Examine individual changes

'[[Image:Neutrophil with anthrax copy.jpg|right|thumb|[[Scanning electron microscope|Scanning electron micrograph]] of a neutrophil phagocytosing [[Bacillus anthracis|anthrax bacilli]] (orange)|alt= Long rod-shaped bacteria, one of which has been partially engulfed by a larger blob-shaped white blood cell. The shape of the cell is distorted by undigested bacterium inside it.]] '''Phagocytes''' are the [[white blood cell]]s that protect the body by ingesting ([[phagocytosis|phagocytosing]]) harmful foreign particles, [[bacteria]] and dead or [[Apoptosis|dying]] cells. They are essential for fighting infections, and for subsequent [[immunity (medical)|immunity]].<ref name=USC>{{cite web| last = Mayer| first = Gene|title=Immunology&nbsp;— Chapter One: Innate (non-specific) Immunity| work = Microbiology and Immunology On-Line Textbook| publisher = USC School of Medicine| year = 2006|url=http://pathmicro.med.sc.edu/ghaffar/innate.htm| accessdate = November 12, 2008}}</ref> Phagocytes are important throughout the animal kingdom,<ref name=Delves250>Delves p. 250</ref> and are highly developed in vertebrates.<ref>Delves p. 251</ref> One [[liter]] of human blood contains about six billion phagocytes.<ref name=Hoff-values> Hoffbrand p. 331</ref> Their name comes from the [[Greek language|Greek]] ''phagein'', 'to eat or devour', and ''kutos'', 'hollow vessel'.<ref name=ox>{{cite book| coauthors=Little, C., Fowler H.W., Coulson J.| title=The Shorter Oxford English Dictionary| publisher=Oxford University Press (Guild Publishing)| date=1983|pages=1566–67}}</ref> Phagocytes were first discovered in 1882 by [[Ilya Ilyich Mechnikov]] while he was studying [[starfish]] [[larva|larvae]].<ref name= Ilya>[http://nobelprize.org/nobel_prizes/medicine/laureates/1908/mechnikov-bio.html Ilya Mechnikov], retrieved on November 28, 2008. From [http://nobelprize.org/nobelfoundation/publications/lectures/index.html Nobel Lectures], ''Physiology or Medicine 1901–1921'', Elsevier Publishing Company, Amsterdam, 1967.</ref> Mechnikov was awarded the 1908 [[Nobel Prize in Physiology or Medicine]] for his discovery.<ref name= Paul>{{cite journal|title=Ilya Ilich Metchnikoff (1845–1915) and Paul Ehrlich (1854–1915): the centennial of the 1908 Nobel Prize in Physiology or Medicine|journal=Journal of medical biography|date=2008|first=FC|last=Schmalstieg|coauthors=AS Goldman|volume=16|issue=2|pages=96–103|pmid=18463079|unused_data=|http://jmb.rsmjournals.com/cgi/content/full/16/2/96}}</ref> Phagocytes occur in many species; some [[amoeba]]e behave like macrophages, which suggests that phagocytes appeared early in the evolution of life.<ref name=amoebaphage>Janeway, Chapter: [http://www.ncbi.nlm.nih.gov/books/bv.fcgi?highlight=phagocytes,evolution&rid=imm.section.2367#2368 Evolution of the innate immune system.]see Bibliography, retrieved on March 20, 2009</ref> Phagocytes of humans and other animals are called professional or non-professional, depending on how effective they are at [[phagocytosis]].<ref name=Ernst186>Ernst p. 186</ref> The professional phagocytes include cells called [[neutrophils]], [[monocytes]], [[macrophages]], [[dendritic cells]], and [[mast cells]].<ref name= Rob>Robinson p. 187 and Ernst pp. 7–10</ref> The main difference between professional and non-professional phagocytes is that the professional phagocytes have molecules called [[receptor (biochemistry)|receptors]] on their surfaces that can detect harmful objects, such as bacteria, that are not normally found in the body.<ref name= something>Ernst p. 10</ref> Phagocytes are therefore crucial in fighting infections, as well as in maintaining healthy tissues by removing dead and dying cells that have reached the end of their lifespan.<ref name="pathogenesis"/> During an infection, chemical signals attract phagocytes to places where the pathogen has invaded the body. These chemicals may come from bacteria, or from other phagocytes already present. The phagocytes move by a method called [[chemotaxis]]. When phagocytes come into contact with bacteria, the receptors on the phagocyte's surface will bind to it. This binding will lead to the engulfing of the bacteria by the phagocyte.<ref name=money/> When a pathogen enters some phagocytes, this can trigger a chemical attack by the phagocytes that uses [[reactive oxygen species|oxidants]] and [[nitric oxide]] to kill the pathogen.<ref name = pmid15378046>{{cite journal |author=Fang FC |title=Antimicrobial reactive oxygen and nitrogen species: concepts and controversies |journal=Nat. Rev. Microbiol. |volume=2 |issue=10 |pages=820–32 |year=2004 |month=October |pmid=15378046 |doi=10.1038/nrmicro1004}}</ref> After phagocytosis, macrophages and dendritic cells can also participate in [[antigen presentation]], a process in which a phagocyte moves parts of the ingested material back to its surface. This material is then displayed to other cells of the immune system. Some phagocytes then travel to the body's [[lymph node]]s and display the material to white blood cells called [[lymphocytes]]. This process is important in building immunity.<ref name=ATP>Janeway, Chapter: [http://www.ncbi.nlm.nih.gov/books/bv.fcgi?rid=imm.chapter.553 Antigen Presentation to T Lymphocytes.] see Bibliography, retrieved on March 20, 2009</ref> However, many pathogens have evolved methods to evade attacks by phagocytes.<ref name=USC/> ==History== [[Image:Dr Metchnikoff in his Laboratory.jpg|thumb|300px|[[Ilya Ilyich Mechnikov]] in his laboratory|alt=A bearded old man holding up a test tube. He is sitting at a table by a window. The table is covered with many small bottles and test tubes.]] The Russian zoologist [[Ilya Ilyich Mechnikov]] (1845–1916) first recognized that specialized cells were involved in defense against microbial infections. In 1882, he studied [[motility|motile]] (freely moving) cells in the [[larva|larvae]] of [[Sea star|starfishes]], believing they were important to the animals' immune defenses. To test his idea, he inserted small thorns from a [[tangerine]] tree into the larvae. After a few hours he noticed that the motile cells had surrounded the thorns.<ref>Delves p. 3</ref> Mechnikov traveled to [[Vienna]] and shared his ideas with [[Carl Friedrich Wilhelm Claus|Carl Friedrich Claus]] who suggested the name ‘‘phagocyte’’ (from the Greek words ''phagein'', meaning 'to eat or devour', and ''kutos'', meaning 'hollow vessel'<ref name=ox />) for the cells that Mechnikov had observed.<ref name="pmid9544583">{{cite journal | author = Aterman K | title = Medals, memoirs—and Metchnikoff | journal = J. Leukoc. Biol. | volume = 63 | issue = 4 | pages = 515–17 | year = 1998 | month = April | pmid = 9544583 | url = http://www.jleukbio.org/cgi/pmidlookup?view=long&pmid=9544583 | day = 01 }}</ref> A year later, Mechnikov studied a fresh-water [[crustacean]] called ''[[Daphnia]]'', a tiny transparent animal that can be examined directly under a microscope. He discovered that fungal spores that attacked the animal were destroyed by phagocytes. He went on to extend his observations to the white blood cells of mammals and discovered that the [[Bacteria|bacterium]] ''[[Bacillus anthracis]]'' could be engulfed and killed by phagocytes, a process that he called [[phagocytosis]].<ref name=autogenerated5>{{cite web|url=http://nobelprize.org/nobel_prizes/medicine/laureates/1908/mechnikov-bio.html|title=Ilya Mechnikov|accessdate=November 28, 2008|publisher=The Nobel Foundation}}</ref> Mechnikov proposed that phagocytes were a primary defense against invading organisms. In 1903, [[Amroth Wright]] discovered that phagocytosis was reinforced by specific [[antibody|antibodies]] which he called [[opsonin]]s, from the Greek "opson", a dressing or relish.<ref>Delves p. 263</ref> Mechnikov was awarded (jointly with [[Paul Ehrlich]]) the 1908 [[Nobel Prize in Physiology or Medicine]] for his work on phagocytes and phagocytosis.<ref name= Paul/> Although the importance of these discoveries slowly gained acceptance during the early twentieth century, the intricate relationships between phagocytes and all the other components of the immune system were not known until the 1980s.<ref>Robinson p. vii</ref> ==Phagocytosis== {{main|Phagocytosis}} [[Image:Phagocytosis in three steps.png|thumb|Phagocytosis in three steps: 1. Unbound phagocyte surface receptors do not trigger phagocytosis. 2. Binding of receptors causes them to cluster. 3. Phagocytosis is triggered and the particle is taken-up by the phagocyte.|alt=A cartoon: 1. The particle is depicted by an oval and the surface of the phagocyte by a straight line. Different smaller shapes are on the line and the oval. 2. The smaller particles on each surface join. 3. The line is now concave and partially wraps around the oval.]] Phagocytosis is the process of taking in particles such as bacteria, parasites, [[apoptosis|dead host cells]] and cellular and foreign debris by a cell.