Phagocyte
Overview
Phagocytes are the white blood cell
White blood cell
White blood cells, or leukocytes , are cells of the immune system involved in defending the body against both infectious disease and foreign materials. Five different and diverse types of leukocytes exist, but they are all produced and derived from a multipotent cell in the bone marrow known as a...

s that protect the body by ingesting (phagocytosing) harmful foreign particles, bacteria
Bacteria
Bacteria are a large domain of prokaryotic microorganisms. Typically a few micrometres in length, bacteria have a wide range of shapes, ranging from spheres to rods and spirals...

, and dead or dying
Apoptosis
Apoptosis is the process of programmed cell death that may occur in multicellular organisms. Biochemical events lead to characteristic cell changes and death. These changes include blebbing, cell shrinkage, nuclear fragmentation, chromatin condensation, and chromosomal DNA fragmentation...

 cells. Their name comes from the Greek
Greek language
Greek is an independent branch of the Indo-European family of languages. Native to the southern Balkans, it has the longest documented history of any Indo-European language, spanning 34 centuries of written records. Its writing system has been the Greek alphabet for the majority of its history;...

 phagein, "to eat" or "devour", and "-cyte", the suffix in biology denoting "cell", from the Greek kutos, "hollow vessel". They are essential for fighting infections and for subsequent immunity
Immunity (medical)
Immunity is a biological term that describes a state of having sufficient biological defenses to avoid infection, disease, or other unwanted biological invasion. Immunity involves both specific and non-specific components. The non-specific components act either as barriers or as eliminators of wide...

.
Unanswered Questions
Encyclopedia
Phagocytes are the white blood cell
White blood cell
White blood cells, or leukocytes , are cells of the immune system involved in defending the body against both infectious disease and foreign materials. Five different and diverse types of leukocytes exist, but they are all produced and derived from a multipotent cell in the bone marrow known as a...

s that protect the body by ingesting (phagocytosing) harmful foreign particles, bacteria
Bacteria
Bacteria are a large domain of prokaryotic microorganisms. Typically a few micrometres in length, bacteria have a wide range of shapes, ranging from spheres to rods and spirals...

, and dead or dying
Apoptosis
Apoptosis is the process of programmed cell death that may occur in multicellular organisms. Biochemical events lead to characteristic cell changes and death. These changes include blebbing, cell shrinkage, nuclear fragmentation, chromatin condensation, and chromosomal DNA fragmentation...

 cells. Their name comes from the Greek
Greek language
Greek is an independent branch of the Indo-European family of languages. Native to the southern Balkans, it has the longest documented history of any Indo-European language, spanning 34 centuries of written records. Its writing system has been the Greek alphabet for the majority of its history;...

 phagein, "to eat" or "devour", and "-cyte", the suffix in biology denoting "cell", from the Greek kutos, "hollow vessel". They are essential for fighting infections and for subsequent immunity
Immunity (medical)
Immunity is a biological term that describes a state of having sufficient biological defenses to avoid infection, disease, or other unwanted biological invasion. Immunity involves both specific and non-specific components. The non-specific components act either as barriers or as eliminators of wide...

. Phagocytes are important throughout the animal kingdom and are highly developed within vertebrates. One litre
Litre
pic|200px|right|thumb|One litre is equivalent to this cubeEach side is 10 cm1 litre water = 1 kilogram water The litre is a metric system unit of volume equal to 1 cubic decimetre , to 1,000 cubic centimetres , and to 1/1,000 cubic metre...

 of human blood contains about six billion phagocytes. Phagocytes were first discovered in 1882 by Ilya Ilyich Mechnikov
Ilya Ilyich Mechnikov
Ilya Ilyich Mechnikov was a Russian biologist, zoologist and protozoologist, best remembered for his pioneering research into the immune system. Mechnikov received the Nobel Prize in Medicine in 1908, shared with Paul Ehrlich, for his work on phagocytosis...

 while he was studying starfish larva
Larva
A larva is a distinct juvenile form many animals undergo before metamorphosis into adults. Animals with indirect development such as insects, amphibians, or cnidarians typically have a larval phase of their life cycle...

e. Mechnikov was awarded the 1908 Nobel Prize in Physiology or Medicine
Nobel Prize in Physiology or Medicine
The Nobel Prize in Physiology or Medicine administered by the Nobel Foundation, is awarded once a year for outstanding discoveries in the field of life science and medicine. It is one of five Nobel Prizes established in 1895 by Swedish chemist Alfred Nobel, the inventor of dynamite, in his will...

 for his discovery. Phagocytes occur in many species; some amoebae
Amoeboid
Amoeboids are single-celled life-forms characterized by an irregular shape."Amoeboid" and "amœba" are often used interchangeably even by biologists, and especially refer to a creature moving by using pseudopodia. Most references to "amoebas" or "amoebae" are to amoeboids in general rather than to...

 behave like macrophage phagocytes, which suggests that phagocytes appeared early in the evolution of life.

Phagocytes of humans and other animals are called "professional" or "non-professional" depending on how effective they are at phagocytosis. The professional phagocytes include cells called neutrophils, monocytes, macrophages, dendritic cells, and mast cells. The main difference between professional and non-professional phagocytes is that the professional phagocytes have molecules called receptors
Receptor (biochemistry)
In biochemistry, a receptor is a molecule found on the surface of a cell, which receives specific chemical signals from neighbouring cells or the wider environment within an organism...

 on their surfaces that can detect harmful objects, such as bacteria, that are not normally found in the body. Phagocytes are 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.

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
Chemotaxis
Chemotaxis is the phenomenon in which somatic cells, bacteria, and other single-cell or multicellular organisms direct their movements according to certain chemicals in their environment. This is important for bacteria to find food by swimming towards the highest concentration of food molecules,...

. When phagocytes come into contact with bacteria, the receptors on the phagocyte's surface will bind to them. This binding will lead to the engulfing of the bacteria by the phagocyte. Some phagocytes kill the ingested pathogen with oxidants
Reactive oxygen species
Reactive oxygen species are chemically reactive molecules containing oxygen. Examples include oxygen ions and peroxides. Reactive oxygen species are highly reactive due to the presence of unpaired valence shell electrons....

 and nitric oxide
Nitric oxide
Nitric oxide, also known as nitrogen monoxide, is a diatomic molecule with chemical formula NO. It is a free radical and is an important intermediate in the chemical industry...

. After phagocytosis, macrophages and dendritic cells can also participate in antigen presentation
Antigen presentation
Antigen presentation is a process in the body's immune system by which macrophages, dendritic cells and other cell types capture antigens and then enable their recognition by T-cells....

, 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
Lymph node
A lymph node is a small ball or an oval-shaped organ of the immune system, distributed widely throughout the body including the armpit and stomach/gut and linked by lymphatic vessels. Lymph nodes are garrisons of B, T, and other immune cells. Lymph nodes are found all through the body, and act as...

s and display the material to white blood cells called lymphocytes. This process is important in building immunity. However, many pathogens have evolved methods to evade attacks by phagocytes.

History

The Russian zoologist Ilya Ilyich Mechnikov
Ilya Ilyich Mechnikov
Ilya Ilyich Mechnikov was a Russian biologist, zoologist and protozoologist, best remembered for his pioneering research into the immune system. Mechnikov received the Nobel Prize in Medicine in 1908, shared with Paul Ehrlich, for his work on phagocytosis...

 (1845–1916) first recognized that specialized cells were involved in defense against microbial infections. In 1882, he studied motile
Motility
Motility is a biological term which refers to the ability to move spontaneously and actively, consuming energy in the process. Most animals are motile but the term applies to single-celled and simple multicellular organisms, as well as to some mechanisms of fluid flow in multicellular organs, in...

 (freely moving) cells in the larva
Larva
A larva is a distinct juvenile form many animals undergo before metamorphosis into adults. Animals with indirect development such as insects, amphibians, or cnidarians typically have a larval phase of their life cycle...

e of starfishes
Sea star
Starfish or sea stars are echinoderms belonging to the class Asteroidea. The names "starfish" and "sea star" essentially refer to members of the class Asteroidea...

