PHAGOCYTOSIS

Phagocytosis is the cellular process of Phagocytes and Protists of engulfing solid particles by the cell membrane to form an internal phagosome, which is a food vacuole, or pteroid. Phagocytosis is a specific form of endocytosis involving the vesicular internalization of solid particles, such as bacteria, and is therefore distinct from other forms of endocytosis such as pinocytosis, the vesicular internalization of various liquids. Phagocytosis is involved in the acquisition of nutrients for some cells, and in the immune system it is a major mechanism used to remove pathogens and cell debris. Bacteria, dead tissue cells, and small mineral particles are all examples of objects that may be phagocytosed.

The process is only homologous to eating at the level of single-celled organisms; in multicellular animals, the process has been adapted to eliminate debris and pathogens, as opposed to taking in fuel for cellular processes, except in the case of the Trichoplax

1. In immune system
Phagocytosis in mammalian immune cells is activated by attachment to Pathogen-associated molecular patterns (PAMPS), which leads to NF-κB activation. Opsonins such as C3b and antibodies can act as attachment sites and aid phagocytosis of pathogens.[1]
Engulfment of material is facilitated by the actin-myosin contractile system. The phagosome of ingested material is then fused with the lysosome, leading to degradation

Degradation can be oxygen-dependent or oxygen-independent.
• Oxygen-dependent degradation depends on NADPH and the production of reactive oxygen species. Hydrogen peroxide and myeloperoxidase activate a halogenating system which leads to the destruction of bacteria.
• Oxygen-independent degradation depends on the release of granules, containing proteolytic enzymes such as defensins, lysozyme and cationic proteins. Other antimicrobial peptides are present in these granules, including lactoferrin which sequesters iron to provide unfavourable growth conditions for bacteria.

It is possible for cells other than dedicated phagocytes (such as dendritic cells) to engage in phagocytosis.[2]

2. In Apoptosis
Following apoptosis, the dying cells need to be taken up into the surrounding tissues by macrophages in a process called Efferocytosis. One of the features of an apoptotic cell is the presentation of a variety of intracellular molecules on the cell surface, such as Calreticulin, Phosphatidylserine (From the inner layer of the plasma membrane), Annexin A1 and oxidised LDL. These molecules are recognised by receptors on the cell surface of the macrophage such as the Phosphatidylserine Receptor, or by soluble (free floating) receptors such as Thrombospondin 1, Gas-6 and MFG-E8, which then themselves bind to other receptors on the macrophage such as CD36 and Alpha-V Beta-3 Integrin.

2. In protists
In many protists, phagocytosis is used as a means of feeding, providing part or all of their nourishment. This is called phagotrophic nutrition, as distinguished from osmotrophic nutrition, which takes place by absorption.
• In some, such as amoeba, phagocytosis takes place by surrounding the target object with pseudopods, as in animal phagocytes. In humans, Entamoeba histolytica can phagocytose red blood cells.[3] This process is known as "erythrophagocystosis", and is considered the only reliable way to distinguish Entamoeba histolytica from noninvasive species such as Entamoeba dispar.[4]
• Ciliates also engage in phagocytosis.[5] In ciliates there is a specialized groove or chamber in the cell where phagocytosis takes place, called the cytostome or mouth.
The resulting phagosome may be merged with lysosomes containing digestive enzymes, forming a phagolysosome. The food particles will then be digested, and the released nutrients are diffused or transported into the cytosol for use in other metabolic processes.

Mixotrophy can involve phagotrophic nutrition and phototrophic nutrition.[6]

CELL (BIOLOGY)

often called the building bricks of life.[1] Some organisms, such as most bacteria, are unicellular (consist of a single cell). Other organisms, such as humans, are multicellular. (Humans have an estimated 100 trillion or 1014 cells; a typical cell size is 10 µm; a typical cell mass is 1 nanogram.) The largest known cell is an unfertilized ostrich egg cell.[2]

