Immune system 14958 225127207 2008-07-12T00:43:27Z Orangemarlin 114927 Reverted 1 edit by [[Special:Contributions/24.182.162.154|24.182.162.154]] identified as [[WP:VAND|vandalism]] to last revision by [[User:Fvasconcellos|Fvasconcellos]].using [[WP:TWINKLE|TW]] [[Image:Neutrophil with anthrax copy.jpg|thumb|right|250px|A [[scanning electron microscope]] image of a single [[neutrophil]] (yellow), engulfing [[anthrax]] bacteria (orange).]] An '''immune system''' is a collection of mechanisms within an [[organism]] that protects against [[disease]] by identifying and killing [[pathogen]]s and [[tumor]] cells. It detects a wide variety of agents, from [[virus]]es to [[parasitic worm]]s, and needs to distinguish them from the organism's own healthy [[cell (biology)|cells]] and [[biological tissue|tissues]] in order to function properly. Detection is complicated as pathogens adapt and [[evolution|evolve]] new ways to successfully infect the [[host (biology)|host]] organism. To survive this challenge, multiple mechanisms evolved that recognize and neutralize pathogens. Even simple [[microorganism|unicellular]] organisms such as [[bacteria]] possess [[enzyme]] systems that protect against [[bacteriophage|viral]] infections. Other basic immune mechanisms evolved in ancient [[eukaryote]]s and remain in their modern descendants, such as [[plant]]s, [[fish]], [[reptile]]s, and [[insect]]s. These mechanisms include [[antimicrobial peptides]] called [[defensin]]s, [[phagocytosis]], and the [[complement system]]. More sophisticated mechanisms, however, developed relatively recently, with the evolution of [[vertebrate]]s.<ref name=Beck> {{cite journal | last = Beck | first = Gregory | coauthors = Gail S. Habicht |title=Immunity and the Invertebrates | journal =Scientific American |pages=60–66 | date =November 1996 |url=http://www.scs.carleton.ca/~soma/biosec/readings/sharkimmu-sciam-Nov1996.pdf | format = [[PDF]] | accessdate = 2007-01-01}}</ref> The immune systems of [[vertebrate]]s such as [[human]]s consist of many types of [[protein]]s, cells, [[organ (biology)|organs]], and tissues, which interact in an elaborate and dynamic network. As part of this more complex immune response, the vertebrate system adapts over time to recognize particular pathogens more efficiently. The adaptation process creates [[immunity (medical)|immunological memories]] and allows even more effective protection during future encounters with these pathogens. This process of [[adaptive immune system|acquired immunity]] is the basis of [[vaccination]]. Disorders in the immune system can result in disease. [[Immunodeficiency]] diseases occur when the immune system is less active than normal, resulting in recurring and life-threatening infections. Immunodeficiency can either be the result of a [[genetic disease]], such as [[severe combined immunodeficiency]], or be produced by pharmaceuticals or an infection, such as the [[AIDS|acquired immune deficiency syndrome]] (AIDS) that is caused by the [[retrovirus]] [[HIV]]. In contrast, [[autoimmunity|autoimmune]] diseases result from a hyperactive immune system attacking normal tissues as if they were foreign organisms. Common autoimmune diseases include [[rheumatoid arthritis]], [[diabetes mellitus type 1]] and [[lupus erythematosus]]. These critical roles of [[immunology]] in health and disease are areas of intense scientific study. ==Layered defense in immunity== The immune system protects organisms from [[infection]] with layered defenses of increasing specificity. Most simply, physical barriers prevent pathogens such as [[bacteria]] and [[virus]]es from entering the organism. If a pathogen breaches these barriers, the [[innate immune system]] provides an immediate, but non-specific response. Innate immune systems are found in all [[plant]]s and [[animal]]s.<ref name=Litman>{{cite journal | author = Litman G, Cannon J, Dishaw L |title=Reconstructing immune phylogeny: new perspectives. |journal=Nat Rev Immunol |volume=5 |issue=11 |pages=866–79 |year=2005 |pmid= 16261174 |doi=10.1038/nri1712}}</ref> However, if pathogens successfully evade the innate response, vertebrates possess a third layer of protection, the [[adaptive immune system]], which is activated by the innate response. 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=USC>{{cite web | last = Mayer | first = Gene |title=Immunology - Chapter One: Innate (non-specific) Immunity | work = Microbiology and Immunology On-Line Textbook | publisher = USC School of Medicine | date = 2006|url=http://pathmicro.med.sc.edu/ghaffar/innate.htm | accessdate = 2007-01-01}}</ref> <div align="center"> {| class="wikitable" |+ '''Components of the immune system''' ! style="background:#ccccff;" |[[#Innate immunity|Innate immune system]]||style="background:#ccccff;" |[[#Adaptive immunity|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]] |} </div> 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 those components of an organism's body that can be distinguished from foreign substances by the immune system.<ref>Smith A.D. (Ed) ''Oxford dictionary of biochemistry and molecular biology.'' (1997) Oxford University Press. ISBN 0-19-854768-4</ref> Conversely, ''non-self'' molecules are those recognized as foreign molecules. One class of non-self molecules are called [[antigen]]s (short for ''anti''body ''gen''erators) and are defined as substances that bind to specific [[immune receptor]]s and elicit an immune response.<ref name=Alberts/> ==Surface barriers== Several barriers protect organisms from infection, including mechanical, chemical and biological barriers. The waxy [[plant cuticle|cuticle]] of many [[leaf|leaves]], the [[exoskeleton]] of [[insect]]s, the [[eggshell|shell]]s and membranes of externally deposited [[egg (biology)|eggs]], and [[skin]] are examples of the mechanical barriers that are the first line of defense against infection.<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> However, as organisms cannot be completely sealed against their environments, other systems act to protect body openings such as the [[lung]]s, [[intestine]]s, and the [[genitourinary system|genitourinary tract]]. In the lungs, [[cough]]ing and [[sneeze|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 | author = Boyton R, Openshaw P |title=Pulmonary defences to acute respiratory infection. |journal=Br Med Bull |volume=61 |issue=|pages=1–12 |year=2002|pmid= 11997295 |doi=10.1093/bmb/61.1.1}}</ref> Chemical barriers also protect against infection. The skin and respiratory tract secrete [[antimicrobial peptides]] such as the β-[[defensin]]s.<ref>{{cite journal | author = Agerberth B, Gudmundsson G |title=Host antimicrobial defence peptides in human disease. |journal=Curr Top Microbiol Immunol |volume=306 |issue=|pages=67–90 |year=|pmid= 16909918}}</ref> [[Enzyme]]s such as [[lysozyme]] and [[phospholipase A2]] in [[saliva]], tears, and [[breast milk]] are also [[antiseptic|antibacterials]].