, believing they were important to the animals' immune defenses. To test his idea, he inserted small thorns from a tangerine
Tangerine
__notoc__The tangerine is an orange-colored citrus fruit which is closely related to the Mandarin orange . Taxonomically, it should probably be formally named as a subspecies or variety of Citrus reticulata; further work seems to be required to ascertain its correct scientific name...

 tree into the larvae. After a few hours he noticed that the motile cells had surrounded the thorns. Mechnikov traveled to Vienna
Vienna
Vienna is the capital and largest city of the Republic of Austria and one of the nine states of Austria. Vienna is Austria's primary city, with a population of about 1.723 million , and is by far the largest city in Austria, as well as its cultural, economic, and political centre...

 and shared his ideas with Carl Friedrich Claus
Carl Friedrich Wilhelm Claus
Carl Friedrich Wilhelm Claus was a German zoologist. He was an opponent of the ideas of Ernst Haeckel.-Biography:...

 who suggested the name ‘‘phagocyte’’ (from the Greek words phagein, meaning "to eat or devour", and kutos, meaning "hollow vessel") for the cells that Mechnikov had observed.

A year later, Mechnikov studied a fresh-water crustacean
Crustacean
Crustaceans form a very large group of arthropods, usually treated as a subphylum, which includes such familiar animals as crabs, lobsters, crayfish, shrimp, krill and barnacles. The 50,000 described species range in size from Stygotantulus stocki at , to the Japanese spider crab with a leg span...

 called Daphnia
Daphnia
Daphnia are small, planktonic crustaceans, between 0.2 and 5 mm in length. Daphnia are members of the order Cladocera, and are one of the several small aquatic crustaceans commonly called water fleas because of their saltatory swimming style...

, 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 bacterium
Bacteria
Bacteria are a large domain of prokaryotic microorganisms. Typically a few micrometres in length, bacteria have a wide range of shapes, ranging from spheres to rods and spirals...

 Bacillus anthracis
Bacillus anthracis
Bacillus anthracis is the pathogen of the Anthrax acute disease. It is a Gram-positive, spore-forming, rod-shaped bacterium, with a width of 1-1.2µm and a length of 3-5µm. It can be grown in an ordinary nutrient medium under aerobic or anaerobic conditions.It is one of few bacteria known to...

could be engulfed and killed by phagocytes, a process that he called phagocytosis. Mechnikov proposed that phagocytes were a primary defense against invading organisms.

In 1903, Amroth Wright discovered that phagocytosis was reinforced by specific antibodies
Antibody
An antibody, also known as an immunoglobulin, is a large Y-shaped protein used by the immune system to identify and neutralize foreign objects such as bacteria and viruses. The antibody recognizes a unique part of the foreign target, termed an antigen...

 that he called opsonin
Opsonin
An opsonin is any molecule that targets an antigen for an immune response. However, the term is usually used in reference to molecules that act as a binding enhancer for the process of phagocytosis, especially antibodies, which coat the negatively-charged molecules on the membrane. Molecules that...

s, from the Greek opson
Opson
Opson is an important category in Ancient Greek foodways.First and foremost opson refers to a major division of ancient Greek food: the 'relish' that complements the sitos the staple part of the meal, i.e...

, a dressing or relish. Mechnikov was awarded (jointly with Paul Ehrlich
Paul Ehrlich
Paul Ehrlich was a German scientist in the fields of hematology, immunology, and chemotherapy, and Nobel laureate. He is noted for curing syphilis and for his research in autoimmunity, calling it "horror autotoxicus"...

) the 1908 Nobel Prize in Physiology or Medicine
Nobel Prize in Physiology or Medicine
The Nobel Prize in Physiology or Medicine administered by the Nobel Foundation, is awarded once a year for outstanding discoveries in the field of life science and medicine. It is one of five Nobel Prizes established in 1895 by Swedish chemist Alfred Nobel, the inventor of dynamite, in his will...

 for his work on phagocytes and phagocytosis.

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.

yes mate

Phagocytosis

Phagocytosis is the process of taking in particles such as bacteria, parasites, dead host cells
Apoptosis
Apoptosis is the process of programmed cell death that may occur in multicellular organisms. Biochemical events lead to characteristic cell changes and death. These changes include blebbing, cell shrinkage, nuclear fragmentation, chromatin condensation, and chromosomal DNA fragmentation...

, and cellular and foreign debris by a cell. It involves a chain of molecular processes. 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. The phagocyte then stretches itself around the bacterium and engulfs it. Phagocytosis of bacteria by human neutrophils takes on average nine minutes. Once inside this phagocyte, the bacterium is trapped in a compartment called a phagosome
Phagosome
In cell biology, a phagosome is a vacuole formed around a particle absorbed by phagocytosis. The vacuole is formed by the fusion of the cell membrane around the particle. A phagosome is a cellular compartment in which pathogenic microorganisms can be killed and digested...

. Within one minute the phagosome merges with either a lysosome
Lysosome
thumb|350px|Schematic of typical animal cell, showing subcellular components. [[Organelle]]s: [[nucleoli]] [[cell nucleus|nucleus]] [[ribosomes]] [[vesicle |vesicle]] rough [[endoplasmic reticulum]]...

 or a granule
Granule (cell biology)
In cell biology, a granule is a small particle. It can be any structure barely visible by light microscopy. The term is most often used to describe a secretory vesicle.-Leukocytes:...

 to form a phagolysosome
Phagolysosome
A phagolysosome is the membrane-enclosed organelle which forms when a phagosome fuses with a lysosome. After fusion, the food particles or pathogens contained within the phagosome are usually digested by the enzymes contained within the lysosome. Phagolysosome formation follows phagocytosis...

. The bacterium is then subjected to an overwhelming array of killing mechanisms and is dead a few minutes later. Dendritic cells and macrophages are not so fast, and phagocytosis can take many hours in these cells. Macrophages are slow and untidy eaters; 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. Phagocytes have voracious appetites; scientists have even fed macrophages with iron filings
Iron filings
Iron filings are very small pieces of iron that look like a light powder. They are very often used in science demonstrations to show the direction of a magnetic field. Since iron is a ferromagnetic material, a magnetic field induces each particle to become a tiny bar magnet...

 and then used a small magnet to separate them from other cells.
A phagocyte has many types of receptors on its surface that are used to bind material. They include opsonin
Opsonin
An opsonin is any molecule that targets an antigen for an immune response. However, the term is usually used in reference to molecules that act as a binding enhancer for the process of phagocytosis, especially antibodies, which coat the negatively-charged molecules on the membrane. Molecules that...

 receptors, scavenger receptor
Scavenger receptor
Scavenger receptors are a group of receptors that recognize modified low-density lipoprotein by oxidation or acetylation. This naming is based on a function of cleaning : Scavenger receptors widely recognize and uptake macromolecules having a negative charge as well as modified LDL.-Function:It is...

s, and Toll-like receptors. Opsonin receptors increase the phagocytosis of bacteria that have been coated with immunoglobulin G
Immunoglobulin G
Immunoglobulin G are antibody molecules. Each IgG is composed of four peptide chains — two heavy chains γ and two light chains. Each IgG has two antigen binding sites. Other immunoglobulins may be described in terms of polymers with the IgG structure considered the monomer.IgG constitutes 75%...

 (IgG) antibodies or with complement
Complement system
The complement system helps or “complements” the ability of antibodies and phagocytic cells to clear pathogens from an organism. It is part of the immune system called the innate immune system that is not adaptable and does not change over the course of an individual's lifetime...

. "Complement" is the name given to a complex series of protein molecules found in the blood that destroy cells or mark them for destruction. 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)
The Toll genes encode members of the Toll-like receptor class of proteins. "Toll" is German for "amazing" or "great". Mutants in the Toll gene were originally identified by 1995 Nobel Laureates Christiane Nüsslein-Volhard and Eric Wieschaus and colleagues in the fruit fly Drosophila melanogaster...

