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A pathogen’s success depends on its ability to evade the host’s immune responses.
- List the mechanisms that bacteria use for intracellular pathogenesis
- Bacteria usually overcome physical barriers by secreting enzymes to digest the barrier in the manner of a type II secretion system.
- Some pathogens avoid the immune system by hiding within the cells of the host, a process referred to as intracellular pathogenesis.
- Other pathogens invade the body by changing the non-essential epitopes on their surface rapidly, while keeping the essential epitopes hidden.
- pathogen: Any organism or substance, especially a microorganism, capable of causing disease, such as bacteria, viruses, protozoa, or fungi. Microorganisms are not considered to be pathogenic until they have reached a population size that is large enough to cause disease.
- biofilm: A thin film of mucus created by and containing a colony of bacteria and other microorganisms.
- antigenic variation: The mechanism by which an infectious organism changes its surface proteins in favor of circumventing a host immune response.
Extracellular Immune Avoidance
A pathogen’s success depends on its ability to evade the host’s immune responses. Thus, pathogens have evolved several methods that allow them to successfully infect a host by evading the immune system’s detection and destruction. Bacteria usually overcome physical barriers by secreting enzymes that digest the barrier in the manner of a type II secretion system. They also use a type III secretion system that allows bacteria to insert a hallow tube, which provides proteins a direct route to enter the host cell. These proteins often shutdown the defenses of the host.
Some pathogens avoid the immune system by hiding within the cells of the host, a process referred to as intracellular pathogenesis. The pathogen hides inside the host cell where it is protected from direct contact with the complement, antibodies, and immune cells. A lot of pathogens release compounds that misdirect or diminish the host’s immune response. Some bacteria even form biofilms which protect them from the proteins and cells of the immune system. Many successful infections often involve biofilms. Some bacteria create surface proteins, such as Streptococcus, that will bind to antibodies making them ineffective.
Other pathogens invade the body by changing the non-essential epitopes on their surface rapidly while keeping the essential epitopes hidden. This is referred to as antigenic variation. HIV rapidly mutates so the proteins that are on its viral envelope, which are essential for its entry into the host’s target cell, are consistently changing. The constant change of these antigens is why vaccines have not been created. Another common strategy that is used is to mask antigens with host molecules in order to evade detection by the immune system. With HIV, the envelope covering the viron is created from the host cell’s outermost membrane making it difficult for the immune system to identify as a non-self structure.
Frontiers in Immunology
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In December 2019, the outbreak of novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) – the causative agent of Coronavirus disease 2019 (COVID-19) – began in Wuhan, Hubei Province, China, from where it spread rapidly. On March 11, 2020 the World Health Organization declared COVID-19 a global pandemic (1, 2). COVID-19 is not the first severe respiratory disease outbreak caused by coronaviruses (CoVs) in humans, with two epidemic diseases – severe acute respiratory syndrome (SARS-CoV) in 2003 and Middle East respiratory syndrome (MERS𠄼oV) in 2012 – caused by similar zoonotic transmission of CoVs (3). The primary symptoms of COVID-19 are similar to those of SARS-CoV and MERS-CoV: fever, fatigue, dry cough, discomfort in the upper chest, occasional diarrhea, and dyspnea. Severe cases exhibit secondary infections, cytokine-storm driven sepsis, and multi-organ failure (4, 5). COVID-19 patients primarily develop pneumonia, lymphopenia, and feature pulmonary ground glass opacity on chest CT (6, 7).
Coronaviruses are in the Coronaviridae family, enveloped viruses with a positive-sense single-stranded RNA genome ranging from 26 to 32 kb in size (8). In humans CoV infections are common, with four CoVs (229E, NL63, OC43, and HKU1) causing % of common cold cases (4). The infection of human cells by CoVs is mediated by interactions between envelope-anchored spike glycoprotein (S-protein) of CoV with one of two host cell receptors: angiotensin-converting enzyme 2 (ACE2) or CD147 (9, 10). The S-protein consists of two subunits: S1 which functions as the receptor-binding domain (RBD), and S2 which drives the fusion of the viral membrane with the host cell membrane (11). Spike glycoprotein activation and viral entry is mediated by cleavage of the S protein by the host transmembrane protease, serine 2 (TMPRSS2) (12, 13). Sequencing of SARS-CoV-2 from patients revealed that it shares 79.6% homology to SARS-CoV, 50% MERS-CoV, and 96% to bat SARS-like CoV at the whole genome level (12, 14). The RBD of SARS-CoV-2 is derived from a pangolin-infecting CoV and exhibits a 10-fold increase in affinity between the RBD and ACE2 compared to SARS-CoV, further consistent with ACE2 as the prominent receptor for SARS-CoV-2 (15). This increase in receptor affinity was generated by the recombination of the pangolin CoV and a bat SARS-like CoV within the RBD region, a characteristic which could lead to a more efficient cell entry (16). Interestingly, crytal structure evaluation by cryo-electron microscopy (Cryo-EM) showed that SARS-CoV-2 RBD is biased toward the lying state conformation, which reduces receptor binding by burying the RBD within the spike protein trimer. In contrast, the SARS-CoV RBD is mostly in the exposed “standing up” state which favors receptor binding (17). This bias toward the lying state may favor SARS-CoV-2 immune evasion by masking the RBD domain from neutralizing antibodies. There have been reports that SARS-CoV-2 can also gain entry into cells via CD147, but the importance of this pathway for viral entry, and the concordant receptor-binding motifs, remain largely unelucidated (10).
Less well understood than SARS-CoV-2’s biology is it resulting immune responses, immunopathology, and immune evasion mechanisms. Understanding these responses will be vital for the development of immunotherapies or vaccines against COVID-19 (1, 20). Coronaviruses are adept at manipulating immune responses and interfere with the interferon (IFN) pathway, with several structural proteins (M and N) and non-structural protein (NSP1 and NSP3) from SARS-CoV and MERS-CoV acting as interferon antagonists (21). These CoVs also interfere with pattern recognition receptor (PRR) signaling such as Toll-like receptors (TLRs) and retinoic acid-inducible gene I (RIG-I) like receptors (22), and generate a strong inflammatory response (23, 24). This drives a non-productive inflammation, resulting in a cytokine storm and disseminated damage to the host, while avoiding induction of an anti-viral interferon response. Indeed, an early study of 41 COVID-19 patients identified increased levels of pro-inflammatory cytokines including IL-2 and IL-7, with more severe disease producing elevated G-CSF, MCP-1, MIP-1α, IP-10, and TNF-α (25). These pro-inflammatory cytokines drive an influx of neutrophils and other myeloid cells into the lung, producing a strong local inflammatory response and significant immunopathology (26). This is consistent with SARS and MERS, indicating that a cytokine storm and lymphopenia play a crucial role in the COVID-19 pathogenesis (25, 27, 28). In addition to manipulating cytokines, CoVs also manipulate other immunological processes including antigen presentation (29). In this review we discuss the major innate immunological pathways involved in responses to CoV infection, and the mechanisms used by SARS-CoV-2 and related CoVs to overcome these defenses.
Department of Biosystems Science and Engineering, ETH Zurich, Basel, Switzerland
Leo Scheller, Tobias Strittmatter, David Fuchs, Daniel Bojar & Martin Fussenegger
University of Basel, Faculty of Science, Basel, Switzerland
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L.S. and M.F. designed the project, analyzed the results and wrote the manuscript, and L.S., T.S., D.F. and D.B. designed and performed the experiments.
Ectopic tertiary lymphoid structures
Secondary lymphoid organs mediate the immune response to antigenic stimuli however, non-resolving inflammation leads to the formation of tertiary lymphoid structures, which organize the response to disease-causing antigens. These structures are ectopic aggregates of immune cells that assemble postnatally in the periphery of, within or near the antigen-hosting tissue 136 . Tertiary lymphoid tissues are structurally similar to secondary lymphoid organs, for example, they may contain segregated B and T cell zones, follicular dendritic cells networks and high endothelial venules, but they are less ordered and can contain different cell types 136 , such as pro-inflammatory macrophages and T helper 17 (TH17) cells 136,139 . B and T cells also show chronic hyperactivation. As in primary and secondary lymphoid organs, the spatiotemporal regulation of biochemical and biophysical factors within the microenvironment plays a key role in tertiary lymphoid organogenesis 136 .
Tertiary lymphoid structures have been detected in tissues affected by autoimmune disease 139,140 , cancer 141 and infection 142 and during allograft and implant rejection 143,144 and other inflammatory conditions 145 however, it is not yet clear whether they have protective or detrimental effects on disease progression because their often transient nature makes their characterization challenging 136 . Different disease conditions can vary widely in their capacity to induce tertiary lymphoid structures. Evidence suggests that tertiary lymphoid structures can function as immune inductive sites for protective immunity in infectious diseases and contribute to pathology in autoimmunity and cancers 146,147 . Owing to the complexity, heterogeneity and undefined nature of these ectopic lymph node-like structures and limited in vivo models 2 , engineered models of tertiary lymphoid organs are required to not only delineate their immunological functions but also inform the design of immunotherapies.