In 1835 before the final cell theory was developed, a Czech Jan Evangelista Purkyně observed small "granules" while looking at the plant tissue through a microscope. The cell theory, first developed in 1839 by Matthias Jakob Schleiden and Theodor Schwann, states that all organisms are composed of one or more cells. All cells come from preexisting cells. Vital functions of an organism occur within cells, and all cells contain the hereditary information necessary for regulating cell functions and for transmitting information to the next generation of cells.[3]
The word cell comes from the Latin cellula, meaning, a small room. The descriptive name for the smallest living biological structure was chosen by Robert Hooke in a book he published in 1665 when he compared the cork cells he saw through his microscope to the small rooms monks lived in.[4]

General Principles
Each cell is at least somewhat self-contained and self-maintaining: it can take in nutrients, convert these nutrients into energy, carry out specialized functions, and reproduce as necessary. Each cell stores its own set of instructions for carrying out each of these activities.

All cells have several different abilities:[5]
• Reproduction by cell division: (binary fission/mitosis or meiosis).
• Use of enzymes and other proteins coded for by DNA genes and made via messenger RNA intermediates and ribosomes.
• Metabolism, including taking in raw materials, building cell components, converting energy, molecules and releasing by-products. The functioning of a cell depends upon its ability to extract and use chemical energy stored in organic molecules. This energy is released and then used in metabolic pathways.
• Response to external and internal stimuli such as changes in temperature, pH or levels of nutrients.
• Cell contents are contained within a cell surface membrane that is made from a lipid bilayer with proteins embedded in it.
Some prokaryotic cells contain important internal membrane-bound compartments,[6] but eukaryotic cells have a specialized set of internal membrane compartments.

Anatomy of cells
There are two types of cells: eukaryotic and prokaryotic. Prokaryotic cells are usually independent, while eukaryotic cells are often found in multicellular organisms.

Prokaryotic cells
eukaryotes. There are two kinds of prokaryotes: bacteria and archaea; these share a similar overall structure.

A prokaryotic cell has three architectural regions:
• on the outside, flagella and pili project from the cell's surface. These are structures (not present in all prokaryotes) made of proteins that facilitate movement and communication between cells;
• enclosing the cell is the cell envelope - generally consisting of a cell wall covering a plasma membrane though some bacteria also have a further covering layer called a capsule. The envelope gives rigidity to the cell and separates the interior of the cell from its environment, serving as a protective filter. Though most prokaryotes have a cell wall, there are exceptions such as Mycoplasma (bacteria) and Thermoplasma (archaea)). The cell wall consists of peptidoglycan in bacteria, and acts as an additional barrier against exterior forces. It also prevents the cell from expanding and finally bursting (cytolysis) from osmotic pressure against a hypotonic environment. Some eukaryote cells (in plants and fungi) also have a cell wall;
• inside the cell is the cytoplasmic region that contains the cell genome (DNA) and ribosomes and various sorts of inclusions. A prokaryotic chromosome is usually a circular molecule (an exception is that of the bacterium Borrelia burgdorferi, which causes Lyme disease). Though not forming a nucleus, the DNA is condensed in a nucleoid. Prokaryotes can carry extrachromosomal DNA elements called plasmids, which are usually circular. Plasmids enable additional functions, such as antibiotic resistance.

Eukaryotic cells
Eukaryotic cells are about 10 times the size of a typical prokaryote and can be as much as 1000 times greater in volume. The major difference between prokaryotes and eukaryotes is that eukaryotic cells contain membrane-bound compartments in which specific metabolic activities take place. Most important among these is the presence of a cell nucleus, a membrane-delineated compartment that houses the eukaryotic cell's DNA. It is this nucleus that gives the eukaryote its name, which means "true nucleus." Other differences include:
• The plasma membrane resembles that of prokaryotes in function, with minor differences in the setup. Cell walls may or may not be present.
• The eukaryotic DNA is organized in one or more linear molecules, called chromosomes, which are associated with histone proteins. All chromosomal DNA is stored in the cell nucleus, separated from the cytoplasm by a membrane. Some eukaryotic organelles such as mitochondria also contain some DNA.
• Eukaryotes can move using cilia or flagella. The flagella are more complex than those of prokaryotes.