—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
Inflammation
Inflammation is part of the complex biological response of vascular tissues to harmful stimuli, such as pathogens, damaged cells, or irritants. Inflammation is a protective attempt by the organism to remove the injurious stimuli and to initiate the healing process...

.

Methods of killing

The killing of microbes is a critical function of phagocytes that is either performed within the phagocyte (intracellular
Intracellular
Not to be confused with intercellular, meaning "between cells".In cell biology, molecular biology and related fields, the word intracellular means "inside the cell".It is used in contrast to extracellular...

 killing) or outside of the phagocyte (extracellular
Extracellular
In cell biology, molecular biology and related fields, the word extracellular means "outside the cell". This space is usually taken to be outside the plasma membranes, and occupied by fluid...

 killing).

Oxygen-dependent intracellular

When a phagocyte ingests bacteria (or any material), its oxygen consumption increases. The increase in oxygen consumption, called a respiratory burst
Respiratory burst
Respiratory burst is the rapid release of reactive oxygen species from different types of cells....

, produces reactive oxygen-containing molecules that are anti-microbial. 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.

The first type is the oxygen-dependent production of a superoxide
Superoxide
A superoxide, also known by the obsolete name hyperoxide, is a compound that possesses the superoxide anion with the chemical formula O2−. The systematic name of the anion is dioxide. It is important as the product of the one-electron reduction of dioxygen O2, which occurs widely in nature...

, which is an oxygen-rich bacteria-killing substance. The superoxide is converted to hydrogen peroxide
Hydrogen peroxide
Hydrogen peroxide is the simplest peroxide and an oxidizer. Hydrogen peroxide is a clear liquid, slightly more viscous than water. In dilute solution, it appears colorless. With its oxidizing properties, hydrogen peroxide is often used as a bleach or cleaning agent...

 and singlet oxygen
Singlet oxygen
Singlet oxygen is the common name used for the diamagnetic form of molecular oxygen , which is less stable than the normal triplet oxygen. Because of its unusual properties, singlet oxygen can persist for over an hour at room temperature, depending on the environment...

 by an enzyme called superoxide dismutase
Superoxide dismutase
Superoxide dismutases are a class of enzymes that catalyze the dismutation of superoxide into oxygen and hydrogen peroxide. As such, they are an important antioxidant defense in nearly all cells exposed to oxygen...

. Superoxides also react with the hydrogen peroxide to produce hydroxyl radicals which assist in killing the invading microbe.

The second type involves the use of the enzyme myeloperoxidase
Myeloperoxidase
Myeloperoxidase is a peroxidase enzyme that in humans is encoded by the MPO gene. Myeloperoxidase is most abundantly expressed in neutrophil granulocytes . It is a lysosomal protein stored in azurophilic granules of the neutrophil...

  from neutrophil granules. When granules fuse with a phagosome, myeloperoxidase is released into the phagolysosome, and this enzyme uses hydrogen peroxide and chlorine
Chlorine
Chlorine is the chemical element with atomic number 17 and symbol Cl. It is the second lightest halogen, found in the periodic table in group 17. The element forms diatomic molecules under standard conditions, called dichlorine...

 to create hypochlorite
Hypochlorite
The hypochlorite ion, also known as chlorate anion is ClO−. A hypochlorite compound is a chemical compound containing this group, with chlorine in oxidation state +1.Hypochlorites are the salts of hypochlorous acid...

, a substance used in domestic bleach
Bleach
Bleach refers to a number of chemicals that remove color, whiten, or disinfect, often via oxidation. Common chemical bleaches include household chlorine bleach , lye, oxygen bleach , and bleaching powder...

. Hypochlorite is extremely toxic to bacteria. Myeloperoxidase contains a heme
Heme
A heme or haem is a prosthetic group that consists of an iron atom contained in the center of a large heterocyclic organic ring called a porphyrin. Not all porphyrins contain iron, but a substantial fraction of porphyrin-containing metalloproteins have heme as their prosthetic group; these are...

 pigment, which accounts for the green color of secretions rich in neutrophils, such as pus
Pus
Pus is a viscous exudate, typically whitish-yellow, yellow, or yellow-brown, formed at the site of inflammatory during infection. An accumulation of pus in an enclosed tissue space is known as an abscess, whereas a visible collection of pus within or beneath the epidermis is known as a pustule or...

 and infected sputum
Sputum
Sputum is mucus that is coughed up from the lower airways. It is usually used for microbiological investigations of respiratory infections....

.

Oxygen-independent intracellular

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 that damage the bacterium's membrane
Cell membrane
The cell membrane or plasma membrane is a biological membrane that separates the interior of all cells from the outside environment. The cell membrane is selectively permeable to ions and organic molecules and controls the movement of substances in and out of cells. It basically protects the cell...

. The second type uses lysozymes; these enzymes break down the bacterial cell wall
Cell wall
The cell wall is the tough, usually flexible but sometimes fairly rigid layer that surrounds some types of cells. It is located outside the cell membrane and provides these cells with structural support and protection, and also acts as a filtering mechanism. A major function of the cell wall is to...

. The third type uses lactoferrin
Lactoferrin
Lactoferrin , also known as lactotransferrin , is a multifunctional protein of the transferrin family. Lactoferrin is a globular glycoprotein with a molecular mass of about 80 kDa that is widely represented in various secretory fluids, such as milk, saliva, tears, and nasal secretions...

s, which are present in neutrophil granules and remove essential iron from bacteria. The fourth type uses proteases and hydrolytic enzymes; these enzymes are used to digest the proteins of destroyed bacteria.

Extracellular

Interferon-gamma
Interferon-gamma
Interferon-gamma is a dimerized soluble cytokine that is the only member of the type II class of interferons. This interferon was originally called macrophage-activating factor, a term now used to describe a larger family of proteins to which IFN-γ belongs...

—which was once called macrophage activating factor—stimulates macrophages to produce nitric oxide
Nitric oxide
Nitric oxide, also known as nitrogen monoxide, is a diatomic molecule with chemical formula NO. It is a free radical and is an important intermediate in the chemical industry...

. The source of interferon-gamma can be CD4+ T cells, CD8+ T cells, natural killer cells, B cells, natural killer T cells, monocytes, macrophages, or dendritic cells. Nitric oxide is then released from the macrophage and, because of its toxicity, kills microbes near the macrophage. Activated macrophages produce and secrete tumor necrosis factor
Tumor necrosis factors
Tumor necrosis factors refers to a group of cytokines family that can cause cell death . The first two members of the family to be identified were:...

. This cytokine
Cytokine
Cytokines are small cell-signaling protein molecules that are secreted by the glial cells of the nervous system and by numerous cells of the immune system and are a category of signaling molecules used extensively in intercellular communication...

—a class of signaling molecule—kills cancer cells and cells infected by viruses, and helps to activate the other cells of the immune system.

In some diseases, e.g., the rare chronic granulomatous disease
Chronic granulomatous disease
Chronic granulomatous disease is a diverse group of hereditary diseases in which certain cells of the immune system have difficulty forming the reactive oxygen compounds used to kill certain ingested pathogens...

, the efficiency of phagocytes is impaired, and recurrent bacterial infections are a problem. In this disease there is an abnormality affecting different elements of oxygen-dependent killing. Other rare congenital abnormalities, such as Chediak-Higashi syndrome
Chédiak-Higashi syndrome
Chédiak–Higashi syndrome is a rare autosomal recessive disorder that arises from a microtubule polymerization defect which leads to a decrease in phagocytosis. The decrease in phagocytosis results in recurrent pyogenic infections, partial albinism and peripheral neuropathy...

, are also associated with defective killing of ingested microbes.

Viruses

Virus
Virus
A virus is a small infectious agent that can replicate only inside the living cells of organisms. Viruses infect all types of organisms, from animals and plants to bacteria and archaea...

es can reproduce only 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. At the sites of viral infections, lymphocytes often vastly outnumber all the other cells of the immune system; this is common in viral meningitis
Meningitis
Meningitis is inflammation of the protective membranes covering the brain and spinal cord, known collectively as the meninges. The inflammation may be caused by infection with viruses, bacteria, or other microorganisms, and less commonly by certain drugs...

