What blood cells are macrophages? Functions of leukocytes
Literally translated, the definition of "macrophage" has a rather sinister and frightening meaning: "macro" in Greek means "large", and "phagos" means devourer. “Big Eater”... The imagination pictures some kind of monster, but we're talking about just about blood cells. However, if we judge macrophages at the cellular level, then they fully justify their name.
What are macrophage cells and where do they come from?
Functions of macrophages:
When a foreign object enters the body, be it a microbe or a foreign body, the immune system immediately “unleashes the dogs” on it: it is attacked by phagocytes. These cells, including macrophages, recognize, capture and devour strangers that threaten well-being internal environment body.
In addition, macrophages destroy dead cells that have completed their existence through the process of apoptosis (programmed, natural, normal cell death). Also, the functions of macrophages are to provide antitumor immunity: having detected the appearance of atypical in the body, cancer cells, macrophages attack and eat them.
Types of macrophages:
7. Where are the m acrophages of lymph nodes, is clear from the name. It is thanks to them that the lymph nodes are known as filters that cleanse the lymph.
Macrophages and the immune system:
Macrophage cells do not just mindlessly destroy harmful objects: by breaking them down into fragments, they carry out the process of presenting their antigens. Antigens are molecules of harmful particles that indicate their genetic foreignness and cause an appropriate protective reaction from the immune system. In themselves they do not pose a threat of infection or other negative impact, but this is a mark of a stranger, so the body reacts to their presence with a defensive reaction, as if it were a full-fledged aggressor.
During the process of phagocytosis, macrophages present the antigens of killed “enemies” - they expose them to the surface of their membranes. They also form cytokines - information molecules that carry data about the defeated aggressor.
With this invaluable cargo, macrophages are sent to representatives of another part of the immune system - lymphocytes. They transmit information to them and teach them what to do if a carrier of the same antigen ever enters the body again. As a result, the immune system remains fully combat-ready against it.
Unfortunately, sometimes personal experience our macrophages or other phagocytes are not enough to immune system worked as expected and responded correctly to malicious objects. To increase its effectiveness and at the same time improve your overall health, it is recommended to take the drug Transfer Factor. It contains cytokines that carry data about various pathogens, toxins and other harmful agents. The drug trains the immune system to function fully, which immediately and favorably affects the course of existing diseases, the state of metabolism and organ function. The product can be used for therapeutic and prophylactic purposes.
Macrophages are immune cells that are found in tissues. However, they do not spend their entire lives there; along the way they “move” several times.
Tissue macrophages arise from cells called promonocytes. Those are formed in bone marrow. They leave there and move into the blood, transforming into monocytes. The last few hours circulate in the bloodstream, and only after that they move into the tissues. It is at this stage that true macrophages are formed, which subsequently settle in the liver, spleen, muscles and all other tissues. What are the functions of these cells?
First, the role of macrophages h It lies in the fact that they phagocytose (devour, destroy) bacteria, foreign substances, etc. that enter the body.
They have the ability to move, so they constantly “monitor the territory” for the presence of aggressors in it.
A large number of mitochondria allows them to have a sufficient supply of energy to move and “hunt” aggressors, and lysosomes that produce various enzymes are their weapon against foreign objects. When it comes to phagocytosis, monocytes and macrophages are somewhat different: the precursors of macrophages, which “live” in the blood, are less aggressive than tissue phagocytes.
Secondly, tissue macrophages have a training effect on the immune system. Having dealt with a bacterium or other “enemy,” they present its antigens: they expose the components of the destroyed object to the surface of their membrane, from which other immune cells can receive information about its foreignness. In addition, macrophages secrete cytokines - information molecules. With all this baggage, the cells move to the lymphocytes and share valuable information with them. Macrophages “tell” lymphocytes that this or that object is harmful, and the next time they meet it they must deal with it in the harshest way.