Ectopic transplantable bone marrow niches can be engineered by fabricating β-tricalcium phosphate (β-TCP) scaffolds with controlled, interconnected porous geometries using slip casting. Collagen type I and III or Matrigel can then be incorporated to recreate the bone marrow ECM 148 . Co-culture of HSCs, progenitor cells and MSCs on the β-TCP-matrix scaffolds and subsequent subcutaneous transplantation in C57Bl/6 mice support ectopic haematopoiesis and bone deposition, enabling the study of haematopoietic-mesenchymal interactions.
Cell-free artificial tertiary lymphoid structures can be generated to eliminate the use of genetically engineered stromal cells and to produce transplantable tissues that are more clinically translatable than tissues containing virally transduced cells. For example, lymphoid organogenesis-stimulating factors can be loaded into slow-releasing Medgel beads, which can then be trapped in a collagen sponge 149 . Three weeks after transplantation of the sponge into the renal subcapsular space of pre-immunized BALB/c mice, artificial tertiary lymphoid organs are formed. The lymphoid structures display organized B and T cell zones, a functional vasculature and fibroblastic reticular cell and follicular dendritic cell networks characteristic of native ectopic lymphoid tissue. Importantly, excising and re-transplanting the artificial lymphoid tissue into immune-deficient mice lacking the normal haematopoietic microenvironment lead to an increase in the production of antigen-specific high-affinity antibody-forming cells 1 week after immunization 149 .
Alternatively, to target the immune response in vivo, a macroporous PLGA matrix can be functionalized with granulocyte-macrophage colony-stimulating factor (GM-CSF), which is a potent stimulator of dendritic cell recruitment, danger signals, such as CpG oligodeox-ynucleotide (CpG-ODN) sequences, which are uniquely expressed in bacterial DNA, and tumour-derived antigens 150 . Upon subcutaneous implantation of the matrix in mice, dendritic cells are recruited and reprogrammed in situ at the implant site, which triggers an increase in dendritic cell homing to the lymph nodes, resulting in 90% animal survival in mice that would otherwise die from cancer in less than 25 days 150 . This approach demonstrates that functionalized materials can be used to target immune cells to ectopic sites of immune activation. Similarly, in situ crosslinkable hydrogels carrying chemokines and microparticle vaccines can be used as a depot for the recruitment and priming of immune cells at ectopic sites, such as muscles. Such hydrogel-based approaches for delivering factors that attract immature dendritic cells and that drive T cell responses towards tumour-suppressive activation states in lymphoma 151 provide a tool for the development of vaccines against cancer and infectious diseases.
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 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 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 is the process of taking in particles such as bacteria, 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. Binding to Toll-like receptors increases phagocytosis and causes the phagocyte to release a group of hormones that cause inflammation. 
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 Edit
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 Edit
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. 
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.  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 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.  Virus-infected cells that have been killed by lymphocytes are cleared from the body by phagocytes. 
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. 
Dying cells that undergo the final stages of apoptosis  display molecules, such as phosphatidylserine, on their cell surface to attract phagocytes.  Phosphatidylserine is normally found on the cytosolic surface of the plasma membrane, but is redistributed during apoptosis to the extracellular surface by a protein known as scramblase.   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. 
Phagocytes are usually 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.  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.  The adaptive immune system is not dependent on phagocytes but lymphocytes, which produce protective proteins called antibodies, which tag invaders for destruction and prevent viruses from infecting cells.  Phagocytes, in particular dendritic cells and macrophages, stimulate lymphocytes to produce antibodies by an important process called antigen presentation. 
Antigen presentation Edit
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 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 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 nodes, 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 Edit
Dendritic cells also promote immunological tolerance,  which stops the body from attacking itself. The first type of tolerance is central tolerance, that occurs in the thymus. T cells that bind (via their T cell receptor) to self antigen (presented by dendritic cells on MHC molecules) too strongly are induced to die. The second type of immunological tolerance is peripheral tolerance. Some self reactive T cells escape the thymus for a number of reasons, mainly due to the lack of expression of some self antigens in the thymus. Another type of T cell T regulatory cells can down regulate self reactive T cells in the periphery.  When immunological tolerance fails, autoimmune diseases can follow. 
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 cells and mast cells.  One litre of human blood contains about six billion phagocytes. 
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. 
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. 
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, clotting system peptides, complement 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, 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.  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 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 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. 
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 stem cells, or the cell division of pre-existing macrophages.  Human macrophages are about 21 micrometers in diameter. 
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.  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 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.  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 to stimulate the production of monocytes and neutrophils, and they secrete some of the cytokines that are responsible for the migration of monocytes and neutrophils out of the bloodstream.  Th1 cells come from the differentiation of CD4 + T cells once they have responded to antigen in the secondary lymphoid tissues.  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. 
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.  One litre of human blood contains about five billion neutrophils,  which are about 10 micrometers 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 and complement, and damaged cells or cellular debris. Neutrophils do not return to the blood they turn into pus cells and die.  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 metamyelocytes, myelocytes and promyelocytes 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 Edit
Dendritic cells are specialized antigen-presenting cells that have long outgrowths called dendrites,  that 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 cells and cytotoxic T cells.  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 Edit
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.  Mast cells can consume and kill gram-negative bacteria (e.g., salmonella), and process their antigens.  They specialize in processing the fimbrial proteins 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 phenotypes Blood neutrophils, monocytes Bone marrow macrophages, monocytes, sinusoidal cells, lining cells Bone tissue osteoclasts Gut and intestinal Peyer's patches macrophages Connective tissue histiocytes, macrophages, monocytes, dendritic cells Liver Kupffer cells, monocytes Lung self-replicating macrophages, monocytes, mast cells, dendritic cells Lymphoid tissue free and fixed macrophages and monocytes, dendritic cells Nervous tissue microglial cells (CD4 + ) Spleen free and fixed macrophages, monocytes, sinusoidal cells Thymus free and fixed macrophages and monocytes Skin resident Langerhans cells, other dendritic cells, conventional macrophages, mast cells
Dying cells and foreign organisms are consumed by cells other than the "professional" phagocytes.  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.  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, in particular opsonins—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) Blood Eosinophils and Basophils  Skin Epithelial cells Blood vessels Endothelial cells Connective tissue Fibroblasts
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 Edit
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—the bacterium that causes syphilis—hides from phagocytes by coating its surface with fibronectin,  which is produced naturally by the body and plays a crucial role in wound healing. 
Avoiding engulfment Edit
Bacteria often produce capsules made of proteins or sugars that coat their cells and interfere with phagocytosis.  Some examples are the K5 capsule and O75 O antigen found on the surface of Escherichia coli,  and the exopolysaccharide capsules of Staphylococcus epidermidis.  Streptococcus pneumoniae produces several types of capsule that provide different levels of protection,  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.  Enteropathogenic species of the genus Yersinia bind with the use of the virulence factor YopH to receptors of phagocytes from which they influence the cells capability to exert phagocytosis. 
Survival inside the phagocyte Edit
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, create a highly modified vacuole inside the phagocyte, which helps them persist and replicate.  Some 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.  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 and phospholipase C. 
Bacteria have developed several ways of killing phagocytes.  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,   and exotoxins that 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. 
Disruption of cell signaling Edit
Some survival strategies often involve disrupting cytokines and other methods of cell signaling to prevent the phagocyte's responding to invasion.  The protozoan parasites Toxoplasma gondii, Trypanosoma cruzi, and Leishmania 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. 
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. 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, 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 kidney failure. 
Neutrophils also play a key role in the development of most forms of acute lung injury.  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, damage by neutrophils can contribute to 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. 
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 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. 
Phagocytosis is common and probably appeared early in evolution,  evolving first in unicellular eukaryotes.  Amoebae are unicellular protists that separated from the tree leading to metazoa shortly after the divergence of plants, and they share many specific functions with mammalian phagocytic cells.  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 it has other biological functions in common with macrophages.  Dictyostelium discoideum is social it aggregates when starved to form a migrating pseudoplasmodium or slug. This multicellular organism eventually will produce a fruiting body with spores that are resistant to environmental dangers. Before the formation of fruiting bodies, the cells will migrate as a slug-like organism for several days. During this time, exposure to toxins or bacterial pathogens has the potential to compromise survival of the species 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 their self-sacrifice to protect the other amoebae from bacteria is similar to the self-sacrifice of phagocytes seen in the immune system of higher vertebrates. This ancient immune function in social amoebae suggests an evolutionarily conserved cellular foraging mechanism that might have been adapted to defense functions well before the diversification of amoebae into higher forms.  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 of amoeba. 