. Virus-infected cells that have been killed by lymphocytes are cleared from the body by phagocytes.

Role in apoptosis

In an animal, cells are constantly dying. A balance between cell division
Cell division
Cell division is the process by which a parent cell divides into two or more daughter cells . Cell division is usually a small segment of a larger cell cycle. This type of cell division in eukaryotes is known as mitosis, and leaves the daughter cell capable of dividing again. The corresponding sort...

 and cell death keeps the number of cells relatively constant in adults. There are two different ways a cell can die: by necrosis
Necrosis
Necrosis is the premature death of cells in living tissue. Necrosis is caused by factors external to the cell or tissue, such as infection, toxins, or trauma. This is in contrast to apoptosis, which is a naturally occurring cause of cellular death...

 or by apoptosis. In contrast to necrosis, which often results from disease or trauma, apoptosis—or programmed cell death
Programmed cell death
Programmed cell-death is death of a cell in any form, mediated by an intracellular program. PCD is carried out in a regulated process which generally confers advantage during an organism's life-cycle...

—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.

Dying cells that undergo the final stages of apoptosis
Apoptosis
Apoptosis is the process of programmed cell death that may occur in multicellular organisms. Biochemical events lead to characteristic cell changes and death. These changes include blebbing, cell shrinkage, nuclear fragmentation, chromatin condensation, and chromosomal DNA fragmentation...

 display molecules, such as phosphatidylserine
Phosphatidylserine
Phosphatidylserine is a phospholipid component, usually kept on the inner-leaflet of cell membranes by an enzyme called flippase...

, on their cell surface to attract phagocytes. Phosphatidylserine is normally found on the cytosolic
Cytoplasm
The cytoplasm is a small gel-like substance residing between the cell membrane holding all the cell's internal sub-structures , except for the nucleus. All the contents of the cells of prokaryote organisms are contained within the cytoplasm...

 surface of the plasma membrane, but is redistributed during apoptosis to the extracellular surface by a hypothetical protein known as scramblase
Scramblase
Scramblase is a protein responsible for the translocation of phospholipids between the two monolayers of a lipid bilayer of a cell membrane. In humans, phospholipid scramblases constitute a family of five homologous proteins that are named as hPLSCR1–hPLSCR5. Scramblases are members of the...

. These molecules mark the cell for phagocytosis by cells that possess the appropriate receptors, such as macrophages. The removal of dying cells by phagocytes occurs in an orderly manner without eliciting an inflammatory response and is an important function of phagocytes.

Interactions with other cells

Phagocytes are usually not bound to any particular organ
Organ (anatomy)
In biology, an organ is a collection of tissues joined in structural unit to serve a common function. Usually there is a main tissue and sporadic tissues . The main tissue is the one that is unique for the specific organ. For example, main tissue in the heart is the myocardium, while sporadic are...

 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
Lymphocyte
A lymphocyte is a type of white blood cell in the vertebrate immune system.Under the microscope, lymphocytes can be divided into large lymphocytes and small lymphocytes. Large granular lymphocytes include natural killer cells...

s. Phagocytes form part of the innate immune system
Innate immune system
The innate immune system, also known as non-specific immune system and secondary line of defence, comprises the cells and mechanisms that defend the host from infection by other organisms in a non-specific manner...

, 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
Adaptive immune system
The adaptive immune system is composed of highly specialized, systemic cells and processes that eliminate or prevent pathogenic growth. Thought to have arisen in the first jawed vertebrates, the adaptive or "specific" immune system is activated by the “non-specific” and evolutionarily older innate...

 of jawed vertebrates—the basis of acquired immunity—is highly specialized and can protect against almost any type of invader. The adaptive immune system is dependent on lymphocytes, which are not phagocytes but produce protective proteins called antibodies
Antibody
An antibody, also known as an immunoglobulin, is a large Y-shaped protein used by the immune system to identify and neutralize foreign objects such as bacteria and viruses. The antibody recognizes a unique part of the foreign target, termed an antigen...

, which tag invaders for destruction and prevent virus
Virus
A virus is a small infectious agent that can replicate only inside the living cells of organisms. Viruses infect all types of organisms, from animals and plants to bacteria and archaea...

es from infecting cells. Phagocytes, in particular dendritic cells and macrophages, stimulate lymphocytes to produce antibodies by an important process called antigen
Antigen
An antigen is a foreign molecule that, when introduced into the body, triggers the production of an antibody by the immune system. The immune system will then kill or neutralize the antigen that is recognized as a foreign and potentially harmful invader. These invaders can be molecules such as...

 presentation.

Antigen presentation

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. There are two "professional" antigen-presenting cells: macrophages and dendritic cells. After engulfment, foreign proteins (the antigen
Antigen
An antigen is a foreign molecule that, when introduced into the body, triggers the production of an antibody by the immune system. The immune system will then kill or neutralize the antigen that is recognized as a foreign and potentially harmful invader. These invaders can be molecules such as...

s) are broken down into peptide
Peptide
Peptides are short polymers of amino acid monomers linked by peptide bonds. They are distinguished from proteins on the basis of size, typically containing less than 50 monomer units. The shortest peptides are dipeptides, consisting of two amino acids joined by a single peptide bond...

s inside dendritic cells and macrophages. These peptides are then bound to the cell's major histocompatibility complex
Major histocompatibility complex
Major histocompatibility complex is a cell surface molecule encoded by a large gene family in all vertebrates. MHC molecules mediate interactions of leukocytes, also called white blood cells , which are immune cells, with other leukocytes or body cells...

 (MHC) glycoproteins, which carry the peptides back to the phagocyte's surface where they can be "presented" to lymphocytes. Mature macrophages do not travel far from the site of infection, but dendritic cells can reach the body's lymph node
Lymph node
A lymph node is a small ball or an oval-shaped organ of the immune system, distributed widely throughout the body including the armpit and stomach/gut and linked by lymphatic vessels. Lymph nodes are garrisons of B, T, and other immune cells. Lymph nodes are found all through the body, and act as...

s where there are millions of lymphocytes. 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. But dendritic cells can also destroy or pacify lymphocytes if they recognize components of the host body; this is necessary to prevent autoimmune reactions. This process is called tolerance.

Immunological tolerance

Dendritic cells also promote immunological tolerance, which stops the body from attacking itself. The first type of tolerance is central tolerance
Central tolerance
Central tolerance is the mechanism by which newly developing T cells and B cells are rendered non-reactive to self. The concept of central tolerance was proposed in 1959 by Joshua Lederberg, as part of his general theory of immunity and tolerance, and is often mistakenly attributed to MacFarlane...

: when T cell
T cell
T cells or T lymphocytes belong to a group of white blood cells known as lymphocytes, and play a central role in cell-mediated immunity. They can be distinguished from other lymphocytes, such as B cells and natural killer cells , by the presence of a T cell receptor on the cell surface. They are...

s first depart from the thymus
Thymus
The thymus is a specialized organ of the immune system. The thymus produces and "educates" T-lymphocytes , which are critical cells of the adaptive immune system....

, 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
Peripheral tolerance
Peripheral tolerance is immunological tolerance developed after T and B cells mature and enter the periphery. These include the suppression of autoreactive cells by 'regulatory' T cells and the generation of hyporesponsiveness in lymphocytes which encounter antigen in the absence of the...

. 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
Regulatory T cell
Regulatory T cells , sometimes known as suppressor T cells, are a specialized subpopulation of T cells which suppresses activation of the immune system and thereby maintains tolerance to self-antigens. The existence of regulatory T cells was the subject of significant controversy among...

s to inactivate the harmful T cells' activities. When immunological tolerance fails, autoimmune disease
Autoimmune disease
Autoimmune diseases arise from an overactive immune response of the body against substances and tissues normally present in the body. In other words, the body actually attacks its own cells. The immune system mistakes some part of the body as a pathogen and attacks it. This may be restricted to...

s can follow. On the other hand, too much tolerance allows some infections, like HIV
HIV
Human immunodeficiency virus is a lentivirus that causes acquired immunodeficiency syndrome , a condition in humans in which progressive failure of the immune system allows life-threatening opportunistic infections and cancers to thrive...