<ref name=superman2>Ernst p. 4</ref> It involves a chain of molecular processes.<ref>Ernst p. 78</ref> Phagocytosis occurs after the foreign body, a bacterial cell for example, has bound to molecules called "receptors" that are on the surface of the phagocyte. Then the phagocyte stretches itself around the bacterium and engulfs it. Phagocytosis of bacteria by human neutrophils takes on average nine minutes.<ref name="pmid8301210">{{cite journal | author = Hampton MB, Vissers MC, Winterbourn CC | title = A single assay for measuring the rates of phagocytosis and bacterial killing by neutrophils | journal = J. Leukoc. Biol. | volume = 55 | issue = 2 | pages = 147–52 | year = 1994 | month = February | pmid = 8301210 | doi = | url = http://www.jleukbio.org/cgi/pmidlookup?view=long&pmid=8301210 | issn = }}</ref> Once inside this phagocyte, the bacterium is trapped in a compartment called a [[phagosome]]. Within one minute the phagosome merges with either a [[lysosome]] or a [[Granule (cell biology)|granule]] to form a [[phagolysosome]]. The imprisoned bacterium is then submitted to a formidable battery of killing mechanisms,<ref>Delves pp. 6–7</ref> and is dead a few minutes later.<ref name="pmid8301210"/> Dendritic cells and macrophages are not so fast and phagocytosis can take many hours in these cells. Macrophages are slow and untidy eaters but they engulf huge quantities of material and frequently release some undigested back into the tissues. This debris serves as a signal to recruit more phagocytes from the blood.<ref>Sompayrac p. 3</ref> Phagocytes will eat almost anything; scientists have fed macrophages with [[iron filings]] and then used a small magnet to separate them from other cells in a mixture.<ref>Sompayrac p. 2</ref> [[Image:Opsonin.png|thumb|left|Macrophages have special receptors that enhance phagocytosis (not to scale)|alt=A cartoon: The macrophage is depicted as a distorted solid circle. On the surface of the circle is a small y-shaped figure that is connected to a solid rectangle which depicts a bacterium.]] A phagocyte has many types of receptors on its surface that are used to bind material.<ref name=USC/> They include [[opsonin]] receptors, scavenger receptors, and [[Toll-like receptors]]. Opsonin receptors increase the phagocytosis of bacteria that have been coated with [[complement system|complement]] or [[IgG]] [[antibodies]]. Complement is the name given to a complex series of protein molecules found in the blood that destroy or mark cells for destruction.<ref>Sompayrac pp. 13–16</ref> Scavenger receptors bind to a large range of molecules on the surface of bacterial cells, and Toll-like receptors—so called because of their similarity to well-studied receptors in fruit flies that are encoded by the [[Toll (gene)|Toll gene]]—bind to more specific molecules. Binding to Toll-like receptors increases phagocytosis and causes the phagocyte to release a group of hormones that cause [[inflammation]].<ref name=USC/> ==Methods of killing== [[image:Phagocytosis2.png|thumb|Simplified diagram of the phagocytosis and destruction of a bacterial cell|alt=A cartoon that depicts the engulfment of a single bacterium, its passage through a cell where it is digested and released as debris.]] The killing of microbes is a critical function of phagocytes,<ref name="pmid18684880">{{cite journal | author = Dale DC, Boxer L, Liles WC | title = The phagocytes: neutrophils and monocytes | journal = Blood | volume = 112 | issue = 4 | pages = 935–45 | year = 2008 | month = August | pmid = 18684880 | doi = 10.1182/blood-2007-12-077917 | url = http://www.bloodjournal.org/cgi/pmidlookup?view=long&pmid=18684880 }}</ref> and is either performed within the phagocyte ([[intracellular]] killing) or outside of the phagocyte ([[extracellular]] killing). ===Oxygen-dependent intracellular=== When a phagocyte ingests bacteria (or any material), its oxygen consumption increases. The increase in oxygen consumption is called a [[respiratory burst]], which produces reactive oxygen-containing molecules that are anti-microbial.<ref>{{cite journal|title=Respiratory burst in human neutrophils.|journal=Journal of Immunological Methods|date=December 17, 1999|first=C|last=Dahlgren|coauthors=A Karlsson|volume=232|issue=1–2|pages=3–14|pmid=10618505|doi=10.1016/S0022-1759(99)00146-5}}</ref> The oxygen compounds are toxic to both the invader and the cell itself, so they are kept in compartments inside the cell. This method of killing invading microbes by using the reactive oxygen-containing molecules is referred to as oxygen-dependent intracellular killing, of which there are two types.<ref name = pmid15378046/> The first type is the oxygen-dependent production of a [[superoxide]],<ref name=USC/> which is an important, oxygen-rich, bacteria-killing substance.<ref>{{cite journal|title=NADPH oxidase.|journal=The international journal of biochemistry and cell biology.|date=1996|first=KP|last=Shatwell|coauthors=AW Segal|volume=28|issue=11|pages=1191–95|pmid=9022278|doi=10.1016/S1357-2725(96)00084-2}}</ref> The superoxide is converted to [[hydrogen peroxide]] and [[singlet oxygen]] by an enzyme called [[superoxide dismutase]]. Superoxides also react with the hydrogen peroxide to produce [[hydroxyl radicals]] which assist in killing the invading microbe.<ref name=USC/> The second type involves the use of the enzyme [[myeloperoxidase]] from neutrophil granules.<ref name="pmid10519157">{{cite journal | author = Klebanoff SJ | title = Myeloperoxidase | journal = Proc. Assoc. Am. Physicians | volume = 111 | issue = 5 | pages = 383–89 | year = 1999 | pmid = 10519157 | doi = | issn = | }}</ref> When granules fuse with a phagosome, myeloperoxidase is released into the phagolysosome and this enzyme uses hydrogen peroxide and [[chlorine]] to create [[hypochlorite]], a substance used in domestic [[bleach]]. Hypochlorite is extremely toxic to bacteria.<ref name=USC/> Myeloperoxidase contains a [[heme]] pigment, which makes secretions rich in neutrophils, such as pus and infected [[sputum]], green.<ref name="pmid15478278">{{cite journal | author = Meyer KC | title = Neutrophils, myeloperoxidase, and bronchiectasis in cystic fibrosis: green is not good | journal = J. Lab. Clin. Med. | volume = 144 | issue = 3 | pages = 124–26 | year = 2004 | month = September | pmid = 15478278 | doi = 10.1016/j.lab.2004.05.014| url =http://www.journals.elsevierhealth.com/periodicals/ymlc/article/PIIS0022214304001453/fulltext }}</ref> ===Oxygen-independent intracellular=== [[image:Gonococcal urethritis PHIL 4085 lores.jpg|right|thumb|Micrograph of [[Gram-stain]]ed pus showing ''[[Neisseria gonorrhoeae]]'' bacteria inside phagocytes and their relative sizes|alt=Pus under a microscope, there are many white blood cells with lobed nuclei. Inside some of the cells there are hundreds of bacteria which have been engulfed.]] Phagocytes can also kill microbes by oxygen-independent methods, but these are not as effective as the oxygen-dependent ones. There are four main types: The first uses electrically charged proteins which damage the bacterium's [[cell membrane|membrane]]. The second type uses lysozymes; these enzymes break down the bacterial [[cell wall]]. The third type uses [[lactoferrin]]s, which are present in neutrophil granules and remove essential iron from bacteria.<ref>Hoffbrand p. 118</ref> The fourth type uses [[proteases]] and [[hydrolytic enzymes]]; these enzymes are used to digest the proteins of destroyed bacteria.<ref>Delves pp. 6–10</ref> ===Extracellular=== [[Interferon-gamma]]—which was once called macrophage activating factor—stimulates macrophages to produce [[nitric oxide]]. The source of interferon-gamma can be [[CD4+ T cells|CD4⁺ T cells]], [[CD8+ T cells|CD8⁺ T cells]], [[NK cell|natural killer cells]], [[B cells]], [[NKT cell|natural killer T cells]], monocytes, macrophages, or dendritic cells.<ref name="pmid14525967">{{cite journal | author = Schroder K, Hertzog PJ, Ravasi T, Hume DA | title = Interferon-gamma: an overview of signals, mechanisms and functions | journal = J. Leukoc. Biol. | volume = 75 | issue = 2 | pages = 163–89 | year = 2004 | month = February | pmid = 14525967 | doi = 10.1189/jlb.0603252 | url = http://www.jleukbio.org/cgi/content/full/75/2/163 }}</ref> Nitric oxide is then released from the macrophage and, because of its toxicity, kills microbes near the macrophage.<ref name=USC/> Activated macrophages produce and secrete [[tumor necrosis factors|tumor necrosis factor]]. This [[cytokine]]—a class of signaling molecules<ref>Delves p. 188</ref>—kills cancer cells and cells infected by viruses, and helps to activate the other cells of the immune system.<ref name=autogenerated2>Sompayrac p. 17</ref> In some diseases, e.g. the rare [[chronic granulomatous disease]], the efficiency of phagocytes is impaired and recurrent bacterial infections are a problem.