is to identify and eliminate [[tumor]]s. This is called '''immune surveillance'''.<!-- for redirect --> The ''transformed cells'' of tumors express [[antigen#Tumor antigens|antigens]] that are not found on normal cells. To the immune system, these antigens appear foreign, and their presence causes immune cells to attack the transformed tumor cells. The antigens expressed by tumors have several sources;<ref name = anderson>{{cite journal | vauthors = Andersen MH, Schrama D, Thor Straten P, Becker JC | title = Cytotoxic T cells | journal = The Journal of Investigative Dermatology | volume = 126 | issue = 1 | pages = 32–41 | date = Jan 2006 | pmid = 16417215 | doi = 10.1038/sj.jid.5700001 | doi-access = free }}</ref> some are derived from [[oncogenic]] viruses like [[human papillomavirus]], which causes cancer of the [[cervical cancer|cervix]],<ref>{{cite journal | vauthors = Boon T, van der Bruggen P | title = Human tumor antigens recognized by T lymphocytes | journal = The Journal of Experimental Medicine | volume = 183 | issue = 3 | pages = 725–29 | date = Mar 1996 | pmid = 8642276 | pmc = 2192342 | doi = 10.1084/jem.183.3.725 }}</ref> [[vulva cancer|vulva]], [[vaginal cancer|vagina]], [[penis cancer|penis]], [[anal cancer|anus]], [[oropharynx|mouth, and throat]],<ref name=Lj2014>{{cite journal | vauthors = Ljubojevic S, Skerlev M | title = HPV-associated diseases | journal = Clinics in Dermatology | volume = 32 | issue = 2 | pages = 227–34 | year = 2014 | pmid = 24559558 | doi = 10.1016/j.clindermatol.2013.08.007 }}</ref> while others are the organism's own proteins that occur at low levels in normal cells but reach high levels in tumor cells. One example is an enzyme called [[tyrosinase]] that, when expressed at high levels, transforms certain skin cells (for example, [[melanocyte]]s) into tumors called [[melanoma]]s.<ref>{{cite journal | vauthors = Castelli C, Rivoltini L, Andreola G, Carrabba M, Renkvist N, Parmiani G | title = T-cell recognition of melanoma-associated antigens | journal = Journal of Cellular Physiology | volume = 182 | issue = 3 | pages = 323–31 | date = Mar 2000 | pmid = 10653598 | doi = 10.1002/(SICI)1097-4652(200003)182:3<323::AID-JCP2>3.0.CO;2-# | s2cid = 196590144 }}</ref><ref name = romera>{{cite book | vauthors = Romero P, Cerottini JC, Speiser DE | title = The Human T Cell Response to Melanoma Antigens | volume = 92 | pages = 187–224 | year = 2006 | pmid = 17145305 | doi = 10.1016/S0065-2776(06)92005-7 | isbn = 978-0-12-373636-9 | series = Advances in Immunology }}</ref> A third possible source of [[tumor antigen]]s are proteins normally important for regulating [[cell growth]] and survival, that commonly mutate into cancer inducing molecules called [[oncogene]]s.<ref name = anderson /><ref name = guevara>{{cite journal | vauthors = Guevara-Patiño JA, Turk MJ, Wolchok JD, Houghton AN | title = Immunity to cancer through immune recognition of altered self: studies with melanoma | volume = 90 | pages = 157–77 | year = 2003 | pmid = 14710950 | doi = 10.1016/S0065-230X(03)90005-4 | isbn = 978-0-12-006690-2 | journal = Advances in Cancer Research }}</ref><ref>{{cite journal | vauthors = Renkvist N, Castelli C, Robbins PF, Parmiani G | title = A listing of human tumor antigens recognized by T cells | journal = Cancer Immunology, Immunotherapy | volume = 50 | issue = 1 | pages = 3–15 | date = Mar 2001 | pmid = 11315507 | doi = 10.1007/s002620000169 | s2cid = 42681479 | doi-access = free | pmc = 11036832 }}</ref>

[[File:Macs killing cancer cell.jpg|thumb|right|upright=1.15 |alt=See caption |[[Macrophage]]s have identified a cancer cell (the large, spiky mass). Upon fusing with the cancer cell, the macrophages (smaller white cells) inject toxins that kill the tumor cell. [[Immunotherapy]] for the treatment of [[Cancer#Immunotherapy|cancer]] is an active area of medical research.<ref>{{cite journal  |vauthors=Morgan RA, Dudley ME, Wunderlich JR, etal |title=Cancer Regression in Patients After Transfer of Genetically Engineered Lymphocytes |journal=Science |volume=314 |issue=5796 |pages=126–29 |date=October 2006 |pmid=16946036 |pmc=2267026 |doi=10.1126/science.1129003|bibcode = 2006Sci...314..126M }}</ref>]]

