Innate immune system 3113497 221786282 2008-06-26T02:40:31Z Malljaja 3242335 /* Functions */ reference is provided here--so no need to tag, unless it's misattribution (?) {{See also|Immune system|Adaptive immune system}} The '''innate immune system''' comprises the cells and mechanisms that defend the host from infection by other organisms, in a non-specific manner. This means that the cells of the innate system recognize, and respond to, [[pathogens]] in a generic way, but unlike the [[adaptive immune system]], it does not confer long-lasting or protective immunity to the host.<ref name=Alberts>{{cite book | last = Alberts| first = Bruce| coauthors = Alexander Johnson, Julian Lewis, Martin Raff, Keith Roberts, and Peter Walters | title = Molecular Biology of the Cell; Fourth Edition | publisher = Garland Science| date = 2002 | location = New York and London | url = http://www.ncbi.nlm.nih.gov/books/bv.fcgi?call=bv.View..ShowTOC&rid=mboc4.TOC&depth=2 | id = ISBN 0-8153-3218-1}}</ref> Innate immune systems provide immediate defense against infection, and are found in all classes of [[plant]] and [[animal]] life. ==Functions== The innate system is thought to constitute an evolutionarily older defense strategy, and is the dominant immune system found in [[plant]]s, [[fungi]], [[insect]]s, and in primitive [[multicellular organisms]] (see [[#Other forms of innate immunity|Other forms of innate immunity]]).<ref name=Janeway>{{cite book | last = Janeway | first = Charles | authorlink = Charles Janeway | coauthors = Paul Travers, Mark Walport, and Mark Shlomchik | title = Immunobiology; Fifth Edition | publisher = Garland Science | date = 2001 | location = New York and London| pages = | url = http://www.ncbi.nlm.nih.gov/books/bv.fcgi?call=bv.View..ShowTOC&rid=imm.TOC&depth=10| doi = | id = ISBN 0-8153-4101-6}}.</ref> The major functions of the [[vertebrate]] innate immune system include: *Recruiting immune cells to sites of infection and [[#inflammation|inflammation]], through the production of chemical factors, including specialized chemical mediators, called [[cytokine]]s. *Activation of the [[complement cascade]] to identify bacteria, activate cells and to promote clearance of dead cells or [[immune complex|antibody complexes]]. *The identification and removal of foreign substances present in organs, tissues, the blood and lymph, by specialized [[white blood cells]]. *Activation of the [[adaptive immune system]] through a process known as [[antigen presentation]]. ==Inflammation== {{main|Inflammation}} [[Inflammation]] is one of the first responses of the immune system to infection or irritation. Inflammation is stimulated by chemical factors released by injured cells and serves to establish a physical barrier against the spread of infection, and to promote healing of any damaged tissue following the clearance of pathogens.<ref name="IandF">{{cite book| last = Stvrtinová | first = Viera | coauthors = Ján Jakubovský and Ivan Hulín| title = ''Inflammation and Fever'' from Pathophysiology: Principles of Disease | publisher = Academic Electronic Press| date = 1995 | location = Computing Centre, Slovak Academy of Sciences | url = http://nic.sav.sk/logos/books/scientific}}</ref> Chemical factors produced during inflammation ([[histamine]], [[bradykinin]], [[serotonin]], [[leukotriene]]s also prostaglandilins) sensitize [[pain receptor]]s, cause [[vasodilation]] of the [[blood vessel]]s at the scene, and attract phagocytes, especially neutrophils.