PHAGOCYTES

Phagocytes are the white blood cells that protect the body by ingesting (phagocytosing) harmful foreign particles, bacteria and dead or dying cells. They are essential for fighting infections, and for subsequent immunity.[1] Phagocytes are important throughout the animal kingdom,[2] and are highly developed in vertebrates.[3] One liter of human blood contains about six billion phagocytes.[4] Their name comes from the Greek phagein, 'to eat or devour', and kutos, 'hollow vessel'.[5] Phagocytes were first discovered in 1882 by Ilya Ilyich Mechnikov while he was studying starfish larvae.[6] Mechnikov was awarded the 1908 Nobel Prize in Physiology or Medicine for his discovery.[7] Phagocytes occur in many species; some amoebae behave like macrophages which suggests that phagocytes appeared early in the evolution of life.[8]

Phagocytes of humans and other animals are called professional or non-professional, depending on how effective they are at phagocytosis.[9] The professional phagocytes include cells called neutrophils, monocytes, macrophages, dendritic cells, and mast cells.[10] The main difference between professional and non-professional phagocytes is that the professional phagocytes have molecules called receptors on their surfaces that can detect harmful objects, such as bacteria, that are not normally found in the body.[11] 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 life-span.[12]

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 bacteria touch a phagocyte, they bind to the receptors on the phagocyte's surface and are consumed.[13] When a pathogen enters some phagocytes, this can trigger a chemical attack by the phagocytes that uses oxidants and nitric oxide to kill the pathogen.[14] After phagocytosis, macrophages and dendritic cells can also participate in antigen presentation: this is when the 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 nodes and display the material to white blood cells called lymphocytes. This process is important in building immunity.[15] However, many pathogens have evolved methods to counter attacks by phagocytes.[1]

History
The Russian zoologist Ilya Ilyich Mechnikov (1845–1916) first recognized that specialized cells were involved in defense against microbial infections. In 1882, he studied motile (freely moving) cells in the larvae of 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.[16] Mechnikov traveled to Vienna and shared his ideas with Carl Friedrich Claus who suggested the name ‘‘phagocyte’’ (from the Greek words phagein, meaning 'to eat or devour', and kutos, meaning 'hollow vessel'[5]) for the cells that Mechnikov had observed.[17]
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 bacterium Bacillus anthracis could be engulfed and killed by phagocytes, a process that he called phagocytosis.[18] Mechnikov proposed that phagocytes were a primary defense against invading organisms.

In 1903, Amroth Wright discovered that phagocytosis was reinforced by specific antibodies which he called opsonins, from the Greek "opson", a dressing or relish.[19] Mechnikov was awarded (jointly with Paul Ehrlich) the 1908 Nobel Prize in Physiology or Medicine for his work on phagocytes and phagocytosis.[7]
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.[20]

Phagocytosis
Phagocytosis is the process of taking in particles such as bacteria, parasites, dead host cells and cellular and foreign debris by a cell.[21] It involves a chain of molecular processes.[22] 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.[23] 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 to form a phagolysosome. The imprisoned bacterium is then submitted to a formidable battery of killing mechanisms,[24] and is dead a few minutes later.[23] 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.[25] 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.[26]

A phagocyte has many types of receptors on its surface that are used to bind material.[1] They include opsonin receptors, scavenger receptors, and Toll-like receptors. Opsonin receptors increase the phagocytosis of bacteria that have been coated with 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.[27] 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—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.[1]

Methods of killing
The killing of microbes is a critical function of phagocytes,[28] and is either performed within the phagocyte (intracellular killing) or outside of the phagocyte (extracellular killing).

Oxygen-dependent intracellular killing
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.[29] 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.[14]

The first type is the oxygen-dependent production of a superoxide,[1] which is an important, oxygen-rich, bacteria-killing substance.[30] 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.[1]
The second type involves the use of the enzyme myeloperoxidase from neutrophil granules.[31] 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.[1] Myeloperoxidase contains a heme pigment, which makes secretions rich in neutrophils, such as pus and infected sputum, green.[32]

Oxygen-independent intracellular killing
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 membrane. The second type uses lysozymes; these enzymes break down the bacterial cell wall. The third type uses lactoferrins which are present in neutrophil granules and remove essential iron from bacteria.[33] The fourth type uses proteases and hydrolytic enzymes; these enzymes are used to digest the proteins of destroyed bacteria.[34]
Gambar 4. Micrograph of Gram-stained pus showing Neisseria gonorrhoeae bacteria inside phagocytes and their relative sizes

Intracellular : In cell biology, molecular biology and related fields, the word intracellular means "inside the cell".
It is used in contrast to extracellular (outside the cell). The cell membrane (and, in plants, the cell wall) is the barrier between the two, and chemical composition of intra- and extracellular milieu can be radically different. In most organisms, for example, a Na+/K+ ATPase maintains a high potassium level inside cells while keeping sodium low, leading to chemical excitability.