Third, the role of macrophages lies in the formation of many biologically active substances . For example, they synthesize:
About a dozen different enzymes that break down proteins, fats and carbohydrates: all this is necessary for the active destruction of aggressors;
Oxygen radicals, also necessary to combat foreign agents;
prostaglandins, leukotrienes, interleukins, tumor necrosis factor - compounds that allow macrophages to enhance the work of their “relatives”, other phagocytes and other parts of the immune system, causing inflammation and fever;
Substances that activate the maturation and release of new future macrophages and other phagocytes from the bone marrow;
Components of the complement system (this is a special system of the body that is responsible for its general protection);
A number of serum proteins;
Transport proteins, which ensure the transport of iron, vitamins and other substances in the body;
Substances that stimulate healing processes, angiogenesis (formation of new blood vessels), etc.
Thus, macrophages not only “put on the ears” the entire immune system, but also actively promote the body’s recovery processes in case of onset of diseases, which only benefits us.
Next. Macrophages try to limit harmful effects many other diseases besides infectious ones. For example, they prevent the rapid progression of atherosclerosis, fight cancer cells, etc. And even in autoimmune processes, when phagocytes destroy the human body’s own structures, macrophages try to help: they filter immune complexes from the blood, a large number of which are associated with high activity diseases.
If we draw conclusions, then monocytes and macrophages are big hard workers, without whose participation functioning and even existence would be impossible immune defense. And without immunity, in turn, it is impossible to maintain health.
With this in mind, it is very important to take care to maintain 
immunity. To do this it is necessary to conduct healthy image life, promptly treat emerging diseases, take vitamins, as well as specialized immunomodulators. Among the latter, it is advisable to choose the safest and most natural ones, which will naturally affect the course of immune processes.
The drug is perfect for this role Transfer Factor. His active ingredient– information molecules – are themselves products of phagocytosis, so they exert their effect gently, without creating a conflict in the immune defense system. Transfer Factor can be used both for the prevention of diseases and for existing disorders. In any case, its action will be natural, physiological, gentle, but at the same time strong and effective.
- Carry out phagocytosis.
- The antigen is processed, and then its peptides are recommended (presented) to T helper cells, supporting the implementation of the immune response (Fig. 6).
Phagocytosis
see Phagocytosis
The main property of a macrophage (Fig. 4) is the ability for phagocytosis - selective endocytosis and further destruction of objects containing pathogen-associated molecular templates or attached opsonins (Fig. 5, 6).
Macrophage receptors
Macrophages on their surface express receptors that provide adhesion processes (for example, CDllc and CDllb), perception of regulatory influences and participation in intercellular interaction. Thus, there are receptors for various cytokines, hormones, and biologically active substances.
Bacteriolysis
see Bacteriolysis
Antigen presentation
see Antigen presentation
While the captured object is being destroyed, the number of pattern recognition receptors and opsonin receptors on the macrophage membrane significantly increases, which allows phagocytosis to continue, and the expression of class II major histocompatibility complex molecules involved in presentation processes also increases (recommendations) antigen to immunocompetent cells. In parallel, the macrophage synthesizes preimmune cytokines (primarily IL-1β, IL-6 and tumor necrosis factor α), which attract other phagocytes to work and activate immunocompetent cells, preparing them for the upcoming antigen recognition. The remains of the pathogen are removed from the macrophage by exocytosis, and immunogenic peptides in complex with HLA II enter the cell surface to activate T helper cells, i.e. maintaining the immune response.
Macrophages and inflammation
The important role of macrophages in aseptic inflammation, which develops in foci of non-infectious necrosis (in particular, ischemic), is well known. Thanks to the expression of receptors for “garbage” (scavenger receptor), these cells effectively phagocytose and neutralize elements of tissue detritus.
Also, it is macrophages that capture and process foreign particles (for example, dust, metal particles), various reasons entered the body. The difficulty of phagocytosis of such objects is that they are absolutely devoid of molecular templates and do not fix opsonins. To get out of this difficult situation, the macrophage begins to synthesize components of the intercellular matrix (fibronectin, proteoglycans, etc.), which envelop the particle, i.e. artificially creates such surface structures that are easily recognized. Material from the site http://wiki-med.com
It has been established that due to the activity of macrophages, a restructuring of metabolism occurs during inflammation. Thus, TNF-α activates lipoprotein lipase, which mobilizes lipids from the depot, which, when long term inflammation leads to weight loss. Due to the synthesis of pre-immune cytokines, macrophages are able to inhibit the synthesis of a number of products in the liver (for example, TNF-α inhibits the synthesis of albumin by hepatocytes) and increase the formation of acute-phase proteins (primarily due to IL-6), related mainly to globulin fraction. Such repurposing of hepatocytes, along with an increase in the synthesis of antibodies (immunoglobulins), leads to a decrease in the albumin-globulin ratio, which is used as a laboratory marker of the inflammatory process.