The main response of the immune system to tumors is to destroy the abnormal cells using killer T cells, sometimes with the assistance of helper T cells.<ref name = romera /><ref>{{cite journal | vauthors = Gerloni M, Zanetti M | s2cid = 25182066 | title = CD4 T cells in tumor immunity | journal = Springer Seminars in Immunopathology | volume = 27 | issue = 1 | pages = 37–48 | date = Jun 2005 | pmid = 15965712 | doi = 10.1007/s00281-004-0193-z | url = https://zenodo.org/record/1066157 }}</ref> [[Tumor antigen]]s are presented on MHC class I molecules in a similar way to viral antigens. This allows killer T cells to recognize the tumor cell as abnormal.<ref name = seliger>{{cite journal | vauthors = Seliger B, Ritz U, Ferrone S | title = Molecular mechanisms of HLA class I antigen abnormalities following viral infection and transformation | journal = International Journal of Cancer | volume = 118 | issue = 1 | pages = 129–38 | date = Jan 2006 | pmid = 16003759 | doi = 10.1002/ijc.21312 | s2cid = 5655726 | doi-access = free }}</ref> NK cells also kill tumorous cells in a similar way, especially if the tumor cells have fewer MHC class I molecules on their surface than normal; this is a common phenomenon with tumors.<ref>{{cite journal | vauthors = Hayakawa Y, Smyth MJ | title = Innate immune recognition and suppression of tumors | volume = 95 | pages = 293–322 | year = 2006 | pmid = 16860661 | doi = 10.1016/S0065-230X(06)95008-8 | isbn = 978-0-12-006695-7 | journal = Advances in Cancer Research }}</ref> Sometimes antibodies are generated against tumor cells allowing for their destruction by the [[complement system]].<ref name = guevara />

Some tumors evade the immune system and go on to become cancers.<ref name="Syn-2017">{{cite journal | vauthors = Syn NL, Teng MW, Mok TS, Soo RA | title = De-novo and acquired resistance to immune checkpoint targeting | journal = The Lancet. Oncology | volume = 18 | issue = 12 | pages = e731–e741 | date = December 2017 | pmid = 29208439 | doi = 10.1016/s1470-2045(17)30607-1 }}</ref><ref name = selig>{{cite journal | vauthors = Seliger B | title = Strategies of tumor immune evasion | journal = BioDrugs | volume = 19 | issue = 6 | pages = 347–54 | year = 2005 | pmid = 16392887 | doi = 10.2165/00063030-200519060-00002 | s2cid = 1838144 }}</ref> Tumor cells often have a reduced number of MHC class I molecules on their surface, thus avoiding detection by killer T cells.<ref name = seliger /><ref name="Syn-2017" /> Some tumor cells also release products that inhibit the immune response; for example by secreting the cytokine [[TGF beta|TGF-β]], which suppresses the activity of [[macrophage]]s and [[lymphocyte]]s.<ref name="Syn-2017" /><ref>{{cite journal | vauthors = Frumento G, Piazza T, Di Carlo E, Ferrini S | title = Targeting tumor-related immunosuppression for cancer immunotherapy | journal = Endocrine, Metabolic & Immune Disorders Drug Targets | volume = 6 | issue = 3 | pages = 233–7 | date = September 2006 | pmid = 17017974 | doi = 10.2174/187153006778250019 }}</ref> In addition, [[immune tolerance|immunological tolerance]] may develop against tumor antigens, so the immune system no longer attacks the tumor cells.<ref name="Syn-2017" /><ref name = selig />

Paradoxically, macrophages can promote tumor growth<ref>{{cite journal|vauthors=Stix G |title=A malignant flame. Understanding chronic inflammation, which contributes to heart disease, Alzheimer's and a variety of other ailments, may be a key to unlocking the mysteries of cancer |journal=Scientific American |volume=297 |issue=1 |pages=60–67 |date=Jul 2007 |pmid=17695843 |doi=10.1038/scientificamerican0707-60 |url=http://podcast.sciam.com/daily/pdf/sa_d_podcast_070619.pdf |archive-url=https://web.archive.org/web/20110716015048/http://podcast.sciam.com/daily/pdf/sa_d_podcast_070619.pdf |archive-date=16 July 2011 |bibcode=2007SciAm.297a..60S }}</ref> when tumor cells send out cytokines that attract macrophages, which then generate cytokines and growth factors such as [[Tumor necrosis factor alpha|tumor-necrosis factor alpha]] that nurture tumor development or promote stem-cell-like plasticity.<ref name="Syn-2017" /> In addition, a combination of hypoxia in the tumor and a cytokine produced by macrophages induces tumor cells to decrease production of a protein that blocks [[metastasis]] and thereby assists spread of cancer cells.<ref name="Syn-2017" /> Anti-tumor M1 macrophages are recruited in early phases to tumor development but are progressively differentiated to M2 with pro-tumor effect, an immunosuppressor switch. The hypoxia reduces the cytokine production for the anti-tumor response and progressively macrophages acquire pro-tumor M2 functions driven by the tumor microenvironment, including IL-4 and IL-10.<ref>{{cite journal | vauthors = Cervantes-Villagrana RD, Albores-García D, Cervantes-Villagrana AR, García-Acevez SJ | title = Tumor-induced Neurogenesis and Immune Evasion as Targets of Innovative Anti-Cancer Therapies | journal = Signal Transduct Target Ther | volume = 5 | issue = 1 | page = 99 | date = 18 June 2020 | pmid = 32555170 | pmc = 7303203 | doi = 10.1038/s41392-020-0205-z }}</ref> [[Cancer immunotherapy]] covers the medical ways to stimulate the immune system to attack cancer tumors.<ref name="pmid26325031">{{cite journal |vauthors=Yang Y |title=Cancer immunotherapy: harnessing the immune system to battle cancer |journal=The Journal of Clinical Investigation |volume=125 |issue=9 |pages=3335–7 |date=September 2015 |pmid=26325031 |pmc=4588312 |doi=10.1172/JCI83871 }}</ref>