<ref>{{cite journal | author = Moreau J, Girgis D, Hume E, Dajcs J, Austin M, O'Callaghan R |title=Phospholipase A(2) in rabbit tears: a host defense against Staphylococcus aureus. | url=http://www.iovs.org/cgi/content/full/42/10/2347 |journal=Invest Ophthalmol Vis Sci |volume=42 |issue=10 |pages=2347–54 |year=2001 |pmid= 11527949}}</ref><ref>{{cite journal | author = Hankiewicz J, Swierczek E |title=Lysozyme in human body fluids. |journal=Clin Chim Acta |volume=57 |issue=3 |pages=205–9 |year=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 | author = Fair W, Couch J, Wehner N |title=Prostatic antibacterial factor. Identity and significance. |journal=Urology |volume=7 |issue=2 |pages=169–77 |year=1976 |pmid= 54972 |doi=10.1016/0090-4295(76)90305-8}}</ref><ref>{{cite journal | author = Yenugu S, Hamil K, Birse C, Ruben S, French F, Hall S |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. | url=http://www.pubmedcentral.nih.gov/picrender.fcgi?artid=1223422&blobtype=pdf |journal=Biochem J |volume=372 |issue=Pt 2 |pages=473–83 |year=2003 |pmid= 12628001 |doi=10.1042/BJ20030225}}</ref> In the [[stomach]], [[gastric acid]] and [[protease]]s serve as powerful chemical defenses against ingested pathogens. 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, by changing the conditions in their environment, such as [[pH]] or available iron.<ref>{{cite journal | author = Gorbach S |title=Lactic acid bacteria and human health |journal=Ann Med |volume=22 |issue=1 |pages=37–41 |year=1990 |pmid= 2109988 |doi=10.3109/07853899009147239}}</ref> This reduces the probability that pathogens will be able to reach sufficient numbers to cause illness. However, since most [[antibiotic]]s non-specifically target bacteria and do not affect fungi, oral antibiotics can lead to an “overgrowth” of [[fungus|fungi]] and cause conditions such as a vaginal candidiasis ([[yeast infection]]).<ref>{{cite journal | author = Hill L, Embil J |title=Vaginitis: current microbiologic and clinical concepts. | url=http://www.pubmedcentral.nih.gov/picrender.fcgi?artid=1490817&blobtype=pdf |journal=CMAJ |volume=134 |issue=4 |pages=321–31 |year=1986 |pmid= 3510698}}</ref> There is good evidence that re-introduction of [[probiotic]] flora, such as pure cultures of the [[lactobacillus|lactobacilli]] normally found in [[yoghurt]], helps restore a healthy balance of microbial populations in intestinal infections in children and encouraging preliminary data in studies on [[bacterial gastroenteritis]], [[inflammatory bowel disease]]s, [[urinary tract infection]] and [[post-surgical infections]].<ref>{{cite journal |author=Reid G, Bruce A |title=Urogenital infections in women: can probiotics help? |url=http://pmj.bmj.com/cgi/content/full/79/934/428 |journal=Postgrad Med J |volume=79 |issue=934 |pages=428–32 |year=2003 |pmid=12954951 |doi=10.1136/pmj.79.934.428}}</ref><ref>{{cite journal | author = Salminen S, Gueimonde M, Isolauri E |title=Probiotics that modify disease risk | url=http://jn.nutrition.org/cgi/content/full/135/5/1294 |journal=J Nutr |volume=135 |issue=5 |pages=1294–8 |year=2005 |pmid= 15867327}}</ref><ref>{{cite journal |author=Reid G, Jass J, Sebulsky M, McCormick J |title=Potential uses of probiotics in clinical practice |journal=Clin Microbiol Rev |volume=16 |issue=4 |pages=658–72 |year=2003 |pmid=14557292 |doi=10.1128/CMR.16.4.658-672.2003}}</ref> ==Innate immunity== {{details|Innate immune system}} Microorganisms that successfully enter an organism will 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 |author=Medzhitov R |title=Recognition of microorganisms and activation of the immune response |journal=Nature |volume=449 |issue=7164 |pages=819–26 |year=2007 |pmid=17943118 |doi=10.1038/nature06246}}</ref> Innate immune defenses are non-specific, meaning these systems respond to pathogens in a generic way.<ref name=Alberts/> 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/> ===Humoral and chemical barriers=== ====Inflammation==== {{details|Inflammation}} Inflammation is one of the first responses of the immune system to infection.<ref>{{cite journal | author = Kawai T, Akira S |title=Innate immune recognition of viral infection |journal=Nat Immunol |volume=7 |issue=2 |pages=131–7 |year=2006 |pmid= 16424890 |doi=10.1038/ni1303}}</ref> The symptoms of inflammation are redness and swelling, which are caused by increased [[blood]] flow into a 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 vessels associated with inflammation, and [[leukotriene]]s that attract certain [[white blood cell]]s (leukocytes).<ref>{{cite journal | author = Miller, SB |title=Prostaglandins in Health and Disease: An Overview |journal=Seminars in Arthritis and Rheumatism |volume=36 |issue=1 |pages=37–49|year=2006 |pmid= 16887467 |doi=10.1016/j.semarthrit.2006.03.005}}</ref><ref>{{cite journal | author = Ogawa Y, Calhoun WJ. |title=The role of leukotrienes in airway inflammation. |journal=J Allergy Clin Immunol. |volume=118 |issue=4 |pages=789–98|year=2006 |pmid= 17030228 |doi=10.1016/j.jaci.2006.08.009}}</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 anti-viral effects, such as shutting down [[protein biosynthesis|protein synthesis]] in the host cell.<ref>{{cite journal | author = Le Y, Zhou Y, Iribarren P, Wang J |title=Chemokines and chemokine receptors: their manifold roles in homeostasis and disease | url=http://www.nature.com/bjp/journal/v147/n1s/pdf/0706475a.pdf |journal=Cell Mol Immunol |volume=1 |issue=2 |pages=95–104 |year=2004 |pmid= 16212895}}</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 healing of any damaged tissue following the removal of pathogens.<ref>{{cite journal | author = Martin P, Leibovich S |title=Inflammatory cells during wound repair: the good, the bad and the ugly. |journal=Trends Cell Biol |volume=15 |issue=11 |pages=599–607 |year=2005 |pmid= 16202600 |doi=10.1016/j.tcb.2005.09.002}}</ref> ====Complement system==== {{details|Complement system}} 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 immunity|humoral]] component of the innate immune response.<ref name=Rus>{{cite journal | author = Rus H, Cudrici C, Niculescu F |title=The role of the complement system in innate immunity. |journal=Immunol Res |volume=33 |issue=2 |pages=103–12 |year=2005 |pmid= 16234578 |doi=10.1385/IR:33:2:103}}</ref><ref name=USCcomp>{{cite web | last = Mayer | first =Gene |title=Immunology - Chapter Two: Complement | work = Microbiology and Immunology On-Line Textbook | publisher = USC School of Medicine | date = 2006 |url=http://pathmicro.med.sc.edu/ghaffar/complement.htm | accessdate = 2007-01-01}}</ref> Many species have complement systems, including non-[[mammal]]s like plants, fish, and some [[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> 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 journal | author = Liszewski M, Farries T, Lublin D, Rooney I, Atkinson J |title=Control of the complement system. |journal=Adv Immunol |volume=61 |issue=|pages=201–83 |year=|pmid= 8834497}}</ref> The speed of the response is a result of signal amplification that occurs following sequential [[proteolysis|proteolytic]] activation of complement molecules, which are also [[protease]]s. 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 | author = Sim R, Tsiftsoglou S |title=Proteases of the complement system. | url=http://www.biochemsoctrans.org/bst/032/0021/0320021.pdf |journal=Biochem Soc Trans |volume=32 |issue=Pt 1 |pages=21–7 |year=2004 |pmid= 14748705 |doi=10.1042/BST0320021}}</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]].<ref name=Rus/> ===Cellular barriers of the innate system=== [[Image:SEM blood cells.jpg|thumb|right|220px|A [[scanning electron microscope]] image of normal circulating human [[blood]]. One can see [[red blood cell]]s, several knobby white blood cells including [[lymphocyte]]s, a [[monocyte]], a [[neutrophil]], and many small disc-shaped [[platelet]]s.]] Leukocytes ([[white blood cell]]s) act like independent, single-celled organisms and are the second arm of the innate immune system.