Extracellular killing
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, CD8+ T cells, Natural Killer cells, B cells, Natural Killer T cells, monocytes, macrophages, or dendritic cells.[35] Nitric oxide is then released from the macrophage and, because of its toxicity, kills microbes near the macrophage.[1] Activated macrophages produce and secrete tumor necrosis factor. This cytokine—a class of signaling molecules[36]—kills cancer cells and cells infected by viruses, and helps to activate the other cells of the immune system.[37]
In some diseases, e.g. the rare chronic granulomatous disease, the efficiency of phagocytes is impaired and recurrent bacterial infections are a problem.[38] 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.[39]

Extracellular : In cell biology, molecular biology and related fields, the word extracellular (or sometimes extracellular space) means "outside the cell". This space is usually taken to be outside the plasma membranes, and occupied by fluid. The term is used in contrast to intracellular (inside the cell).
The composition of the extracellular space includes metabolites, ions, proteins, and many other substances that might affect cellular function. For example, hormones act by travelling the extracellular space towards biochemical receptors on cells. Other proteins that are active outside the cell are the digestive enzymes.
The term 'extracellular' is often used in reference to the extracellular fluid (ECF) which composes about 15 litres of the average human body. The cell membrane (and, in plants and fungi, the cell wall) is the barrier between the two, and chemical composition of intra- and extracellular milieu can be radically different. In most organisms, for example, a Na+/K+-ATPase pump maintains a high concentration of sodium ions outside cells while keeping that of potassium low, leading to chemical excitability. Many cold-tolerant plants force water into the extracellular space when the temperature drops below 0 degrees Celsius, so that when it freezes, it does not lyse the plants' cells. [1]

Two compartments comprise the extracellular space: the vascular space and the interstitial space.[2]

Viruses
Viruses 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 they are inside cells the adaptive immune responses, particularly the lymphocytes, are more important for defense.[40] At the sites of viral infections, lymphocytes often vastly outnumber all the other cells of the immune system; this is common in viral meningitis.[41] Virus infected cells that have been killed by lymphocytes are cleared from the body by phagocytes.[42]

Role in apoptosis
Animals' cells constantly die and are replaced by cell division. In adults, the number of cells is kept relatively constant. Cells are usually replaced when they malfunction or become diseased, but cell proliferation must be offset by cell death.[12] 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.[43]

Dying cells that undergo the final stages of apoptosis[44] display molecules, such as phosphatidylserine, on their cell surface to attract phagocytes.[45] Phosphatidylserine is normally found on the cytosolic surface of the plasma membrane, but is redistributed during apoptosis to the extracellular surface by a hypothetical protein known as scramblase.[46] These molecules mark the cell for phagocytosis by cells that possess the appropriate receptors, such as macrophages.[47] The removal of dying cells by phagocytes occurs in an orderly manner without eliciting an inflammatory response and is an important function of phagocytes.[48]
Gambar 5. Apoptosis—phagocytes clear fragments of dead cells from the body

Interactions with other cells
Phagocytes are not bound to any particular 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 lymphocytes.[49] 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.[50] The adaptive immune system is dependent on lymphocytes, which are not phagocytes, but produce protective proteins called antibodies which tag invaders for destruction and prevent viruses from infecting cells.[51] Phagocytes, in particular dendritic cells and macrophages, stimulate lymphocytes to produce antibodies by an important process called antigen presentation.[52]

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.[53] There are two "professional" antigen-presenting cells: macrophages and dendritic cells.[54] After engulfment, foreign proteins (the antigens) are broken down into peptides 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 phagocytes surface where they can be "presented" to lymphocytes.[15] Mature macrophages do not travel far from the site of infection, but dendritic cells can reach the body's lymph nodes where there are millions of lymphocytes.[55] 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.[56] 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.[57]