<ref name="pmid18846805">{{cite journal | author = Lipu HN, Ahmed TA, Ali S, Ahmed D, Waqar MA| title = Chronic granulomatous disease| journal = J Pak Med Assoc| volume = 58| issue = 9| pages = 516–18| year = 2008| month = September| pmid = 18846805| accessdate = February 20, 2009}}</ref> In this disease there is an abnormality affecting different elements of oxygen-dependent killing. Other rare congenital abnormalities, such as [[Chediak-Higashi syndrome]], are also associated with defective killing of ingested microbes.<ref name="pmid18043242">{{cite journal | author = Kaplan J, De Domenico I, Ward DM | title = Chediak-Higashi syndrome | journal = Curr. Opin. Hematol. | volume = 15 | issue = 1 | pages = 22–29 | year = 2008 | month = January | pmid = 18043242 | doi = 10.1097/MOH.0b013e3282f2bcce | url = http://meta.wkhealth.com/pt/pt-core/template-journal/lwwgateway/media/landingpage.htm?an=00062752-200801000-00005 | accessdate = April 11, 2009}}</ref> ===Viruses=== [[Virus]]es can only reproduce inside cells and they gain entry by using many of the receptors involved in immunity. Once inside the cell, viruses use the cell's biological machinery to their own advantage—forcing the cell to make hundreds of identical copies of themselves. Although phagocytes and other components of the innate immune system can, to a limited extent, control viruses, once a virus is inside a cell the adaptive immune responses, particularly the lymphocytes, are more important for defense.<ref>Sompayrac p. 7</ref> At the sites of viral infections, lymphocytes often vastly outnumber all the other cells of the immune system; this is common in viral [[meningitis]].<ref name="pmid17962876">{{cite journal | author = de Almeida SM, Nogueira MB, Raboni SM, Vidal LR | title = Laboratorial diagnosis of lymphocytic meningitis | journal = Braz J Infect Dis | volume = 11 | issue = 5 | pages = 489–95 | year = 2007 | month = October | pmid = 17962876 | doi = | url = http://www.scielo.br/scielo.php?script=sci_arttext&pid=S1413-86702007000500010&lng=en&nrm=iso&tlng=en | accessdate = March 29, 2009}}</ref> Virus infected cells that have been killed by lymphocytes are cleared from the body by phagocytes.<ref>Sompayrac p. 22</ref> ==Role in apoptosis== {{main|Apoptosis}} [[Image:Apoptosis.png|thumb|Apoptosis—phagocytes clear fragments of dead cells from the body]] In an animal there are constantly cells that die. A balance between [[cell division]] and cell death keeps the number of cells relatively constant in adults.<ref name="pathogenesis">{{cite journal | author=Thompson, CB| title=Apoptosis in the pathogenesis and treatment of disease| journal=Science| year=1995| volume=267| issue=5203| pages=1456–62| doi=10.1126/science.7878464| pmid=7878464}}</ref> There are two different ways a cell can die: by [[necrosis]] or by apoptosis. In contrast to necrosis, which often results from disease or trauma, apoptosis—or [[programmed cell death]]—is a normal healthy function of cells. The body has to rid itself of millions of dead or dying cells every day and phagocytes play a crucial role in this process.<ref>Sompayrac p. 63</ref> Dying cells that undergo the final stages of [[apoptosis]]<ref> {{cite web|url=http://www.merriam-webster.com/dictionary/apoptosis |title=Apoptosis |accessdate=March 19, 2009 |work=Merriam-Webster Online Dictionary }}</ref> display molecules, such as [[phosphatidylserine]], on their cell surface to attract phagocytes.<ref name="pmid14645847">{{cite journal | author = Li MO, Sarkisian MR, Mehal WZ, Rakic P, Flavell RA | title = Phosphatidylserine receptor is required for clearance of apoptotic cells | journal = Science (journal) | volume = 302 | issue = 5650 | pages = 1560–63 | year = 2003 | month = November | pmid = 14645847 | doi = 10.1126/science.1087621 | url = http://www.sciencemag.org/cgi/content/full/302/5650/1560 }} (Free registration required for online access)</ref> Phosphatidylserine is normally found on the [[cytoplasm|cytosolic]] surface of the plasma membrane, but is redistributed during apoptosis to the extracellular surface by a hypothetical protein known as [[scramblase]].<ref name="phago2">{{cite journal| author=Wang X, ''et al.''| title=Cell corpse engulfment mediated by ''C. elegans'' phosphatidylserine receptor through CED-5 and CED-12| journal=Science| year=2003| volume=302| issue=5650| pages=1563–1566| doi=10.1126/science.1087641| pmid=14645848 | url=http://www.sciencemag.org/cgi/content/full/302/5650/1563 }} (Free registration required for online access)</ref> These molecules mark the cell for phagocytosis by cells that possess the appropriate receptors, such as macrophages.<ref name="phago1">{{cite journal| author=Savill J, Gregory C, Haslett C.| title=Eat me or die| journal=Science| year=2003| volume=302| issue=5650| pages=1516–17| doi=10.1126/science.1092533| pmid=14645835}}</ref> The removal of dying cells by phagocytes occurs in an orderly manner without eliciting an [[inflammatory response]] and is an important function of phagocytes.<ref name="pmid18774293">{{cite journal | author = Zhou Z, Yu X | title = Phagosome maturation during the removal of apoptotic cells: receptors lead the way | journal = Trends Cell Biol. | volume = 18 | issue = 10 | pages = 474–85 | year = 2008 | month = October | pmid = 18774293 | doi = 10.1016/j.tcb.2008.08.002 }}</ref> ==Interactions with other cells== Phagocytes are not bound to any particular [[organ (anatomy)|organ]] but move through the body, interacting with the other phagocytic and non-phagocytic cells of the immune system. They can communicate with other cells by producing chemicals called [[cytokines]], which recruit other phagocytes to the site of infections or stimulate dormant [[lymphocyte]]s.<ref>Sompayrac p. 44</ref> Phagocytes form part of the [[innate immune system]] which animals, including humans, are born with. Innate immunity is very effective but non-specific in that it does not discriminate between different sorts of invaders. On the other hand, the [[adaptive immune system]] of jawed vertebrates—the basis of acquired immunity—is highly specialized and can protect against almost any type of invader.<ref>Sompayrac p. 4</ref> The adaptive immune system is dependent on lymphocytes, which are not phagocytes, but produce protective proteins called [[antibody|antibodies]] which tag invaders for destruction and prevent [[virus]]es from infecting cells.<ref>Sompayrac pp. 24–35</ref> Phagocytes, in particular dendritic cells and macrophages, stimulate lymphocytes to produce antibodies by an important process called [[antigen]] presentation.<ref>Delves pp. 171–184</ref> ===Antigen presentation=== {{main|Antigen presentation}} [[Image:MHC_Class_I_processing.svg|thumb|A schematic diagram of the presentation of foreign peptides by MHC&nbsp;1 molecules]] Antigen presentation is a process in which some phagocytes move parts of engulfed materials back to the surface of their cells and "present" them to other cells of the immune system.<ref>Delves p. 456</ref> There are two "professional" antigen-presenting cells: macrophages and dendritic cells.<ref name= paper>{{cite web|url=http://pim.medicine.dal.ca/apc.htm|archiveurl=http://web.archive.org/web/20080112211805/http://pim.medicine.dal.ca/apc.htm|archivedate=2008-01-12|title=Antigen Presenting Cells (APC)|accessdate=November 12, 2008|publisher=Dalhousie University|work=Immunology for 1st Year Medical Students|author=Timothy Lee|year=2004}}</ref> After engulfment, foreign proteins (the [[antigen]]s) are broken down into [[peptide]]s inside dendritic cells and macrophages. These peptides are then bound to the cell's [[major histocompatibility complex]] (MHC) glycoproteins, which carry the peptides back to the phagocyte's surface where they can be "presented" to lymphocytes.<ref name=ATP/> Mature macrophages do not travel far from the site of infection, but dendritic cells can reach the body's [[lymph node]]s where there are millions of lymphocytes.<ref>Delves p. 161</ref> This enhances immunity because the lymphocytes respond to the antigens presented by the dendritic cells just as they would at the site of the original infection.<ref>Sompayrac p. 8</ref> But dendritic cells do not always co-operate with lymphocytes and will destroy them if necessary to protect the body. This is seen in a process called tolerance.<ref>Delves pp. 237–242</ref> ===Immunological tolerance=== {{main|Immunological tolerance}} Dendritic cells also promote immunological tolerance,<ref name=somethingcool>{{cite journal | author = Lange C, Dürr M, Doster H, Melms A, Bischof F | title = Dendritic cell-regulatory T-cell interactions control self-directed immunity | journal = Immunol. Cell Biol. | volume = 85 | issue = 8 | pages = 575–81 | year = 2007 | pmid = 17592494 | doi = 10.1038/sj.icb.7100088| accessdate = March 29, 2009}}</ref> which stops the body from attacking itself. The first type of tolerance is [[central tolerance]]: when [[T cell]]s first depart from the [[thymus]], dendritic cells destroy the T cells that carry antigens that would cause the immune system to attack itself. The second type of immunological tolerance is [[peripheral tolerance]]. Some T cells that possess antigens that would cause them to attack "self" slip through the first process of tolerance, some T cells develop self-attacking antigens later in life, and some self-attacking antigens are not found in the thymus; because of this dendritic cells will work, again, to restrain the activities of self-attacking T cells outside of the thymus. Dendritic cells can do this by destroying them or by recruiting the help of [[regulatory T cell]]s to inactivate the harmful T cells' activities.