<ref name=Alberts/> The innate leukocytes include the [[phagocyte]]s ([[macrophage]]s, [[neutrophil granulocyte|neutrophils]], and [[dendritic cell]]s), [[mast cell]]s, [[eosinophil granulocyte|eosinophils]], [[basophil granulocyte|basophils]], and [[natural killer cell]]s. These cells identify and eliminate pathogens, either by attacking larger pathogens through contact or by engulfing and then killing microorganisms.<ref name=Janeway6/> Innate cells are also important mediators in the activation of the [[adaptive immune system]].<ref name=USC/> [[Phagocytosis]] is an important feature of cellular innate immunity performed by cells called '[[phagocyte]]s' that engulf, or eat, pathogens or particles. Phagocytes generally patrol the body searching for pathogens, but can be called to specific locations by [[cytokine]]s.<ref name=Alberts/> 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 [[enzyme]]s or following a [[respiratory burst]] that releases [[radical (chemistry)|free radicals]] into the phagolysosome.<ref>{{cite journal | author = Ryter A |title=Relationship between ultrastructure and specific functions of macrophages. |journal=Comp Immunol Microbiol Infect Dis |volume=8 |issue=2 |pages=119–33 |year=1985 |pmid= 3910340 |doi=10.1016/0147-9571(85)90039-6}}</ref><ref>{{cite journal | author = Langermans J, Hazenbos W, van Furth R |title=Antimicrobial functions of mononuclear phagocytes |journal=J Immunol Methods |volume=174 |issue=1–2 |pages=185–94 |year=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 | author = May R, Machesky L |title=Phagocytosis and the actin cytoskeleton | url=http://jcs.biologists.org/cgi/reprint/114/6/1061 |journal=J Cell Sci |volume=114 |issue=Pt 6 |pages=1061–77 |year=2001 |pmid= 11228151}}</ref> Phagocytosis probably represents the oldest form of host defense, as phagocytes have been identified in both vertebrate and invertebrate animals.<ref>{{cite journal | author = Salzet M, Tasiemski A, Cooper E |title=Innate immunity in lophotrochozoans: the annelids |journal=Curr Pharm Des |volume=12 |issue=24 |pages=3043–50 |year=2006 |pmid= 16918433 |doi=10.2174/138161206777947551}}</ref> Neutrophils and macrophages are phagocytes that travel throughout the body in pursuit of invading pathogens.<ref>{{cite journal | author = Zen K, Parkos C |title=Leukocyte-epithelial interactions |journal=Curr Opin Cell Biol |volume=15 |issue=5 |pages=557–64 |year=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, normally representing 50% to 60% of the total circulating leukocytes.<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://web.archive.org/web/20010711220523/nic.savba.sk/logos/books/scientific/Inffever.html | accessdate = 2007-01-01}}</ref> During the acute phase of inflammation, particularly as a result of bacterial infection, 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 a wide array of chemicals including enzymes, [[complement system|complement proteins]], and regulatory factors such as [[interleukin 1]].<ref name=USCmac>{{cite web | last = Bowers | first = William|title=Immunology -Chapter Thirteen: Immunoregulation | work = Microbiology and Immunology On-Line Textbook | publisher = USC School of Medicine | date = 2006|url=http://pathmicro.med.sc.edu/bowers/imm-reg.htm| accessdate = 2007-01-04}}</ref> Macrophages also act as scavengers, ridding the body of worn-out cells and other debris, and as [[antigen-presenting cell]]s that activate the adaptive immune system.<ref name=USC/> Dendritic cells (DC) are phagocytes in tissues that are in contact with the external environment; therefore, they are located mainly in the [[skin]], [[nose]], [[lung]]s, [[stomach]], and [[intestine]]s.<ref name=Guermonprez>{{cite journal | author = Guermonprez P, Valladeau J, Zitvogel L, Théry C, Amigorena S |title=Antigen presentation and T cell stimulation by dendritic cells |journal=Annu Rev Immunol |volume=20 |issue=|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, but dendritic cells are in no way connected to the [[nervous system]]. Dendritic cells serve as a link between the innate and adaptive immune systems, as they [[antigen presentation|present antigen]] to [[T cell]]s, one of the key cell types of the adaptive immune system.<ref name=Guermonprez/> Mast cells reside in [[connective tissue]]s and [[mucous membrane]]s, and regulate the inflammatory response.<ref>{{cite journal | author = Krishnaswamy G, Ajitawi O, Chi D |title=The human mast cell: an overview. |journal=Methods Mol Biol |volume=315 |issue=|pages=13–34 |year=|pmid= 16110146}}</ref> They are most often associated with [[allergy]] and [[anaphylaxis]].<ref name="IandF"/> Basophils and eosinophils 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 | author = Kariyawasam H, Robinson D |title=The eosinophil: the cell and its weapons, the cytokines, its locations |journal=Semin Respir Crit Care Med |volume=27 |issue=2 |pages=117–27 |year=2006 |pmid= 16612762 |doi=10.1055/s-2006-939514}}</ref> Natural killer ([[NK cells]]) cells are leukocytes that attack and destroy [[tumor]] cells, or cells that have been infected by viruses.<ref>{{cite journal | author = Middleton D, Curran M, Maxwell L |title=Natural killer cells and their receptors |journal=Transpl Immunol |volume=10 |issue=2–3 |pages=147–64 |year=2002 |pmid= 12216946 |doi=10.1016/S0966-3274(02)00062-X}}</ref> ==Adaptive immunity== {{details|Adaptive immune system}} 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 | author = Pancer Z, Cooper M |title=The evolution of adaptive immunity |journal=Annu Rev Immunol |volume=24 |issue=|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. ===Lymphocytes=== The cells of the adaptive immune system are special types of leukocytes, called [[lymphocyte]]s. [[B cell]]s and [[T cell]]s are the major types of lymphocytes and are derived from [[hematopoietic stem cell]]s in the [[bone marrow]].<ref name=Janeway6/> B cells are involved in the [[humoral immunity|humoral immune response]], whereas T cells are involved in [[cell-mediated immunity|cell-mediated immune response]]. [[Image:TCR-MHC bindings.png|thumb|220px|left|Association of a T cell with MHC class I or MHC class II, and antigen (in red)]] 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. There are two major subtypes of T cells: the [[cytotoxic T cell|killer T cell]] and the [[T helper cell|helper T cell]]. Killer T cells only recognize antigens coupled to [[Major histocompatibility complex#MHC class I|Class I MHC]] molecules, while helper 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>{{cite journal | author = Holtmeier W, Kabelitz D |title=gammadelta T cells link innate and adaptive immune responses |journal=Chem Immunol Allergy |volume=86 |issue=|pages=151–83 |year=|pmid= 15976493}}</ref> In contrast, the B cell antigen-specific receptor is an [[antibody]] molecule on the B cell surface, and recognizes whole pathogens without any need for [[antigen processing]]. 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.<ref name= Janeway6/> ====Killer T cells==== [[Image:Cytotoxic T cell.jpg|thumb|200px|right|Killer T cells directly attack other cells carrying foreign or abnormal antigens on their surfaces.