<ref name="IandF"/> Neutrophils then trigger other parts of the immune system by releasing factors that summon other leukocytes and lymphocytes. The inflammatory response is characterized by the following symptom quintet: '''Redness''' (rubor) '''Heat''' (calor) '''Swelling''' (tumor) '''Pain''' (dolor) and '''possible dysfunction''' of the organs or tissues involved (functio laesa). ==Complement system== {{main|Complement system}} The [[complement system]] is a [[biochemical cascade]] of the immune system that helps, or “complements”, the ability of antibodies to clear pathogens or mark them for destruction by other cells. The cascade is composed of many plasma proteins, synthesized in the [[liver]], primarily by [[hepatocytes]]. The proteins work together to: *trigger the recruitment of inflammatory cells. *"tag" pathogens for destruction by other cells by [[Opsonin|''opsonizing'']], or coating, the surface of the pathogen. *disrupt the plasma membrane of an infected cell, resulting in [[cytolysis]] of the infected cell, causing the death of the pathogen. *rid the body of neutralized antigen-antibody complexes. Elements of the complement cascade can be found in many species evolutionarily older than mammals including [[plant]]s, [[bird]]s, [[fish]] and some species of [[invertebrate]]s.<ref name=Janeway6>{{cite book | author = [[Charles Janeway|Janeway CA, Jr.]] ''et al'' | title = Immunobiology. | edition = 6th ed. | publisher = Garland Science | year = 2005 | id = ISBN 0-443-07310-4}}</ref> ==Cells of the innate immune response== {{main|Leukocyte}} [[Image:SEM blood cells.jpg|thumb|right|230px|A [[scanning electron microscope]] image of normal circulating human blood. One can see red blood cells, several knobby white blood cells including [[#Cells of the Adaptive Immune System|lymphocytes]], a [[#Macrophages|monocyte]], a [[#Neutrophils|neutrophil]], and many small disc-shaped [[platelet]]s.]] All white blood cells (WBC) are known as [[leukocyte]]s. Leukocytes are different from other cells of the body in that they are not tightly associated with a particular organ or tissue; thus, they function similar to independent, single-celled organisms. Leukocytes are able to move freely and interact and capture cellular debris, foreign particles, or invading microorganisms. Unlike many other cells in the body, most innate immune leukocytes cannot divide or reproduce on their own, but are the products of pluripotent [[hematopoietic stem cell]]s present in the bone marrow.<ref name=Alberts/> The innate leukocytes include: Natural killer cells, mast cells, eosinophils, basophils; and the phagocytic cells including macrophages, neutrophils and dendritic cells, and function within the immune system by identifying and eliminating pathogens that might cause infection.<ref name=Janeway/> ===Mast cells=== {{main|Mast cell}} Mast cells are a type of innate immune cell that resides in the connective tissue and in the mucous membranes, and are intimately associated with defense against pathogens, wound healing, but are also often associated with [[allergy]] and [[anaphylaxis]].<ref name="IandF"/> When activated, mast cells rapidly release characteristic granules, rich in [[histamine]] and [[heparin]], along with various hormonal mediators, and [[chemokine]]s, or chemotactic [[cytokine]]s into the environment. Histamine dilates [[blood vessel]]s, causing the characteristic signs of inflammation, and recruits neutrophils and macrophages.<ref name="IandF"/> ===Phagocytes=== {{main|Phagocytosis}} The word 'phagocyte' literally means 'eating cell'. These are immune cells that engulf, i.e. phagocytose, pathogens or particles. To engulf a particle or pathogen, a phagocyte extends portions of its [[plasma membrane]], wrapping the membrane around the particle until it is enveloped (i.e. the particle is now inside the cell). Once inside the cell, the invading pathogen is contained inside an [[endosome]] which merges with a [[lysosome]].<ref name=Janeway/> The lysosome contains enzymes and acids that kill and digest the particle or organism. Phagocytes generally patrol the body searching for pathogens, but are also able to react to a group of highly specialized molecular signals produced by other cells, called [[cytokines]]. The phagocytic cells of the immune system include macrophages, neutrophils, and dendritic cells. Phagocytosis of the hosts’ own cells is common as part of regular tissue development and maintenance. When host cells die, either internally induced by processes involving [[programmed cell death]] (also called [[apoptosis]]), or caused by cell injury due to a bacterial or viral infection, phagocytic cells are responsible for their removal from the affected site.