, to go unnoticed.

Professional phagocytes

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. The professional phagocytes are the monocytes, macrophages, neutrophils, tissue dendritic cell
Dendritic cell
Dendritic cells are immune cells forming part of the mammalian immune system. Their main function is to process antigen material and present it on the surface to other cells of the immune system. That is, dendritic cells function as antigen-presenting cells...

s and mast cell
Mast cell
A mast cell is a resident cell of several types of tissues and contains many granules rich in histamine and heparin...

s. One litre
Litre
pic|200px|right|thumb|One litre is equivalent to this cubeEach side is 10 cm1 litre water = 1 kilogram water The litre is a metric system unit of volume equal to 1 cubic decimetre , to 1,000 cubic centimetres , and to 1/1,000 cubic metre...

 of human blood contains about six billion phagocytes.

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 II
MHC class II
MHC Class II molecules are found only on a few specialized cell types, including macrophages, dendritic cells and B cells, all of which are professional antigen-presenting cells ....

 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
Protozoa
Protozoa are a diverse group of single-cells eukaryotic organisms, many of which are motile. Throughout history, protozoa have been defined as single-cell protists with animal-like behavior, e.g., movement...

.

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.

Migration

When an infection occurs, a chemical "SOS" signal is given off to attract phagocytes to the site. These chemical signals may include proteins from invading bacteria
Bacteria
Bacteria are a large domain of prokaryotic microorganisms. Typically a few micrometres in length, bacteria have a wide range of shapes, ranging from spheres to rods and spirals...

, clotting system peptides, complement
Complement system
The complement system helps or “complements” the ability of antibodies and phagocytic cells to clear pathogens from an organism. It is part of the immune system called the innate immune system that is not adaptable and does not change over the course of an individual's lifetime...

 products, and cytokines that have been given off by macrophages located in the tissue near the infection site. Another group of chemical attractants are cytokines that recruit neutrophils and monocytes from the blood.

To reach the site of infection, phagocytes leave the bloodstream and enter the affected tissues. Signals from the infection cause the endothelial cells that line the blood vessels to make a protein called selectin
Selectin
Selectins are a family of cell adhesion molecules . All selectins are single-chain transmembrane glycoproteins that share similar properties to C-type lectins due to a related amino terminus and calcium-dependent binding...

, which neutrophils stick to on passing by. Other signals called vasodilators loosen the junctions connecting endothelial cells, allowing the phagocytes to pass through the wall. Chemotaxis
Chemotaxis
Chemotaxis is the phenomenon in which somatic cells, bacteria, and other single-cell or multicellular organisms direct their movements according to certain chemicals in their environment. This is important for bacteria to find food by swimming towards the highest concentration of food molecules,...

 is the process by which phagocytes follow the cytokine "scent" to the infected spot. 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. During an infection, millions of neutrophils are recruited from the blood, but they die after a few days.

Monocytes

Monocytes develop in the bone marrow and reach maturity in the blood. Mature monocytes have large, smooth, lobed nuclei and abundant cytoplasm
Cytoplasm
The cytoplasm is a small gel-like substance residing between the cell membrane holding all the cell's internal sub-structures , except for the nucleus. All the contents of the cells of prokaryote organisms are contained within the 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 that 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 or dendritic cells depending on the signals they receive. There are about 500 million monocytes in one litre of human blood.

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. They derive from monocytes, granulocyte
Granulocyte
Granulocytes are a category of white blood cells characterized by the presence of granules in their cytoplasm. They are also called polymorphonuclear leukocytes because of the varying shapes of the nucleus, which is usually lobed into three segments...

 stem cells, or the cell division
Cell division
Cell division is the process by which a parent cell divides into two or more daughter cells . Cell division is usually a small segment of a larger cell cycle. This type of cell division in eukaryotes is known as mitosis, and leaves the daughter cell capable of dividing again. The corresponding sort...

 of pre-existing macrophages. Human macrophages are about 21 micrometers in diameter.
This type of phagocyte does not have granules but contains many lysosome
Lysosome
thumb|350px|Schematic of typical animal cell, showing subcellular components. [[Organelle]]s: [[nucleoli]] [[cell nucleus|nucleus]] [[ribosomes]] [[vesicle |vesicle]] rough [[endoplasmic reticulum]]...

s. Macrophages are found throughout the body in almost all tissues and organs (e.g., microglial cells in the brain
Brain
The brain is the center of the nervous system in all vertebrate and most invertebrate animals—only a few primitive invertebrates such as sponges, jellyfish, sea squirts and starfishes do not have one. It is located in the head, usually close to primary sensory apparatus such as vision, hearing,...

 and alveolar
Pulmonary alveolus
An alveolus is an anatomical structure that has the form of a hollow cavity. Found in the lung parenchyma, the pulmonary alveoli are the dead ends of the respiratory tree, which outcrop from either alveolar sacs or alveolar ducts, which are both sites of gas exchange with the blood as well...

 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 TNF-alpha. 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.

Macrophages can be activated to perform functions that a resting monocyte cannot. T helper cell
T helper cell
T helper cells are a sub-group of lymphocytes, a type of white blood cell, that play an important role in the immune system, particularly in the adaptive immune system. These cells have no cytotoxic or phagocytic activity; they cannot kill infected host cells or pathogens. Rather, they help other...

s (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. Other signals include TNF-alpha and lipopolysaccharides from bacteria. Th1 cells can recruit other phagocytes to the site of the infection in several ways. They secrete cytokines that act on the bone marrow
Bone marrow
Bone marrow is the flexible tissue found in the interior of bones. In humans, bone marrow in large bones produces new blood cells. On average, bone marrow constitutes 4% of the total body mass of humans; in adults weighing 65 kg , bone marrow accounts for approximately 2.6 kg...

 to stimulate the production of monocytes and neutrophils, and they secrete some of the cytokine
Cytokine
Cytokines are small cell-signaling protein molecules that are secreted by the glial cells of the nervous system and by numerous cells of the immune system and are a category of signaling molecules used extensively in intercellular communication...

s that are responsible for the migration of monocytes and neutrophils out of the bloodstream. Th1 cells come from the differentiation
Cellular differentiation
In developmental biology, cellular differentiation is the process by which a less specialized cell becomes a more specialized cell type. Differentiation occurs numerous times during the development of a multicellular organism as the organism changes from a simple zygote to a complex system of...

 of CD4+ T cells once they have responded to antigen in the secondary lymphoid tissues
Lymphatic system
The lymphoid system is the part of the immune system comprising a network of conduits called lymphatic vessels that carry a clear fluid called lymph unidirectionally toward the heart. Lymphoid tissue is found in many organs, particularly the lymph nodes, and in the lymphoid follicles associated...

. Activated macrophages play a potent role in tumor
Tumor
A tumor or tumour is commonly used as a synonym for a neoplasm that appears enlarged in size. Tumor is not synonymous with cancer...

 destruction by producing TNF-alpha, IFN-gamma, nitric oxide, reactive oxygen compounds, cationic proteins, and hydrolytic enzymes.

Neutrophils

Neutrophils are normally found in the bloodstream
Circulatory system
The circulatory system is an organ system that passes nutrients , gases, hormones, blood cells, etc...

 and are the most abundant type of phagocyte, constituting 50% to 60% of the total circulating white blood cells. One litre of human blood contains about five billion neutrophils, which are about 10 micrometer
Micrometer
A micrometer , sometimes known as a micrometer screw gauge, is a device incorporating a calibrated screw used widely for precise measurement of small distances in mechanical engineering and machining as well as most mechanical trades, along with other metrological instruments such as dial, vernier,...

s in diameter and live for only about five days. Once they have received the appropriate signals, it takes them about thirty minutes to leave the blood and reach the site of an infection. They are ferocious eaters and rapidly engulf invaders coated with antibodies
Antibody
An antibody, also known as an immunoglobulin, is a large Y-shaped protein used by the immune system to identify and neutralize foreign objects such as bacteria and viruses. The antibody recognizes a unique part of the foreign target, termed an antigen...

 and complement
Complement system
The complement system helps or “complements” the ability of antibodies and phagocytic cells to clear pathogens from an organism. It is part of the immune system called the innate immune system that is not adaptable and does not change over the course of an individual's lifetime...