<ref name=NIAID>{{cite web |title=Understanding the Immune System: How it Works | publisher = [[National Institute of Allergy and Infectious Diseases]] (NIAID) |url=http://www.niaid.nih.gov/publications/immune/the_immune_system.pdf | format = [[PDF]] | accessdate = 2007-01-01}}</ref>]] [[Cytotoxic T cell|Killer T cell]] are a sub-group of T cells that kill cells infected with viruses (and other pathogens), or are otherwise damaged or dysfunctional.<ref>{{cite journal | author = Harty J, Tvinnereim A, White D |title=CD8+ T cell effector mechanisms in resistance to infection |journal=Annu Rev Immunol |volume=18 |issue=|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 recognises a different antigen. Killer T cells are activated when their [[T cell receptor]] (TCR) 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 | author = Radoja S, Frey A, Vukmanovic S |title=T-cell receptor signaling events triggering granule exocytosis |journal=Crit Rev Immunol |volume=26 |issue=3 |pages=265–90 |year=2006 |pmid= 16928189}}</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==== [[Image:Lymphocyte activation simple.png|thumb|right|300px|Function of T helper cells: Antigen presenting cells ([[Antigen presenting cell|APC]]s) present antigen on their Class II MHC molecules ([[Class II MHC molecule|MHC2]]). Helper T cells recognize these, with the help of their expression of CD4 co-receptor ([[CD4+]]). The activation of a resting helper T cell causes it to release cytokines and other stimulatory signals (green arrows) that stimulate the activity of [[macrophages]], [[killer T cells]] and [[B cells]], the latter producing [[antibodies]]. The stimulation of B cells and macrophages succeeds a proliferation of T helper cells.]] [[T helper cell|Helper T cells]] regulate both the innate and adaptive immune responses and help determine which types of immune responses the body will make to a particular pathogen.<ref>{{cite journal | author = Abbas A, Murphy K, Sher A |title=Functional diversity of helper T lymphocytes |journal=Nature |volume=383 |issue=6603 |pages=787–93 |year=1996 |pmid= 8893001 |doi=10.1038/383787a0}}</ref><ref>{{cite journal | author = McHeyzer-Williams L, Malherbe L, McHeyzer-Williams M |title=Helper T cell-regulated B cell immunity |journal=Curr Top Microbiol Immunol |volume=311 |issue=|pages=59–83 |year=|pmid= 17048705}}</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. Helper T cells express T cell receptors (TCR) 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 (e.g. [[Lck]]) that are responsible for 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 in order 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 | author = Kovacs B, Maus M, Riley J, Derimanov G, Koretzky G, June C, Finkel T |title=Human CD8+ T cells do not require the polarization of lipid rafts for activation and proliferation | url=http://www.ncbi.nlm.nih.gov/sites/entrez?db=pubmed&uid=12419850&cmd=showdetailview |journal=Proc Natl Acad Sci U S A |volume=99 |issue=23 |pages=15006–11 |year=2002 |pmid= 12419850 |doi=10.1073/pnas.232058599}}</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.<ref name= Alberts/> 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 | author = Grewal I, Flavell R |title=CD40 and CD154 in cell-mediated immunity |journal=Annu Rev Immunol |volume=16 |issue=|pages=111–35 |year=1998|pmid= 9597126 |doi=10.1146/annurev.immunol.16.1.111}}</ref> ====γδ T cells==== [[Gamma/delta T cells|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 | author = Girardi M |title=Immunosurveillance and immunoregulation by γδ T cells |journal=J Invest Dermatol |volume=126 |issue=1 |pages=25–31 |year=2006 |pmid= 16417214 |doi=10.1038/sj.jid.5700003}}</ref> On one hand, γδ T cells are a component of [[adaptive immune system|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]] will respond to stressed epithelial cells.<ref>{{cite journal | author = Holtmeier W, Kabelitz D |title=γδ T cells link innate and adaptive immune responses |journal=Chem Immunol Allergy |volume=86 |pages=151–183 |year=2005 |pmid= 15976493}}</ref> [[Image:Antibody.JPG|thumb|220px|right|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/>]] ====B lymphocytes and antibodies==== A [[B cell]] identifies pathogens when antibodies on its surface bind to a specific foreign antigen.<ref name=Sproul>{{cite journal | author = Sproul T, Cheng P, Dykstra M, Pierce S |title=A role for MHC class II antigen processing in B cell development |journal=Int Rev Immunol |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 peptides. 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 | author = Kehry M, Hodgkin P |title=B-cell activation by helper T-cell membranes |journal=Crit Rev Immunol |volume=14 |issue=3–4 |pages=221–38 |year=1994 |pmid= 7538767}}</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 phagocytes. 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.<ref name=USCcells>{{cite web | last =Bowers | first = William |title=Immunology - Chapter nine: Cells involved in immune responses| work = Microbiology and Immunology On-Line Textbook | publisher = USC School of Medicine | date = 2006|url=http://pathmicro.med.sc.edu/bowers/immune%20cells.htm | accessdate = 2007-01-04}}</ref>[[CD20]] antigen is also found on B lymphocytes. ====Alternative adaptive immune system==== Although the classical molecules of the adaptive immune system (e.g. antibodies 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 receptors (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 antibodies, and with the same degree of specificity.<ref>{{cite journal | author = M.N. Alder, I.B. Rogozin, L.M. Iyer, G.V. Glazko, M.D. Cooper, Z. Pancer |title=Diversity and Function of Adaptive Immune Receptors in a Jawless Vertebrate |journal=Science|volume=310 |issue=5756 |pages=1970–1973 |year=2005 |pmid= 16373579 |doi=10.1126/science.1119420}}</ref> ===Immunological memory=== {{details|Immunity (medical)}} When B cells and T cells are activated and begin to replicate, some of their offspring will become long-lived memory cells. Throughout the lifetime of an animal, these memory cells will remember each specific pathogen encountered and can mount a strong response if the pathogen is detected again. 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 either be in the form of passive short-term memory or active long-term memory. ====Passive memory==== Newborn [[infant]]s 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 across 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 | author = Saji F, Samejima Y, Kamiura S, Koyama M |title=Dynamics of immunoglobulins at the feto-maternal interface. | url=http://ror.reproduction-online.org/cgi/reprint/4/2/81.pdf |journal=Rev Reprod |volume=4 |issue=2 |pages=81–9 |year=1999 |pmid= 10357095 |doi=10.1530/ror.0.0040081}}</ref> [[Breast milk]] 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 | author = Van de Perre P |title=Transfer of antibody via mother's milk. |journal=Vaccine |volume=21 |issue=24 |pages=3374–6 |year=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 via antibody-rich [[blood plasma|serum]].<ref name= Keller>{{cite journal | author = Keller, Margaret A. and E. Richard Stiehm |title=Passive Immunity in Prevention and Treatment of Infectious Diseases. | url=http://cmr.asm.org/cgi/content/full/13/4/602 |journal=Clinical Microbiology Reviews|volume=13 |issue=4 |pages=602–614 |year=2000 |pmid= 11023960 |doi=10.1128/CMR.13.4.602-614.2000}}</ref> [[Image:Immune response.jpg|thumb|left|360px|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.]] ====Active memory and immunization==== 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 in order to stimulate the immune system and develop specific immunity against that particular pathogen without causing disease associated with that organism.