<ref name=Alberts/> By helping to remove dead cells preceding growth and development of new healthy cells, [[phagocytosis]] is an important part of the healing process following tissue injury. [[Image:Macrophage.jpg|thumb|left|150px|A macrophage]] ====Macrophages==== [[Macrophages]], from the Greek, meaning "large eating cell", are large phagocytic leukocytes, which are able to move outside of the vascular system by moving across the cell membrane of [[capillary]] vessels and entering the areas between cells in pursuit of invading pathogens. In tissues, organ-specific macrophages are differentiated from phagocytic cells present in the blood called [[monocyte]]s. Macrophages are the most efficient phagocytes, and can phagocytose substantial numbers of bacteria or other cells or microbes.<ref name=Janeway/> The binding of bacterial molecules to receptors on the surface of a macrophage triggers it to engulf and destroy the bacteria through the generation of a “[[respiratory burst]]”, causing the release of [[reactive oxygen species]]. Pathogens also stimulate the macrophage to produce chemokines, which summons other cells to the site of infection.<ref name=Janeway/> ====Neutrophils==== [[Image:PBNeutrophil.jpg|thumb|right|120px|A neutrophil]] [[Neutrophils]], along with two other cell types; eosinophils and basophils (see below), are known as [[granulocyte]]s due to the presence of granules in their cytoplasm, or as polymorphonuclear cells (PMNs) due to their distinctive lobed [[Cell nucleus|nuclei]]. Neutrophil granules contain a variety of toxic substances that kill or inhibit growth of bacteria and fungi. Similar to macrophages, neutrophils attack pathogens by activating a "respiratory burst". The main products of the neutrophil respiratory burst are strong [[oxidizing agent]]s including [[hydrogen peroxide]], free oxygen radicals and [[hypochlorite]]. Neutrophils are the most abundant type of phagocyte, normally representing 50 to 60% of the total circulating leukocytes, and are usually the first cells to arrive at the site of an infection.<ref name="IandF"/> The bone marrow of a normal healthy adult produces more than 100 billion neutrophils per day, and more than 10 times that many per day during [[Acute (medical)|acute]] inflammation.<ref name="IandF"/> ====Dendritic cells==== [[Dendritic cell]]s (DC) are phagocytic cells present in tissues that are in contact with the external environment, mainly the [[skin]] (where they are often called [[Langerhans cell]]s), and the inner mucosal lining of the [[nose]], [[lung]]s, [[stomach]] and [[intestine]]s.<ref name=Alberts/> They are named for their resemblance to [[neuronal]] [[dendrite]]s, but dendritic cells are not connected to the [[nervous system]]. Dendritic cells are very important in the process of [[antigen presentation]], and serve as a link between the innate and [[adaptive immune system]]s. [[Image:PBEosinophil.jpg|thumb|left|120px|An eosinophil]] ===Basophils and eosinophils=== {{main|Basophil granulocyte|Eosinophil granulocyte}} [[Basophils]] and [[eosinophils]] are cells related to the neutrophil (see above). When activated by a pathogen encounter, basophils releasing [[histamine]] are important in defense against [[parasite]]s, and play a role in [[allergic reactions]] (such as [[asthma]]).<ref name=Janeway/> Upon activation, eosinophils secrete a range of highly [[toxic]] proteins and free radicals that are highly effective in killing bacteria and parasites, but are also responsible for tissue damage occurring during allergic reactions. Activation and toxin release by eosinophils is therefore tightly regulated to prevent any inappropriate tissue destruction.<ref name="IandF"/> ===Natural killer cells=== {{main|Natural killer cell}} [[Natural killer cells]], or NK cells, are a component of the innate immune system. NK cells attack host cells that have been infected by microbes, but do not directly attack invading microbes. For example, NK cells attack and destroy [[tumor]] cells, and virus-infected cells, through a process 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.