In addition to the classically activated macrophages discussed above, there is a subpopulation of alternatively activated macrophages that provide the wound healing process and repair after an inflammatory reaction. These cells produce a large number of growth factors - platelet, insulin, growth factors, transforming growth factor β and vascular endothelial growth factor. Alternatively activated macrophages are formed under the influence of the cytokines IL-13 and IL-4, i.e. in conditions of implementation of a predominantly humoral immune response.
what are macrophages?
antibacterial immunity is
main functions of macrophages:
macrophage surface receptors
what are microphages in the lungs
Main articles: Nonspecific cellular immunity, Antibody-dependent cytotoxicity
Functions of macrophages
Macrophages perform the following functions:
- Carry out phagocytosis.
- They process the antigen and then recommend (present) its peptides to T helper cells, supporting the immune response (Fig.
- Execute secretory function, consisting of the synthesis and release of enzymes (acid hydrolases and neutral proteinases), complement components, enzyme inhibitors, components of the intercellular matrix, biologically active lipids (prostaglandins and leukotrienes), endogenous pyrogens, cytokines (IL-1β, IL-6, TNF -α, etc.).
- They have a cytotoxic effect on target cells provided that the antithesis is fixed on them and appropriate stimulation from T-lymphocytes (the so-called antibody-dependent cell-mediated cytotoxicity reactions).
- Changes metabolism during inflammation.
- They take part in aseptic inflammation and destruction of foreign particles.
- Provides wound healing process.
Phagocytosis
Phagocytosis
The main property of a macrophage (Fig. 4) is the ability for phagocytosis - selective endocytosis and further destruction of objects containing pathogen-associated molecular templates or attached opsonins (Fig.
Macrophage receptors
see Receptors innate immunity#Phagocyte receptors
To detect such objects, macrophages contain on their surface template recognition receptors (in particular, the mannose-binding receptor and the receptor for bacterial lipopolysaccharides), as well as receptors for opsonins (for example, for C3b and Fc fragments of antibodies).
Macrophages on their surface express receptors that provide adhesion processes (for example, CDllc and CDllb), perception of regulatory influences and participation in intercellular interaction.
Thus, there are receptors for various cytokines, hormones, and biologically active substances.
Bacteriolysis
see Bacteriolysis
Antigen presentation
see Antigen presentation
While the captured object is being destroyed, the number of pattern recognition receptors and opsonin receptors on the macrophage membrane significantly increases, which allows phagocytosis to continue, and the expression of class II major histocompatibility complex molecules involved in presentation processes also increases (recommendations) antigen to immunocompetent cells.
In parallel, the macrophage synthesizes preimmune cytokines (primarily IL-1β, IL-6 and tumor necrosis factor α), which attract other phagocytes to work and activate immunocompetent cells, preparing them for the upcoming antigen recognition. The remains of the pathogen are removed from the macrophage by exocytosis, and immunogenic peptides in complex with HLA II enter the cell surface to activate T helper cells, i.e.
maintaining the immune response.
Macrophages and inflammation
The important role of macrophages in aseptic inflammation, which develops in foci of non-infectious necrosis (in particular, ischemic), is well known.
Macrophages in the blood
Thanks to the expression of receptors for “garbage” (scavenger receptor), these cells effectively phagocytose and neutralize elements of tissue detritus.
Also, it is macrophages that capture and process foreign particles (for example, dust, metal particles) that enter the body for various reasons.
The difficulty of phagocytosis of such objects is that they are absolutely devoid of molecular templates and do not fix opsonins. To get out of this difficult situation, the macrophage begins to synthesize components of the intercellular matrix (fibronectin, proteoglycans, etc.), which envelop the particle, i.e. artificially creates such surface structures that are easily recognized. Material from the site http://wiki-med.com
It has been established that due to the activity of macrophages, a restructuring of metabolism occurs during inflammation.