<ref name=Alberts/> 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.<ref>[http://www.who.int/healthinfo/bod/en/index.html Death and DALY estimates for 2002 by cause for WHO Member States.] [[World Health Organization]]. Retrieved on [[2007-01-01]].</ref><ref name=Janeway6/> Most viral [[vaccine]]s are based on live [[attenuator (genetics)|attenuated]] viruses, while many bacterial vaccines are based on [[non-cellular life|acellular]] components of micro-organisms, including harmless [[toxin]] components.<ref name=Alberts/> 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 Immunity|innate immune system]] and maximize [[immunogenicity]].<ref>{{cite journal | author = Singh M, O'Hagan D |title=Advances in vaccine adjuvants |journal=Nat Biotechnol |volume=17 |issue=11 |pages=1075–81 |year=1999 |pmid= 10545912 |doi=10.1038/15058}}</ref> ==Disorders of human immunity== The immune system is a remarkably effective structure that incorporates specificity, inducibility and adaptation. Failures of host defense do occur, however, and fall into three broad categories: immunodeficiencies, autoimmunity, and hypersensitivities. ===Immunodeficiencies=== {{details|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 |author=Aw D, Silva A, Palmer D |title=Immunosenescence: emerging challenges for an ageing population |journal=Immunology |volume=120 |issue=4 |pages=435–446 |year=2007 |pmid=17313487 |doi=10.1111/j.1365-2567.2007.02555.x}}</ref><ref name="nutrition">{{cite journal| last = Chandra | first = RK|title=Nutrition and the immune system: an introduction |journal=American Journal of Clinical Nutrition |volume=Vol 66 |pages=460S–463S | date = 1997 |pmid= 9250133 |url = http://www.ajcn.org/cgi/content/abstract/66/2/460S}} Free '''full-text pdf''' available</ref> In [[developed country|developed countries]], [[obesity]], [[alcohol abuse|alcoholism]], and drug use are common causes of poor immune function.<ref name="nutrition"/> However, [[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. Deficiency of single nutrients such as [[iron]]; [[copper]]; [[zinc]]; [[selenium]]; [[vitamin]]s [[Retinol|A]], [[Vitamin C|C]], [[Tocopherol|E]], and [[Vitamin B6|B<sub>6</sub>]]; and [[folic acid]] (vitamin B<sub>9</sub>) also reduces immune responses.<ref name="nutrition"/> Additionally, the loss of the [[thymus]] at an early age through genetic mutation or surgical removal results in severe immunodeficiency and a high susceptibility to infection.<ref>{{cite journal |author=Miller JF |title=The discovery of thymus function and of thymus-derived lymphocytes |url=http://www.blackwell-synergy.com/doi/abs/10.1034/j.1600-065X.2002.18502.x |journal=Immunol. Rev. |volume=185 |issue= |pages=7–14 |year=2002 |pmid=12190917 |doi=}}</ref> Immunodeficiencies can also be inherited or '[[Immunodeficiency#Acquired immune deficiency|acquired']].<ref name=Alberts/> [[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 | author = Joos L, Tamm M |title=Breakdown of pulmonary host defense in the immunocompromised host: cancer chemotherapy | url=http://pats.atsjournals.org/cgi/content/full/2/5/445 |journal=Proc Am Thorac Soc |volume=2 |issue=5 |pages=445–8 |year=2005 |pmid= 16322598 |doi=10.1513/pats.200508-097JS}}</ref><ref>{{cite journal | author = Copeland K, Heeney J |title=T helper cell activation and human retroviral pathogenesis | url=http://www.pubmedcentral.nih.gov/picrender.fcgi?artid=239461&blobtype=pdf |journal=Microbiol Rev |volume=60 |issue=4 |pages=722–42 |year=1996 |pmid= 8987361}}</ref> ===Autoimmunity=== {{details|Autoimmunity}} Overactive immune responses comprise the other end of immune dysfunction, particularly the [[autoimmunity|autoimmune disorders]]. Here, the immune system fails to properly distinguish between 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 | author = Miller J |title=Self-nonself discrimination and tolerance in T and B lymphocytes |journal=Immunol Res |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 antigens produced throughout the body and to eliminate those cells that recognize self-antigens, preventing autoimmunity.<ref name=Sproul/> ===Hypersensitivity=== {{details|Hypersensitivity}} [[Hypersensitivity]] is an immune response that damages the body's own tissues. They are divided into four classes (Type I – 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]] released from [[mast cell]]s and [[basophil granulocyte|basophils]].<ref name=USCH>{{cite web | last = Ghaffar | first = Abdul |title=Immunology - Chapter Seventeen: Hypersensitivity Reactions | work = Microbiology and Immunology On-Line Textbook | publisher = USC School of Medicine | date = 2006 |url=http://pathmicro.med.sc.edu/ghaffar/hyper00.htm | accessdate = 2007-01-01 }}</ref> Type II hypersensitivity occurs when antibodies bind to antigens on the patient'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]]'' ([[poison ivy]]). These reactions are mediated by [[T cell]]s, [[monocyte]]s, and [[macrophage]]s.<ref name=USCH/> ==Other mechanisms of host defense== {{details|Innate immune system#Other forms of innate immunity}} 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=Beck/> Many species, however, utilize mechanisms that appear to be precursors of these aspects of vertebrate immunity. Immune systems appear even in the most structurally-simple 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 | author = Bickle T, Krüger D |title=Biology of DNA restriction | url=http://www.pubmedcentral.nih.gov/picrender.fcgi?artid=372918&blobtype=pdf |journal=Microbiol Rev |volume=57 |issue=2 |pages=434–50 |year=1993 |pmid=8336674}}</ref> [[Pattern recognition receptor]]s are proteins used by nearly all organisms to identify molecules associated with pathogens. [[Antimicrobial peptides]] called defensins 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 (medical)|immunity]].<ref name=Beck/> 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 | author = Stram Y, Kuzntzova L. |title=Inhibition of viruses by RNA interference |journal=Virus Genes |volume=32|issue=3 |pages=299–306 |year=2006 |pmid=16732482 |doi=10.1007/s11262-005-6914-0}}</ref> Unlike animals, plants lack phagocytic cells, and most plant immune responses involve systemic chemical signals that are sent through a plant.<ref name= Plant>{{cite web | last = Schneider | first = David |title=Innate Immunity - Lecture 4: Plant immune responses| publisher = Stanford University Department of Microbiology and Immunology | date = Spring 2005 |url=http://cmgm.stanford.edu/micro/Schneider-lab/Innate%20immunity%20course.html | accessdate = 2007-01-01}}</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]] (SAR) is a type of defensive response used by plants that renders the entire plant [[Disease resistance in fruit and vegetables|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 | 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> ==Tumor immunology== {{See|Cancer immunology}} [[Image:Macs killing cancer cell.jpg|thumb|right|250px|[[Macrophage]]s have identified a cancer cell (the large, spiky mass). Upon fusing with the cancer cell, the macrophages (smaller white cells) will 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 | author = Morgan R ''et al''. |title=Cancer regression in patients after transfer of genetically engineered lymphocytes |journal=[[Science (journal)|Science]] |year=2006 |volume=314 |pages=126–129 |pmid=16946036 |doi=10.1126/science.1129003}}</ref>]] Another important role of the immune system is to identify and eliminate [[tumor]]s. 