=== Predicting immunogenicity ===
Some drugs can cause a neutralizing immune response, meaning that the immune system produces [[neutralizing antibodies]] that counteract the action of the drugs, particularly if the drugs are administered repeatedly, or in larger doses. This limits the effectiveness of drugs based on larger peptides and proteins (which are typically larger than 6000 [[Dalton (unit)|Da]]).<ref name="Baker2010">{{cite journal | vauthors = Baker MP, Reynolds HM, Lumicisi B, Bryson CJ | title = Immunogenicity of protein therapeutics: The key causes, consequences and challenges | journal = Self/Nonself | volume = 1 | issue = 4 | pages = 314–322 | date = October 2010 | pmid = 21487506 | pmc = 3062386 | doi = 10.4161/self.1.4.13904 }}</ref> In some cases, the drug itself is not immunogenic, but may be co-administered with an immunogenic compound, as is sometimes the case for [[paclitaxel|Taxol]]. Computational methods have been developed to predict the immunogenicity of peptides and proteins, which are particularly useful in designing therapeutic antibodies, assessing likely virulence of mutations in viral coat particles, and validation of proposed peptide-based drug treatments. Early techniques relied mainly on the observation that [[hydrophile|hydrophilic]] [[amino acid]]s are overrepresented in [[epitope]] regions than [[hydrophobe|hydrophobic]] amino acids;<ref name="Welling">{{cite journal | vauthors = Welling GW, Weijer WJ, van der Zee R, Welling-Wester S | title = Prediction of sequential antigenic regions in proteins | journal = FEBS Letters | volume = 188 | issue = 2 | pages = 215–18 | date = Sep 1985 | pmid = 2411595 | doi = 10.1016/0014-5793(85)80374-4 | doi-access = free | bibcode = 1985FEBSL.188..215W }}</ref> however, more recent developments rely on [[machine learning]] techniques using databases of existing known epitopes, usually on well-studied virus proteins, as a [[training set]].<ref name="Sollner">{{cite journal | vauthors = Söllner J, Mayer B | title = Machine learning approaches for prediction of linear B-cell epitopes on proteins | journal = Journal of Molecular Recognition | volume = 19 | issue = 3 | pages = 200–08 | year = 2006 | pmid = 16598694 | doi = 10.1002/jmr.771 | s2cid = 18197810 }}</ref> A publicly accessible database has been established for the cataloguing of epitopes from pathogens known to be recognizable by B cells.<ref name="Saha">{{cite journal | vauthors = Saha S, Bhasin M, Raghava GP | title = Bcipep: a database of B-cell epitopes | journal = BMC Genomics | volume = 6 | page = 79 | year = 2005 | pmid = 15921533 | pmc = 1173103 | doi = 10.1186/1471-2164-6-79 | doi-access = free }}</ref> The emerging field of [[bioinformatics]]-based studies of immunogenicity is referred to as ''[[immunoinformatics]]''.<ref name="Flower">{{cite journal | vauthors = Flower DR, Doytchinova IA | title = Immunoinformatics and the prediction of immunogenicity | journal = Applied Bioinformatics | volume = 1 | issue = 4 | pages = 167–76 | year = 2002 | pmid = 15130835 }}</ref> [[Immunoproteomics]] is the study of large sets of proteins ([[proteomics]]) involved in the immune response.<ref name="pmid31356379">{{cite journal |vauthors=Kanduc D |title=From hepatitis C virus immunoproteomics to rheumatology via cross-reactivity in one table |journal=Current Opinion in Rheumatology |volume=31 |issue=5 |pages=488–492 |date=September 2019 |pmid=31356379 |doi=10.1097/BOR.0000000000000606|s2cid=198982175 }}</ref>

== Evolution and other mechanisms ==
{{further|Innate immune system#Beyond vertebrates}}

===Evolution of the immune system===

It is likely that a multicomponent, adaptive immune system arose with the first [[vertebrate]]s, as [[invertebrate]]s do not generate lymphocytes or an antibody-based humoral response.<ref name="pmid19997068" >{{cite journal |vauthors=Flajnik MF, Kasahara M |title=Origin and evolution of the adaptive immune system: genetic events and selective pressures |journal=Nature Reviews. Genetics |volume=11 |issue=1 |pages=47–59 |date=January 2010 |pmid=19997068 |pmc=3805090 |doi=10.1038/nrg2703 }}</ref> Immune systems evolved in [[deuterostome]]s as shown in the cladogram.<ref name="pmid19997068"/>