Thus, TNF-α activates lipoprotein lipase, which mobilizes lipids from the depot, which, with prolonged inflammation, leads to weight loss. Due to the synthesis of pre-immune cytokines, macrophages are able to inhibit the synthesis of a number of products in the liver (for example, TNF-α inhibits the synthesis of albumin by hepatocytes) and increase the formation of acute-phase proteins (primarily due to IL-6), related mainly to globulin fraction.
Such repurposing of hepatocytes, along with an increase in the synthesis of antibodies (immunoglobulins), leads to a decrease in the albumin-globulin ratio, which is used as a laboratory marker of the inflammatory process.
In addition to the classically activated macrophages discussed above, there is a subpopulation of alternatively activated macrophages that provide the wound healing process and repair after an inflammatory reaction.
These cells produce a large number of growth factors - platelet, insulin, growth factors, transforming growth factor β and vascular endothelial growth factor. Alternatively activated macrophages are formed under the influence of the cytokines IL-13 and IL-4, i.e. in conditions of implementation of a predominantly humoral immune response.
Material from the site http://Wiki-Med.com
On this page there is material on the following topics:
how can a macrophage suppress an antigen?
macrophage analysis
performs the function of a macrophage
what are microphages in the blood responsible for?
macrophages increased cause
Macrophage receptors
The surface of macrophages contains a large set of receptors that ensure the participation of cells in a wide range of physiological reactions, including the innate and adaptive immune response.
First of all, MFs are expressed on the membrane pattern recognition receptors of innate immunity, ensuring recognition of PAMS of most pathogens and OAMS - molecular structures associated with life-threatening influences and situations, primarily stress proteins.
Leading PRR MN/MF are Toll-like and NOD receptors.
The surface of these cells contains all known proteins expressed on plasma membranes TLR cells: TLR1, TLR2, TLR4, TLR5, TLR6 and TLR10. The cytoplasm contains intracellular TLR3, TLR7, TLR8, TLR9, as well as NOD1 and NOD2 receptors.
The binding of bacterial LPS by TLR4 MF receptors is mediated by the membrane protein CD14, which is a marker of MF.
CD14 interacts with the bacterial LPS-LPS-binding protein complex, which facilitates the interaction of LPS with TLR4.
The surface of monocytes contains aminopeptidase N (CD13), which also belongs to the PRR of monocytes, but is absent in MF. The CD13 molecule has the ability to bind the envelope proteins of some viruses.
A large amount is expressed on MN/MF phagocytic receptors.
This lectin receptors (first of all mannose receptor , Dectin-1 and DC-SIGN), as well as scavenger receptors , with the help of which it is carried out direct recognition pathogens and other objects of phagocytosis.
(See Part II, Chapter 2 “Innate immune receptors and molecular structures recognized by them”). Ligands for scavenger receptors are components of a number of bacteria, including staphylococci, neisseria, listeria, as well as modified structures of their own cells, modified low-density lipoproteins and fragments of apoptotic cells.
The mannose receptor mediates the uptake of MN/MF in many bacterial species, including Mycobacteria, Leismania, Legionella, Pseudomonas aeruginosa, and others.
The structure of this receptor determines its ability to bind peptidoglycan with high affinity cell wall bacteria. Interestingly, cytokines that activate MF (IFN-γ, TNF-α) cause inhibition of the synthesis of this receptor and a decrease in its expression. In contrast, anti-inflammatory corticosteroids increase the synthesis of the mannose receptor and its expression on MF.
Vitamin D stimulates the expression of this receptor.
Special receptors for binding advanced glycation end products (AGEs) are also found on the membrane of macrophages, which progressively accumulate in tissues as the body ages and accumulates rapidly in diabetes. These glycosylation products cause tissue damage by cross-linking proteins.
Macrophages, which have special receptors for AGEs, capture and degrade proteins modified by these products, thereby preventing the development of tissue destruction.
Almost all phagocytic receptors are also expressed on MN/MF, with the help of which mediated recognition of pathogens opsonized by antibodies and complement and other foreign particles and cells.