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 | author = Andersen MH, Schrama D, Thor Straten P, Becker JC |title=Cytotoxic T cells |journal=J Invest Dermatol |volume=126 |issue=1 |pages=32–41 |year=2006 |pmid=16417215 |doi=10.1038/sj.jid.5700001}}</ref> some are derived from [[oncogenic]] viruses like [[human papillomavirus]], which causes [[cervical cancer]],<ref>{{cite journal | author = Boon T, van der Bruggen P |title=Human tumor antigens recognized by T lymphocytes |journal=J Exp Med |volume=183 |issue=|pages=725–29 |year=1996 |pmid=8642276 |doi=10.1084/jem.183.3.725 }}</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 (e.g. [[melanocyte]]s) into tumors called [[melanoma]]s.<ref>{{cite journal | author = Castelli C, Rivoltini L, Andreola G, Carrabba M, Renkvist N, Parmiani G |title=T cell recognition of melanoma-associated antigens |journal=J Cell Physiol |volume=182 |issue=|pages=323–31 |year=2000 |pmid= 10653598 |doi=10.1002/(SICI)1097-4652(200003)182:3<323::AID-JCP2>3.0.CO;2-# }}</ref><ref name = romera>{{cite journal | author = Romero P, Cerottini JC, Speiser DE |title=The human T cell response to melanoma antigens |journal=Adv Immunol. |volume=92 |issue=|pages=187–224 |year=2006 |pmid=17145305}}</ref> A third possible source of tumor antigens 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 | author = Guevara-Patino JA, Turk MJ, Wolchok JD, Houghton AN |title=Immunity to cancer through immune recognition of altered self: studies with melanoma |journal=Adv Cancer Res. |volume=90 |issue=|pages=157–77 |year=2003 |pmid= 14710950}}</ref><ref>{{cite journal | author = Renkvist N, Castelli C, Robbins PF, Parmiani G |title=A listing of human tumor antigens recognized by T cells |journal=Cancer Immunol Immunother |volume=50 |issue=|pages=3–15 |year=2001 |pmid=11315507 |doi=10.1007/s002620000169}}</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 | author = Gerloni M, Zanetti M. |title=CD4 T cells in tumor immunity |journal=. Springer Semin Immunopathol |volume=27 |issue=1 |pages=37–48 |year=2005 |pmid=15965712 |doi=10.1007/s00281-004-0193-z }}</ref> Tumor antigens 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 | author = Seliger B, Ritz U, Ferrone S |title=Molecular mechanisms of HLA class I antigen abnormalities following viral infection and transformation |journal=Int J Cancer |volume=118 |issue=1 |pages=129–38|year=2006 |pmid=16003759 |doi=10.1002/ijc.21312 }}</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 | author = Hayakawa Y, Smyth MJ. |title=Innate immune recognition and suppression of tumors |journal=Adv Cancer Res |volume=95 |issue=|pages=293–322 |year=2006 |pmid=16860661 |doi=10.1016/S0065-230X(06)95008-8 }}</ref> Sometimes antibodies are generated against tumor cells allowing for their destruction by the [[complement system]].<ref name = guevara/> Clearly, some tumors evade the immune system and go on to become cancers.<ref name = selig>{{cite journal | author = 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 }}</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/> 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>{{cite journal | author = Frumento G, Piazza T, Di Carlo E, Ferrini S |title=Targeting tumor-related immunosuppression for cancer immunotherapy |journal=Endocr Metab Immune Disord Drug Targets |volume=6 |issue=3 |pages=233–7 |year=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 = selig/> Paradoxically, macrophages can promote tumor growth <ref>{{cite journal | last = Stix | first = Gary |title=A Malignant Flame | journal =Scientific American |pages=60–67 | date =July 2007 |url=http://podcast.sciam.com/daily/pdf/sa_d_podcast_070619.pdf | format = [[PDF]] | accessdate = 2007-01-01}}</ref> when tumor cells send out cytokines that attract macrophages which then generate cytokines and growth factors that nurture tumor development. 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. ==Physiological regulation== [[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<ref>{{cite book | last = Wira | first = CR | coauthors = Crane-Godreau M, Grant K |year=2004 | chapter = Endocrine regulation of the mucosal immune system in the female reproductive tract |title=Mucosal Immunology | editor = In: Ogra PL, Mestecky J, Lamm ME, Strober W, McGhee JR, Bienenstock J (eds.) | publisher = Elsevier | location = San Francisco | id = ISBN 0124915434}}</ref> and innate immune responses.<ref>{{cite journal| last = Lang | first = TJ |year=2004 |title=Estrogen as an immunomodulator |journal=Clin Immunol |volume=113 |pages=224&ndash;230 |pmid=15507385 |doi=10.1016/j.clim.2004.05.011}}<br />{{cite journal | last = Moriyama | first = A | coauthors = Shimoya K, Ogata I ''et al.'' |year=1999 |title=Secretory leukocyte protease inhibitor (SLPI) concentrations in cervical mucus of women with normal menstrual cycle |journal=Molecular Human Reproduction |volume=5 |pages=656&ndash;661 |pmid=10381821 |url=http://molehr.oxfordjournals.org/cgi/content/full/5/7/656 |doi=10.1093/molehr/5.7.656}}<br />{{cite journal | last = Cutolo |first= M |coauthors= Sulli A, Capellino S, Villaggio B, Montagna P, Seriolo B, Straub RH|year=2004 |title=Sex hormones influence on the immune system: basic and clinical aspects in autoimmunity |journal=Lupus |volume=13 |pages=635&ndash;638 |pmid=15485092 |doi=10.1191/0961203304lu1094oa}}<br />{{cite journal | last = King | first = AE | coauthors = Critchley HOD, Kelly RW |year=2000 |title=Presence of secretory leukocyte protease inhibitor in human endometrium and first trimester decidua suggests an antibacterial role |journal=Molecular Human Reproduction |volume=6 |pages=191&ndash;196 |pmid=10655462 |url=http://molehr.oxfordjournals.org/cgi/content/full/6/2/191 |doi=10.1093/molehr/6.2.191}}</ref> Some autoimmune diseases such as [[lupus erythematosus]] strike women preferentially, and their onset often coincides with [[puberty]]. By contrast, [[androgen|male sex hormone]]s such as [[testosterone]] seem to be [[immunosuppressive]].<ref>{{cite journal | last = Fimmel | fist = S | coauthors = Zouboulis CC |year=2005 |title=Influence of physiological androgen levels on wound healing and immune status in men |journal=Aging Male |volume=8 |pages=166&ndash;174 |pmid=16390741 |doi=10.1080/13685530500233847}}</ref> Other hormones appear to regulate the immune system as well, most notably [[prolactin]], [[growth hormone]] and [[vitamin D]].<ref>{{cite journal | last = Dorshkind | first = K | coauthors = Horseman ND |year=2000 |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 Hormones and Hormone Receptor Deficiency | url=http://edrv.endojournals.org/cgi/content/full/21/3/292?maxtoshow=&HITS=10&hits=10&RESULTFORMAT=&author1=Dorshkind%2C+K%3B+Horseman+ND+&searchid=1&FIRSTINDEX=0&sortspec=relevance&resourcetype=HWCIT|journal=Endocrine Reviews |volume=21 |pages=292&ndash;312|pmid=10857555 |doi=10.1210/er.21.3.292}}</ref><ref>{{cite journal | last =Nagpal | first = Sunil |coauthors = Songqing Naand and Radhakrishnan Rathnachalam |year=2005|title=Noncalcemic Actions of Vitamin D Receptor Ligands | url= http://edrv.endojournals.org/cgi/content/full/26/5/662 |journal=Endocrine Reviews |volume=26| issue= 5|pages=662&ndash;687|pmid=15798098|doi=10.1210/er.2004-0002}}.