, and damaged cells or cellular debris. Neutrophils do not return to the blood; they turn into pus
Pus
Pus is a viscous exudate, typically whitish-yellow, yellow, or yellow-brown, formed at the site of inflammatory during infection. An accumulation of pus in an enclosed tissue space is known as an abscess, whereas a visible collection of pus within or beneath the epidermis is known as a pustule or...

 cells and die. Mature neutrophils are smaller than monocytes and have a segmented nucleus
Cell nucleus
In cell biology, the nucleus is a membrane-enclosed organelle found in eukaryotic cells. It contains most of the cell's genetic material, organized as multiple long linear DNA molecules in complex with a large variety of proteins, such as histones, to form chromosomes. The genes within these...

 with several sections; each section is connected by chromatin
Chromatin
Chromatin is the combination of DNA and proteins that make up the contents of the nucleus of a cell. The primary functions of chromatin are; to package DNA into a smaller volume to fit in the cell, to strengthen the DNA to allow mitosis and meiosis and prevent DNA damage, and to control gene...

 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
Myelocyte
A myelocyte is a young cell of the granulocytic series, occurring normally in bone marrow, but not in circulating blood .-Histology:...

s and promyelocyte
Promyelocyte
A promyelocyte is a granulocyte precursor, developing from the myeloblast and developing into the myelocyte.-External links: - "18. Bone Marrow and Hemopoiesis: bone marrow smear, promyelocyte and erythroblasts " "Bone marrow" "Bone marrow"* - "Bone marrow smear"...

s are released.

The intra-cellular granules of the human neutrophil have long been recognized for their protein-destroying and bactericidal properties. Neutrophils can secrete products that stimulate monocytes and macrophages. Neutrophil secretions increase phagocytosis and the formation of reactive oxygen compounds involved in intracellular killing. Secretions from the primary granules of neutrophils stimulate the phagocytosis of IgG-antibody-coated bacteria.

Dendritic cells

Dendritic cells are specialized antigen-presenting cells that have long outgrowths called dendrites, which help to engulf microbes and other invaders. Dendritic cells are present in the tissues that are in contact with the external environment, mainly the skin, the inner lining of the nose, the lungs, the stomach, and the intestines. 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.
Mature dendritic cells activate T helper cell
T helper cell
T helper cells are a sub-group of lymphocytes, a type of white blood cell, that play an important role in the immune system, particularly in the adaptive immune system. These cells have no cytotoxic or phagocytic activity; they cannot kill infected host cells or pathogens. Rather, they help other...

s and cytotoxic T cell
Cytotoxic T cell
A cytotoxic T cell belongs to a sub-group of T lymphocytes that are capable of inducing the death of infected somatic or tumor cells; they kill cells that are infected with viruses , or are otherwise damaged or...

s. 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.

Mast cells

Mast cells have Toll-like receptor
Toll-like receptor
Toll-like receptors are a class of proteins that play a key role in the innate immune system. They are single, membrane-spanning, non-catalytic receptors that recognize structurally conserved molecules derived from microbes...

s and interact with dendritic cells, B cells, and T cells to help mediate adaptive immune functions. Mast cells express MHC class II
MHC class II
MHC Class II molecules are found only on a few specialized cell types, including macrophages, dendritic cells and B cells, all of which are professional antigen-presenting cells ....

 molecules and can participate in antigen presentation; however, the mast cell's role in antigen presentation is not very well understood. Mast cells can consume and kill gram-negative bacteria (e.g., salmonella
Salmonella
Salmonella is a genus of rod-shaped, Gram-negative, non-spore-forming, predominantly motile enterobacteria with diameters around 0.7 to 1.5 µm, lengths from 2 to 5 µm, and flagella which grade in all directions . They are chemoorganotrophs, obtaining their energy from oxidation and reduction...

), and process their antigens. They specialize in processing the fimbrial proteins
Fimbria (bacteriology)
In bacteriology, a Cilli is a proteinaceous appendage in many Gram-negative and some Gram-positive bacteria that is thinner and shorter than a flagellum. This appendage ranges from 3-10 nanometers in diameter and can be up to several micrometers long...

 on the surface of bacteria, which are involved in adhesion to tissues. In addition to these functions, mast cells produce cytokines that induce an inflammatory response. This is a vital part of the destruction of microbes because the cytokines attract more phagocytes to the site of infection.
Professional Phagocytes
Main location Variety of phenotype
Phenotype
A phenotype is an organism's observable characteristics or traits: such as its morphology, development, biochemical or physiological properties, behavior, and products of behavior...

s
Blood neutrophils, monocytes
Bone marrow macrophages, monocytes, sinusoidal cells
Sinusoid (blood vessel)
A sinusoid is a small blood vessel similar to a capillary but with a fenestrated endothelium. Fenestrations are pores in the endothelial cells that greatly increase their permeability. In addition, permeability is increased by large inter-cellular clefts and fewer tight junctions...

, lining cells
Bone tissue osteoclast
Osteoclast
An osteoclast is a type of bone cell that removes bone tissue by removing its mineralized matrix and breaking up the organic bone . This process is known as bone resorption. Osteoclasts were discovered by Kolliker in 1873...

s
Gut and intestinal Peyer's patches macrophages
Connective tissue
Connective tissue
"Connective tissue" is a fibrous tissue. It is one of the four traditional classes of tissues . Connective Tissue is found throughout the body.In fact the whole framework of the skeleton and the different specialized connective tissues from the crown of the head to the toes determine the form of...

histiocyte
Histiocyte
A histiocyte is a cell that is part of the mononuclear phagocyte system . The mononuclear phagocytic system is part of the organism's immune system...

s, macrophages, monocytes, dendritic cells
Liver Kupffer cell
Kupffer cell
Kupffer cells, also known as Browicz-Kupffer cells and stellate macrophages, are specialized macrophages located in the liver lining the walls of the sinusoids that form part of the reticuloendothelial system .-History:The cells were first observed by Karl Wilhelm von Kupffer in 1876...

s, monocytes
Lung self-replicating macrophages, monocytes, mast cells, dendritic cells
Lymphoid tissue
Lymphatic system
The lymphoid system is the part of the immune system comprising a network of conduits called lymphatic vessels that carry a clear fluid called lymph unidirectionally toward the heart. Lymphoid tissue is found in many organs, particularly the lymph nodes, and in the lymphoid follicles associated...

free and fixed macrophages and monocytes, dendritic cells
Nervous tissue microglial cells (CD4
CD4
CD4 is a glycoprotein expressed on the surface of T helper cells, monocytes, macrophages, and dendritic cells. It was discovered in the late 1970s and was originally known as leu-3 and T4 before being named CD4 in 1984...

+)
Spleen
Spleen
The spleen is an organ found in virtually all vertebrate animals with important roles in regard to red blood cells and the immune system. In humans, it is located in the left upper quadrant of the abdomen. It removes old red blood cells and holds a reserve of blood in case of hemorrhagic shock...

free and fixed macrophages, monocytes, sinusoidal cells
Thymus
Thymus
The thymus is a specialized organ of the immune system. The thymus produces and "educates" T-lymphocytes , which are critical cells of the adaptive immune system....

free and fixed macrophages and monocytes
Skin resident Langerhans cell
Langerhans cell
Langerhans cells are dendritic cells of the skin and mucosa, and contain large granules called Birbeck granules. They are present in all layers of the epidermis, but are most prominant in the stratum spinosum. They also occur in the papillary dermis, particularly around blood vessels, as well as...