<ref name=rocky>{{cite web|url=http://www.rockefeller.edu/labheads/steinman/dendritic_intro/immuneTolerance.php|title=Dendritic Cells and Immune Tolerance|accessdate=February 15, 2009|last=Steinman|first=Ralph M.|date=2004|publisher=The Rockefeller University}}</ref> When immunological tolerance fails, [[autoimmune disease]]s can follow.<ref>{{cite journal|title=Immunological tolerance and autoimmunity.|journal=Internal and emergency medicine.|date=2006|first=S|last=Romagnani|volume=1|issue=3|pages=187–96|pmid=17120464|doi=10.1007/BF02934736}}</ref> On the other hand, too much tolerance allows some infections, like [[HIV]], to go unnoticed.<ref name=rocky /> ==Professional phagocytes== [[Image:Myeloid cells.png|thumb|300px|Phagocytes derive from stem cells in the bone marrow|alt=A cartoon showing the relationships between a stem cell and mature white blood cells. Eight different types of white blood cell can derive from the same stem cell.]] Phagocytes of humans and other jawed vertebrates are divided into "professional" and "non-professional" groups based on the efficiency with which they participate in phagocytosis.<ref name=Ernst186/> The professional phagocytes are the [[monocytes]], [[macrophages]], [[neutrophils]], tissue [[dendritic cell]]s and [[mast cell]]s.<ref name= Rob/> One [[liter]] of human blood contains about six billion phagocytes.<ref name=Hoff-values/> ===Activation=== All phagocytes, and especially macrophages, exist in degrees of readiness. Macrophages are usually relatively dormant in the tissues and proliferate slowly. In this semi-resting state they clear away dead host cells and other non-infectious debris and rarely take part in antigen presentation. But during an infection they receive chemical signals—usually [[interferon gamma]]—which increases their production of [[MHC class II|MHC II]] molecules and which prepares them for presenting antigens. In this state, macrophages are good antigen presenters and killers. However, if they receive a signal directly from an invader they become "hyperactivated", stop proliferating and concentrate on killing. Their size and rate of phagocytosis increases—some become large enough to engulf invading [[protozoa]].<ref>Sompayrac pp. 16–17</ref> In the blood, neutrophils are inactive but are swept along at high speed. When they receive signals from macrophages at the sites of inflammation, they slow down and leave the blood. In the tissues they are activated by cytokines and arrive at the battle scene ready to kill.<ref>Sompayrac pp. 18–19</ref> ===Migration=== [[Image:NeutrophilerAktion.png|thumb|upright|Neutrophils move from the blood to the site of infection|alt=A cartoon depicting a blood vessel and its surrounding tissue cells. There are three similar white blood cells, one in the blood and two among the tissue cells. The ones in the tissue are producing granules that can destroy bacteria.]] When an infection occurs, a chemical "SOS" signal is given off to attract phagocytes to the site.<ref>Delves p. 6</ref> These chemical signals may include proteins from invading [[bacteria]], clotting system [[peptides]], [[Complement system|complement]] products, and cytokines that have been given off by macrophages located in the tissue near the infection site.<ref name=USC/> Another group of chemical attractants are [[cytokines]] which recruit neutrophils and monocytes from the blood.<ref name=money>Janeway, Chapter: [http://www.ncbi.nlm.nih.gov/books/bv.fcgi?highlight=migration&rid=imm.section.203#206 Induced innate responses to infection.] see Bibliography, retrieved on March 20, 2009</ref> To reach the site of infection, phagocytes leave the blood stream and enter the affected tissues. Signals from the infection cause the [[endothelial]] cells that line the blood vessels to make a protein called [[selectin]] which neutrophils stick to on passing by. Other signals called [[vasodilator]]s loosen the junctions connecting endothelial cells, allowing the phagocytes to pass through the wall. [[Chemotaxis]] is the process by which phagocytes follow the cytokine "scent" to the infected spot.<ref name=USC/> Neutrophils travel across [[epithelial]] cell-lined organs to sites of infection and although this is an important component of fighting infection, the migration itself can result in disease-like symptoms.<ref name="pmid14519390">{{cite journal | author = Zen K, Parkos CA | title = Leukocyte-epithelial interactions | journal = Curr. Opin. Cell Biol. | volume = 15 | issue = 5 | pages = 557–64 | year = 2003 | month = October | pmid = 14519390 | doi = | url = http://linkinghub.elsevier.com/retrieve/pii/S0955067403001030 | issn = | accessdate = March 29, 2009}}</ref> During an infection millions of neutrophils are recruited from the blood but they die after a few days.<ref>Sompayrac p. 79</ref> ===Monocytes=== {{main|Monocytes}} [[Image:Echaff.jpg|thumb|upright|Monocytes with lobed nuclei surrounded by red blood cells (low magnification)]] Monocytes develop in the bone marrow and reach maturity in the blood. Mature monocytes have large, smooth, lobed nuclei and abundant [[cytoplasm]] that contains granules. Monocytes ingest foreign or dangerous substances and present [[antigens]] to other cells of the immune system. Monocytes form two groups: a circulating group and a marginal group which remain in other tissues (approximately 70% are in the marginal group). Most monocytes leave the blood stream after 20–40 hours to travel to tissues and organs, and in doing so transform into macrophages<ref>Hoffbrand p. 117</ref> or dendritic cells depending on the signals they receive.<ref>Delves pp. 1–6</ref> There are about 500 million monocytes in one liter of human blood.<ref name=Hoff-values /> ===Macrophages=== {{main|Macrophages}} Mature macrophages do not travel far but stand guard over those areas of the body that are exposed to the outside world. There they act as garbage collectors, antigen presenting cells, or ferocious killers depending on the signals they receive.<ref>Sompayrac p. 45</ref> They derive from monocytes, [[granulocyte]] stem cells, or the [[cell division]] of pre-existing macrophages.<ref name="pmid8870002">{{cite journal | author = Takahashi K, Naito M, Takeya M | title = Development and heterogeneity of macrophages and their related cells through their differentiation pathways | journal = Pathol. Int. | volume = 46 | issue = 7 | pages = 473–85 | year = 1996 | month = July | pmid = 8870002 | doi = 10.1111/j.1440-1827.1996.tb03641.x }}</ref> Human macrophages are about 21 micrometers in diameter.<ref>{{cite journal |author=Krombach F, Münzing S, Allmeling AM, Gerlach JT, Behr J, Dörger M |title=Cell size of alveolar macrophages: an interspecies comparison |journal=Environ. Health Perspect. |volume=105 Suppl 5 |pages=1261–63 |year=1997 |month=September |pmid=9400735 |pmc=1470168 |doi= 10.2307/3433544}}</ref> [[Image:Cutaneous abscess MRSA staphylococcus aureus 7826 lores.jpg|thumb|left|[[Pus]] oozing from an [[abscess]] caused by bacteria—pus contains millions of phagocytes|alt=A person's thigh with a red area that is inflamed. At the centre of the inflammation is a wound with pus.]] This type of phagocyte does not have granules but contains many [[lysosome]]s. Macrophages are found throughout the body in almost all tissues and organs (e.g., [[microglial cell]]s in the [[brain]] and [[pulmonary alveolus|alveolar]] macrophages in the [[lungs]]) where they silently lie in wait. A macrophage's location can determine its size and appearance. Macrophages cause inflammation through the production of [[interleukin-1]], [[interleukin-6]], and [[Tumor necrosis factor-alpha|TNF-alpha]].<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| year = 2006|url=http://pathmicro.med.sc.edu/bowers/imm-reg.htm| accessdate = November 14, 2008}}</ref> Macrophages are usually only found in tissue and are rarely seen in blood circulation. The life-span of tissue macrophages has been estimated to range from four to fifteen days.<ref> Ernst p. 8 </ref> Macrophages can be activated to perform functions that a resting monocyte cannot.<ref name=USCmac/> [[T helper cells]] (also known as effector T cells or Th cells), a sub-group of lymphocytes, are responsible for the activation of macrophages. Th1 cells activate macrophages by signaling with [[IFN-gamma]] and displaying the protein [[CD40 ligand]].