Phagocytic cells.html



Neutrophil phagocytosing anthrax bacilli

Phagocytes are cells that are found in the blood, bone marrow and other tissues of vertebrates.¹ Phagocytes ingest pathogenic and infectious agents in the body.² Like all cells that are involved in the immune system they originate in the bone marrow. Phagocytes derive from a group of stem cells in the bone marrow called myeloid progenitor cells. Phagocytes are the basis of defense in the innate immune system: these cells ingest pathogens and often take part in antigen presentation.³ Their name comes from the Greek word phagein (meaning to eat or devour) and from the Greek word kutos (meaning hollow vessel).⁴⁵ The types of phagocytes include neutrophils, macrophages, and monocytes.⁶ Dendritic cells also participate in phagocytosis and presentation of antigens to other cells that are important in the immune response.⁷

History

Ilya Ilyich Mechnikov

In 1882 Ilya Ilyich Mechnikov studied motile cells in the larvae of starfishes that he believed were important to their immune defenses. To test his idea he inserted small thorns from a tangerine tree into the larvae. He noticed that the motile cells surrounded the thorns. Mechnikov knew that in animals that have a vascular system leukocytes migrate from the blood stream during an infection. He deduced that these leukocytes might migrate from the blood to engulf and digest bacteria. Mechnikov went to Vienna and explained his ideas to a Professor Claus (of Zoology). It was Professor Claus who created the name phagocyte. To advance his hypothesis, Mechnikov studied a fresh-water crustacean called Daphnia. He discovered that fungal spores that attacked the crustacean were destroyed by phagocytes. He later studied the bacterium Bacillus anthracis and found that this organism could also be destroyed by phagocytes.⁸ Mechnikov was awarded the 1908 Nobel Prize in Physiology or Medicine for his discovery of phagocytes and phagocytosis.⁹

Phagocytosis

Main article: Phagocytosis

Phagocytosis is the process of taking in foreign material. ¹⁰ It is one of the of the endocytic processes. ¹¹ Phagocytosis occurs after the bacterium is bound to one of the receptors. In this process the phagocyte stretches its pseudopodium around the bacterium and engulfs it. The bacterium is then trapped in a phagosome. The phagosome then combines with either a lysosome or a granule (from a neutrophil). The contents of the granule or lysosome are then released into the phagosome—the combination of a phagosome and a lysosome (or granule) produces a phagolysosome. ³

Initiation of phagocytosis

Phagocytes possess receptors on their surface that are used to bind infectious agents to the cell.³ These receptors increase the ability of a phagocyte to phagocytize foreign material.¹¹ These receptors include Fc receptors, complement receptors, scavenger receptors, and toll-like receptors.

• Fc receptors are used to increase the phagoctyosis of bacteria that have been coated with IgG antibodies. When bacteria coated with IgG antibodies are bound to the Fc receptors, it also increases the metabolic activity of phagocytes that is used in intracellular killing.
• Complement receptors also are specialized for binding to bacteria coated with complement. These bacteria must be coated with C3b. Binding to the Complement receptors increases phagocytosis and intracellular killing.
• Scavenger receptors are used to bind to large range of polyanions on bacteria. This increases phagocytosis of bacteria.
• Toll-like receptors are used to bind to recognized molecular patterns on infectious agents. Binding to toll-like receptors increases phagocytosis and causes the phagocyte to release a group of cytokines related to inflammation.³

Migration

Initial signaling

When infection occurs, a signal (SOS signals) is given off to attract monocyte (macrophage ¹² and dendritic cell precursors ¹³) and neutrophils. Chemical signals may include N-formyl-methionine peptides that originate in invading bacteria, clotting system peptides, complement products, and cytokines that have been given off by macrophages located in the tissue near the infection site.³ Another group of chemical attractants are chemokines (a type of cytokine) that are released by phagocytes near the infection. Like the other attractants, chemokines serve as recruiting agent for neutrophils and monocytes. For example, interleukin-8 attracts neutrophils from the blood stream into surrounding tissues, and macrophage chemoattractant protein-1 causes monocytes to leave the blood stream and enter tissues near the infection where the monocytes then develop into tissue macrophages.

Endothelial and epithelial migration

Signaling then promotes the phagocytes to attach to cell adhesion molecules. Selectins are the first group of endothelial adhesion molecules. Selectins—cytokines from macrophages are responsible for the release of granules found in endothelial cells that contain P-selectins— are found on the membrane of the endothelial cell and bond with certain carbohydrate groups, like the oligosaccharides on the surface of the monocytes and neutrophils. Intracellular adhesion molecules (or ICAMs) are responsible for producing a tighter attachment to the phagocyte. These molecules form bonds with the integral proteins on the surface of the circulating monocytes and neutrophils. ICAM-1 promotes strong endothelial and phagocytic bonds on the surface of irritated endothelial cells. Chemokines also help to create a better connection by changing the shape of molecules such as leukocyte functional antigen-1 (LFA-1) found on traveling monocytes and neutrophils. While ICAM-1 binds to LFA-1 on both neutrophils and monocytes (after exposure to the macrophage cytokine TNF-a), ICAM-2 is used to help only monocytes get into the infected tissue.¹⁴ Other signals from the infection site called vasodilators enable the phagocytes to cross through the spaces of endothelial cells by loosening the junctions connecting them (a process called diapedesis). Once the phagocytes are in the tissue in which the infection is occurring, chemotaxis allows the phagocytes to find the exact area. SOS signals may also enhance a phagocyte’s ability to ingest and kill organisms through the respective processes of phagocytosis and intracellular killing.³