{{clade|style=font-size:95%;line-height:110%;
|label1=[[Deuterostome]]s
|sublabel1='''[[innate immunity]]'''
|1={{clade
   |1=[[Echinoderm]]s, [[hemichordate]]s, [[cephalochordate]]s, [[urochordate]]s
   |label2=[[Vertebrates]]
   |2={{clade
      |sublabel1='''[[variable lymphocyte receptor|VLR adaptive immunity]]'''
      |1=[[Agnatha|Jawless fishes]]
      |sublabel2='''[[V(D)J recombination|V(D)J adaptive immunity]]'''
      |2=[[Osteichthyes|Jawed fishes and tetrapods]]
      }}
   }}
}}

Many species, however, use mechanisms that appear to be precursors of these aspects of vertebrate immunity. Immune systems appear even in the structurally simplest forms of life, with bacteria using a unique defense mechanism, called the [[restriction modification system]] to protect themselves from viral pathogens, called [[bacteriophage]]s.<ref>{{cite journal | vauthors = Bickle TA, Krüger DH | title = Biology of DNA restriction | journal = Microbiological Reviews | volume = 57 | issue = 2 | pages = 434–50 | date = Jun 1993 | pmid = 8336674 | pmc = 372918 | doi = 10.1128/MMBR.57.2.434-450.1993 }}</ref> [[Prokaryote]]s ([[bacteria]] and [[archaea]]) also possess acquired immunity, through a system that uses [[CRISPR]] sequences to retain fragments of the genomes of phage that they have come into contact with in the past, which allows them to block virus replication through a form of [[RNA interference]].<ref>{{cite journal | vauthors = Barrangou R, Fremaux C, Deveau H, Richards M, Boyaval P, Moineau S, Romero DA, Horvath P | title = CRISPR provides acquired resistance against viruses in prokaryotes | journal = Science | volume = 315 | issue = 5819 | pages = 1709–12 | date = Mar 2007 | pmid = 17379808 | doi = 10.1126/science.1138140 | bibcode = 2007Sci...315.1709B | hdl = 20.500.11794/38902 | s2cid = 3888761 | hdl-access = free }}</ref><ref>{{cite journal | vauthors = Brouns SJ, Jore MM, Lundgren M, Westra ER, Slijkhuis RJ, Snijders AP, Dickman MJ, Makarova KS, Koonin EV, van der Oost J | title = Small CRISPR RNAs guide antiviral defense in prokaryotes | journal = Science | volume = 321 | issue = 5891 | pages = 960–64 | date = Aug 2008 | pmid = 18703739 | pmc = 5898235 | doi = 10.1126/science.1159689 | bibcode = 2008Sci...321..960B }}</ref> Prokaryotes also possess other defense mechanisms.<ref>{{cite journal | vauthors = Hille F, Charpentier E | title = CRISPR-Cas: biology, mechanisms and relevance | journal = Philosophical Transactions of the Royal Society of London. Series B, Biological Sciences | volume = 371 | issue = 1707 | article-number = 20150496 | date = November 2016 | pmid = 27672148 | pmc = 5052741 | doi = 10.1098/rstb.2015.0496 }}</ref><ref>{{cite journal | vauthors = Koonin EV | title = Evolution of RNA- and DNA-guided antivirus defense systems in prokaryotes and eukaryotes: common ancestry vs convergence | journal = Biology Direct | volume = 12 | issue = 1 | page = 5 | date = February 2017 | pmid = 28187792 | pmc = 5303251 | doi = 10.1186/s13062-017-0177-2 | doi-access = free }}</ref> Offensive elements of the immune systems are also present in [[protist|unicellular eukaryotes]], but studies of their roles in defense are few.<ref>{{cite journal | vauthors = Bayne CJ | year = 2003 | title = Origins and evolutionary relationships between the innate and adaptive arms of immune systems | journal = Integr. Comp. Biol. | volume = 43 | issue = 2| pages = 293–99 | pmid = 21680436 | doi=10.1093/icb/43.2.293| doi-access = free }}</ref>

[[Pattern recognition receptor]]s are proteins used by nearly all organisms to identify molecules associated with pathogens. [[Antimicrobial peptides]] called [[defensin]]s are an evolutionarily conserved component of the innate immune response found in all animals and plants, and represent the main form of invertebrate systemic immunity.<ref name="pmid19997068" /> The [[complement system]] and phagocytic cells are also used by most forms of invertebrate life. [[Ribonuclease]]s and the [[RNA interference]] pathway are conserved across all [[eukaryote]]s, and are thought to play a role in the immune response to viruses.<ref>{{cite journal | vauthors = Stram Y, Kuzntzova L | title = Inhibition of viruses by RNA interference | journal = Virus Genes | volume = 32 | issue = 3 | pages = 299–306 | date = Jun 2006 | pmid = 16732482 | doi = 10.1007/s11262-005-6914-0 | pmc = 7088519 }}</ref>