<ref>Delves p. 156</ref> Other signals include TNF-alpha and [[lipopolysaccharides]] from bacteria.<ref name=USCmac/> Th1 cells can recruit other phagocytes to the site of the infection in several ways. They secrete cytokines that act on the [[bone marrow]] to stimulate the production of monocytes and neutrophils and they secrete some of the [[cytokine]]s and that are responsible for the migration of monocytes and neutrophils out of the blood stream.<ref>Delves p. 187</ref> Th1 cells come from the [[cellular differentiation|differentiation]] of CD4⁺ T cells once they have responded to antigen in the [[lymphatic system|secondary lymphoid tissues]].<ref name=USCmac/> Activated macrophages play a potent role in [[tumor]] destruction by producing TNF-alpha, IFN-gamma, nitric oxide, reactive oxygen compounds, [[cation]]ic proteins, and hydrolytic enzymes.<ref name=USCmac/> ===Neutrophils=== {{main|Neutrophils}} [[Image:Neutrophil2.jpg|thumb|A neutrophil with a segmented nucleus (center and surrounded by [[erythrocytes]]), the intra-cellular granules are visible in the [[cytoplasm]] ([[Giemsa stain]]ed high magnification)|alt=A round cell with a lobed nucleus surrounded by many slightly smaller red blood cells.]] Neutrophils are normally found in the [[circulatory system|bloodstream]] and are the most abundant type of phagocyte, constituting 50% to 60% of the total circulating white blood cells.<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 | year = 1995 | location = Computing Centre, Slovak Academy of Sciences |url=http://nic.sav.sk/logos/books/scientific/node15.html |isbn = 80-967366-1-2 | accessdate = March 28, 2009 | chapter=Neutrophils, central cells in acute inflammation}}</ref> One liter of human blood contains about five billion neutrophils,<ref name=Hoff-values /> which are about 10 [[micrometer]]s in diameter,<ref>Delves p. 4</ref> and live for only about five days.<ref name=autogenerated2 /> Once they have received the appropriate signals, it takes them about thirty minutes to leave the blood and reach the site of an infection.<ref name=Som18> Sompayrac p. 18</ref> They are ferocious eaters and rapidly engulf invaders coated with [[antibody|antibodies]] and [[complement system|complement]], and damaged cells or cellular debris. Neutrophils do not return to the blood; they turn into [[pus]] cells and die.<ref name=Som18/> Mature neutrophils are smaller than monocytes, and have a segmented [[Cell nucleus|nucleus]] with several sections; each section is connected by [[chromatin]] filaments—neutrophils can have 2–5 segments. Neutrophils do not normally exit the bone marrow until maturity but during an infection neutrophil precursors called [[myelocyte]]s and [[promyelocyte]]s are released.<ref name="pmid9853933">{{cite journal | author = Linderkamp O, Ruef P, Brenner B, Gulbins E, Lang F | title = Passive deformability of mature, immature, and active neutrophils in healthy and septicemic neonates | journal = Pediatr. Res. | volume = 44 | issue = 6 | pages = 946–50 | year = 1998 | month = December | pmid = 9853933 | doi = | url = http://meta.wkhealth.com/pt/pt-core/template-journal/lwwgateway/media/landingpage.htm?issn=0031-3998&volume=44&issue=6&spage=946 | issn = | accessdate = April 6, 2009}}</ref> The intra-cellular granules of the human neutrophil have long been recognized for their protein-destroying and bactericidal properties.<ref>Paoletti p. 62</ref> Neutrophils can secrete products that stimulate monocytes and macrophages. Neutrophil secretions increase phagocytosis and the formation of reactive oxygen compounds involved in intracellular killing.<ref name="pmid17991288">{{cite journal | author = Soehnlein O, Kenne E, Rotzius P, Eriksson EE, Lindbom L | title = Neutrophil secretion products regulate anti-bacterial activity in monocytes and macrophages | journal = Clin. Exp. Immunol. | volume = 151 | issue = 1 | pages = 139–45 | year = 2008 | month = January | pmid = 17991288 | pmc = 2276935 | doi = 10.1111/j.1365-2249.2007.03532.x. | url = http://www3.interscience.wiley.com/resolve/openurl?genre=article&sid=nlm:pubmed&issn=0009-9104&date=2008&volume=151&issue=1&spage=139| accessdate = March 29, 2009}}</ref> Secretions from the [[azurophilic granules|primary granules]] of neutrophils stimulate the phagocytosis of [[IgG]] antibody-coated bacteria.<ref name="pmid18787642">{{cite journal | author = Soehnlein O, Kai-Larsen Y, Frithiof R, ''et al'' | title = Neutrophil primary granule proteins HBP and HNP1-3 boost bacterial phagocytosis by human and murine macrophages | journal = J. Clin. Invest. | volume = 118 | issue = 10 | pages = 3491–502 | year = 2008 | month = October | pmid = 18787642 | pmc = 2532980 | doi = 10.1172/JCI35740 | accessdate = March 29, 2009}}</ref> ===Dendritic cells=== {{main|Dendritic cell}} [[Image:Dendritic cell.JPG|thumb|A dendritic cell|alt=One dendritic cell which is almost the shape of a star. Its edges are ragged.]] Dendritic cells are specialized antigen-presenting cells that have long outgrowths called dendrites,<ref name=Steinman>{{cite journal|author=Steinman RM, Cohn ZA|title=Identification of a novel cell type in peripheral lymphoid organs of mice. I. Morphology, quantitation, tissue distribution|journal=J. Exp. Med.|volume=137|issue=5|pages=1142–62|year=1973|pmid=4573839|doi=10.1084/jem.137.5.1142|pmc=2139237}}</ref> which help to engulf microbes and other invaders.<ref name=rock>{{cite web|url=http://www.rockefeller.edu/labheads/steinman/steinman-lab.php|title=Dendritic Cells|accessdate=November 14, 2008|last=Steinman|first=Ralph|publisher=The Rockefeller University}}</ref><ref name=antigen>{{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 | url = http://arjournals.annualreviews.org/doi/abs/10.1146/annurev.immunol.20.100301.064828?url_ver=Z39.88-2003&rfr_id=ori:rid:crossref.org&rfr_dat=cr_pub%3dncbi.nlm.nih.gov| accessdate = March 29, 2009}} </ref> Dendritic cells are present in the tissues that are in contact with the external environment; mainly the skin, the inner lining of the nose, lungs, stomach and intestines.<ref>Hoffbrand p. 134</ref> Once activated, they mature and migrate to the lymphoid tissues where they interact with [[T cells]] and [[B cells]] to initiate and orchestrate the adaptive immune response.<ref>{{cite journal|author=Sallusto F, Lanzavecchia A|title=The instructive role of dendritic cells on T-cell responses|journal=Arthritis Res.|volume=4 Suppl 3|pages=S127–32|year=2002|pmid=12110131|doi=10.1186/ar567|url=http://arthritis-research.com/content/4/S3/S127/?mkt=}}</ref> Mature dendritic cells activate [[T helper cell]]s and [[cytotoxic T cell]]s.<ref>Sompayrac pp. 42–46</ref> The activated helper T cells interact with macrophages and B cells to activate them in turn. In addition, dendritic cells can influence the type of immune response produced; when they travel to the lymphoid areas where T cells are held they can activate T cells which then differentiate into cytotoxic T cells or helper T cells.<ref name=autogenerated1>{{cite web|url=http://www.rockefeller.edu/labheads/steinman/steinman-lab.php|title=Dendritic Cells|accessdate=November 16, 2008|last=Steinman|first=Ralph|publisher=The Rockefeller University}}</ref> ===Mast cells=== {{main|Mast cell}} Mast cells have [[Toll-like receptor]]s and interact with dendritic cells, B cells, and T cells, to help mediate adaptive immune functions. Mast cells express [[MHC class II]] molecules and can participate in antigen presentation; however, the mast cell's role in antigen presentation is not very well understood.<ref name="pmid17544835">{{cite journal | author = Stelekati E, Orinska Z, Bulfone-Paus S | title = Mast cells in allergy: innate instructors of adaptive responses | journal = Immunobiology | volume = 212 | issue = 6 | pages = 505–19 | year = 2007 | pmid = 17544835 | doi = 10.1016/j.imbio.2007.03.012 | url = http://linkinghub.elsevier.com/retrieve/pii/S0171-2985(07)00031-9 | accessdate = March 29, 2009}}</ref> Mast cells can consume and kill [[gram-negative bacteria]] (e.g., [[salmonella]]), and process their antigens.<ref name=mast>{{cite journal | author = Malaviya R, Abraham SN | title = Mast cell modulation of immune responses to bacteria | journal = Immunol. Rev. | volume = 179 | issue = | pages = 16–24 | year = 2001 | month = February | pmid = 11292019 | doi = 10.1034/j.1600-065X.2001.790102.x| url = http://www3.interscience.wiley.com/resolve/openurl?genre=article&sid=nlm:pubmed&issn=0105-2896&date=2001&volume=179&spage=16| accessdate = March 29, 2009}}</ref> They specialize in processing the [[fimbria (bacteriology)|fimbrial proteins]] on the surface of bacteria, which are involved in adhesion to tissues.