Neutrophils also travel across epithelial-lined organs to sites of infection. This involves a series of interactions that have not yet been fully studied. Several protein interactions that have been identified are those between leukocyte CD11b (and CD18) with fucosylated glycoproteins that have been expressed by signaling. Following this reaction is a binding of the leukocyte proteins and desmosomal-associated JAM-C. Two other binding proteins have also been studied: junctional adhesion molecule-like protein (from the neutrophil) and epithelial coxsackie and adenovirus receptor.¹⁵ Although neutrophil migration across epithelial-lined organs is an important component of fighting infection, the migration itself can result in disease-like symptoms.¹⁶

Intracellular killing

Oxygen-dependent intracellular killing

When a phagocyte phagocytizes bacteria (or any material) its oxygen consumption increases. The increase in oxygen consumption is called a respiratory burst. A respiratory burst results in the production of anti-microbial reactive oxygen-containing molecules.¹⁷ Killing invading microbes by using the reactive oxygen-containing molecules is referred to as oxygen-dependent intracellular killing. The oxygen compounds are toxic to both the invader and the cell itself, so the phagocyte uses a series of detoxification reactions to protect itself by breaking down the substances. There are two types of oxygen-dependent intracellular killing methods:

• Oxygen-dependent myeloperoxidase-independent intracellular killing—when glucose is used during phagocytosis, NADPH is formed. Then NADPH oxidase is activated, this enzyme’s role is to oxidize NADPH. The oxidation of NADPH creates superoxide anion. The superoxide anion is then converted to hydrogen peroxide and singlet oxygen with the help of the enzyme superoxide dismutase. In addition to these compounds, superoxide anion reacts with hydrogen peroxide to produce hydroxyl radicals. All of these products are used to kill the invading microbe.
• Oxygen-dependent myeloperoxidase-dependent intracellular killing—this process occurs in neutrophils because it involves the use of myeloperoxidase from granules. When granules fuse with a phagosome myeloperoxidase is released into the phagolysosome—this enzyme uses hydrogen peroxide and halide ions (primarily chloride ions) to create hypochlorite. Hypochlorite is an extremely toxic substance that can be broken down by itself into singlet oxygen. Both the hypochlorite and the singlet oxygen are used to kill microbes in the phagolysosome.

Oxygen-independent intracellular killing

Another way that phagocytes kill microbes is by oxygen-independent methods. However, these methods are not as effective as the oxygen-dependent methods. There are four main types of oxygen-independent methods:

• Cationic proteins—when the phagosome becomes a phagolysosome these proteins are released and are used to damage the bacterium’s membrane.
• Lysozymes—these enzymes are used to break down the bacterial cell wall.
• Lactoferrins are used to take away iron from the bacterium.
• Proteolytic and hydrolytic enzymes—these enzymes are used to digest the proteins of killed bacteria.³

Extracellular killing

In macrophages, IFN-gamma stimulates the production of nitric oxide by increasing the use of inducible nitric oxide synthase (iNOS). TNF-alpha is also used in this process to promote anti-microbial iNOS methods. ¹⁸ Nitric oxide is then released from the macrophage; and, because of its toxicity, kills invading microbes near the macrophage. ³

Antigen presentation

Main article: Antigen presentation

There are two “professional” antigen presenting cells. They are macrophages and dendritic cells. ¹⁹ After phagocytosis, these cells derive antigens from either the pathogen itself or from its products. Protein antigens are turned into peptides inside of the dendritic cells and macrophages; then the peptides are carried to the surface by linking to major histocompatibility complex (MHC) glycoproteins. There are two different classes of MHC molecules that carry peptides originating from different places inside the cell: MHC class I and MHC class II. MHC class I molecules carry peptides from the cytosol to the surface of the cell where CD8 T cells recognize them. MHC class II molecules transport peptides from vesicles to the surface of the cell where they are recognized by CD4 T cells. MHC molecules are polygenic (meaning that the cell possesses several genes that code for each class of MHC molecules) and polymorphic (meaning that the genes have many variations capable of producing different molecules). Because of the MHC molecules’ combination of being both polygenic and polymorphic, it covers a great range of peptides that can be carried to the surface of a cell to be recognized by T cells. ²⁰