<ref name=Janeway6/> They were named "natural killer" because of the initial notion that they do not require activation in order to kill cells that are "missing self." ===γδ T cells=== {{main|gamma/delta T cells}} Like other 'unconventional' T cell subsets bearing invariant [[T cell receptor]]s (TCRs), such as [[CD1d receptor|CD1d]]-restricted [[Natural Killer T cell]]s, γδ T cells exhibit characteristics that place them at the border between innate and adaptive immunity. On one hand, γδ T cells may be considered a component of [[adaptive immune system|adaptive immunity]] in that they [[V(D)J recombination|rearrange TCR genes]] to produce junctional diversity and develop a memory phenotype. However, the various subsets may also be considered part of the innate immune system where a restricted TCR or NK receptors may be used as a [[pattern recognition receptor]]. For example, according to this paradigm, large numbers of Vγ9/Vδ2 T cells respond within hours to [[non-peptidic antigen|common molecules]] produced by microbes, and highly restricted intraepithelial Vδ1 T cells will respond to stressed epithelial cells. ==Pathogen-specificity== The parts of the innate immune system have different specificity for different pathogens. {|class="wikitable" ! Pathogen !! Main examples <ref name=Immunology172Unless> Unless else specified in boxes, then ref is: Lippincott's Illustrated Reviews: Immunology. Paperback: 384 pages. Publisher: Lippincott Williams & Wilkins; (July 1, 2007). Language: English. ISBN-10: 0781795435. ISBN-13: 978-0781795432. Page 172 </ref> !! [[Phagocytosis]] <ref name=Immunology172Unless/> !! [[Complement system|complement]]<ref name=Immunology172Unless/> !! [[NK cell]]s<ref name=Immunology172Unless/> |- | Intracellular and cytoplasmic '''[[virus]]''' || *[[influenza]] *[[mumps]] *[[measles]] *[[rhinovirus]] || yes || no || yes |- | Intracellular '''[[bacteria]]''' || *''[[Listeria monocytogenes]]'' *''[[Legionella]]'' *''[[Mycobacterium]]'' *''[[Rickettsia]]'' || yes (specifically [[neutrophils]], no for rickettsia) || no || yes (no for rickettsia) |- | Extracellular '''[[bacteria]]''' || *''[[Staphylococcus]]'' *''[[Streptococcus]]'' *''[[Neisseria]]'' *''[[Salmonella typhi]]'' || yes || yes || no |- | Intracellular '''[[protozoa]]''' || *''[[Plasmodium malariae]]'' *''[[Leishmania|Leishmania donovani]]'' || no || no || no |- | Extracellular '''[[protozoa]]''' || *''[[Entamoeba histolytica]]'' *''[[Giardia lamblia]]'' || yes || yes || no |- | Extracellular '''[[fungi]]''' || *''[[Candida (genus)|Candida]]'' *''[[Histoplasma]]'' *''[[Cryptococcus]]'' || no || yes || no |- |} ==Innate immune evasion== Cells of the innate immune system effectively prevent free growth of bacteria within the body; however, many pathogens have evolved mechanisms allowing them to evade the innate immune system.<ref name="Evasion"> {{cite web| last = Kennedy| first = Alan| title = Immune Evasion by bacteria| url = http://alan.kennedy.name/crohns/primer/imunevad.htm}}</ref><ref name=Finlay>{{cite journal | author = Finlay B, McFadden G | title = Anti-immunology: evasion of the host immune system by bacterial and viral pathogens | journal = Cell | volume = 124 | issue = 4 | pages = 767–82 | year = 2006 | pmid = 16497587 | doi = 10.1016/j.cell.2006.01.034}}</ref> Evasion strategies that circumvent the innate immune system include intracellular replication, such as in ''[[Salmonella]]'', or a protective capsule that prevents lysis by complement and by phagocytes, as in ''[[Mycobacterium tuberculosis]]''.<ref>{{cite journal | author = Finlay B, Falkow S | title = Common themes in microbial pathogenicity revisited | url=http://mmbr.asm.org/cgi/reprint/61/2/136.pdf | journal = Microbiol Mol Biol Rev | volume = 61 | issue = 2 | pages = 136–69 | year = 1997 | pmid = 9184008}}</ref> ''[[Bacteroides]]'' species are normally [[commensal]] bacteria, making up a substantial portion of the mammalian [[gut flora|gastrointestinal flora]].