<ref name="pmid8790416">{{cite journal |author=Connell I, Agace W, Klemm P, Schembri M, Mărild S, Svanborg C |title=Type 1 fimbrial expression enhances ''Escherichia coli'' virulence for the urinary tract |journal=Proc. Natl. Acad. Sci. U.S.A. |volume=93 |issue=18 |pages=9827–32 |year=1996 |month=September |pmid=8790416 |pmc=38514 |doi= 10.1073/pnas.93.18.9827|url=http://www.pnas.org/cgi/pmidlookup?view=long&pmid=8790416}}</ref><ref name="pmid8568252">{{cite journal | author = Malaviya R, Twesten NJ, Ross EA, Abraham SN, Pfeifer JD | title = Mast cells process bacterial Ags through a phagocytic route for class I MHC presentation to T cells | journal = J. Immunol. | volume = 156 | issue = 4 | pages = 1490–96 | year = 1996 | month = February | pmid = 8568252 | doi = | url = http://www.jimmunol.org/cgi/pmidlookup?view=long&pmid=8568252 | accessdate = March 29, 2009}}</ref> In addition to these functions, mast cells produce cytokines that induce an inflammatory response.<ref name="pmid11424870">{{cite journal | author = Taylor ML, Metcalfe DD | title = Mast cells in allergy and host defense | journal = Allergy Asthma Proc | volume = 22 | issue = 3 | pages = 115–19 | year = 2001 | pmid = 11424870 | doi = 10.2500/108854101778148764| url = http://openurl.ingenta.com/content/nlm?genre=article&issn=1088-5412&volume=22&issue=3&spage=115&aulast=Taylor| accessdate = March 29, 2009}}</ref> This is a vital part of the destruction of microbes because they attract more phagocytes to the site of infection.<ref name=mast/> {| class="wikitable" border="1" b style="margin:1em auto 1em auto" |+ '''Professional Phagocytes'''<ref name=superman>Paoletti p. 427</ref> ! Main location ! Variety of [[phenotype]]s |- | Blood | neutrophils, monocytes |- | Bone marrow | macrophages, monocytes, [[sinusoid (blood vessel)|sinusoidal cells]], [[List of distinct cell types in the adult human body#Epithelial cells lining closed internal body cavities|lining cells]] |- | Bone tissue | [[osteoclast]]s |- | Gut and intestinal [[Peyer's patches]] | macrophages |- | [[Connective tissue]] | [[histiocyte]]s, macrophages, monocytes, dendritic cells |- | Liver | [[Kupffer cell]]s, monocytes |- | Lung | self-replicating macrophages, monocytes, mast cells, dendritic cells |- | [[Lymphatic system|Lymphoid tissue]] | free and fixed macrophages and monocytes, dendritic cells |- | Nervous tissue | [[microglial cell]]s ([[CD4]]⁺) |- | [[Spleen]] | free and fixed macrophages, monocytes, sinusoidal cells |- | [[Thymus]] | free and fixed macrophages and monocytes |- | Skin | resident [[Langerhans cell]]s, other dendritic cells, conventional macrophages, mast cells |} ==Non-professional phagocytes== Dying cells and foreign organisms are consumed by cells other than the "professional" phagocytes.<ref name="pmid18451871">{{cite journal | author = Birge RB, Ucker DS | title = Innate apoptotic immunity: the calming touch of death | journal = Cell Death Differ. | volume = 15 | issue = 7 | pages = 1096–1102 | year = 2008 | month = July | pmid = 18451871 | doi = 10.1038/cdd.2008.58 }}</ref> These cells include [[epithelial cell]]s, [[endothelial cell]]s, [[fibroblast]]s, and mesenchymal cells. They are called non-professional phagocytes, to emphasize that, in contrast to professional phagocytes, phagocytosis is not their principal function.<ref name="pmid11083817">{{cite journal | author = Couzinet S, Cejas E, Schittny J, Deplazes P, Weber R, Zimmerli S | title = Phagocytic uptake of ''Encephalitozoon cuniculi'' by nonprofessional phagocytes | journal = Infect. Immun. | volume = 68 | issue = 12 | pages = 6939–45 | year = 2000 | month = December | pmid = 11083817 | pmc = 97802 | url = http://iai.asm.org/cgi/pmidlookup?view=long&pmid=11083817 | doi = 10.1128/IAI.68.12.6939-6945.2000 }}</ref> Fibroblasts, for example, only make ineffective attempts to ingest foreign particles.<ref name=autogenerated3>Paoletti p. 426</ref> Non-professional phagocytes are more limited than professional phagocytes in the type of particles they can take up. This is due to their lack of efficient phagocytic receptors, particularly [[opsonin]]s—which are antibodies and complement attached to invaders by the immune system.<ref name= something/> Additionally, most nonprofessional phagocytes do not produce reactive oxygen-containing molecules in response to phagocytosis.<ref name="pmid14732160">{{cite journal |author=Rabinovitch M |title=Professional and non-professional phagocytes: an introduction |journal=Trends Cell Biol. |volume=5 |issue=3 |pages=85–87 |year=1995 |month=March |pmid=14732160 |doi= |url=http://linkinghub.elsevier.com/retrieve/pii/S0962892400889552}}</ref> {| class="wikitable" border="1" b style="margin:1em auto 1em auto" |+ '''Non-professional Phagocytes'''<ref name=superman /> ! Main location ! Variety of phenotypes |- | Blood, lymph and lymph nodes | Lymphocytes |- | Blood, lymph and lymph nodes | [[natural killer cells|NK]] and LGL cells (large granular lymphocytes) |- | Skin | [[Epithelial cell]]s |- | Blood vessels | [[Endothelial cell]]s |- | Connective tissue | Fibroblasts |- |Blood | [[Erythrocyte]]s |} ==Pathogen evasion and resistance== [[image:Staphylococcus aureus, 50,000x, USDA, ARS, EMU.jpg|right|thumb|Cells of ''Staphylococcus aureus'' bacteria: the large, stringy capsules protect the organisms from attack by phagocytes.|alt=Two round bacteria that are close together and are almost completely covered in a string-like substance.]] A pathogen is only successful in infecting an organism if it can get past its defenses. Pathogenic bacteria and protozoa have developed a variety of methods to resist attacks by phagocytes and many actually survive and replicate within phagocytic cells.<ref name=chicken>{{cite web|url=http://textbookofbacteriology.net/antiphago.html|title=Mechanisms of Bacterial Pathogenicity: Bacterial Defense Against Phagocytes|accessdate=December 10, 2008|last=Todar|first=Kenneth|publisher=2008}}</ref><ref>{{cite journal |author=Alexander J, Satoskar AR, Russell DG |title=Leishmania species: models of intracellular parasitism |journal=J. Cell. Sci. |volume=112 Pt 18 |issue= |pages=2993–3002 |year=1999 |month=September |pmid=10462516 |doi= |url=http://jcs.biologists.org/cgi/pmidlookup?view=long&pmid=10462516}}</ref> ===Avoiding contact=== There are several ways bacteria avoid contact with phagocytes. First, they can grow in sites that phagocytes are not capable of traveling to (e.g., the surface of unbroken skin). Second, bacteria can suppress the [[inflammatory response]]; without this response to infection phagocytes cannot respond adequately. Third, some species of bacteria can inhibit the ability of phagocytes to travel to the site of infection by interfering with chemotaxis.<ref name=chicken/> Fourth, some bacteria can avoid contact with phagocytes by tricking the immune system into "thinking" that the bacteria are "self". ''[[Treponema pallidum]]''—the bacterium that causes [[syphilis]]—hides from phagocytes by coating its surface with [[fibronectin]],<ref name="pmid11973157">{{cite journal| author = Celli J, Finlay BB| title = Bacterial avoidance of phagocytosis| journal = Trends Microbiol.| volume = 10| issue = 5| pages = 232–37| year = 2002| month = May| pmid = 11973157| doi = 10.1016/S0966-842X(02)02343-0}}</ref> which is produced naturally by the body and plays a crucial role in [[wound healing]].<ref name="pmid15992798">{{cite journal | author = Valenick LV, Hsia HC, Schwarzbauer JE | title = Fibronectin fragmentation promotes alpha4beta1 integrin-mediated contraction of a fibrin-fibronectin provisional matrix | journal = Experimental cell research | volume = 309 | issue = 1 | pages = 48–55 | year = 2005 | month = September | pmid = 15992798 | doi = 10.1016/j.yexcr.2005.05.024 | url = }}</ref> ===Avoiding engulfment=== Bacteria often produce proteins or sugars that coat their cells and interfere with phagocytosis; these are called [[bacterial capsule|capsules]].<ref name=chicken/> Some examples are the K5 capsule and O75 [[O antigen]] found on the surface of ''[[Escherichia coli]]'',<ref name="pmid10417134">{{cite journal | author = Burns SM, Hull SI | title = Loss of resistance to ingestion and phagocytic killing by O(-) and K(-) mutants of a uropathogenic ''Escherichia coli'' O75:K5 strain | journal = Infect. Immun. | volume = 67 | issue = 8 | pages = 3757–62 | year = 1999 | month = August | pmid = 10417134 | pmc = 96650 | doi = | url = http://iai.asm.org/cgi/pmidlookup?view=long&pmid=10417134 | issn = | accessdate = March 29, 2009}}</ref> and the [[exopolysaccharide]] capsules of ''[[Staphylococcus epidermidis]]''.