Phagocytes are cells that protect the body by ingesting harmful foreign particles, bacteria, and dead or dying cells. They include monocytes, macrophages, neutrophils, tissue dendritic cells, and mast cells. Their name comes from the Greek , "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. Phagocytes are important throughout the animal kingdom and are highly developed within vertebrates. One litre of human blood contains about six billion phagocytes. They were discovered in 1882 by Ilya Ilyich Mechnikov while he was studying starfish larvae.Ilya Mechnikov, retrieved on November 28, 2008. From Nobel Lectures, Physiology or Medicine 1901–1921, Elsevier Publishing Company, Amsterdam, 1967. Mechnikov was awarded the 1908 Nobel Prize in Physiology or Medicine for his discovery. Phagocytes occur in many species; some amoebae behave like macrophage phagocytes, which suggests that phagocytes appeared early in the evolution of life.Janeway, Chapter: Evolution of the innate immune system. retrieved on March 20, 2009 Discovered in 2019, species of bacteria Candidatus Uabimicrobium amorphum can perform phagocytosis by eating other bacteria.
Phagocytes of humans and other animals are called "professional" or "non-professional" depending on how effective they are at phagocytosis. The professional phagocytes include many types of white blood cells (such as neutrophils, monocytes, macrophages, mast cells, and dendritic cells). and 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. Non-professional phagocytes do not have efficient phagocytic receptors, such as those for opsonins. 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. 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 and nitric oxide. After phagocytosis, macrophages and dendritic cells can also participate in antigen presentation, a process in which a phagocyte moves parts of the ingested material back to its surface. This material is then displayed to other cells of the immune system. Some phagocytes then travel to the body's lymph nodes and display the material to white blood cells called lymphocytes. This process is important in building immunity, and many pathogens have evolved methods to evade attacks by phagocytes.
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. Mechnikov traveled to Vienna and shared his ideas with Carl Friedrich Claus who suggested the name "phagocyte" (from the Greek words , meaning "to eat or devour", and , meaning "hollow vessel") for the cells that Mechnikov had observed.
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. Mechnikov proposed that phagocytes were a primary defense against invading organisms.
In 1903, Almroth Wright discovered that phagocytosis was reinforced by specific antibodies that he called opsonins, from the Greek opson, "a dressing or relish". Mechnikov was awarded (jointly with Paul Ehrlich) the 1908 Nobel Prize in Physiology or Medicine 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.
Phagocytosis
Phagocytosis is the process of taking in particles such as bacteria, invasive fungi, parasites, dead host cells, 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. Within one minute the phagosome merges with either a lysosome or a granule to form a phagolysosome. 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 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 receptors, scavenger receptors, and Toll-like receptors. Opsonin receptors increase the phagocytosis of bacteria that have been coated with immunoglobulin G (IgG) antibodies or with complement. "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—bind to more specific molecules including foreign DNA and RNA. Binding to Toll-like receptors increases phagocytosis and causes the phagocyte to release a group of hormones that cause inflammation.
Methods of killing
The killing of microbes is a critical function of phagocytes that is performed either within the phagocyte (intracellular killing) or outside of the phagocyte (extracellular killing).
Oxygen-dependent intracellular When a phagocyte ingests bacteria (or any material), its oxygen consumption increases. The increase in oxygen consumption, called a respiratory burst, 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, which is an oxygen-rich bacteria-killing substance. 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.
The second type involves the use of the enzyme myeloperoxidase from neutrophil granules. 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. Myeloperoxidase contains a heme pigment, which accounts for the green color of secretions rich in neutrophils, such as pus and infected sputum.
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. 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. The fourth type uses proteases and hydrolytic enzymes; these enzymes are used to digest the proteins of destroyed bacteria.
Extracellular Interferon-gamma—which was once called macrophage activating factor—stimulates macrophages to produce nitric oxide. The source of interferon-gamma can be CD4+ T cells, CD8+ T cells, natural killer cells, B cells, natural killer T cells, monocytes, other 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. This cytokine—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, 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 Chédiak–Higashi syndrome, are also associated with defective killing of ingested microbes.
Viruses Viruses can reproduce only inside cells, and they can 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. 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 and cell death keeps the number of cells relatively constant in adults. 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.