</ref> It is conjectured that a progressive decline in hormone levels with age is partially responsible for weakened immune responses in aging individuals.<ref>{{cite journal | last = Hertoghe | first = T |year=2005 |title=The “multiple hormone deficiency” theory of aging: Is human senescence caused mainly by multiple hormone deficiencies? |journal=Annals of the New York Academy of Science |volume=1051 |pages=448&ndash;465|pmid=16399912 |doi=10.1196/annals.1322.035}}</ref> Conversely, some hormones are regulated by the immune system, notably [[thyroid hormone]] activity.<ref>{{cite journal | last = Klein | first = JR |year=2006 |title=The immune system as a regulator of thyroid hormone activity |journal=Exp Biol Med |volume=231 |pages=229&ndash;236|pmid=16514168}}</ref> The immune system is enhanced by sleep and rest,<ref>{{cite journal | last = Lange | first = T | coauthors = Perras B, Fehm HL, Born J |year=2003 |title=Sleep Enhances the Human Antibody response to Hepatitis A Vaccination | url= http://www.psychosomaticmedicine.org/cgi/content/full/65/5/831 |journal = Psychosomatic Medicine |volume=65 |pages=831&ndash;835|pmid=14508028 |doi=10.1097/01.PSY.0000091382.61178.F1}}</ref> and is impaired by stress.<ref>{{cite journal | last = Khansari | first = DN | coauthors = Murgo AJ, Faith RE |year=1990 |title=Effects of stress on the immune system |journal=Immunology Today |volume=11 |pages=170&ndash;175 |pmid=2186751 |doi=10.1016/0167-5699(90)90069-L}}</ref> Diet may affect the immune system; for example, fresh [[fruit]]s, [[vegetable]]s, and foods rich in certain [[fatty acid]]s may foster a healthy immune system.<ref>{{cite journal | last = Pond | first = CM |year=2005 |title=Adipose tissue and the immune system |journal=Prostaglandins, Leukotrienes, and Essential Fatty Acids |volume=73 |pages=17–30|pmid= 15946832 |doi=10.1016/j.plefa.2005.04.005}}</ref> Likewise, [[prenatal development|fetal undernourishment]] can cause a lifelong impairment of the immune system.<ref>{{cite journal | last = Langley-Evans | first = SC | coauthors = Carrington LJ |year=2006 |title=Diet and the developing immune system |journal=Lupus |volume=15 |pages=746&ndash;752 |pmid=17153845 |doi=10.1177/0961203306070001}}</ref> In [[traditional medicine]], some herbs are believed to stimulate the immune system, such as [[echinacea]], [[licorice]], [[ginseng]], [[astragalus]], [[Common sage|sage]], [[garlic]], [[elderberry]], [[shiitake]] and [[lingzhi]] mushrooms, and [[hyssop]], as well as [[honey]]. Studies have suggested that such herbs can indeed stimulate the immune system,<ref>{{cite journal | last = Spelman | first = K | coauthors = Burns J, Nichols D, Winters N, Ottersberg S, Tenborg M |year=2006 |title=Modulation of cytokine expression by traditional medicines: a review of herbal immunomodulators |journal=Alternative Medicine reviews |pages=128&ndash;150 |pmid=16813462 |volume=11}}<br />{{cite journal | last = Brush | first = J | coauthors = Mendenhall E, Guggenheim A, Chan T, Connelly E, Soumyanth A, Buresh R, Barrett R, Zwickey H |year=2006 |title=The effect of Echinacea purpurea, Astragalus membranaceus and Glycyrrhiza glabra on CD69 expression and immune cell activation in humans |journal=Phytotherapy Research |volume=20 |pages=687&ndash;695 |pmid=16807880 |doi=10.1002/ptr.1938}}</ref> although their mode of action is complex and difficult to characterize. ==Manipulation in medicine== [[Image:Dexamethasone.svg|thumb|right|200px|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 & immunization|immunization]]). [[Immunosuppressive drug]]s are used to control autoimmune disorders or [[inflammation]] when excessive tissue damage occurs, and to prevent [[transplant rejection]] after an [[organ transplant]].<ref name= Janeway6/><ref name= Taylor>{{cite journal | author = Taylor A, Watson C, Bradley J |title=Immunosuppressive agents in solid organ transplantation: Mechanisms of action and therapeutic efficacy |journal=Crit Rev Oncol Hematol |volume=56 |issue=1 |pages=23–46 |year=2005 |pmid=16039869 |doi=10.1016/j.critrevonc.2005.03.012}}</ref> [[Anti-inflammatory]] drugs are often used to control the effects of inflammation. The [[glucocorticoid]]s are the most powerful of these drugs; however, these drugs can have many undesirable side effects (''e.g.'', [[central obesity]], [[hyperglycemia]], [[osteoporosis]]) and their use must be tightly controlled.<ref>{{cite journal | author = Barnes P |title=Corticosteroids: the drugs to beat |journal=Eur J Pharmacol |volume=533 |issue=1–3 |pages=2–14 |year=2006 |pmid=16436275 |doi=10.1016/j.ejphar.2005.12.052}}</ref> Therefore, lower doses of anti-inflammatory drugs are often used in conjunction with [[cytotoxicity|cytotoxic]] or [[immunosuppressive drug]]s such as [[methotrexate]] or [[azathioprine]]. [[Chemotherapy|Cytotoxic drugs]] inhibit the immune response by killing dividing cells such as activated T cells. However, the 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 | author = Masri M |title=The mosaic of immunosuppressive drugs |journal=Mol Immunol |volume=39 |issue=17–18 |pages=1073–7 |year=2003 |pmid=12835079 |doi=10.1016/S0161-5890(03)00075-0}}</ref> Larger drugs (>500 [[atomic mass unit|Da]]) can provoke a neutralizing immune response, 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 Da). 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|author = Welling GW, Wiejer WJ, van der Zee R, Welling-Werster S. |date = 1985 |title= Prediction of sequential antigenic regions in proteins|journal=J Mol Recognit|volume=88|issue=2|pages=215–8|pmid=2411595}}</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|author = Sollner J, Mayer B. | date = 2006 |title=Machine learning approaches for prediction of linear B-cell epitopes on proteins. | volume=19 |issue=3 |pages=200–8 |pmid=16598694 |doi=10.1002/jmr.771 |journal=Journal of Molecular Recognition}}</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|author=Saha S, Bhasin M, Raghava GP.|date=2005|title=Bcipep: a database of B-cell epitopes.|journal=BMC Bioinformatics |volume=6 |issue=1 |pages=79 |pmid=15921533|doi=10.1186/1471-2105-6-79 }}</ref> The emerging field of [[bioinformatics]]-based studies of immunogenicity is referred to as ''immunoinformatics''.<ref name="Flower">{{cite journal|author=Flower DR, Doytchinova IA.|date=2002|title=Immunoinformatics and the prediction of immunogenicity.|journal=Appl Bioinformatics |volume=1 |issue=4 |pages=167–76 |pmid=15130835}}</ref> ==Manipulation by pathogens== The success of any pathogen is dependent on its ability to elude host immune responses. Therefore, pathogens have developed several methods that allow them to successfully infect a host, while evading immune-mediated destruction.<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> Bacteria often overcome physical barriers by secreting [[enzyme]]s that digest the barrier — for example, by using a [[type II secretion system]].<ref>{{cite journal | author = Cianciotto NP.