These primarily include Fc receptors And receptors for activated complement fragments (CR1, CR3 And CR4 , and also receptors for the C1q fragment and anaphylatoxins C3a and C5a) .
Hc receptors provide recognition and stimulate phagocytosis of objects opsonized by antibodies.
There are three different receptors for IgG binding: FcγRI, FcγRII and FcγRIII (CD64, CD32 and CD16, respectively).
FcγRI is the only one of these receptors that has high affinity for monomeric IgG and is expressed almost exclusively on macrophages.
In contrast, the low-affinity FcγRII receptor is expressed on monocytes and macrophages. FcγRIII is also expressed on monocytes and macrophages, has low affinity for IgG and binds primarily immune complexes or aggregated IgG. All three types of receptors mediate the phagocytosis of bacteria and other cells opsonized by IgG and participate in the antibody-dependent cellular cytotoxicity of natural killer cells (ADCCT) and phagocytes towards target cells carrying antigen-antibody complexes on the membrane.
Activation of macrophages through Fc receptors leads to lysis of target cells due to the release of a number of mediators (primarily TNF-α), which cause the death of these cells. Some cytokines (IFN-γ and GM-CSF) can increase the effectiveness of ADCT with the participation of monocytes and macrophages.
An important group of receptors are receptors for chemokines and other chemoattractants.
In addition to the receptors for C3a, C5a, C5b67, which cause chemotaxis of MN/MF to the site of inflammation or infection, the surface of these cells contains receptors for inflammatory chemokines (CXCR1, CCR1, CCR2, CCR3, CCR4, CCR5, CCR8, etc.).
Inflammatory chemokines produced by epithelial cells and vascular endothelial cells, as well as resident MFs located at the site of the reaction that have been activated by contact with pathogens or tissue damage, stimulate the chemotaxis of new cells involved in the defense.
Neutrophils are the first to enter the site of inflammation; later, monocyte-macrophage infiltration begins, caused by contact of the chemokine receptors of these cells with the corresponding ligands.
A large amount is expressed on MN/MF membranes glycoprotein receptors for cytokines.
The binding of cytokines to the corresponding receptors serves as the first link in the chain of transmission of the activation signal to the cell nucleus. Most specific for MN/MF receptor for GM-CSF (CD115) . The presence of this receptor makes it possible to differentiate MNs and their precursors from granulocyte cells that lack this receptor.
Particularly important for MN/MF are receptors for IFN-γ (IFNγRI and IFNγRII) , because through them, many functions of these cells are activated .
There are also receptors for pro-inflammatory cytokines (IL-1, IL-6, TNF-α, IL-12, IL-18, GM-CSF), activating, including autocrine, MN/MF involved in the inflammatory response.
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Tissue macrophages
Several populations of tissue macrophages, descendants of mononuclear phagocytes, have also been characterized for surface markers and biological functions. Granulomas usually contain epithelioid cells, which appear to be formed from blood monocytes activated during the immune response to a foreign antigen, e.g. skin reaction delayed type hypersensitivity.
Epithelioid cells have many morphological characteristics macrophages and carry Fc and S3 receptors. In general, they have less phagocytic activity than macrophages. Another cell type, multinucleated giant cells, appears to be formed by macrophage fusion rather than by nuclear division in the absence of cytoplasmic division.
Two types of such cells have been identified: Langhans cells with a relatively small number of nuclei at the periphery of the cytoplasm, and cells of the type foreign body, in which many nuclei are distributed throughout the cytoplasm.
The fate of monocytes penetrating into areas of inflammation can be different: they can turn into sedentary macrophages, transform into epithelioid cells, or merge with other macrophages and become multinucleated giant cells.
When inflammation subsides, macrophages disappear - how is still unclear. Their number may decrease as a result of either death or their migration from the site of inflammation.
Kupffer cells are resident macrophages of the liver. They border the bloodstream, which allows them to constantly come into contact with foreign antigens and other immunostimulating agents. Anatomical location between the veins carrying blood from gastrointestinal tract, and the liver’s own bloodstream leads to the fact that Kupffer cells are one of the first in a series of mononuclear phagocytes to interact with immunogens absorbed from the intestine.