- ^ ab Little, C., Fowler H.W., Coulson J. (1983). The Shorter Oxford English Dictionary. Oxford University Press (Guild Publishing). pp. 1566–67. CS1 maint: uses authors parameter (link)
- ^ abcdefghijDelves et al. 2006, pp. 2–10
- ^ abDelves et al. 2006, p. 250
- ^Delves et al. 2006, p. 251
- ^ abcdHoffbrand, Pettit & Moss 2005, p. 331
- ^Ilya Mechnikov, retrieved on November 28, 2008. From Nobel Lectures, Physiology or Medicine 1901–1921, Elsevier Publishing Company, Amsterdam, 1967. Archived August 22, 2008, at the Wayback Machine
- ^ ab
- Schmalstieg, FC AS Goldman (2008). "Ilya Ilich Metchnikoff (1845–1915) and Paul Ehrlich (1854–1915): the centennial of the 1908 Nobel Prize in Physiology or Medicine". Journal of Medical Biography. 16 (2): 96–103. doi:10.1258/jmb.2008.008006. PMID18463079. S2CID25063709.
- ^ ab Janeway, Chapter: Evolution of the innate immune system. retrieved on March 20, 2009
- ^ abErnst & Stendahl 2006, p. 186
- ^ abRobinson & Babcock 1998, p. 187 and Ernst & Stendahl 2006, pp. 7–10
- ^ abErnst & Stendahl 2006, p. 10
- ^ ab
- Thompson, CB (1995). "Apoptosis in the pathogenesis and treatment of disease". Science. 267 (5203): 1456–62. Bibcode:1995Sci. 267.1456T. doi:10.1126/science.7878464. PMID7878464. S2CID12991980.
- ^ abc Janeway, Chapter: Induced innate responses to infection.
- ^ ab
- Fang FC (October 2004). "Antimicrobial reactive oxygen and nitrogen species: concepts and controversies". Nat. Rev. Microbiol. 2 (10): 820–32. doi:10.1038/nrmicro1004. PMID15378046. S2CID11063073.
- ^ abDelves et al. 2006, pp. 172–84
- ^ abc
- Kaufmann SH (2019). "Immunology's Coming of Age". Frontiers in Immunology. 10: 684. doi:10.3389/fimmu.2019.00684. PMC6456699 . PMID31001278.
- Aterman K (April 1, 1998). "Medals, memoirs—and Metchnikoff". J. Leukoc. Biol. 63 (4): 515–17. doi: 10.1002/jlb.63.4.515 . PMID9544583. S2CID44748502.
- "Ilya Mechnikov". The Nobel Foundation . Retrieved December 19, 2014 .
- ^Delves et al. 2006, p. 263
- ^Robinson & Babcock 1998, p. vii
- ^Ernst & Stendahl 2006, p. 4
- ^Ernst & Stendahl 2006, p. 78
- ^ ab
- Hampton MB, Vissers MC, Winterbourn CC Vissers Winterbourn (February 1994). "A single assay for measuring the rates of phagocytosis and bacterial killing by neutrophils". J. Leukoc. Biol. 55 (2): 147–52. doi:10.1002/jlb.55.2.147. PMID8301210. S2CID44911791. Archived from the original on December 28, 2012 . Retrieved December 19, 2014 . CS1 maint: multiple names: authors list (link)
- ^Delves et al. 2006, pp. 6–7
- ^Sompayrac 2019, p. 2
- ^Sompayrac 2019, p. 2
- ^Sompayrac 2019, pp. 13–16
- Dale DC, Boxer L, Liles WC Boxer Liles (August 2008). "The phagocytes: neutrophils and monocytes". Blood. 112 (4): 935–45. doi: 10.1182/blood-2007-12-077917 . PMID18684880. S2CID746699. CS1 maint: multiple names: authors list (link)
- Dahlgren, C A Karlsson (December 17, 1999). "Respiratory burst in human neutrophils". Journal of Immunological Methods. 232 (1–2): 3–14. doi:10.1016/S0022-1759(99)00146-5. PMID10618505.
- Shatwell, KP AW Segal (1996). "NADPH oxidase". The International Journal of Biochemistry & Cell Biology. 28 (11): 1191–95. doi:10.1016/S1357-2725(96)00084-2. PMID9022278.
- Klebanoff SJ (1999). "Myeloperoxidase". Proc. Assoc. Am. Physicians. 111 (5): 383–89. doi:10.1111/paa.19126.96.36.1993. PMID10519157.
- Meyer KC (September 2004). "Neutrophils, myeloperoxidase, and bronchiectasis in cystic fibrosis: green is not good". J. Lab. Clin. Med. 144 (3): 124–26. doi:10.1016/j.lab.2004.05.014. PMID15478278.
- ^Hoffbrand, Pettit & Moss 2005, p. 118
- ^Delves et al. 2006, pp. 6–10
- Schroder K, Hertzog PJ, Ravasi T, Hume DA Hertzog Ravasi Hume (February 2004). "Interferon-gamma: an overview of signals, mechanisms and functions". J. Leukoc. Biol. 75 (2): 163–89. doi: 10.1189/jlb.0603252 . PMID14525967. S2CID15862242. CS1 maint: multiple names: authors list (link)
- ^Delves et al. 2006, p. 188
- ^ abSompayrac 2019, p. 136
- Lipu HN, Ahmed TA, Ali S, Ahmed D, Waqar MA Ahmed Ali Ahmed Waqar (September 2008). "Chronic granulomatous disease". J Pak Med Assoc. 58 (9): 516–18. PMID18846805. CS1 maint: multiple names: authors list (link)
- Kaplan J, De Domenico I, Ward DM De Domenico Ward (January 2008). "Chediak-Higashi syndrome". Curr. Opin. Hematol. 15 (1): 22–29. doi:10.1097/MOH.0b013e3282f2bcce. PMID18043242. S2CID43243529. CS1 maint: multiple names: authors list (link)
- ^Sompayrac 2019, p. 7
- de Almeida SM, Nogueira MB, Raboni SM, Vidal LR Nogueira Raboni Vidal (October 2007). "Laboratorial diagnosis of lymphocytic meningitis". Braz J Infect Dis. 11 (5): 489–95. doi: 10.1590/s1413-86702007000500010 . PMID17962876. CS1 maint: multiple names: authors list (link)
- ^Sompayrac 2019, p. 22
- ^Sompayrac 2019, p. 68
- "Apoptosis". Merriam-Webster Online Dictionary . Retrieved December 19, 2014 .
- Li MO, Sarkisian MR, Mehal WZ, Rakic P, Flavell RA Sarkisian Mehal Rakic Flavell (November 2003). "Phosphatidylserine receptor is required for clearance of apoptotic cells". Science. 302 (5650): 1560–63. doi:10.1126/science.1087621. PMID14645847. S2CID36252352. CS1 maint: multiple names: authors list (link) (Free registration required for online access)
- Nagata S, Sakuragi T, Segawa K (December 2019). "Flippase and scramblase for phosphatidylserine exposure". Current Opinion in Immunology. 62: 31–38. doi: 10.1016/j.coi.2019.11.009 . PMID31837595.
- Wang X (2003). "Cell corpse engulfment mediated by C. elegans phosphatidylserine receptor through CED-5 and CED-12". Science. 302 (5650): 1563–1566. Bibcode:2003Sci. 302.1563W. doi:10.1126/science.1087641. PMID14645848. S2CID25672278. (Free registration required for online access)
- Savill J, Gregory C, Haslett C (2003). "Eat me or die". Science. 302 (5650): 1516–17. doi:10.1126/science.1092533. hdl: 1842/448 . PMID14645835. S2CID13402617.
- Zhou Z, Yu X Yu (October 2008). "Phagosome maturation during the removal of apoptotic cells: receptors lead the way". Trends Cell Biol. 18 (10): 474–85. doi:10.1016/j.tcb.2008.08.002. PMC3125982 . PMID18774293.
- ^Sompayrac 2019, p. 3
- ^Sompayrac 2019, p. 4
- ^Sompayrac 2019, pp. 27–35
- ^Delves et al. 2006, pp. 171–184
- ^Delves et al. 2006, pp. 456
- Timothy Lee (2004). "Antigen Presenting Cells (APC)". Immunology for 1st Year Medical Students. Dalhousie University. Archived from the original on January 12, 2008 . Retrieved December 19, 2014 .