<ref name="pmid15501828">{{cite journal | author = Vuong C, Kocianova S, Voyich JM, ''et al'' | title = A crucial role for exopolysaccharide modification in bacterial biofilm formation, immune evasion, and virulence | journal = J. Biol. Chem. | volume = 279 | issue = 52 | pages = 54881–86 | year = 2004 | month = December | pmid = 15501828 | doi = 10.1074/jbc.M411374200 | url = http://www.jbc.org/cgi/pmidlookup?view=long&pmid=15501828| accessdate = March 29, 2009}}</ref> ''[[Streptococcus pneumoniae]]'' produces several types of capsule which provide different levels of protection,<ref name="pmid19047408">{{cite journal | author = Melin M, Jarva H, Siira L, Meri S, Käyhty H, Väkeväinen M | title = ''Streptococcus pneumoniae'' capsular serotype 19F is more resistant to C3 deposition and less sensitive to opsonophagocytosis than serotype 6B | journal = Infect. Immun. | volume = 77 | issue = 2 | pages = 676–84 | year = 2009 | month = February | pmid = 19047408 | doi = 10.1128/IAI.01186-08 | url = http://iai.asm.org/cgi/pmidlookup?view=long&pmid=19047408| accessdate = March 29, 2009}}</ref> and [[group A streptococci]] produce proteins such as [[M protein (Streptococcus)|M protein]] and [[fimbria (bacteriology)|fimbrial proteins]] to block engulfment. Some proteins hinder opsonin-related ingestion; ''[[Staphylococcus aureus]]'' produces [[Protein A]] to block antibody receptors which decreases the effectiveness of opsonins.<ref name="pmid16322743">{{cite journal| author = Foster TJ| title = Immune evasion by staphylococci| journal = Nat. Rev. Microbiol.| volume = 3| issue = 12| pages = 948–58| year = 2005| month = December| pmid = 16322743| doi = 10.1038/nrmicro1289}}</ref> ===Survival inside the phagocyte=== [[Image:Rickettsia rickettsii.jpg|thumb|right|[[Rickettsia]] are small bacteria—here stained red—that ''grow'' in the cytoplasm of non-professional phagocytes.|alt=Two round cells with many tiny rod-shaped bacteria inside.]] Bacteria have developed ways to survive inside phagocytes, where they continue to evade the immune system.<ref name="pmid11708894">{{cite journal | author = Sansonetti P | title = Phagocytosis of bacterial pathogens: implications in the host response | journal = Semin. Immunol. | volume = 13 | issue = 6 | pages = 381–90 | year = 2001 | month = December | pmid = 11708894 | doi = 10.1006/smim.2001.0335 }}</ref> To get safely inside the phagocyte they express proteins called "invasins". When inside the cell they remain in the cytoplasm and avoid toxic chemicals contained in the phagolysosomes.<ref name="pmid10064587">{{cite journal | author = Dersch P, Isberg RR| title = A region of the ''Yersinia pseudotuberculosis'' invasin protein enhances integrin-mediated uptake into mammalian cells and promotes self-association| journal = Embo J.| volume = 18| issue = 5| pages = 1199–1213| year = 1999| month = March| pmid = 10064587| pmc = 1171211| doi = 10.1093/emboj/18.5.1199 }}</ref> Some bacteria prevent the fusion of a phagosome and lysosome, to form the phagolysosome.<ref name=chicken/> Other pathogens, such as ''[[Leishmania]]'', create a highly modified [[vacuole]] inside the phagocyte, which helps them persist and replicate.<ref>{{cite journal |author=Antoine JC, Prina E, Lang T, Courret N |title=The biogenesis and properties of the parasitophorous vacuoles that harbour ''Leishmania'' in murine macrophages |journal=Trends Microbiol. |volume=6 |issue=10 |pages=392–401 |year=1998 |month=October |pmid=9807783 |doi=10.1016/S0966-842X(98)01324-9}}</ref> ''[[Legionella pneumophila]]'' produces secretions which cause the phagosome to fuse with vesicles other than the ones that contain toxic substances.<ref>{{cite book| last = Masek| first = Katherine S.| coauthors = Christopher A. Hunter| title = Eurekah Bioscience Collection: Evasion of Phagosome Lysosome Fusion and Establishment of a Replicative Organelle by the Intracellular Pathogen Legionella pneumophila| publisher = Landes Bioscience| date = 2007| url = http://www.ncbi.nlm.nih.gov/books/bv.fcgi?rid=eurekah.chapter.19451| accessdate = March 20, 2009}}</ref> Other bacteria are capable of living inside of the phagolysosome. ''Staphylococcus aureus'', for example, produces the enzymes [[catalase]] and [[superoxide dismutase]] which break down chemicals—such as hydrogen peroxide—produced by phagocytes to kill bacteria.<ref name="pmid18607538">{{cite journal | author = Das D, Saha SS, Bishayi B | title = Intracellular survival of ''Staphylococcus aureus'': correlating production of catalase and superoxide dismutase with levels of inflammatory cytokines | journal = Inflamm. Res. | volume = 57 | issue = 7 | pages = 340–49 | year = 2008 | month = July | pmid = 18607538 | doi = 10.1007/s00011-007-7206-z| accessdate = March 29, 2009}}</ref> Bacteria may escape from the phagosome before the formation of the phagolysosome: ''[[Listeria monocytogenes]]'' can make a hole in the phagosome wall using enzymes called [[hemolysin|listeriolysin O]] and [[phospholipase|phospholipase C]].<ref name="pmid17517863">{{cite journal| author = Hara H, Kawamura I, Nomura T, Tominaga T, Tsuchiya K, Mitsuyama M| title = Cytolysin-dependent escape of the bacterium from the phagosome is required but not sufficient for induction of the Th1 immune response against Listeria monocytogenes infection: distinct role of Listeriolysin O determined by cytolysin gene replacement| journal = Infect. Immun.| volume = 75| issue = 8| pages = 3791–3801| year = 2007| month = August| pmid = 17517863| pmc = 1951982| doi = 10.1128/IAI.01779-06| url = http://iai.asm.org/cgi/pmidlookup?view=long&pmid=17517863 }}</ref> ===Killing=== Bacteria have developed several ways of killing phagocytes.<ref name="pmid16322743" /> These include: [[Cytolysin|cytolysins]] which form pores in the phagocyte's cell membranes; [[streptolysins]] and [[leukocidin]]s which cause neutrophils' granules to rupture and release toxic substances,<ref name="pmid15819624">{{cite journal| author = Datta V, Myskowski SM, Kwinn LA, Chiem DN, Varki N, Kansal RG, Kotb M, Nizet V| title = Mutational analysis of the group A streptococcal operon encoding streptolysin S and its virulence role in invasive infection| journal = Mol. Microbiol.| volume = 56| issue = 3| pages = 681–95| year = 2005| month = May| pmid = 15819624| doi = 10.1111/j.1365-2958.2005.04583.x}}</ref><ref name="pmid16679003">{{cite journal|author=Iwatsuki K, Yamasaki O, Morizane S, Oono T|title=Staphylococcal cutaneous infections: invasion, evasion and aggression|journal=J. Dermatol. Sci.|volume=42|issue=3|pages=203–14|year=2006|month=June|pmid=16679003|doi=10.1016/j.jdermsci.2006.03.011}}</ref> and [[exotoxins]] which reduce the supply of a phagocyte's [[Adenosine triphosphate|ATP]], needed for phagocytosis. After a bacterium is ingested it may kill the phagocyte by releasing toxins that travel through the phagosome or phagolysosome membrane to target other parts of the cell.<ref name=chicken/> ===Disruption of cell signaling=== [[image:Leish amast WBC1 DPDx.JPG|right|thumb|''Leishmania tropica'' amastigotes (arrows) in a macrophage from skin|Many small cells of leishmania inside a much larger cell.]] Some survival strategies often involve disrupting cytokines and other methods of [[cell signaling]] to prevent the phagocyte's responding to invasion.<ref name="pmid15639739">{{cite journal | author = Denkers EY, Butcher BA | title = Sabotage and exploitation in macrophages parasitized by intracellular protozoans | journal = Trends Parasitol. | volume = 21 | issue = 1 | pages = 35–41 | year = 2005 | month = January | pmid = 15639739 | doi = 10.1016/j.pt.2004.10.004 | url = http://linkinghub.elsevier.com/retrieve/pii/S1471-4922(04)00261-2| accessdate = March 29, 2009}}</ref> The protozoan parasites ''[[Toxoplasma gondii]]'', ''[[Trypanosoma cruzi]]'' and ''[[Leishmania]]'' infect macrophages and each has unique ways of taming them. Some species of ''Leishmania'' alter the infected macrophage's signalling and repress the production of cytokines and microbicidal molecules—nitric oxide and reactive oxygen species—and compromise antigen presentation.<ref name="pmid16281989">{{cite journal| author = Gregory DJ, Olivier M| title = Subversion of host cell signalling by the protozoan parasite ''Leishmania''| journal = Parasitology| volume = 130 Suppl| pages = S27–35| year = 2005| pmid = 16281989| doi = 10.1017/S0031182005008139| url = http://journals.cambridge.org/abstract_S0031182005008139| accessdate = March 29, 2009 }}</ref> ==Host damage by phagocytes== Macrophages and neutrophils, in particular, play a central role in the inflammatory process, by releasing proteins and small-molecule inflammatory mediators that both control infection and can damage host tissue. In general phagocytes aim to destroy pathogens by engulfing them and subjecting them to battery of toxic chemicals inside a phagolysosome. If a phagocyte fails to engulf its target, these toxic agents can be released into the environment (an action referred to as "frustrated phagocytosis"). As these agents are also toxic to host cells they can cause extensive damage to healthy cells and tissues.<ref name=autogenerated3 /> When neutrophils release their granule contents in the [[kidney]], the contents of the granule (reactive oxygen compounds and proteases) degrade the [[extracellular matrix]] of host cells and can cause damage to [[glomerular]] cells, affecting their ability to filter blood and causing changes in shape. In addition, [[phospholipase]] products (e.g., [[leukotrienes]]) intensify the damage. This release of substances promotes chemotaxis of more neutrophils to the site of infection and glomerular cells can be damaged further by the adhesion molecules during the migration of neutrophils. The injury done to the glomerular cells can cause [[renal failure]].