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. These cells include epithelial cells, endothelial cells, fibroblast
Fibroblast
A fibroblast is a type of cell that synthesizes the extracellular matrix and collagen, the structural framework for animal tissues, and plays a critical role in wound healing...

s, and mesenchymal cells. They are called non-professional phagocytes, to emphasize that, in contrast to professional phagocytes, phagocytosis is not their principal function. Fibroblasts, for example, which can phagocytose collagen in the process of remolding scars will also make some attempt to ingest foreign particles.

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
Opsonin
An opsonin is any molecule that targets an antigen for an immune response. However, the term is usually used in reference to molecules that act as a binding enhancer for the process of phagocytosis, especially antibodies, which coat the negatively-charged molecules on the membrane. Molecules that...

s—which are antibodies and complement attached to invaders by the immune system. Additionally, most nonprofessional phagocytes do not produce reactive oxygen-containing molecules in response to phagocytosis.
Non-professional Phagocytes
Main location Variety of phenotypes
Blood, lymph and lymph nodes Lymphocytes
Blood, lymph and lymph nodes NK and LGL cells (large granular lymphocytes)
Skin Epithelial cells
Blood vessels Endothelial cells
Connective tissue Fibroblasts
Blood Erythrocytes

Pathogen evasion and resistance

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.

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. Fourth, some bacteria can avoid contact with phagocytes by tricking the immune system into "thinking" that the bacteria are "self". Treponema pallidum
Treponema pallidum
Treponema pallidum is a species of spirochaete bacterium with subspecies that cause treponemal diseases such as syphilis, bejel, pinta and yaws. The treponemes have a cytoplasmic and outer membrane...

—the bacterium that causes syphilis
Syphilis
Syphilis is a sexually transmitted infection caused by the spirochete bacterium Treponema pallidum subspecies pallidum. The primary route of transmission is through sexual contact; however, it may also be transmitted from mother to fetus during pregnancy or at birth, resulting in congenital syphilis...

—hides from phagocytes by coating its surface with fibronectin
Fibronectin
Fibronectin is a high-molecular weight glycoprotein of the extracellular matrix that binds to membrane-spanning receptor proteins called integrins. In addition to integrins, fibronectin also binds extracellular matrix components such as collagen, fibrin and heparan sulfate proteoglycans...

, which is produced naturally by the body and plays a crucial role in wound healing
Wound healing
Wound healing, or cicatrisation, is an intricate process in which the skin repairs itself after injury. In normal skin, the epidermis and dermis exists in a steady-state equilibrium, forming a protective barrier against the external environment...

.

Avoiding engulfment

Bacteria often produce proteins or sugars that coat their cells and interfere with phagocytosis; these are called capsules. Some examples are the K5 capsule and O75 O antigen found on the surface of Escherichia coli
Escherichia coli
Escherichia coli is a Gram-negative, rod-shaped bacterium that is commonly found in the lower intestine of warm-blooded organisms . Most E. coli strains are harmless, but some serotypes can cause serious food poisoning in humans, and are occasionally responsible for product recalls...

, and the exopolysaccharide
Exopolysaccharide
Exopolysaccharides are high-molecular-weight polymers that are composed of sugar residues and are secreted by a microorganism into the surrounding environment. Microorganisms synthesize a wide spectrum of multifunctional polysaccharides including intracellular polysaccharides, structural...

 capsules of Staphylococcus epidermidis
Staphylococcus epidermidis
Staphylococcus epidermidis is one of thirty-three known species belonging to the genus Staphylococcus. It is part of human skin flora, and consequently part of human flora. It can also be found in the mucous membranes and in animals. Due to contamination, it is probably the most common species...

. Streptococcus pneumoniae
Streptococcus pneumoniae
Streptococcus pneumoniae, or pneumococcus, is Gram-positive, alpha-hemolytic, aerotolerant anaerobic member of the genus Streptococcus. A significant human pathogenic bacterium, S...

produces several types of capsule which provide different levels of protection, and group A streptococci produce proteins such as M protein
M protein (Streptococcus)
M protein is a virulence factor that can be produced by certain species of Streptococcus.Viruses, parasites and bacteria are covered in protein and sugar molecules that help them gain entry into a host by counteracting the host's defences. One such molecule is the M protein produced by certain...

 and fimbrial proteins
Fimbria (bacteriology)
In bacteriology, a Cilli is a proteinaceous appendage in many Gram-negative and some Gram-positive bacteria that is thinner and shorter than a flagellum. This appendage ranges from 3-10 nanometers in diameter and can be up to several micrometers long...

 to block engulfment. Some proteins hinder opsonin-related ingestion; Staphylococcus aureus
Staphylococcus aureus
Staphylococcus aureus is a facultative anaerobic Gram-positive coccal bacterium. It is frequently found as part of the normal skin flora on the skin and nasal passages. It is estimated that 20% of the human population are long-term carriers of S. aureus. S. aureus is the most common species of...

produces Protein A
Protein A
Protein A is a 40-60 kDa MSCRAMM surface protein originally found in the cell wall of the bacterium Staphylococcus aureus. It is encoded by the spa gene and its regulation is controlled by DNA topology, cellular osmolarity, and a two-component system called ArlS-ArlR. It has found use in...

 to block antibody receptors which decreases the effectiveness of opsonins.

Survival inside the phagocyte

Bacteria have developed ways to survive inside phagocytes, where they continue to evade the immune system. 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. Some bacteria prevent the fusion of a phagosome and lysosome, to form the phagolysosome. Other pathogens, such as Leishmania
Leishmania
Leishmania is a genus of Trypanosomatid protozoa, and is the parasite responsible for the disease leishmaniasis. It is spread through sandflies of the genus Phlebotomus in the Old World, and of the genus Lutzomyia in the New World. Their primary hosts are vertebrates; Leishmania commonly infects...

, create a highly modified vacuole
Vacuole
A vacuole is a membrane-bound organelle which is present in all plant and fungal cells and some protist, animal and bacterial cells. Vacuoles are essentially enclosed compartments which are filled with water containing inorganic and organic molecules including enzymes in solution, though in certain...

 inside the phagocyte, which helps them persist and replicate. Legionella pneumophila
Legionella pneumophila
Legionella pneumophila is a thin, ærobic, pleomorphic, flagellated, non-spore forming, Gram-negative bacterium of the genus Legionella. L. pneumophila is the primary human pathogenic bacterium in this group and is the causative agent of legionellosis or Legionnaires' disease.-Characterization:L...

produces secretions which cause the phagosome to fuse with vesicles other than the ones that contain toxic substances. Other bacteria are capable of living inside of the phagolysosome. Staphylococcus aureus, for example, produces the enzymes catalase
Catalase
Catalase is a common enzyme found in nearly all living organisms that are exposed to oxygen, where it catalyzes the decomposition of hydrogen peroxide to water and oxygen...

 and superoxide dismutase
Superoxide dismutase
Superoxide dismutases are a class of enzymes that catalyze the dismutation of superoxide into oxygen and hydrogen peroxide. As such, they are an important antioxidant defense in nearly all cells exposed to oxygen...

 which break down chemicals—such as hydrogen peroxide—produced by phagocytes to kill bacteria. 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 listeriolysin O
Hemolysin
Hemolysins are exotoxins produced by bacteria that cause lysis of red blood cells in vitro. Visualization of hemolysis of red blood cells in agar plates facilitates the categorization of some pathogenic bacteria such as Streptococcus and Staphylococcus...

 and phospholipase C
Phospholipase
A phospholipase is an enzyme that hydrolyzes phospholipids into fatty acids and other lipophilic substances. There are four major classes, termed A, B, C and D, distinguished by the type of reaction which they catalyze:*Phospholipase A...

.