- ^Delves et al. 2006, p. 161
- ^Sompayrac 2019, p. 8
- ^Delves et al. 2006, pp. 237–242
- Lange C, Dürr M, Doster H, Melms A, Bischof F Dürr Doster Melms Bischof (2007). "Dendritic cell-regulatory T-cell interactions control self-directed immunity". Immunol. Cell Biol. 85 (8): 575–81. doi:10.1038/sj.icb.7100088. PMID17592494. S2CID36342899. CS1 maint: multiple names: authors list (link)
- Steinman, Ralph M. (2004). "Dendritic Cells and Immune Tolerance". The Rockefeller University. Archived from the original on March 11, 2009 . Retrieved December 19, 2014 .
- Romagnani, S (2006). "Immunological tolerance and autoimmunity". Internal and Emergency Medicine. 1 (3): 187–96. doi:10.1007/BF02934736. PMID17120464. S2CID27585046.
- ^Sompayrac 2019, pp. 16–17
- ^Sompayrac 2019, pp. 18–19
- ^Delves et al. 2006, p. 6
- Zen K, Parkos CA Parkos (October 2003). "Leukocyte-epithelial interactions". Curr. Opin. Cell Biol. 15 (5): 557–64. doi:10.1016/S0955-0674(03)00103-0. PMID14519390.
- ^Sompayrac 2019, p. 18
- ^Hoffbrand, Pettit & Moss 2005, p. 117
- ^Delves et al. 2006, pp. 1–6
- ^Sompayrac 2019, p. 136
- Takahashi K, Naito M, Takeya M Naito Takeya (July 1996). "Development and heterogeneity of macrophages and their related cells through their differentiation pathways". Pathol. Int. 46 (7): 473–85. doi:10.1111/j.1440-1827.1996.tb03641.x. PMID8870002. S2CID6049656. CS1 maint: multiple names: authors list (link)
- Krombach F, Münzing S, Allmeling AM, Gerlach JT, Behr J, Dörger M Münzing Allmeling Gerlach Behr Dörger (September 1997). "Cell size of alveolar macrophages: an interspecies comparison". Environ. Health Perspect. 105 Suppl 5 (Suppl 5): 1261–63. doi:10.2307/3433544. JSTOR3433544. PMC1470168 . PMID9400735. CS1 maint: multiple names: authors list (link)
- ^ abcdeDelves et al. 2006, pp. 31–36
- ^Ernst & Stendahl 2006, p. 8
- ^Delves et al. 2006, p. 156
- ^Delves et al. 2006, p. 187
- Stvrtinová, Viera Ján Jakubovský and Ivan Hulín (1995). "Neutrophils, central cells in acute inflammation". Inflammation and Fever from Pathophysiology: Principles of Disease. Computing Centre, Slovak Academy of Sciences: Academic Electronic Press. ISBN978-80-967366-1-4 . Archived from the original on December 31, 2010 . Retrieved December 19, 2014 .
- ^Delves et al. 2006, p. 4
- ^ abSompayrac 2019, p. 18
- Linderkamp O, Ruef P, Brenner B, Gulbins E, Lang F Ruef Brenner Gulbins Lang (December 1998). "Passive deformability of mature, immature, and active neutrophils in healthy and septicemic neonates". Pediatr. Res. 44 (6): 946–50. doi: 10.1203/00006450-199812000-00021 . PMID9853933. CS1 maint: multiple names: authors list (link)
- ^Paoletti, Notario & Ricevuti 1997, p. 62
- Soehnlein O, Kenne E, Rotzius P, Eriksson EE, Lindbom L Kenne Rotzius Eriksson Lindbom (January 2008). "Neutrophil secretion products regulate anti-bacterial activity in monocytes and macrophages". Clin. Exp. Immunol. 151 (1): 139–45. doi:10.1111/j.1365-2249.2007.03532.x. PMC2276935 . PMID17991288. CS1 maint: multiple names: authors list (link)
- Soehnlein O, Kai-Larsen Y, Frithiof R (October 2008). "Neutrophil primary granule proteins HBP and HNP1-3 boost bacterial phagocytosis by human and murine macrophages". J. Clin. Invest. 118 (10): 3491–502. doi:10.1172/JCI35740. PMC2532980 . PMID18787642.
- Steinman RM, Cohn ZA Cohn (1973). "Identification of a novel cell type in peripheral lymphoid organs of mice. I. Morphology, quantitation, tissue distribution". J. Exp. Med. 137 (5): 1142–62. doi:10.1084/jem.137.5.1142. PMC2139237 . PMID4573839.
- ^ ab
- Steinman, Ralph. "Dendritic Cells". The Rockefeller University . Retrieved December 19, 2014 .
- Guermonprez P, Valladeau J, Zitvogel L, Théry C, Amigorena S Valladeau Zitvogel Théry Amigorena (2002). "Antigen presentation and T cell stimulation by dendritic cells". Annu. Rev. Immunol. 20: 621–67. doi:10.1146/annurev.immunol.20.100301.064828. PMID11861614. CS1 maint: multiple names: authors list (link)
- ^Hoffbrand, Pettit & Moss 2005, p. 134
- Sallusto F, Lanzavecchia A Lanzavecchia (2002). "The instructive role of dendritic cells on T-cell responses". Arthritis Res. 4 Suppl 3 (Suppl 3): S127–32. doi:10.1186/ar567. PMC3240143 . PMID12110131.
- ^Sompayrac 2019, pp. 45–46
- Novak N, Bieber T, Peng WM Bieber Peng (2010). "The immunoglobulin E-Toll-like receptor network". International Archives of Allergy and Immunology. 151 (1): 1–7. doi: 10.1159/000232565 . PMID19672091 . Retrieved December 19, 2014 . CS1 maint: multiple names: authors list (link)
- Kalesnikoff J, Galli SJ Galli (November 2008). "New developments in mast cell biology". Nature Immunology. 9 (11): 1215–23. doi:10.1038/ni.f.216. PMC2856637 . PMID18936782.
- ^ ab
- Malaviya R, Abraham SN Abraham (February 2001). "Mast cell modulation of immune responses to bacteria". Immunol. Rev. 179: 16–24. doi:10.1034/j.1600-065X.2001.790102.x. PMID11292019. S2CID23115222.
- Connell I, Agace W, Klemm P, Schembri M, Mărild S, Svanborg C Agace Klemm Schembri Mărild Svanborg (September 1996). "Type 1 fimbrial expression enhances Escherichia coli virulence for the urinary tract". Proc. Natl. Acad. Sci. U.S.A. 93 (18): 9827–32. Bibcode:1996PNAS. 93.9827C. doi:10.1073/pnas.93.18.9827. PMC38514 . PMID8790416. CS1 maint: multiple names: authors list (link)
- Malaviya R, Twesten NJ, Ross EA, Abraham SN, Pfeifer JD Twesten Ross Abraham Pfeifer (February 1996). "Mast cells process bacterial Ags through a phagocytic route for class I MHC presentation to T cells". J. Immunol. 156 (4): 1490–96. PMID8568252 . Retrieved December 19, 2014 . CS1 maint: multiple names: authors list (link)
- Taylor ML, Metcalfe DD Metcalfe (2001). "Mast cells in allergy and host defense". Allergy Asthma Proc. 22 (3): 115–19. doi:10.2500/108854101778148764. PMID11424870.
- Urb M, Sheppard DC (2012). "The role of mast cells in the defence against pathogens". PLOS Pathogens. 8 (4): e1002619. doi:10.1371/journal.ppat.1002619. PMC3343118 . PMID22577358.
- ^ abPaoletti, Notario & Ricevuti 1997, p. 427
- Birge RB, Ucker DS Ucker (July 2008). "Innate apoptotic immunity: the calming touch of death". Cell Death Differ. 15 (7): 1096–1102. doi: 10.1038/cdd.2008.58 . PMID18451871.
- Couzinet S, Cejas E, Schittny J, Deplazes P, Weber R, Zimmerli S Cejas Schittny Deplazes Weber Zimmerli (December 2000). "Phagocytic uptake of Encephalitozoon cuniculi by nonprofessional phagocytes". Infect. Immun. 68 (12): 6939–45. doi:10.1128/IAI.68.12.6939-6945.2000. PMC97802 . PMID11083817. CS1 maint: multiple names: authors list (link)
- Segal G, Lee W, Arora PD, McKee M, Downey G, McCulloch CA Lee Arora McKee Downey McCulloch (January 2001). "Involvement of actin filaments and integrins in the binding step in collagen phagocytosis by human fibroblasts". Journal of Cell Science. 114 (Pt 1): 119–129. doi:10.1242/jcs.114.1.119. PMID11112696. CS1 maint: multiple names: authors list (link)
- Rabinovitch M (March 1995). "Professional and non-professional phagocytes: an introduction". Trends Cell Biol. 5 (3): 85–87. doi:10.1016/S0962-8924(00)88955-2. PMID14732160.