Unlike animals, plants lack phagocytic cells, but many plant immune responses involve systemic chemical signals that are sent through a plant.<ref name= Plant>{{cite web | vauthors = Schneider D | title = Innate Immunity&nbsp;– Lecture 4: Plant immune responses | publisher = Stanford University Department of Microbiology and Immunology | url = https://web.stanford.edu/class/mi104/Plant%20immunity.pdf | access-date = 1 January 2007 | archive-date = 14 March 2023 | archive-url = https://web.archive.org/web/20230314002612/http://web.stanford.edu/class/mi104/Plant%20immunity.pdf }}</ref> Individual plant cells respond to molecules associated with pathogens known as [[pathogen-associated molecular patterns]] or PAMPs.<ref>{{cite journal | vauthors = Jones JD, Dangl JL | title = The plant immune system | journal = Nature | volume = 444 | issue = 7117 | pages = 323–29 | date = Nov 2006 | pmid = 17108957 | doi = 10.1038/nature05286 | bibcode = 2006Natur.444..323J | doi-access = free }}</ref> When a part of a plant becomes infected, the plant produces a localized [[hypersensitive response]], whereby cells at the site of infection undergo rapid [[apoptosis]] to prevent the spread of the disease to other parts of the plant. [[Systemic acquired resistance]] is a type of defensive response used by plants that renders the entire plant resistant to a particular infectious agent.<ref name= Plant /> [[RNA interference|RNA silencing]] mechanisms are particularly important in this systemic response as they can block [[virus replication]].<ref>{{cite journal | vauthors = Baulcombe D | title = RNA silencing in plants | journal = Nature | volume = 431 | issue = 7006 | pages = 356–63 | date = Sep 2004 | pmid = 15372043 | doi = 10.1038/nature02874 | bibcode = 2004Natur.431..356B | s2cid = 4421274 }}</ref>

===Alternative adaptive immune system ===
[[adaptive immune system#Evolution|Evolution of the adaptive immune system]] occurred in an ancestor of the [[jawed vertebrates]]. Many of the classical molecules of the adaptive immune system (for example, [[immunoglobulin]]s and [[T-cell receptor]]s) exist only in jawed vertebrates. A distinct [[lymphocyte]]-derived molecule has been discovered in primitive [[agnatha|jawless vertebrates]], such as the [[lamprey]] and [[hagfish]]. These animals possess a large array of molecules called [[Variable lymphocyte receptor]]s (VLRs) that, like the antigen receptors of jawed vertebrates, are produced from only a small number (one or two) of [[gene]]s. These molecules are believed to bind pathogenic [[antigen]]s in a similar way to [[antibody|antibodies]], and with the same degree of specificity.<ref>{{cite journal | vauthors = Alder MN, Rogozin IB, Iyer LM, Glazko GV, Cooper MD, Pancer Z | title = Diversity and function of adaptive immune receptors in a jawless vertebrate | journal = Science | volume = 310 | issue = 5756 | pages = 1970–73 | date = Dec 2005 | pmid = 16373579 | doi = 10.1126/science.1119420 | bibcode = 2005Sci...310.1970A | doi-access = free }}</ref>

=== Manipulation by pathogens ===
The success of any pathogen depends on its ability to elude host immune responses. Therefore, pathogens evolved several methods that allow them to successfully infect a host, while evading detection or destruction by the immune system.<ref name=Finlay>{{cite journal | vauthors = Finlay BB, McFadden G | s2cid = 15418509 | title = Anti-immunology: evasion of the host immune system by bacterial and viral pathogens | journal = Cell | volume = 124 | issue = 4 | pages = 767–82 | date = Feb 2006 | pmid = 16497587 | doi = 10.1016/j.cell.2006.01.034 | doi-access = free }}</ref> Bacteria often overcome physical barriers by secreting enzymes that digest the barrier, for example, by using a [[type II secretion system]].<ref>{{cite journal | vauthors = Cianciotto NP | title = Type II secretion: a protein secretion system for all seasons | journal = Trends in Microbiology | volume = 13 | issue = 12 | pages = 581–88 | date = Dec 2005 | pmid = 16216510 | doi = 10.1016/j.tim.2005.09.005 }}</ref> Alternatively, using a [[type III secretion system]], they may insert a hollow tube into the host cell, providing a direct route for proteins to move from the pathogen to the host. These proteins are often used to shut down host defenses.<ref>{{cite journal | vauthors = Winstanley C, Hart CA | title = Type III secretion systems and pathogenicity islands | journal = Journal of Medical Microbiology | volume = 50 | issue = 2 | pages = 116–26 | date = Feb 2001 | pmid = 11211218 | doi = 10.1099/0022-1317-50-2-116 }}</ref>