|title=Type II secretion: a protein secretion system for all seasons |journal=Trends Microbiol. |volume=13 |issue=12 |pages=581–8 |year=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, which provides a direct conduit for proteins to move from the pathogen to the host; the proteins transported along the tube are often used to shut down host defenses.<ref>{{cite journal | author = Winstanley C, Hart CA|title=Type III secretion systems and pathogenicity islands |journal=J Med Microbiol. |volume=50 |issue=2 |pages=116–26 |year=2001 |pmid=11211218}}</ref> An evasion strategy used by several pathogens to circumvent the innate immune system is intracellular replication (also called [[intracellular]] [[pathogenesis]]). Here, a pathogen spends a majority of its 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]] [[bacteria|bacterium]] ''[[Salmonella]]'' and the [[eukaryote|eukaryotic]] parasites that cause [[malaria]] (''[[Plasmodium falciparum]]'') and [[leishmaniasis]] (''[[Leishmania|Leishmania spp.]]''). Other bacteria, such as ''[[Mycobacterium tuberculosis]]'', live inside a protective capsule that prevents [[lysis]] by complement.<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> 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, e.g., 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 bacteria generate surface proteins that bind to antibodies, rendering them ineffective; examples include ''[[Streptococcus]]'' (protein G), ''[[Staphylococcus aureus]]'' (protein A), and ''[[Peptostreptococcus|Peptostreptococcus magnus]]'' (protein L).<ref>{{cite journal | author = Housden N, Harrison S, Roberts S, Beckingham J, Graille M, Stura E, Gore M |title=Immunoglobulin-binding domains: Protein L from Peptostreptococcus magnus | url=http://www.biochemsoctrans.org/bst/031/0716/0310716.pdf |journal=Biochem Soc Trans |volume=31 |issue=Pt 3 |pages=716–8 |year=2003 |pmid=12773190 |doi=10.1042/BST0310716}}</ref> The mechanisms used by viruses 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 invader's surface, while keeping essential epitopes concealed. HIV, for example, regularly mutates the proteins on its [[viral envelope]] that are essential for entry into its host target cell. These frequent changes in antigens may explain the failures of [[vaccine]]s directed at these proteins.<ref>{{cite journal | last = Burton | first = Dennis R. | coauthors = Robyn L. Stanfield and Ian A. Wilson |title=Antibody vs. HIV in a clash of evolutionary titans | journal =Proc Natl Acad Sci U S A.|volume=102 |issue=42 |pages=14943–8 |year=2005 |pmid=16219699 |doi=10.1073/pnas.0505126102}}</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|viron]] 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".<ref>{{cite journal | author = Cantin R, Methot S, Tremblay MJ.|title=Plunder and stowaways: incorporation of cellular proteins by enveloped viruses |journal=J Virol. |volume=79 |issue=11 |pages=6577–87 |year=2005 |pmid=15890896|doi=10.1128/JVI.79.11.6577-6587.2005}}</ref> ==History of immunology== {{details|History of immunology}} [[Image:Paul Ehrlich.png|right|frame|[[Paul Ehrlich]]]] [[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 mention of 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 | author = Retief F, Cilliers L |title=The epidemic of Athens, 430-426 BC |journal=S Afr Med J |volume=88 |issue=1 |pages=50–3 |year=1998 |pmid=9539938}}</ref> This observation of acquired immunity was later exploited by [[Louis Pasteur]] in his development of [[vaccination]] and his proposed [[germ theory of disease]].<ref>{{cite journal | author = Plotkin S |title=Vaccines: past, present and future |journal=Nat Med |volume=11 |issue=4 Suppl |pages=S5–11 |year=2005 |pmid=15812490 |doi=10.1038/nm1209}}</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 [[microorganism]]s 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] Nobelprize.org Accessed [[January 8]] 2007.</ref> Viruses were confirmed as human pathogens in 1901, with the discovery of the [[yellow fever]] virus by [[Walter Reed]].<ref>[http://www.wramc.amedd.army.mil/welcome/history/ Major Walter Reed, Medical Corps, U.S. Army] Walter Reed Army Medical Center. Accessed [[January 8]] [[2007]].</ref> Immunology made a great advance towards the end of the 19th century, through rapid developments, in the study of [[humoral immunity]] and [[cellular immunity]].<ref name= Metch> {{cite book| last =Metchnikoff | first = Elie | authorlink =Elie Metchnikoff | coauthors = Translated by F.G. Binnie.| title =Immunity in Infective Diseases| publisher =Cambridge University Press| date =1905 |url=http://books.google.com/books?vid=OCLC03666307&id=ywKp9YhK5t0C&printsec=titlepage&vq=Ehrlich&dq=history+of+humoral+immunity | format =Full Text Version: Google Books| doi = | id = ISBN 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 Nobel Prize in 1908, which was jointly awarded to the founder of cellular immunology, [[Elie Metchnikoff]].<ref>[http://nobelprize.org/nobel_prizes/medicine/laureates/1908/ The Nobel Prize in Physiology or Medicine 1908] Nobelprize.org Accessed [[January 8]] [[2007]]</ref> ==See also== {{commonscat|Immunology}} *[[Clonal selection]] *[[Epitope]] *[[Hapten]] *[[Human physiology]] *[[Immunostimulator]] *[[Monoclonal antibodies]] *[[Original antigenic sin]] *[[Polyclonal antibodies]] *[[Antigen#Tumor antigens|Tumor antigens]] *[[Immune system receptors]] *[[Polyclonal response]] ==References== {{reflist|2}} ==External links== *[http://health.howstuffworks.com/immune-system.htm How Your Immune System Works] - from [[HowStuffWorks]] *[http://uhaweb.hartford.edu/BUGL/immune.htm Immune System] - from the [[University of Hartford]] *[http://www.ncbi.nlm.nih.gov/books/bv.fcgi?call=bv.View..ShowTOC&rid=imm.TOC&depth=10 Immunobiology; Fifth Edition] – Online version of the textbook by [[Charles Janeway]] (Advanced undergraduate/graduate level) *[http://www.biomedcentral.com/bmcimmunol/ Immunology] - [[BioMed Central]] (free content) scientific journal *[http://multimedia.mcb.harvard.edu/media.html The Inner Life of a Cell] - Rendering of the inner functions of the human body *[http://www.microbiologytext.com/index.php?module=Book&func=displayarticlesinchapter&chap_id=74 The Microbial World - Animal defenses against microbes] - Chapter in on-line microbiology textbook *[http://pathmicro.med.sc.edu/book/immunol-sta.htm Microbiology and Immunology On-Line Textbook] - from the [[University of South Carolina]] School of Medicine *[http://www.gsf.de/biop/en/plantimmuenglisch.phtml Plant Immunity] - Institute of Biochemical Plant Pathology at the GSF-National Research Center for Environment and Health {{immune_system}} {{lymphatic system}} {{organ systems}} {{Immune receptors}} {{featured article}} [[Category:Immune system|*]] [[Category:Immunology]] {{Link FA|pt}} [[ar:جهاز مناعي]] [[bn:অনাক্রম্যতন্ত্র]] [[bg:Имунна система]] [[ca:Sistema immunitari]] [[cs:Imunitní systém]] [[da:Immunforsvar]] [[de:Immunsystem]] [[et:Immuunsüsteem]] [[es:Sistema inmune]] [[eo:Imuna sistemo]] [[eu:Immunitate-sistema]] [[fr:Système immunitaire]] [[gl:Sistema inmunitario]] [[ko:면역체계]] [[id:Imunitas]] [[it:Sistema immunitario]] [[he:מערכת החיסון]] [[lt:Imuninė sistema]] [[mk:Имунолошки систем]] [[nl:Afweer]] [[ja:免疫系]] [[no:Immunforsvar]] [[pl:Układ odpornościowy]] [[pt:Sistema imunitário]] [[ro:Sistemul imunitar]] [[ru:Иммунная система]] [[sk:Imunitný systém]] [[sr:Имунски систем]] [[fi:Immuunijärjestelmä]] [[sv:Immunförsvar]] [[tl:Sistemang imyuno]] [[ta:நோய் எதிர்ப்பாற்றல் முறைமை]] [[tr:Bağışıklık sistemi]] [[yi:אימיון סיסטעם]] [[zh:免疫系统]]