- Lin A, Loré K (2017). "Granulocytes: New Members of the Antigen-Presenting Cell Family". Frontiers in Immunology. 8: 1781. doi:10.3389/fimmu.2017.01781. PMC5732227 . PMID29321780.
- ^ abcde
- Todar, Kenneth. "Mechanisms of Bacterial Pathogenicity: Bacterial Defense Against Phagocytes". 2008 . Retrieved December 19, 2014 .
- Alexander J, Satoskar AR, Russell DG Satoskar Russell (September 1999). "Leishmania species: models of intracellular parasitism". J. Cell Sci. 112 (18): 2993–3002. doi:10.1242/jcs.112.18.2993. PMID10462516 . Retrieved December 19, 2014 . CS1 maint: multiple names: authors list (link)
- Celli J, Finlay BB Finlay (May 2002). "Bacterial avoidance of phagocytosis". Trends Microbiol. 10 (5): 232–37. doi:10.1016/S0966-842X(02)02343-0. PMID11973157.
- Valenick LV, Hsia HC, Schwarzbauer JE Hsia Schwarzbauer (September 2005). "Fibronectin fragmentation promotes alpha4beta1 integrin-mediated contraction of a fibrin-fibronectin provisional matrix". Experimental Cell Research. 309 (1): 48–55. doi:10.1016/j.yexcr.2005.05.024. PMID15992798. CS1 maint: multiple names: authors list (link)
- Burns SM, Hull SI Hull (August 1999). "Loss of resistance to ingestion and phagocytic killing by O(-) and K(-) mutants of a uropathogenic Escherichia coli O75:K5 strain". Infect. Immun. 67 (8): 3757–62. doi:10.1128/IAI.67.8.3757-3762.1999. PMC96650 . PMID10417134.
- Vuong C, Kocianova S, Voyich JM (December 2004). "A crucial role for exopolysaccharide modification in bacterial biofilm formation, immune evasion, and virulence". J. Biol. Chem. 279 (52): 54881–86. doi: 10.1074/jbc.M411374200 . PMID15501828.
- Melin M, Jarva H, Siira L, Meri S, Käyhty H, Väkeväinen M Jarva Siira Meri Käyhty Väkeväinen (February 2009). "Streptococcus pneumoniae capsular serotype 19F is more resistant to C3 deposition and less sensitive to opsonophagocytosis than serotype 6B". Infect. Immun. 77 (2): 676–84. doi:10.1128/IAI.01186-08. PMC2632042 . PMID19047408. CS1 maint: multiple names: authors list (link)
- ^ ab
- Foster TJ (December 2005). "Immune evasion by staphylococci". Nat. Rev. Microbiol. 3 (12): 948–58. doi:10.1038/nrmicro1289. PMID16322743. S2CID205496221.
- Fällman M, Deleuil F, McGee K (February 2002). "Resistance to phagocytosis by Yersinia". International Journal of Medical Microbiology. 291 (6–7): 501–9. doi:10.1078/1438-4221-00159. PMID11890550.
- Sansonetti P (December 2001). "Phagocytosis of bacterial pathogens: implications in the host response". Semin. Immunol. 13 (6): 381–90. doi:10.1006/smim.2001.0335. PMID11708894.
- Dersch P, Isberg RR Isberg (March 1999). "A region of the Yersinia pseudotuberculosis invasin protein enhances integrin-mediated uptake into mammalian cells and promotes self-association". EMBO J. 18 (5): 1199–1213. doi:10.1093/emboj/18.5.1199. PMC1171211 . PMID10064587.
- Antoine JC, Prina E, Lang T, Courret N Prina Lang Courret (October 1998). "The biogenesis and properties of the parasitophorous vacuoles that harbour Leishmania in murine macrophages". Trends Microbiol. 6 (10): 392–401. doi:10.1016/S0966-842X(98)01324-9. PMID9807783. CS1 maint: multiple names: authors list (link)
- Das D, Saha SS, Bishayi B Saha Bishayi (July 2008). "Intracellular survival of Staphylococcus aureus: correlating production of catalase and superoxide dismutase with levels of inflammatory cytokines". Inflamm. Res. 57 (7): 340–49. doi:10.1007/s00011-007-7206-z. PMID18607538. S2CID22127111. CS1 maint: multiple names: authors list (link)
- Hara H, Kawamura I, Nomura T, Tominaga T, Tsuchiya K, Mitsuyama M Kawamura Nomura Tominaga Tsuchiya Mitsuyama (August 2007). "Cytolysin-dependent escape of the bacterium from the phagosome is required but not sufficient for induction of the Th1 immune response against Listeria monocytogenes infection: distinct role of Listeriolysin O determined by cytolysin gene replacement". Infect. Immun. 75 (8): 3791–3801. doi:10.1128/IAI.01779-06. PMC1951982 . PMID17517863. CS1 maint: multiple names: authors list (link)
- Datta V, Myskowski SM, Kwinn LA, Chiem DN, Varki N, Kansal RG, Kotb M, Nizet V Myskowski Kwinn Chiem Varki Kansal Kotb Nizet (May 2005). "Mutational analysis of the group A streptococcal operon encoding streptolysin S and its virulence role in invasive infection". Mol. Microbiol. 56 (3): 681–95. doi: 10.1111/j.1365-2958.2005.04583.x . PMID15819624. S2CID14748436. CS1 maint: multiple names: authors list (link)
- Iwatsuki K, Yamasaki O, Morizane S, Oono T Yamasaki Morizane Oono (June 2006). "Staphylococcal cutaneous infections: invasion, evasion and aggression". J. Dermatol. Sci. 42 (3): 203–14. doi:10.1016/j.jdermsci.2006.03.011. PMID16679003. CS1 maint: multiple names: authors list (link)
- ^ ab
- Denkers EY, Butcher BA Butcher (January 2005). "Sabotage and exploitation in macrophages parasitized by intracellular protozoans". Trends Parasitol. 21 (1): 35–41. doi:10.1016/j.pt.2004.10.004. PMID15639739.
- Gregory DJ, Olivier M Olivier (2005). "Subversion of host cell signalling by the protozoan parasite Leishmania". Parasitology. 130 Suppl: S27–35. doi:10.1017/S0031182005008139. PMID16281989. S2CID24696519.
- ^ Paoletti pp. 426–30
- Heinzelmann M, Mercer-Jones MA, Passmore JC Mercer-Jones Passmore (August 1999). "Neutrophils and renal failure". Am. J. Kidney Dis. 34 (2): 384–99. doi:10.1016/S0272-6386(99)70375-6. PMID10430993. CS1 maint: multiple names: authors list (link)
- Lee WL, Downey GP Downey (February 2001). "Neutrophil activation and acute lung injury". Curr Opin Crit Care. 7 (1): 1–7. doi:10.1097/00075198-200102000-00001. PMID11373504. S2CID24164360.
- ^ ab
- Moraes TJ, Zurawska JH, Downey GP Zurawska Downey (January 2006). "Neutrophil granule contents in the pathogenesis of lung injury". Curr. Opin. Hematol. 13 (1): 21–27. doi:10.1097/01.moh.0000190113.31027.d5. PMID16319683. S2CID29374195. CS1 maint: multiple names: authors list (link)
- Abraham E (April 2003). "Neutrophils and acute lung injury". Crit. Care Med. 31 (4 Suppl): S195–99. doi:10.1097/01.CCM.0000057843.47705.E8. PMID12682440. S2CID4004607.
- Ricevuti G (December 1997). "Host tissue damage by phagocytes". Ann. N. Y. Acad. Sci. 832 (1): 426–48. Bibcode:1997NYASA.832..426R. doi:10.1111/j.1749-6632.1997.tb46269.x. PMID9704069. S2CID10318084.
- Charley B, Riffault S, Van Reeth K Riffault Van Reeth (October 2006). "Porcine innate and adaptative immune responses to influenza and coronavirus infections". Ann. N. Y. Acad. Sci. 1081 (1): 130–36. Bibcode:2006NYASA1081..130C. doi: 10.1196/annals.1373.014 . hdl:1854/LU-369324. PMC7168046 . PMID17135502. CS1 maint: multiple names: authors list (link)
- ^Sompayrac 2019, p. 2
- ^ ab
- Cosson P, Soldati T Soldati (June 2008). "Eat, kill or die: when amoeba meets bacteria". Curr. Opin. Microbiol. 11 (3): 271–76. doi:10.1016/j.mib.2008.05.005. PMID18550419.