Immunological tolerance
Dendritic cells also promote immunological tolerance,[58] which stops the body attacking itself. The first type of tolerance is central tolerance: when T cells 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 cells to inactivate the harmful T cells' activities.[59] When immunological tolerance fails, autoimmune diseases can follow.[60] On the other hand, too much tolerance allows some infections, like HIV, to go unnoticed.[59]

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.[9] The professional phagocytes are the monocytes, macrophages, neutrophils, tissue dendritic cells and mast cells.[10] One liter of human blood contains about six billion phagocytes.[4]
Gambar 7. Phagocytes derive from stem cells in the bone marrow

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 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.[61]
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.[62]

Migration
When an infection occurs, a chemical "SOS" signal is given off to attract phagocytes to the site.[63] These chemical signals may include proteins from invading bacteria, clotting system peptides, complement products, and cytokines that have been given off by macrophages located in the tissue near the infection site.[1] Another group of chemical attractants are cytokines which recruit neutrophils and monocytes from the blood.[13]

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 vasodilators 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.[1] 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.[64] During an infection millions of neutrophils are recruited from the blood but they die after a few days.[65]

Monocytes
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[66] or dendritic cells depending on the signals they receive.[67] There are about 500 million monocytes in one liter of human blood.[4]

magnification
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.[68] They derive from monocytes, granulocyte stem cells, or the cell division of pre-existing macrophages.[69] Human macrophages are about 21 micrometers in diameter.[70]
This type of phagocyte does not have granules but contains many lysosomes. Macrophages are found throughout the body in almost all tissues and organs (e.g., microglial cells in the brain and 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 TNF-alpha.[71] 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.[72]

Macrophages can be activated to perform functions that a resting monocyte cannot.[71] 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.[73] Other signals include TNF-alpha and lipopolysaccharides from bacteria.[71] 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 cytokines and that are responsible for the migration of monocytes and neutrophils out of the blood stream.[74] Th1 cells come from the differentiation of CD4 T cells once they have responded to antigen in the secondary lymphoid tissues.[71] Activated macrophages play a potent role in tumor destruction by producing TNF-alpha, IFN-gamma, nitric oxide, reactive oxygen compounds, cationic proteins, and hydrolytic enzymes.[71]
Gambar 10. Pus oozing from an abscess caused by bacteria—pus contains millions of phagocytes

Neutrophils
Neutrophils are normally found in the bloodstream and are the most abundant type of phagocyte, constituting 50% to 60% of the total circulating white blood cells.[75] One liter of human blood contains about five billion neutrophils,[4] which are about 10 micrometers in diameter,[76] and live for only about five days.[37] Once they have received the appropriate signals, it takes them about thirty minutes to leave the blood and reach the site of an infection.[77] They are ferocious eaters and rapidly engulf invaders coated with antibodies and complement, and damaged cells or cellular debris. Neutrophils do not return to the blood; they turn into pus cells and die.[77] Mature neutrophils are smaller than monocytes, and have a segmented 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 myelocytes and promyelocytes are released.[78]

The intra-cellular granules of the human neutrophil have long been recognized for their protein-destroying and bactericidal properties.[79] Neutrophils can secrete products that stimulate monocytes and macrophages. Neutrophil secretions increase phagocytosis and the formation of reactive oxygen compounds involved in intracellular killing.[80] Secretions from the primary granules of neutrophils stimulate the phagocytosis of IgG antibody-coated bacteria.[81]
Gambar 11. A neutrophil with a segmented nucleus (center and surrounded by erythrocytes), the intra-cellular granules are visible in the cytoplasm (Giemsa stained high magnification)

Dendritic cells
Dendritic cells are specialized antigen-presenting cells that have long outgrowths called dendrites,[82] which help to engulf microbes and other invaders.[83][84] 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.[85] 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.[86] Mature dendritic cells activate T helper cells and cytotoxic T cells.[87] 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 killer T cells or helper T cells.[88]

