Editing Immune system (section)

== 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 [[archea]]) 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 | pages = 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 | pages = 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}}</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 | url-status = dead | 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>