<ref name=Dorland>{{cite book | author = Dorland WAN (editor) | title = [[Dorland's Illustrated Medical Dictionary]]| edition = 30th| publisher = W.B. Saunders| year = 2003| id = ISBN 0-7216-0146-4}}</ref> Some species (''B. fragilis'', for example) are [[opportunistic infection|opportunistic pathogens]], causing infections of the [[peritoneal cavity]]. These species evade the immune system through inhibition of phagocytosis by affecting the receptors that phagocytes use to engulf bacteria or by mimicking host cells so that the immune system does not recognize them as foreign. ''[[Staphylococcus aureus]]'' inhibits the ability of the phagocyte to respond to chemokine signals. Other organisms such as ''M. tuberculosis'', ''[[Streptococcus pyogenes]]'' and ''[[Bacillus anthracis]]'' utilize mechanisms that directly kill the phagocyte. Bacteria and fungi may also form complex [[biofilm]]s, providing protection from the cells and proteins of the immune system; recent studies indicate that such biofilms are present in many successful infections, including the chronic ''[[Pseudomonas aeruginosa]]'' and ''[[Burkholderia cenocepacia]]'' infections characteristic of [[cystic fibrosis]].<ref>{{cite journal | author = Kobayashi H | title = Airway biofilms: implications for pathogenesis and therapy of respiratory tract infections | journal = Treat Respir Med | volume = 4 | issue = 4 | pages = 241–53 | year = 2005 | pmid = 16086598}}</ref> ==Other forms of innate immunity== ===Host defense in prokaryotes=== [[Bacteria]] (and perhaps other [[prokaryotic]] organisms), utilize a unique defense mechanism, called the [[restriction modification system]] to protect themselves from pathogens, such as [[bacteriophage]]s. In this system, bacteria produce [[enzyme]]s, called [[restriction endonuclease]]s, that attack and destroy specific regions of the viral [[DNA]] of invading bacteriophages. [[Methylation]] of the host's own DNA marks it as "self" and prevents it from being attacked by endonucleases.<ref>[http://www.accessexcellence.org/AE/AEC/CC/restriction.html Restriction Enzymes] Access Excellence Classic Collection Background Paper.</ref> Restriction endonucleases and the restriction modification system exist exclusively in prokaryotes. ===Host defense in invertebrates=== [[Invertebrate]]s do not possess lymphocytes or an antibody-based humoral immune system, and it is likely that a multicomponent, adaptive immune system arose with the first vertebrates.<ref name=Beck>Beck, Gregory and Habicht, Gail S. [http://www.scs.carleton.ca/~soma/biosec/readings/sharkimmu-sciam-Nov1996.pdf ''Immunity and the Invertebrates''] Scientific American. November 1996:60-66.</ref> Nevertheless, invertebrates possess mechanisms that appear to be precursors of these aspects of vertebrate immunity. ''[[Pattern recognition receptor]]s'' are proteins used by nearly all organisms to identify molecules associated with microbial pathogens. ''[[Toll-like receptor]]s'' are a major class of pattern recognition receptor, that exists in all [[coelomate]]s (animals with a body-cavity), including humans.<ref name= Toll>Imler JL, Hoffmann JA. (2001) ''Toll receptors in innate immunity.'' Trends Cell Biol. Jul;11(7):304-11. Review. PMID 11413042</ref> The [[complement system]], as discussed above, is a biochemical cascade of the immune system that helps clear pathogens from an organism, and exists in most forms of life. Some invertebrates, including various insects, [[crab]]s, and [[worm]]s utilize a modified form of the complement response known as the [[prophenoloxidase]] (proPO) system.