An evasion strategy used by several pathogens to avoid the innate immune system is to hide within the cells of their host (also called [[intracellular]] [[pathogenesis]]). Here, a pathogen spends most of its [[Biological life cycle|life-cycle]] inside host cells, where it is shielded from direct contact with immune cells, antibodies and complement. Some examples of intracellular pathogens include viruses, the [[foodborne illness|food poisoning]] bacterium ''[[Salmonella]]'' and the [[eukaryote|eukaryotic]] parasites that cause [[malaria]] (''[[Plasmodium]] spp.'') and [[leishmaniasis]] (''[[Leishmania]] spp.''). Other bacteria, such as ''[[Mycobacterium tuberculosis]]'', live inside a protective capsule that prevents [[lysis]] by complement.<ref>{{cite journal | vauthors = Finlay BB, Falkow S | title = Common themes in microbial pathogenicity revisited | journal = Microbiology and Molecular Biology Reviews | volume = 61 | issue = 2 | pages = 136–69 | date = Jun 1997 | doi = 10.1128/mmbr.61.2.136-169.1997 | pmid = 9184008 | pmc = 232605 }}</ref> Many pathogens secrete compounds that diminish or misdirect the host's immune response.<ref name=Finlay /> Some bacteria form [[biofilm]]s to protect themselves from the cells and proteins of the immune system. Such biofilms are present in many successful infections, such as the chronic ''[[Pseudomonas aeruginosa]]'' and ''[[Burkholderia cenocepacia]]'' infections characteristic of [[cystic fibrosis]].<ref>{{cite journal | vauthors = Kobayashi H | s2cid = 31788349 | title = Airway biofilms: implications for pathogenesis and therapy of respiratory tract infections | journal = Treatments in Respiratory Medicine | volume = 4 | issue = 4 | pages = 241–53 | year = 2005 | pmid = 16086598 | doi = 10.2165/00151829-200504040-00003 }}</ref> Other bacteria generate surface proteins that bind to antibodies, rendering them ineffective; examples include ''[[Streptococcus]]'' (protein G), ''[[Staphylococcus aureus]]'' (protein A), and ''[[Peptostreptococcus]] magnus'' (protein L).<ref>{{cite journal | vauthors = Housden NG, Harrison S, Roberts SE, Beckingham JA, Graille M, Stura E, Gore MG | title = Immunoglobulin-binding domains: Protein L from Peptostreptococcus magnus | journal = Biochemical Society Transactions | volume = 31 | issue = Pt 3 | pages = 716–18 | date = Jun 2003 | pmid = 12773190 | doi = 10.1042/BST0310716 | s2cid = 10322322| url = http://pdfs.semanticscholar.org/a2a4/223fb0694e0137c5c82d002e7e9e07b7143b.pdf | archive-url = https://web.archive.org/web/20190302214414/http://pdfs.semanticscholar.org/a2a4/223fb0694e0137c5c82d002e7e9e07b7143b.pdf | archive-date = 2019-03-02 }}</ref>

The mechanisms used to evade the adaptive immune system are more complicated. The simplest approach is to rapidly change non-essential [[epitope]]s ([[amino acid]]s and/or sugars) on the surface of the pathogen, while keeping essential epitopes concealed. This is called [[antigenic variation]]. An example is HIV, which mutates rapidly, so the proteins on its [[viral envelope]] that are essential for entry into its host target cell are constantly changing. These frequent changes in antigens may explain the failures of [[vaccine]]s directed at this virus.<ref>{{cite journal | vauthors = Burton DR, Stanfield RL, Wilson IA | title = Antibody vs. HIV in a clash of evolutionary titans | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 102 | issue = 42 | pages = 14943–48 | date = Oct 2005 | pmid = 16219699 | pmc = 1257708 | doi = 10.1073/pnas.0505126102 | bibcode = 2005PNAS..10214943B | doi-access = free }}</ref> The parasite ''[[Trypanosoma brucei]]'' uses a similar strategy, constantly switching one type of surface protein for another, allowing it to stay one step ahead of the antibody response.<ref>{{cite journal | vauthors = Taylor JE, Rudenko G | title = Switching trypanosome coats: what's in the wardrobe? | journal = Trends in Genetics | volume = 22 | issue = 11 | pages = 614–20 | date = Nov 2006 | pmid = 16908087 | doi = 10.1016/j.tig.2006.08.003 }}</ref> Masking antigens with host molecules is another common strategy for avoiding detection by the immune system. In HIV, the envelope that covers the [[virus|virion]] is formed from the outermost membrane of the host cell; such "self-cloaked" viruses make it difficult for the immune system to identify them as "non-self" structures.<ref>{{cite journal | vauthors = Cantin R, Méthot S, Tremblay MJ | title = Plunder and stowaways: incorporation of cellular proteins by enveloped viruses | journal = Journal of Virology | volume = 79 | issue = 11 | pages = 6577–87 | date = Jun 2005 | pmid = 15890896 | pmc = 1112128 | doi = 10.1128/JVI.79.11.6577-6587.2005 }}</ref>

== History of immunology ==
{{further|History of immunology}}
[[File:Paul Ehrlich 1915.jpg|thumb|right|alt= Portrait of an older, thin man with a beard wearing glasses and dressed in a suit and tie|[[Paul Ehrlich]] (1854–1915) was awarded a Nobel Prize in 1908 for his contributions to immunology.<ref name= 1908Nobel/>]]