- Bozzaro S, Bucci C, Steinert M Bucci Steinert (2008). Phagocytosis and host-pathogen interactions in Dictyostelium with a look at macrophages. Int Rev Cell Mol Biol. International Review of Cell and Molecular Biology. 271. pp. 253–300. doi:10.1016/S1937-6448(08)01206-9. ISBN9780123747280 . PMID19081545. CS1 maint: multiple names: authors list (link)
- Chen G, Zhuchenko O, Kuspa A Zhuchenko Kuspa (August 2007). "Immune-like phagocyte activity in the social amoeba". Science. 317 (5838): 678–81. Bibcode:2007Sci. 317..678C. doi:10.1126/science.1143991. PMC3291017 . PMID17673666. CS1 maint: multiple names: authors list (link)
- ^Delves et al. 2006, pp. 251–252
- Hanington PC, Tam J, Katzenback BA, Hitchen SJ, Barreda DR, Belosevic M Tam Katzenback Hitchen Barreda Belosevic (April 2009). "Development of macrophages of cyprinid fish". Dev. Comp. Immunol. 33 (4): 411–29. doi:10.1016/j.dci.2008.11.004. PMID19063916. CS1 maint: multiple names: authors list (link)
- Delves, P. J. Martin, S. J. Burton, D. R. Roit, I. M. (2006). Roitt's Essential Immunology (11th ed.). Malden, MA: Blackwell Publishing. ISBN978-1-4051-3603-7 .
- Ernst, J. D. Stendahl, O., eds. (2006). Phagocytosis of Bacteria and Bacterial Pathogenicity. New York: Cambridge University Press. ISBN978-0-521-84569-4 . Website
- Hoffbrand, A. V. Pettit, J. E. Moss, P. A. H. (2005). Essential Haematology (4th ed.). London: Blackwell Science. ISBN978-0-632-05153-3 .
- Paoletti, R. Notario, A. Ricevuti, G., eds. (1997). Phagocytes: Biology, Physiology, Pathology, and Pharmacotherapeutics. New York: The New York Academy of Sciences. ISBN978-1-57331-102-1 .
- Robinson, J. P. Babcock, G. F., eds. (1998). Phagocyte Function — A guide for research and clinical evaluation . New York: Wiley–Liss. ISBN978-0-471-12364-4 .
- Sompayrac, L. (2019). How the Immune System Works (6th ed.). Malden, MA: Blackwell Publishing. ISBN978-1-119-54212-4 .
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The extracellular matrix modulates the hallmarks of cancer.
The extracellular matrix regulates tissue development and homeostasis, and its dysregulation contributes to neoplastic progression. The extracellular matrix serves not only as the scaffold upon which tissues are organized but provides critical biochemical and biomechanical cues that direct cell growth, survival, migration and differentiation and modulate vascular development and immune function. Thus, while genetic modifications in tumor cells undoubtedly initiate and drive malignancy, cancer progresses within a dynamically evolving extracellular matrix that modulates virtually every behavioral facet of the tumor cells and cancer-associated stromal cells. Hanahan and Weinberg defined the hallmarks of cancer to encompass key biological capabilities that are acquired and essential for the development, growth and dissemination of all human cancers. These capabilities include sustained proliferation, evasion of growth suppression, death resistance, replicative immortality, induced angiogenesis, initiation of invasion, dysregulation of cellular energetics, avoidance of immune destruction and chronic inflammation. Here, we argue that biophysical and biochemical cues from the tumor-associated extracellular matrix influence each of these cancer hallmarks and are therefore critical for malignancy. We suggest that the success of cancer prevention and therapy programs requires an intimate understanding of the reciprocal feedback between the evolving extracellular matrix, the tumor cells and its cancer-associated cellular stroma.
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Théry, C., Ostrowski, M. & Segura, E. Membrane vesicles as conveyors of immune responses. Nat. Rev. Immunol. 9, 581–593 (2009).
György, B. et al. Membrane vesicles, current state-of-the-art: emerging role of extracellular vesicles. Cell. Mol. Life Sci. 68, 2667–2688 (2011).
van der Pol., E., Böing, A. N., Harrison, P., Sturk, A. & Nieuwland, R. Classification, functions, and clinical relevance of extracellular vesicles. Pharmacol. Rev. 64, 676–705 (2012).
Akers, J. C., Gonda, D., Kim, R., Carter, B. S. & Chen, C. C. Biogenesis of extracellular vesicles (EV): exosomes, microvesicles, retrovirus-like vesicles, and apoptotic bodies. J. Neurooncol. 113, 1–11 (2013).
Morello, M. et al. Large oncosomes mediate intercellular transfer of functional microRNA. Cell Cycle 12, 3526–3536 (2013).
Witwer, K. W. et al. Standardization of sample collection, isolation and analysis methods in extracellular vesicle research. J. Extracell. Vesicles 2, 20360 (2013).
Muralidharan-Chari, V., Clancy, J. W., Sedgwick, A. & D' Souza-Schorey, C. Microvesicles: mediators of extracellular communication during cancer progression. J. Cell Sci. 123, 1603–1611 (2010).
Nolte-'t Hoen, E. N., Quantitative and qualitative flow cytometric analysis of nanosized cell-derived membrane vesicles. Nanomedicine 8, 712–720 (2012).
van der Pol., E., van Gemert, M. J., Sturk, A., Nieuwland, R. & van Leeuwen, T. G. Single vs. swarm detection of microparticles and exosomes by flow cytometry. J. Thromb. Haemost. 10, 919–930 (2012).
Lacroix, R., Robert, S., Poncelet, P., Kasthuri, R. S., Key, N. S. & Dignat-George, F. Standardization of platelet-derived microparticle enumeration by flow cytometry with calibrated beads: results of the International Society on Thrombosis and Haemostasis SSC Collaborative workshop. J. Thromb. Haemost. 8, 2571–2574 (2010).
Johnstone, R. M., Adam, M., Hammond, J. R., Orr, L. & Turbide, C. Vesicle formation during reticulocyte maturation. Association of plasma membrane activities with released vesicles (exosomes). J. Biol. Chem. 262, 9412–9420 (1987).
Verweij, F. J. et al. LMP1 association with CD63 in endosomes and secretion via exosomes limits constitutive NF-κB activation. EMBO J. 30, 2115–2129 (2011).
Valadi, H. et al. Exosome-mediated transfer of mRNAs and microRNAs is a novel mechanism of genetic exchange between cells. Nat. Cell. Biol. 9, 654–659 (2007).
Pilzer, D., Gasser, O., Moskovich, O., Schifferli, J. A. & Fishelson, Z. Emission of membrane vesicles: roles in complement resistance, immunity and cancer. Springer Semin. Immunopathol. 27, 375–387 (2005).
Regev-Rudzki, N. et al. Cell-cell communication between malaria-infected red blood cells via exosome-like vesicles. Cell. 153, 1120–1133 (2013).
Timar, C. I. et al. Antibacterial effect of microvesicles released from human neutrophilic granulocytes. Blood 121, 510–518 (2013).
Goh, F. G. & Midwood, K. S. Intrinsic danger: activation of Toll-like receptors in rheumatoid arthritis. Rheumatology (Oxford) 51, 7–23, (2012).
Deatherage, B. L. & Cookson, B. T. Membrane vesicle release in bacteria, eukaryotes, and archaea: a conserved yet underappreciated aspect of microbial life. Infect. Immun. 80, 1948–1957 (2012).
Nakao, R. et al. Outer membrane vesicles of Porphyromonas gingivalis elicit a mucosal immune response. PLoS ONE 6, e26163 (2011).
Kaparakis, M. et al. Bacterial membrane vesicles deliver peptidoglycan to NOD1 in epithelial cells. Cell. Microbiol. 12, 372–385 (2010).
Hong, S. W. et al. Extracellular vesicles derived from Staphylococcus aureus induce atopic dermatitis-like skin inflammation. Allergy 66, 351–359 (2011).
Kim, M. R. et al. Staphylococcus aureus-derived extracellular vesicles induce neutrophilic pulmonary inflammation via both TH1 and TH17 cell responses. Allergy 67, 1271–1281 (2012).
Prados-Rosales, R. et al. Mycobacteria release active membrane vesicles that modulate immune responses in a TLR2-dependent manner in mice. J. Clin. Invest. 121, 1471–1483 (2011).
Gehrmann, U. et al. Nanovesicles from Malassezia sympodialis and host exosomes induce cytokine responses--novel mechanisms for host-microbe interactions in atopic eczema. PLoS ONE 6, e21480 (2011).
Schiller, M. et al. During apoptosis HMGB1 is translocated into apoptotic cell-derived membraneous vesicles. Autoimmunity 46, 342–346 (2013).
Ayna, G. et al. ATP release from dying autophagic cells and their phagocytosis are crucial for inflammasome activation in macrophages. PLoS ONE 7, e40069, (2012).