Macrophages in the blood
Like other tissue macrophages, Kupffer cells are long-lived descendants of monocytes that take up residence in the liver and differentiate into macrophages.
They live in the liver for an average of about 21 days. The most important function of Kupffer cells is to absorb and degrade dissolved and insoluble materials in the portal blood.
Kupffer cells play vital role in clearing the bloodstream of many potentially harmful biological materials, including bacterial endotoxins, microorganisms, activated coagulation factors and soluble immune complexes. In accordance with their function, Kupffer cells contain an unusually large number of lysosomes containing acid hydrolases and capable of active intracellular digestion.
Previously, it was believed that the ability of Kupffer cells to perform any functions other than phagocytic ones is relatively low.
Therefore, one might think that by absorbing and digesting large, potentially immunogenic compounds, allowing only small, difficult-to-absorb fragments to remain in the bloodstream, Kupffer cells are involved in creating a state of tolerance. However, recent in vitro studies of highly purified Kupffer cells have shown that they are capable of functioning as antigen-presenting cells in many known T cell activating assays. Apparently, anatomical and physiological characteristics The normal liver microenvironment imposes restrictions on the activity of Kupffer cells, preventing them from participating in the induction of an immune response in vivo.
Alveolar macrophages line the alveoli and are the first immunologically competent cells to engulf inhaled pathogens. It was therefore important to find out whether macrophages from an organ such as the lungs, which have an extensive epithelial surface that is constantly in contact with external antigens, are capable of functioning as auxiliary cells. Macrophages located on the surface of the alveoli are ideally positioned to interact with the antigen and then present it to T lymphocytes.
Alveolar macrophages guinea pig proved to be very active support cells in both antigen- and mitogen-induced T-cell proliferation assays.
It was then shown that an antigen injected into an animal's trachea could induce a primary immune response and selectively enrich antigen-specific T cells in the lungs.
Our body is surrounded by a huge number of negative and damaging factors. external environment: ionizing and magnetic radiation, sudden temperature fluctuations, various pathogenic bacteria and viruses. To counteract their negative influence and maintain homeostasis at a constant level, the biocomputer human body Built-in powerful protective complex. It unites organs such as the thymus, spleen, liver and lymph nodes. In this article we will study the functions of macrophages that are part of the mononuclear phagocytic system, and also clarify their role in the formation immune status human body.
General characteristics
Macrophages are “big devourers”, this is how the name of these protective cells, proposed by I.I. Mechnikov, is translated. They are capable of amoeboid movement, rapid capture and breakdown of pathogenic bacteria and their metabolic products. These properties are explained by the presence in the cytoplasm of a powerful lysosomal apparatus, the enzymes of which easily destroy the complex membranes of bacteria. Histiocytes quickly recognize antigens and transmit information about them to lymphocytes.
The characteristics of macrophages as cells produced by organs of the immune system indicate that they can be found in all vital structures of the body: in the kidneys, in the heart and lungs, in the blood and lymphatic beds. They have oncoprotective and signaling properties. The membrane contains receptors that recognize antigens, the signal of which is transmitted to active lymphocytes that produce interleukins.
Currently, histologists and immunologists believe that macrophages are cells formed from multipotent stem structures of the red bone marrow. They are heterogeneous in structure and function, differ in location in the body, degree of maturation and activity towards antigens. Let's consider them further.
Types of protective cells
The largest group is represented by phagocytes circulating in connective tissues: lymph, blood, osteoclasts and membranes internal organs. In the serous cavities of the stomach and intestines, in the pleura and pulmonary vesicles there are both free and fixed macrophages. This provides protection and detoxification of both the cells themselves and their blood supply elements - the capillaries of the pulmonary alveoli, small and large intestines, as well as the digestive glands. The liver, as one of the most significant organs, has an additional protective system of mononuclear phagocytic structures - Kupffer cells. Let us dwell on their structure and mechanism of action in more detail.
How is the main biochemical laboratory of the body protected?