[[Immunology]] is a science that examines the structure and function of the immune system. It originates from [[medicine]] and early studies on the causes of immunity to disease. The earliest known reference to immunity was during the [[plague of Athens]] in 430 BC. [[Thucydides]] noted that people who had recovered from a previous bout of the disease could nurse the sick without contracting the illness a second time.<ref>{{cite journal | vauthors = Retief FP, Cilliers L | title = The epidemic of Athens, 430–426 BC | journal = South African Medical Journal = Suid-Afrikaanse Tydskrif vir Geneeskunde | volume = 88 | issue = 1 | pages = 50–53 | date = Jan 1998 | pmid = 9539938 }}</ref> In the 18th century, [[Pierre Louis Maupertuis|Pierre-Louis Moreau de Maupertuis]] experimented with scorpion venom and observed that certain dogs and mice were immune to this venom.<ref>{{cite journal | vauthors = Ostoya P |title=Maupertuis et la biologie |journal=Revue d'histoire des sciences et de leurs applications |year=1954 |volume=7 |issue=1 |pages=60–78 |doi=10.3406/rhs.1954.3379}}</ref> In the 10th century, Persian physician [[Muhammad ibn Zakariya al-Razi|al-Razi]] (also known as Rhazes) wrote the first recorded theory of acquired immunity,<ref name="early_trends">{{cite journal | vauthors = Doherty M, Robertson MJ | title = Some early Trends in Immunology | journal = Trends in Immunology | volume = 25 | issue = 12 | pages = 623–31 | date = December 2004 | pmid =  15530829| doi = 10.1016/j.it.2004.10.008 }}</ref>{{sfn |Silverstein |1989 |p=6}} noting that a [[smallpox]] bout protected its survivors from future infections. Although he explained the immunity in terms of "excess moisture" being expelled from the blood—therefore preventing a second occurrence of the disease—this theory explained many observations about smallpox known during this time.{{sfn |Silverstein |1989 |p=7}}

These and other observations of acquired immunity were later exploited by [[Louis Pasteur]] in his development of vaccination and his proposed [[germ theory of disease]].<ref>{{cite journal | vauthors = Plotkin SA | title = Vaccines: past, present and future | journal = Nature Medicine | volume = 11 | issue = 4 Suppl | pages = S5–11 | date = Apr 2005 | pmid = 15812490 | doi = 10.1038/nm1209 | pmc = 7095920 }}</ref> Pasteur's theory was in direct opposition to contemporary theories of disease, such as the [[miasma theory of disease|miasma theory]]. It was not until [[Robert Koch]]'s 1891 [[Koch's postulates|proofs]], for which he was awarded a [[Nobel Prize in Physiology or Medicine|Nobel Prize]] in 1905, that microorganisms were confirmed as the cause of [[infectious disease]].<ref>[http://nobelprize.org/nobel_prizes/medicine/laureates/1905/ The Nobel Prize in Physiology or Medicine 1905] {{Webarchive|url=https://web.archive.org/web/20061210184150/http://nobelprize.org/nobel_prizes/medicine/laureates/1905/ |date=10 December 2006 }} Nobelprize.org Retrieved on 8 January 2009.</ref> Viruses were confirmed as human pathogens in 1901, with the discovery of the [[yellow fever]] virus by [[Walter Reed]].<ref>[https://web.archive.org/web/20071023070838/http://www.wramc.amedd.army.mil/welcome/history/ Major Walter Reed, Medical Corps, U.S. Army] Walter Reed Army Medical Center. Retrieved on 8 January 2007.</ref>

Immunology made a great advance towards the end of the 19th century, through rapid developments in the study of [[humoral immunity]] and [[Cell-mediated immunity|cellular immunity]].<ref name= Metch>{{cite book| vauthors = Metchnikoff E | author-link = Elie Metchnikoff | translator-last = Binnie FG | title =Immunity in Infective Diseases| publisher =Cambridge University Press| year =1905 |url=https://archive.org/details/immunityininfec01metcgoog | quote =history of humoral immunity. | format =Full Text Version: Internet Archive| lccn = 68025143}}</ref> Particularly important was the work of [[Paul Ehrlich]], who proposed the [[side-chain theory]] to explain the specificity of the [[antigen-antibody reaction]]; his contributions to the understanding of humoral immunity were recognized by the award of a joint Nobel Prize in 1908, along with the founder of cellular immunology, [[Elie Metchnikoff]].<ref name= 1908Nobel>{{cite web|url= http://nobelprize.org/nobel_prizes/medicine/laureates/1908/ |title= The Nobel Prize in Physiology or Medicine 1908 |publisher= The Nobel Prize |access-date=8 January 2007}}</ref> In 1974, [[Niels Kaj Jerne]] developed the [[immune network theory]]; he shared a Nobel Prize in 1984 with [[Georges J. F. Köhler]] and [[César Milstein]] for theories related to the immune system.<ref>{{cite web |url= https://www.nobelprize.org/prizes/medicine/1984/jerne/facts/ | title= Niels K. Jerne |access-date= 27 November 2020 |publisher= The Nobel Prize}}</ref><ref>{{cite journal|title=He put the Id in Idiotype|journal=EMBO Reports|date=4 October 2003|vauthors= Yewdell J |volume=4|issue=10|page=931|pmc=1326409|doi=10.1038/sj.embor.embor951|type= Book review}}</ref>