Turiak, L. et al. Proteomic characterization of thymocyte-derived microvesicles and apoptotic bodies in BALB/c mice. J. Proteomics 74, 2025–2033 (2011).
Cloutier, N. et al. The exposure of autoantigens by microparticles underlies the formation of potent inflammatory components: the microparticle-associated immune complexes. EMBO Mol. Med. 5, 235–249 (2013).
Skriner, K., Adolph, K., Jungblut, P. R. & Burmester, G. R. Association of citrullinated proteins with synovial exosomes. Arthritis Rheum. 54, 3809–3814 (2006).
Nielsen, C. T. et al. Increased IgG on cell-derived plasma microparticles in systemic lupus erythematosus is associated with autoantibodies and complement activation. Arthritis Rheum. 64, 1227–1236 (2012).
Pisetsky, D. S. Microparticles as autoantigens: making immune complexes big. Arthritis Rheum. 64, 958–961 (2012).
Ullal, A. J. et al. Microparticles as antigenic targets of antibodies to DNA and nucleosomes in systemic lupus erythematosus. J. Autoimmun. 36, 173–180 (2011).
Ullal, A. J. & Pisetsky, D. S. The role of microparticles in the generation of immune complexes in murine lupus. Clin. Immunol. 146, 1–9 (2013).
Kapsogeorgou, E. K., Abu-Helu, R. F., Moutsopoulos, H. M. & Manoussakis, M. N. Salivary gland epithelial cell exosomes: a source of autoantigenic ribonucleoproteins. Arthritis Rheum. 52, 1517–1521 (2005).
Mor-Vaknin, N. et al. DEK in the synovium of patients with juvenile idiopathic arthritis: characterization of DEK antibodies and posttranslational modification of the DEK autoantigen. Arthritis Rheum. 63, 556–567 (2011).
Silva, M. T. Secondary necrosis: the natural outcome of the complete apoptotic program. FEBS Lett. 584, 4491–4499 (2010).
Lamkanfi, M. Emerging inflammasome effector mechanisms. Nat. Rev. Immunol. 11, 213–220 (2011).
Sheng, H. et al. Insulinoma-released exosomes or microparticles are immunostimulatory and can activate autoreactive T cells spontaneously developed in nonobese diabetic mice. J. Immunol. 187, 1591–1600 (2011).
Rahman, M. J., Regn, D., Bashratyan, R. & Dai, Y. D. Exosomes released by islet-derived mesenchymal stem cells trigger autoimmune responses in NOD mice. Diabetes. http://dx.doi:10.2337/db13-0859.
Kojima, F., Kapoor, M., Kawai, S. & Crofford, L. J. New insights into eicosanoid biosynthetic pathways: implications for arthritis. Expert Rev. Clin. Immunol. 2, 277–291 (2006).
Barry, O. P., Pratico, D., Lawson, J. A. & FitzGerald, G. A. Transcellular activation of platelets and endothelial cells by bioactive lipids in platelet microparticles. J. Clin. Invest. 99, 2118–2127 (1997).
Esser, J. et al. Exosomes from human macrophages and dendritic cells contain enzymes for leukotriene biosynthesis and promote granulocyte migration. J. Allergy Clin. Immunol. 126, 1032–1040 (2010).
Gulinelli, S. et al. IL-18 associates to microvesicles shed from human macrophages by a LPS/TLR-4 independent mechanism in response to P2X receptor stimulation. Eur. J. Immunol. 42, 3334–3345 (2012).
Nickel, W. & Rabouille, C. Mechanisms of regulated unconventional protein secretion. Nat. Rev. Mol. Cell Biol. 10, 148–155 (2009).
Pizzirani, C. et al. Stimulation of P2 receptors causes release of IL-1β-loaded microvesicles from human dendritic cells. Blood 109, 3856–3864 (2007).
Boilard, E. et al. Platelets amplify inflammation in arthritis via collagen-dependent microparticle production. Science 327, 580–583 (2010).
Baj-Krzyworzeka, M. et al. Tumour-derived microvesicles contain interleukin-8 and modulate production of chemokines by human monocytes. Anticancer Res. 31, 1329–1335 (2011).
Truman, L. A. et al. CX3CL1/fractalkine is released from apoptotic lymphocytes to stimulate macrophage chemotaxis. Blood 112, 5026–5036 (2008).
Fabbri, M. TLRs as miRNA receptors. Cancer Res. 72, 6333–6337 (2012).
Ohshima, K. et al. Let-7 microRNA family is selectively secreted into the extracellular environment via exosomes in a metastatic gastric cancer cell line. PLoS ONE 5, e13247 (2010).
Lehmann, S. M. et al. An unconventional role for miRNA: let-7 activates Toll-like receptor 7 and causes neurodegeneration. Nat. Neurosci. 15, 827–835 (2012).
Fabbri, M. et al. MicroRNAs bind to Toll-like receptors to induce prometastatic inflammatory response. Proc. Natl Acad. Sci. USA 109, E2110–E2116 (2012).
Fabbri, M., Paone, A., Calore, F., Galli, R. & Croce, C. M. A new role for microRNAs, as ligands of Toll-like receptors. RNA Biol. 10, 169–174 (2013).
Laffont, B. et al. Activated platelets can deliver mRNA regulatory Ago2–microRNA complexes to endothelial cells via microparticles. Blood 122, 253–261 (2013).
Lo Cicero, A., Majkowska, I., Nagase, H., Di Liegro, I. & Troeberg, L. Microvesicles shed by oligodendroglioma cells and rheumatoid synovial fibroblasts contain aggrecanase activity. Matrix Biol. 31, 229–233 (2012).
Shimoda, M. & Khokha, R. Proteolytic factors in exosomes. Proteomics 13, 1624–1636 (2013).
Li, C. J. et al. Novel proteolytic microvesicles released from human macrophages after exposure to tobacco smoke. Am. J. Pathol. 182, 1552–1562 (2013).
Ortutay, Z. et al. Synovial fluid exoglycosidases are predictors of rheumatoid arthritis and are effective in cartilage glycosaminoglycan depletion. Arthritis Rheum. 48, 2163–2172 (2003).
Pasztoi, M. et al. Gene expression and activity of cartilage degrading glycosidases in human rheumatoid arthritis and osteoarthritis synovial fibroblasts. Arthritis Res. Ther. 11, R68 (2009).
Pasztoi, M. et al. The recently identified hexosaminidase D enzyme substantially contributes to the elevated hexosaminidase activity in rheumatoid arthritis. Immunol. Lett. 149, 71–76 (2013).
Knijff-Dutmer, E. A., Koerts, J., Nieuwland, R., Kalsbeek-Batenburg, E. M. & van de Laar, M. A. Elevated levels of platelet microparticles are associated with disease activity in rheumatoid arthritis. Arthritis Rheum. 46, 1498–1503 (2002).
Berckmans, R. J. et al. Cell-derived microparticles in synovial fluid from inflamed arthritic joints support coagulation exclusively via a factor VII-dependent mechanism. Arthritis Rheum. 46, 2857–2866 (2002).
Sellam, J. et al. Increased levels of circulating microparticles in primary Sjogren's syndrome, systemic lupus erythematosus and rheumatoid arthritis and relation with disease activity. Arthritis Res. Ther. 11, R156 (2009).
György, B. et al. Improved flow cytometric assessment reveals distinct microvesicle (cell-derived microparticle) signatures in joint diseases. PLoS ONE 7, e49726 (2012).
Wang, H. et al. Oxidized low-density lipoprotein-dependent platelet-derived microvesicles trigger procoagulant effects and amplify oxidative stress. Mol. Med. 18, 159–166 (2012).
Rautou, P. E. et al. Microparticles, vascular function, and atherothrombosis. Circ. Res. 109, 593–606 (2011).
Messer, L. et al. Microparticle-induced release of B-lymphocyte regulators by rheumatoid synoviocytes. Arthritis Res. Ther. 11, R40 (2009).
Berckmans, R. J. et al. Synovial microparticles from arthritic patients modulate chemokine and cytokine release by synoviocytes. Arthritis Res. Ther. 7, R536–544 (2005).
Gyorgy, B. et al. Detection and isolation of cell-derived microparticles are compromised by protein complexes due to shared biophysical parameters. Blood 117, e39–e48 (2011).
Jungel, A. et al. Microparticles stimulate the synthesis of prostaglandin E(2) via induction of cyclooxygenase 2 and microsomal prostaglandin E synthase 1. Arthritis Rheum. 56, 3564–3574 (2007).
Distler, J. H. et al. The induction of matrix metalloproteinase and cytokine expression in synovial fibroblasts stimulated with immune cell microparticles. Proc. Natl Acad. Sci. USA 102, 2892–2897 (2005).