Mast cells
Mast cells have Toll-like receptors 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.[89] Mast cells can consume and kill gram-negative bacteria (e.g., salmonella), and process their antigens.[90] They specialize in processing the fimbrial proteins on the surface of bacteria, which are involved in adhesion to tissues.[91][92] In addition to these functions, mast cells produce cytokines that induce an inflammatory response.[93] This is a vital part of the destruction of microbes because they attract more phagocytes to the site of infection.[90]

Non-professional phagocytes
Dying cells and foreign organisms are consumed by cells other than the "professional" phagocytes.[95] These cells include epithelial cells, endothelial cells, fibroblasts, and mesenchymal cells. They are called non-professional phagocytes, to emphasize that, in contrast to professional phagocytes, phagocytosis is not their principal function.[96] Fibroblasts, for example, only make ineffective attempts to ingest foreign particles.[97]

Non-professional phagocytes are more limited limited than professional phagocytes in the type of particles they can take up. This is due to their lack of efficient phagocytic receptors, particularly opsonins—which are antibodies and complement attached to invaders by the immune system.[11] Additionally, most nonprofessional phagocytes do not produce reactive oxygen-containing molecules in response to phagocytosis.[98]

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.[99][100]

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.[99] 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,[101] which is produced naturally by the body and plays a crucial role in wound healing.[102]

Avoiding engulfment
Bacteria often produce proteins or sugars that coat their cells and interfere with phagocytosis; these are called capsules.[99] An example is the K5 capsule and O75 O antigen found on the surface of Escherichia coli,[103] and the exopolysaccharide capsules of Staphylococcus epidermidis.[104] Streptococcus pneumoniae produces several types of capsule which provide different levels of protection,[105] and group A streptococci produce proteins such as M protein and 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.[106]

Survival inside the phagocyte
Bacteria have developed ways to survive inside phagocytes, where they continue to evade the immune system.[107] 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.[108] Some bacteria prevent the fusion of a phagosome and lysosome, to form the phagolysosome.[99] Other pathogens, such as Leishmania, create a highly-modified vacuole inside the phagocyte, which helps them persist and replicate.[109] Legionella pneumophila produces secretions which cause the phagosome to fuse with vesicles other than the ones that contain toxic substances.[110] 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.[111] Bacteria may escape from the phagosome before the formation of the phagolysosome: Listeria monocytogenes can make a hole in the phagosome wall using a enzymes called listeriolysin O and phospholipase C.[112]

Killing
Bacteria have developed several ways of killing phagocytes.[106] These include: cytolysins which form pores in the phagocyte's cell membranes; streptolysins and leukocidins which cause neutrophils' granules to rupture and release toxic substances,[113][114] and exotoxins which reduce the supply of a phagocyte's 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.[99]

Disruption of cell signaling
Some survival strategies often involve disrupting cytokines and other methods of cell signaling to prevent the phagocyte's responding to invasion.[115] 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.[116]

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 it's 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.[97]
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.[117]
Neutrophils also play a key role in the development of most forms of acute lung injury (ALI).[118] In ALI, activated neutrophils release the contents of their toxic granules into the lung environment.[119] Experiments have shown that a reduction in the number of neutrophils lessens the effects of ALI,[120] but treatment by inhibiting neutrophils is not clinically realistic, as it would leave the host vulnerable to infection.[119] Damage by neutrophils can contribute to liver dysfunction and injury in response to the release of endotoxins produced by bacteria, sepsis, trauma, alcoholic hepatitis, ischemia, and hypovolemic shock resulting from acute hemorrhage.[121]
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.[122] However, if a bacterial infection spreads to the blood, TNF-α is released into vital organs which can cause vasodilation and a decrease in 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.[13]

Evolutionary origins
Phagocytosis is common and probably appeared early in evolution,[123] evolving first in unicellular eukaryotes.[124] Amoebae, 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. [124] 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.[125] Dictyostelium discoideum is social and aggregates when starved to form a migrating 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 sacrificing themselves to protect the other amoebae from bacteria is similar to the self-sacrifice by the phagocytes seen in the immune system of higher organisms. 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.[126] But a common ancestry with mammalian phagocytes has not been proven. Phagocytes occur throughout the animal kingdom,[2] from marine sponges to insects and lower and higher vertebrates.[127][128] 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.[8]

NB. From Any Soerce Refference