<ref name="pmid10430993">{{cite journal | author = Heinzelmann M, Mercer-Jones MA, Passmore JC | title = Neutrophils and renal failure | journal = Am. J. Kidney Dis. | volume = 34 | issue = 2 | pages = 384–99 | year = 1999 | month = August | pmid = 10430993 }}</ref> Neutrophils also play a key role in the development of most forms of [[acute lung injury]].<ref name="pmid11373504">{{cite journal | author = Lee WL, Downey GP | title = Neutrophil activation and acute lung injury | journal = Curr Opin Crit Care | volume = 7 | issue = 1 | pages = 1–7 | year = 2001 | month = February | pmid = 11373504 | doi = 10.1097/00075198-200102000-00001 }}</ref> Here, activated neutrophils release the contents of their toxic granules into the lung environment.<ref name="pmid16319683">{{cite journal | author = Moraes TJ, Zurawska JH, Downey GP | title = Neutrophil granule contents in the pathogenesis of lung injury | journal = Curr. Opin. Hematol. | volume = 13 | issue = 1 | pages = 21–27 | year = 2006 | month = January | pmid = 16319683 | doi = 10.1097/01.moh.0000190113.31027.d5 }}</ref> Experiments have shown that a reduction in the number of neutrophils lessens the effects of acute lung injury,<ref name="pmid12682440">{{cite journal | author = Abraham E | title = Neutrophils and acute lung injury | journal = Crit. Care Med. | volume = 31 | issue = 4 Suppl | pages = S195–99 | year = 2003 | month = April | pmid = 12682440 | doi = 10.1097/01.CCM.0000057843.47705.E8 }}</ref> but treatment by inhibiting neutrophils is not clinically realistic, as it would leave the host vulnerable to infection.<ref name="pmid16319683"/> Damage by neutrophils can contribute to [[liver]] dysfunction and injury in response to the release of [[endotoxin]]s produced by bacteria, [[sepsis]], trauma, [[alcoholic hepatitis]], [[ischemia]], and [[hypovolemic shock]] resulting from acute [[hemorrhage]].<ref name="pmid9704069">{{cite journal |author=Ricevuti G |title=Host tissue damage by phagocytes |journal=Ann. N. Y. Acad. Sci. |volume=832 |issue= |pages=426–48 |year=1997 |month=December |pmid=9704069 |doi= |url=http://www3.interscience.wiley.com/resolve/openurl?genre=article&sid=nlm:pubmed&issn=0077-8923&date=1997&volume=832&spage=426}}</ref> Chemicals released by macrophages can also damage host tissue. [[Tumor necrosis factor-alpha|TNF-α]] is an important chemical that is released by macrophages that causes the blood in small vessels to clot to prevent an infection from spreading.<ref name="pmid17135502">{{cite journal | author = Charley B, Riffault S, Van Reeth K | title = Porcine innate and adaptative immune responses to influenza and coronavirus infections | journal = Ann. N. Y. Acad. Sci. | volume = 1081 | issue = | pages = 130–36 | year = 2006 | month = October | pmid = 17135502 | doi = 10.1196/annals.1373.014 | url = http://www3.interscience.wiley.com/resolve/openurl?genre=article&sid=nlm:pubmed&issn=0077-8923&date=2006&volume=1081&spage=130 | accessdate = March 31, 2009}}</ref> However, if a bacterial infection spreads to the blood, TNF-α is released into vital organs which can cause [[vasodilation]] and a decrease in [[blood plasma|plasma]] volume; these in turn can be followed by [[septic shock]]. During septic shock, TNF-α release causes a blockage of the small vessels that supply blood to the vital organs, and the organs may fail. Septic shock can lead to death.<ref name=money/> ==Evolutionary origins== Phagocytosis is common and probably appeared early in [[evolution]],<ref>Sompayrac p. 1</ref> evolving first in unicellular eukaryotes.<ref name="pmid18550419"/> [[Amoeba]]e are unicellular [[protists]] that separated from the tree leading to [[metazoa]] shortly after the divergence of plants, but they share many specific functions with mammalian phagocytic cells. <ref name="pmid18550419">{{cite journal | author = Cosson P, Soldati T | title = Eat, kill or die: when amoeba meets bacteria | journal = Curr. Opin. Microbiol. | volume = 11 | issue = 3 | pages = 271–76 | year = 2008 | month = June | pmid = 18550419 | doi = 10.1016/j.mib.2008.05.005 | url = http://linkinghub.elsevier.com/retrieve/pii/S1369-5274(08)00062-3 | issn = | accessdate = April 5, 2009}}</ref> ''[[Dictyostelium discoideum]]'', for example, is an amoeba that lives in the soil and feeds on bacteria. Like animal phagocytes, it engulfs bacteria by phagocytosis mainly through Toll-like receptors and has other biological functions in common with macrophages.<ref name="pmid19081545">{{cite journal | author = Bozzaro S, Bucci C, Steinert M | title = Phagocytosis and host-pathogen interactions in Dictyostelium with a look at macrophages | journal = Int Rev Cell Mol Biol | volume = 271 | issue = | pages = 253–300 | year = 2008 | pmid = 19081545 | doi = 10.1016/S1937-6448(08)01206-9 | url = http://linkinghub.elsevier.com/retrieve/pii/S1937-6448(08)01206-9 | issn = | accessdate = April 5, 2009}}</ref> ''Dictyostelium discoideum'' is social and aggregates when starved to form a migrating [[Dictyostelid|pseudoplasmodium or slug]]. This multicellular organism eventually produces a [[fruiting body]] with [[spores]] that are resistant to environmental dangers. Before the formation of fruiting bodies, the cells can migrate as slug-like organisms for several days. During this time, exposure to toxins or bacterial pathogens have the potential to compromise survival of the amoebae by limiting spore production. Some of the amoebae engulf bacteria and absorb toxins while circulating within the slug, and these amoebae eventually die. They are genetically identical to the other amoebae in the slug, and their sacrifice of themselves to protect the other amoebae from bacteria is similar to the self-sacrifice of phagocytes seen in the immune system of e.g. humans. This innate immune function in social amoebae suggests an ancient cellular foraging mechanism that may have been adapted to defense functions well before the diversification of the animals.<ref name="pmid17673666">{{cite journal | author = Chen G, Zhuchenko O, Kuspa A | title = Immune-like phagocyte activity in the social amoeba | journal = Science (journal) | volume = 317 | issue = 5838 | pages = 678–81 | year = 2007 | month = August | pmid = 17673666 | doi = 10.1126/science.1143991 | url = http://www.sciencemag.org/cgi/pmidlookup?view=long&pmid=17673666 }}</ref> But a common ancestry with mammalian phagocytes has not been proven. Phagocytes occur throughout the animal kingdom,<ref name=Delves250 /> from marine sponges to insects and lower and higher vertebrates.<ref>Delves pp. 251–252</ref><ref name="pmid19063916">{{cite journal | author = Hanington PC, Tam J, Katzenback BA, Hitchen SJ, Barreda DR, Belosevic M | title = Development of macrophages of cyprinid fish | journal = Dev. Comp. Immunol. | volume = 33 | issue = 4 | pages = 411–29 | year = 2009 | month = April | pmid = 19063916 | doi = 10.1016/j.dci.2008.11.004 | url = http://linkinghub.elsevier.com/retrieve/pii/S0145-305X(08)00257-7 | issn = | accessdate = April 5, 2009}}</ref> The ability of amoebae to distinguish between self and non-self is a pivotal one which is the root of the immune system of many species.<ref name=amoebaphage/> ==References== {{reflist|2}} ;Bibliography {{refbegin}} *Delves, P.J., Martin, S. J., Burton, D. R. and Roit I.M. ''Roitt's Essential Immunology'' (11th edition), Blackwell Publishing, 2006, ISBN 978-1-4051-3603-7. *Ernst J. D. and Stendahl O., (editors), ''Phagocytosis of Bacteria and Bacterial Pathogenicity'', Cambridge University Press, 2006, ISBN 0-521-84569-6 [http://www.cambridge.org/9780521845694 Website] *Hoffbrand, A.V., Pettit, J.E. and Moss, P.A.H., ''Essential Haematology'' (4th edition), Blackwell Science, 2005, ISBN 0-632-05153-1. *Janeway, C.A., Murphy, K.M., Travers, P., Walport, M., ''Immunobiology '' (5th edition), Garland Science, New York, 2001. ISBN 0-8153-3642-X. *Paoletti R., Notario A. and Ricevuti G., (editors), ''Phagocytes: Biology, Physiology, Pathology, and Pharmacotherapeutics'', The New York Academy of Sciences, 1997, ISBN 1-57331-102-2. *Robinson J.P. and Babcock G. F., (editors), ''Phagocyte Function&nbsp;—A guide for research and clinical evaluation'', Wiley–Liss, 1998, ISBN 0471123641 *Sompayrac, L. ''How the Immune System Works'' (3rd edition), Blackwell Publishing, 2008, ISBN 978-1-4051-6221-0 {{refend}} ==External links== * {{MeshName|Phagocytes}} {{Blood}} {{Immune system}} {{featured article}} [[Category:Leukocytes]] {{Link FA|ca}} [[ca:Fagòcit]] [[da:Fagocyt]] [[de:Phagozyt]] [[et:Fagotsüüt]] [[es:Fagocito]] [[fa:بیگانه‌خوار]] [[fr:Phagocyte]] [[io:Fagocito]] [[it:Fagocita]] [[he:פגוציט]] [[no:Fagocytter]] [[pl:Fagocyt]] [[pt:Fagócito]] [[ru:Фагоцит]] [[simple:Phagocyte]] [[sl:Fagocit]] [[fi:Fagosyytti]] [[sv:Fagocyt]] [[tr:Fagosit]] [[zh:吞噬细胞]]'