== See also ==
* [[Fc receptor]]
* [[List of human cell types]]
* [[Neuroimmune system]]
* [[Original antigenic sin]] – when the immune system uses immunological memory upon encountering a slightly different pathogen 
* [[Plant disease resistance]]
* [[Polyclonal response]]

== References ==
=== Citations ===
{{Reflist|33em}}

=== General bibliography ===
{{refbegin|30em}}
* {{cite book | vauthors= Alberts B, Johnson A, Lewis J, Raff M, Roberts K, Walters P  |title=Molecular Biology of the Cell | edition = Fourth | publisher = Garland Science| year = 2002 | location = New York and London |url=https://www.ncbi.nlm.nih.gov/books/NBK21054/?depth=2 | isbn = 978-0-8153-3218-3 }}
* {{cite book |veditors= Bertok L, Chow D |title= Natural Immunity |volume= 5 |edition= 1st |year= 2005 |isbn= 978-0-44451-755-5| vauthors = Bertok L, Chow D |publisher= Elsevier Science }}
* {{cite book | vauthors = Iriti M | title=Plant Innate Immunity 2.0 | publisher=MDPI |location=Basel| year=2019 | isbn=978-3-03897-580-9 | oclc=1105775088 |doi=10.3390/books978-3-03897-581-6 |doi-access=free}}
* {{cite book |vauthors= Ciccone CD |title= Pharmacology in Rehabilitation (Contemporary Perspectives in Rehabilitation) |edition= 5th |publisher= F.A. Davis Company |year= 2015 |isbn=  978-0-80364-029-0}}
* {{cite book | vauthors = Janeway CA, Travers P, Walport M |title=Immunobiology |chapter=Effector mechanisms in allergic reactions | edition = 5th | publisher = Garland Science |year=2001 |url= https://www.ncbi.nlm.nih.gov/books/NBK27112/#A1746 }}
* {{cite book | vauthors = Janeway CA |title=Immunobiology | edition = 6th | publisher = Garland Science |year=2005 | isbn = 0-443-07310-4 |author-link=Charles Janeway }}
* {{cite book | vauthors = Krishnaswamy G, Ajitawi O, Chi DS | title = Mast Cells | chapter = The human mast cell: an overview | series = Methods in Molecular Biology | volume = 315 | pages = 13–34 | year = 2006 | pmid = 16110146 | doi = 10.1385/1-59259-967-2:013 | isbn = 1-59259-967-2 }}
* {{cite book | vauthors = Murphy K, Weaver C | title = Immunobiology | date = 2016 | publisher = Garland Science | isbn = 978-0-8153-4505-3 | edition=9 }}
* {{cite book | vauthors = Rajalingam R | chapter = Overview of the Killer Cell Immunoglobulin-Like Receptor System | title = Immunogenetics | volume = 882 | pages = 391–414 | year = 2012 | pmid = 22665247 | doi = 10.1007/978-1-61779-842-9_23 | isbn = 978-1-61779-841-2 | series = Methods in Molecular Biology }}
* {{cite book | vauthors = Reece J | title=Campbell biology | publisher=Pearson Australia | publication-place=Frenchs Forest, N.S.W | year=2011 | isbn=978-1-4425-3176-5 | oclc=712136178}}
* {{cite book|vauthors=Silverstein AM |title=A History of Immunology|year=1989|author-link=Arthur M. Silverstein|publisher=[[Academic Press]]|isbn=978-0-08-092583-7}}
* {{cite book | vauthors=Sompayrac L | title=How the immune system works | publisher=Wiley-Blackwell | location=Hoboken, NJ | year=2019 | isbn=978-1-119-54212-4 | oclc=1083261548}}
* {{cite book|vauthors= Stvrtinová V, Jakubovský J, Hulín I |title= Pathophysiology: Principles of Disease |publisher=Academic Electronic Press |year=1995 |location=Computing Centre, Slovak Academy of Sciences }}
* {{cite book | vauthors = Wira CR, Crane-Godreau M, Grant K  |year=2004  |title=Mucosal Immunology | veditors = Ogra PL, Mestecky J, Lamm ME, Strober W, McGhee JR, Bienenstock J | publisher = Elsevier | location = San Francisco | isbn = 0-12-491543-4}}
{{refend}}

== Further reading ==
{{Library resources box
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* {{Cite book | vauthors = Dettmer P <!-- The three p's are sic. --> |year=2021 |title=Immune: A Journey into the Mysterious System that Keeps You Alive |url=https://books.google.com/books?id=ry9GEAAAQBAJ |others=Philip Laibacher (illustrations) |location=New York |publisher=Random House |isbn=978-0-593-24131-8 |oclc=1263845194 |access-date=4 January 2022 |archive-date=24 November 2021 |archive-url=https://web.archive.org/web/20211124111657/https://kurzgesagt.org/immune-book-sources/ |url-status=live }} (The book's [https://kurzgesagt.org/immune-book-sources/ sources] are only online.) A popular science explanation of the immune system.

== External links ==
{{Commons category|Immune system}}
{{Wikiquote}}
{{Immune system}}
{{Lymphatic system}}
{{System and organs}}
{{Immune receptors}}
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[[Category:Immune system| ]]