Cell types

Monocytes

Main article: Monocytes

Most mature monocytes are slightly larger than neutrophils. Monocytes also have granules. Monocytes phagocytize foreign or dangerous substances and present antigens to other cells of the immune system. Monocytes are split into two groups: a circulating group and a marginal group (approximately 70% are in the marginal group). Most monocytes leave circulation to travel to tissues and organs. When monocytes leave circulation they transform into macrophages.¹² Monocytes also serve as precursors to dendritic cells.¹³

Macrophages

Main article: Macrophages

Macrophages derive from monocytes, granulocyte-monocyte precursors, or from the division of preexisting macrophages. 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. microglia cells in the brain and alveolar macrophages in the lungs). A macrophage's location can also determine it size and appearance. Macrophages have many functions: they can phagocytize cell debris and foreign or harmful cells and antibodies (they are frequently seen with cytoplasmic projections that are used for engulfment), they are involved in antigen presentation, and they can even store iron. ²¹ Macrophages also participate in inflammation through the production of IL-6, TNF-alpha, and IL-1.²² Macrophages are usually only found in tissue and are rarely seen in circulation. Most macrophages have a lifespan of 3-6 weeks. ²¹

Macrophages can be activated so that they can perform functions that cannot be performed by a resting monocyte.²² Th1 cells are responsible for the activation of macrophages. Th1 cells activate macrophages by signaling with IFN-gamma and displaying the protein CD40 ligand.²³ Other signals include TNF-alpa and lipopolysaccharides from bacteria.²² The signals then allow the macrophage to effectively kill the microbes that were residing in their phagosomes. Th1 cells can recruit other phagocytes 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 chemokines that are responsible for the migration of monocytes and neutrophils out of the blood stream.²³ Th 1 cells come from the differentiation of CD4 T cells once they have responded to antigen in the secondary lymphoid tissues. ²² Macrophages’ NADPH oxidase(an enzyme that plays a role in respiratory bursts)activity increases after activation as well.²⁴ Activated macrophages also play a more potent role in tumor destruction after activation by producing TNF-alpha, IFN-gamma, nitric oxide, reactive oxygen compounds, cationic proteins, and hydrolytic enzymes.²²

Neutrophils

Main article: Neutrophils

Neutrophils participate in phagocytosis of antibody and complement coated antigens. They can also phagocytize damaged cells or cell parts. Neutrophils have a segmented nucleus. This means that they have a nucleus that has several sections; each section is connected by chromatin filaments—neutrophils can have 2-5 segments. Neutrophils do not normally exit the bone marrow until their nucleus has been segmented; but if there is a high need for neutrophils or if there are irregularities in the bone marrow, neutrophil precursors called myelocytes and promyelocytes are released. Neutrophils are also separated between circulating and marginal groups (about 50% of neutrophils are marginated). ²⁵

Neutrophils can also secrete products that stimulate monocytes and macrophages. Neutrophil secretions increase phagocytosis and the formation of reactive oxygen compounds involved in intracellular killing. ²⁶ Heparin-binding protein and human neutrophil peptides 1-3 have been found to mediate the response to neutrophil secretions. Secretion from the primary granules of neutrophils stimulated the phagocytosis of IgG-coated bacteria. ²⁷

Dendritic cells

A dendritic cell

Main article: Dendritic Cell

Dendritic cells are specialized antigen-presenting cells that grow long processes or projections called dendrites.²⁸. These cells derive from the bone marrow and are present in small quantities in tissues that are in contact with the external environment, mainly the skin (where there is a specialized dendritic cell type called Langerhans cells) and the inner lining of the nose, lungs, stomach and intestines. They can also be found in an immature state in the blood. Once activated, they migrate to the lymphoid tissues where they interact with T cells and B cells to initiate and shape the adaptive immune response.²⁹ After monocytes have turned into immature dendritic cells, the immature dendritic cells circulate throughout the body. The dendrites help to engulf microbes and other antigen sources in peripheral tissues. ^{30 7} Once antigens have been engulfed, they are converted into proteolytic peptides and are attached to MHC class I or II molecules. Following the conversion of antigens into proteolytic peptides, dendritic cells travel to secondary lymphoid organs and mature so that they can present the antigens to T lymphocytes. ⁷ Dendritic cells when matured can produce other products that stimulate T lymphocytes and help orchestrate the immune response. How effective the immune response controlled be dendritic cells is, depends on their maturity. Maturity can be increased through signals from captured microbes and antigens and other factors in the immune system. Dendritic cells also activate both helper T cells and killer T cells. The activated helper T cells also interact with macrophages and B cells to activate them. In addition, dendritic cells are capable of influencing the type of immune response (whether it be for viruses or something else); when they travel to the lymphoid areas where T cells are held they select the specific T cells for the job. These T cells then differentiate into killer T cells and helper T cells. ³⁰

Resistance by pathogen

Many pathogens can delay or prevent the creation of the phagolysosome such as Mycobacterium tuberculosis, Salmonella typhi and Legionella. Others, such as the parasites of the genus Leishmania, able to resist or circumvent being digested in the phagolysosome.

One function of T-helper cells is to activate phagocytes to digest intracellular pathogens.

References

External links

• MeSH Phagocytes