Killing

Bacteria have developed several ways of killing phagocytes. These include cytolysin
Cytolysin
Cytolysin refers to the substance or antibody elaborated by microorganisms, plants or animals that is specifically toxic to individual cells, in many cases causing their dissolution through lysis. Cytolysins that have a specific action for certain cells are named accordingly...

s which form pores in the phagocyte's cell membranes, streptolysins and leukocidin
Leukocidin
A leukocidin is a type of cytotoxin created by some types of bacteria. It is a type of pore forming toxin. Leukocidins get their names by killing leukocytes.One type is Panton-Valentine leukocidin....

s which cause neutrophils' granules to rupture and release toxic substances, and exotoxins which reduce the supply of a phagocyte's ATP
Adenosine triphosphate
Adenosine-5'-triphosphate is a multifunctional nucleoside triphosphate used in cells as a coenzyme. It is often called the "molecular unit of currency" of intracellular energy transfer. ATP transports chemical energy within cells for metabolism...

, 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.

Disruption of cell signaling

Some survival strategies often involve disrupting cytokines and other methods of cell signaling
Cell signaling
Cell signaling is part of a complex system of communication that governs basic cellular activities and coordinates cell actions. The ability of cells to perceive and correctly respond to their microenvironment is the basis of development, tissue repair, and immunity as well as normal tissue...

 to prevent the phagocyte's responding to invasion. The protozoan parasites Toxoplasma gondii
Toxoplasma gondii
Toxoplasma gondii is a species of parasitic protozoa in the genus Toxoplasma. The definitive host of T. gondii is the cat, but the parasite can be carried by many warm-blooded animals . Toxoplasmosis, the disease of which T...

, Trypanosoma cruzi
Trypanosoma cruzi
Trypanosoma cruzi is a species of parasitic euglenoid trypanosomes. This species causes the trypanosomiasis diseases in humans and animals in America...

, and Leishmania
Leishmania
Leishmania is a genus of Trypanosomatid protozoa, and is the parasite responsible for the disease leishmaniasis. It is spread through sandflies of the genus Phlebotomus in the Old World, and of the genus Lutzomyia in the New World. Their primary hosts are vertebrates; Leishmania commonly infects...

infect macrophages, and each has a unique way of taming them. Some species of Leishmania alter the infected macrophage's signalling, repress the production of cytokines and microbicidal molecules—nitric oxide and reactive oxygen species—and compromise antigen presentation.

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 control infection but can damage host tissue. In general, phagocytes aim to destroy pathogens by engulfing them and subjecting them to a battery of toxic chemicals inside a phagolysosome
Phagolysosome
A phagolysosome is the membrane-enclosed organelle which forms when a phagosome fuses with a lysosome. After fusion, the food particles or pathogens contained within the phagosome are usually digested by the enzymes contained within the lysosome. Phagolysosome formation follows phagocytosis...

. 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.

When neutrophils release their granule contents in the kidney
Kidney
The kidneys, organs with several functions, serve essential regulatory roles in most animals, including vertebrates and some invertebrates. They are essential in the urinary system and also serve homeostatic functions such as the regulation of electrolytes, maintenance of acid–base balance, and...

, the contents of the granule (reactive oxygen compounds and proteases) degrade the extracellular matrix
Extracellular matrix
In biology, the extracellular matrix is the extracellular part of animal tissue that usually provides structural support to the animal cells in addition to performing various other important functions. The extracellular matrix is the defining feature of connective tissue in animals.Extracellular...

 of host cells and can cause damage to glomerular cells, affecting their ability to filter blood and causing changes in shape. In addition, phospholipase
Phospholipase
A phospholipase is an enzyme that hydrolyzes phospholipids into fatty acids and other lipophilic substances. There are four major classes, termed A, B, C and D, distinguished by the type of reaction which they catalyze:*Phospholipase A...

 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
Renal failure
Renal failure or kidney failure describes a medical condition in which the kidneys fail to adequately filter toxins and waste products from the blood...

.

Neutrophils also play a key role in the development of most forms of acute lung injury
Acute lung injury
Acute lung injury is a diffuse heterogeneous lung injury characterized by hypoxemia, non cardiogenic pulmonary edema, low lung compliance and widespread capillary leakage...

. Here, activated neutrophils release the contents of their toxic granules into the lung environment. Experiments have shown that a reduction in the number of neutrophils lessens the effects of acute lung injury, but treatment by inhibiting neutrophils is not clinically realistic, as it would leave the host vulnerable to infection. In the liver
Liver
The liver is a vital organ present in vertebrates and some other animals. It has a wide range of functions, including detoxification, protein synthesis, and production of biochemicals necessary for digestion...

, damage by neutrophils can contribute to dysfunction and injury in response to the release of endotoxin
Endotoxin
Endotoxins are toxins associated with some Gram-negative bacteria. An "endotoxin" is a toxin that is a structural molecule of the bacteria that is recognized by the immune system.-Gram negative:...

s produced by bacteria, sepsis
Sepsis
Sepsis is a potentially deadly medical condition that is characterized by a whole-body inflammatory state and the presence of a known or suspected infection. The body may develop this inflammatory response by the immune system to microbes in the blood, urine, lungs, skin, or other tissues...

, trauma, alcoholic hepatitis
Alcoholic hepatitis
Alcoholic hepatitis is hepatitis due to excessive intake of alcohol. While distinct from cirrhosis, it is regarded as the earliest stage of alcoholic liver disease. Symptoms are jaundice, ascites , fatigue and hepatic encephalopathy...

, ischemia
Ischemia
In medicine, ischemia is a restriction in blood supply, generally due to factors in the blood vessels, with resultant damage or dysfunction of tissue. It may also be spelled ischaemia or ischæmia...

, and hypovolemic shock resulting from acute hemorrhage.

Chemicals released by macrophages can also damage host tissue. 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. However, if a bacterial infection spreads to the blood, TNF-α is released into vital organs which can cause vasodilation
Vasodilation
Vasodilation refers to the widening of blood vessels resulting from relaxation of smooth muscle cells within the vessel walls, particularly in the large arteries, smaller arterioles and large veins. The process is essentially the opposite of vasoconstriction, or the narrowing of blood vessels. When...

 and a decrease in plasma
Blood plasma
Blood plasma is the straw-colored liquid component of blood in which the blood cells in whole blood are normally suspended. It makes up about 55% of the total blood volume. It is the intravascular fluid part of extracellular fluid...

 volume; these in turn can be followed by septic shock
Septic shock
Septic shock is a medical emergency caused by decreased tissue perfusion and oxygen delivery as a result of severe infection and sepsis, though the microbe may be systemic or localized to a particular site. It can cause multiple organ dysfunction syndrome and death...

. 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.

Evolutionary origins

Phagocytosis is common and probably appeared early in evolution
Evolution
Evolution is any change across successive generations in the heritable characteristics of biological populations. Evolutionary processes give rise to diversity at every level of biological organisation, including species, individual organisms and molecules such as DNA and proteins.Life on Earth...

, evolving first in unicellular eukaryotes. Amoeba
Amoeba
Amoeba is a genus of Protozoa.History=The amoeba was first discovered by August Johann Rösel von Rosenhof in 1757. Early naturalists referred to Amoeba as the Proteus animalcule after the Greek god Proteus, who could change his shape...

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. Dictyostelium discoideum
Dictyostelium discoideum
Dictyostelium discoideum is a species of soil-living amoeba belonging to the phylum Mycetozoa. D. discoideum, commonly referred to as slime mold, is a eukaryote that transitions from a collection of unicellular amoebae into a multicellular slug and then into a fruiting body within its lifetime. D...

, 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 it has other biological functions in common with macrophages. Dictyostelium discoideum is social; it aggregates when starved to form a migrating pseudoplasmodium or slug
Dictyostelid
The dictyostelids are a group of cellular slime molds, or social amoebae.-Slug behavior:When food is readily available they are individual amoebae, which feed and divide normally...

. 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 has 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 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. But a common ancestry with mammalian phagocytes has not been proven. Phagocytes occur throughout the animal kingdom, from marine sponges to insects and lower and higher vertebrates. The ability of amoebae to distinguish between self and non-self is a pivotal one and is the root of the immune system of many species.
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