Reich, N. et al. Microparticles stimulate angiogenesis by inducing ELR(+) CXC-chemokines in synovial fibroblasts. J. Cell. Mol. Med. 15, 756–762 (2011).
Pereira, J. et al. Circulating platelet-derived microparticles in systemic lupus erythematosus. Association with increased thrombin generation and procoagulant state. Thromb. Haemost. 95, 94–99 (2006).
Ostergaard, O. et al. Unique protein signature of circulating microparticles in systemic lupus erythematosus. Arthritis Rheum. http://dx.doi.org/10.1002/art.38065.
Pisetsky, D. S., Gauley, J. & Ullal, A. J. Microparticles as a source of extracellular DNA. Immunol. Res. 49, 227–234 (2011).
Parker, B. et al. Suppression of inflammation reduces endothelial microparticles in active systemic lupus erythematosus. Ann. Rheum. Dis. http://dx.doi.org/10.1136/annrheumdis-2012-203028.
Guiducci, S. et al. The relationship between plasma microparticles and disease manifestations in patients with systemic sclerosis. Arthritis Rheum. 58, 2845–2853 (2008).
Sgonc, R. et al. Endothelial cell apoptosis is a primary pathogenetic event underlying skin lesions in avian and human scleroderma. J. Clin. Invest. 98, 785–792 (1996).
Aharon, A., Tamari, T. & Brenner, B. Monocyte derived microparticles and exosomes induce procoagulant and apoptotic effects on endothelial cells. Thromb. Haemost. 100, 878–885 (2008).
Alvarez-Erviti, L. et al. Delivery of siRNA to the mouse brain by systemic injection of targeted exosomes. Nat. Biotechnol. 29, 341–345 (2011).
Cloutier, N. et al. Platelets can enhance vascular permeability. Blood 120, 1334–1343 (2012).
Sun, D. et al. A novel nanoparticle drug delivery system: the anti-inflammatory activity of curcumin is enhanced when encapsulated in exosomes. Mol. Ther. 18, 1606–1614 (2010).
Kooijmans, S. A. et al. Electroporation-induced siRNA precipitation obscures the efficiency of siRNA loading into extracellular vesicles. J. Control Release 172, 229–238 (2013).
Bolukbasi, M. F. et al. miR-1289 and “Zipcode”-like sequence enrich mRNAs in microvesicles. Mol. Ther. Nucleic. Acids. 1, e10 (2012).
Shen, B., Wu, N., Yang, J. M. & Gould, S. J. Protein targeting to exosomes/microvesicles by plasma membrane anchors. J. Biol. Chem. 286, 14383–14395 (2011).
Maguire, C. A. et al. Microvesicle-associated AAV vector as a novel gene delivery system. Mol. Ther. 20, 960–971 (2012).
Wahlgren, J. et al. Plasma exosomes can deliver exogenous short interfering RNA to monocytes and lymphocytes. Nucleic Acids Res. 40, e130 (2012).
Ohno, S. et al. Systemically injected exosomes targeted to EGFR deliver antitumor microRNA to breast cancer cells. Mol. Ther. 21, 185–191 (2013).
Akao, Y. et al. Microvesicle-mediated RNA molecule delivery system using monocytes/macrophages. Mol. Ther. 19, 395–399 (2011).
Zhuang, X. et al. Treatment of brain inflammatory diseases by delivering exosome encapsulated anti-inflammatory drugs from the nasal region to the brain. Mol. Ther. 19, 1769–1779 (2011).
Wang, G. J. et al. Thymus exosomes-like particles induce regulatory T cells. J. Immunol. 181, 5242–5248 (2008).
Yang, X., Meng, S., Jiang, H., Chen, T. & Wu, W. Exosomes derived from interleukin-10-treated dendritic cells can inhibit trinitrobenzene sulfonic acid-induced rat colitis. Scand. J. Gastroenterol. 45, 1168–1177 (2010).
Kim, S. H. et al. Exosomes derived from IL-10-treated dendritic cells can suppress inflammation and collagen-induced arthritis. J. Immunol. 174, 6440–6448 (2005).
Ruffner, M. A. et al. B7–1/2, but not PD-L1/2 molecules, are required on IL-10-treated tolerogenic DC and DC-derived exosomes for in vivo function. Eur. J. Immunol. 39, 3084–3090 (2009).
Kim, S. H., Bianco, N. R., Shufesky, W. J., Morelli, A. E. & Robbins, P. D. MHC class II+ exosomes in plasma suppress inflammation in an antigen-specific and Fas ligand/Fas-dependent manner. J. Immunol. 179, 2235–2241 (2007).
Cai, Z. et al. Immunosuppressive exosomes from TGF-beta1 gene-modified dendritic cells attenuate Th17-mediated inflammatory autoimmune disease by inducing regulatory T cells. Cell Res. 22, 607–610 (2012).
Kim, S. H., Bianco, N. R., Shufesky, W. J., Morelli, A. E. & Robbins, P. D. Effectivetreatment of inflammatory disease models with exosomes derived from dendritic cells genetically modified to express IL-4. J. Immunol. 179, 2242–2249 (2007).
Kim, S. H. et al. Exosomes derived from genetically modified DC expressing FasL are anti-inflammatory and immunosuppressive. Mol. Ther. 13, 289–300 (2006).
Bianco, N. R., Kim, S. H., Ruffner, M. A. & Robbins, P. D. Therapeutic effect of exosomes from indoleamine 2,3-dioxygenase-positive dendritic cells in collagen-induced arthritis and delayed-type hypersensitivity disease models. Arthritis Rheum. 60, 380–389 (2009).
Zhang, J. et al. Circulating TNFR1 exosome-like vesicles partition with the LDL fraction of human plasma. Biochem. Biophys. Res. Commun. 366, 579–584 (2008).
Meijer, H., Reinecke, J., Becker, C., Tholen, G. & Wehling, P. The production of anti-inflammatory cytokines in whole blood by physico-chemical induction. Inflamm. Res. 52, 404–407 (2003).
Kelly, R. W. et al. Extracellular organelles (prostasomes) are immunosuppressive components of human semen. Clin. Exp. Immunol. 86, 550–556 (1991).
Shen, Y. et al. Outer membrane vesicles of a human commensal mediate immune regulation and disease protection. Cell Host Microbe 12, 509–520 (2012).
Savina, A., Furlan, M., Vidal, M. & Colombo, M. I. Exosome release is regulated by a calcium-dependent mechanism in K562 cells. J. Biol. Chem. 278, 20083–20090 (2003).
Thompson, C. A., Purushothaman, A., Ramani, V. C., Vlodavsky, I. & Sanderson, R. D. Heparanase regulates secretion, composition, and function of tumor cell-derived exosomes. J. Biol. Chem. 288, 10093–10099 (2013).
Blanchard, N. et al. TCR activation of human T cells induces the production of exosomes bearing the TCR/CD3/zeta complex. J. Immunol. 168, 3235–3241 (2002).
Qu, Y. et al. P2X7 receptor-stimulated secretion of MHC class II-containing exosomes requires the ASC/NLRP3 inflammasome but is independent of caspase-1. J. Immunol. 182, 5052–5062 (2009).
Constantinescu, P. et al. P2X7 receptor activation induces cell death and microparticle release in murine erythroleukemia cells. Biochim. Biophys. Acta 1798, 1797–1804 (2010).
Crespin, M., Vidal, C., Picard, F., Lacombe, C. & Fontenay, M. Activation of PAK1/2 during the shedding of platelet microvesicles. Blood Coagul. Fibrinolysis 20, 63–70 (2009).
Parolini, I. et al. Microenvironmental pH is a key factor for exosome traffic in tumor cells. J. Biol. Chem. 284, 34211–34222 (2009).
Trajkovic, K. et al. Ceramide triggers budding of exosome vesicles into multivesicular endosomes. Science 319, 1244–1247 (2008).
Smith, S. K. et al. Mechanisms by which intracellular calcium induces susceptibility to secretory phospholipase A2 in human erythrocytes. J. Biol. Chem. 276, 22732–22741 (2001).
Barteneva, N. S. et al. Circulating microparticles: square the circle. BMC Cell Biol. 14, 23 (2013).
Ostrowski, M. et al. Rab27a and Rab27b control different steps of the exosome secretion pathway. Nat. Cell Biol. 12, 19–30 (2010).
Muralidharan-Chari, V. et al. ARF6-regulated shedding of tumor cell-derived plasma membrane microvesicles. Curr. Biol. 19, 1875–1885 (2009).
Crescitelli, R. et al. Distinct RNA profiles in subpopulations of extracellular vesicles: apoptotic bodies, microvesicles and exosomes. J. Extracellul. Vesicles, 2, 20677 (2013).