<ref name=Beck/> ''[[Antimicrobial peptides]]'' are an evolutionarily conserved component of the innate immune response found among all classes of life and represent the main form of invertebrate systemic [[immunity (medical)|immunity]]. Several species of [[insect]] produce antimicrobial peptides known as ''[[defensin]]s'' and ''[[cecropin]]s''. ===Host defense in plants=== Members of every class of pathogen which infect humans also infect plants. Although the exact pathogenic species vary with the infected species, bacteria, fungi, viruses, nematodes and insects can all cause [[Phytopathology|plant disease]]. As with animals, plants attacked by insects or other pathogens use a set of complex [[metabolic]] responses that lead to the formation of defensive chemical compounds that fight infection or make the plant less attractive to insects and other [[herbivore]]s.<ref name= Plant>Schneider, David (2005) [http://cmgm.stanford.edu/micro/Schneider-lab/Innate%20immunity%20course.html Plant immune responses] Stanford University Department of Microbiology and Immunology.</ref> (see: [[plant defense against herbivory]]). Like invertebrates, plants neither generate antibody or T-cell responses nor possess mobile cells that detect and attack pathogens. In addition, in case of infection, parts of some plants are treated as disposable and replaceable, in ways that very few animals are able to do. Walling off or discarding a part of a plant helps stop spread of an infection.<ref name= Plant/> Most plant immune responses involve systemic chemical signals sent throughout a plant. Plants use pattern-recognition receptors to identify pathogens and to start a basal response, which produces chemical signals that aid in warding off infection. When a part of a plant becomes infected with a microbial or viral pathogen, in case of an [[incompatible interaction]] triggered by specific [[elicitors]], the plant produces a localized [[hypersensitive response]] (HR), in which cells at the site of infection undergo rapid [[programmed cell death]] to prevent the spread of the disease to other parts of the plant. HR has some similarities to animal [[pyroptosis]], such as a requirement of [[caspase]]-1-like proteolytic activity of VPEγ, a [[cysteine protease]] that regulates cell disassembly during cell death.<ref>{{cite journal | author = Rojo, E. et al.| title = VPEgamma exhibits a caspase-like activity that contributes to defense against pathogens. |journal = Curr Biol. | volume = 14 | issue = 21 | pages = 1897–1906| year = 2004 | pmid = 15530390| doi = 10.1016/j.cub.2004.09.056}}</ref> "Resistance" (R) proteins, encoded by [[R gene]]s, are widely present in plants and detect pathogens. These proteins contain domains similar to the [[Pattern recognition receptor#NOD Like Receptors|NOD Like Receptors]] and [[Toll-like receptor]]s utilized in animal innate immunity. [[Systemic acquired resistance]] (SAR) is a type of defensive response that renders the entire plant resistant to a broad spectrum of infectious agents. SAR involves the production of [[chemical messenger]]s, such as [[salicylic acid]] or [[jasmonic acid]]. Some of these travel through the plant and signal other cells to produce defensive compounds to protect uninfected parts, e.g., leaves. Salicylic acid itself, although indispensable for expression of SAR, is not the translocated signal responsible for the systemic response. Recent evidence indicates a role for jasmonates in transmission of the signal to distal portions of the plant. [[RNA interference|RNA silencing]] mechanisms are also important in the plant systemic response, as they can block virus replication.<ref>{{cite journal | author = Baulcombe D | title = RNA silencing in plants | journal = Nature | volume = 431 | issue = 7006 | pages = 356–63 | year = 2004 | pmid = 15372043 | doi = 10.1038/nature02874}}</ref> The ''[[jasmonic acid]] response'', is stimulated in leaves damaged by insects, and involves the production of [[methyl jasmonate]].<ref name= Plant/> ==See also== *[[Apoptosis]] ==References== <div class="references-small"><references/></div> {{immune_system}} {{lymphatic system}} {{organ systems}} [[Category:Immune system]] [[es:Sistema inmunitario innato]] [[pl:Odpowiedź odpornościowa nieswoista]] [[pt:Sistema imune inato]] [[fi:Luonnollinen immuniteetti]] [[sv:Ospecifikt immunförsvar]]