In the systemic circulation there is autonomous system blood supply to the liver, called the circle of the portal vein. Thanks to its functioning, from all organs abdominal cavity the blood immediately flows not into the inferior vena cava, but into a separate blood vessel - the portal vein. Next, it directs the saturated carbon dioxide and decay products venous blood to the liver, where hepatocytes and protective cells formed by the peripheral organs of the immune system break down, digest and neutralize toxic substances and pathogens that enter the venous blood from the gastrointestinal tract. Protective cells have chemotaxis, so they accumulate in areas of inflammation and phagocytose pathogenic compounds that enter the liver. Now let's look at Kupffer cells, which play a special role in protecting the digestive gland.
Phagocytic properties of the reticuloendothelial system
The functions of liver macrophages - Kupffer cells - are to capture and process hepatocytes that have lost their functions. In this case, both the protein part of the blood pigment and the heme itself are broken down. This is accompanied by the release of iron ions and bilirubin. At the same time, lysis of bacteria occurs, primarily coli that enter the bloodstream from the large intestine. Protective cells contact microbes in the sinusoidal capillaries of the liver, then capture pathogenic particles and digest them using their own lysosomal apparatus.
Signaling function of phagocytes
Macrophages are not only protective structures that provide cellular immunity. They can identify foreign particles that have entered the body's cells, since there are receptors on the phagocyte membrane that recognize molecules of antigens or biologically active substances. Most of these compounds cannot directly contact lymphocytes and trigger a protective response. It is phagocytes that deliver antigenic groups to the membrane, which serve as beacons for B-lymphocytes and T-lymphocytes. Macrophage cells apparently perform the most important function transmitting a signal about the presence of a damaging agent to the most active and fastest-acting immune complexes. They, in turn, are able to react with lightning speed to pathogenic particles in the human body and destroy them.
Specific properties
The functions of the elements of the immune system are not limited to protecting the body from foreign environmental components. For example, phagocytes are capable of carrying out the exchange of iron ions in the red bone marrow and spleen. By participating in erythrophagocytosis, protective cells digest and break down old red blood cells. Alveolar macrophages accumulate iron ions in the form of ferritin and hemosiderin molecules. They can be found in the sputum of patients suffering from heart failure with blood stagnation in the pulmonary circulation and various forms heart disease, also in patients who have had a heart attack complicated by thromboembolism pulmonary artery. Presence large quantity immune cells in various types clinical trials, for example in vaginal smears, urine or semen, may indicate inflammatory processes, infectious or oncological diseases occurring in humans.
Peripheral organs of the immune system
Considering the critical role of phagocytes, leukocytes and lymphocytes in maintaining the health and genetic uniqueness of the body, as a result of evolution, two lines of defense were created and improved: the central and peripheral organs of the immune system. They produce various types cells involved in the fight against foreign and pathogenic agents.
These are primarily T-lymphocytes, B-lymphocytes and phagocytes. Spleen, lymph nodes and follicles digestive tract are also capable of forming macrophages. This makes it possible for the tissues and organs of the human body to quickly recognize antigens and mobilize humoral and cellular immunity For effective fight with infection.
Article for the “bio/mol/text” competition: The immune system is a powerful multi-layered defense of our body, which is amazingly effective against viruses, bacteria, fungi and other pathogens from the outside. In addition, the immune system is able to effectively recognize and destroy transformed own cells that can degenerate into malignant tumors. However, malfunctions of the immune system (for genetic or other reasons) lead to the fact that one day malignant cells take over. An overgrown tumor becomes insensitive to attacks from the body and not only successfully avoids destruction, but also actively “reprograms” protective cells to meet its own needs. By understanding the mechanisms that tumors use to suppress the immune response, we can develop countermeasures and try to shift the balance toward activating the body's own defenses to fight the disease.
This article was submitted to the competition of popular scientific works “bio/mol/text”-2014 in the “Best Review” category.
The main sponsor of the competition is the forward-thinking company Genotech.
The competition was supported by RVC OJSC.
Tumor and immunity - a dramatic dialogue in three parts with a prologue
It has long been believed that the reason for the low effectiveness of the immune response in cancer is that tumor cells are too similar to normal, healthy ones for the immune system, tuned to search for “strangers,” to recognize them properly. This explains the fact that the immune system most successfully resists tumors of a viral nature (their frequency increases sharply in people suffering from immunodeficiency). However, it later became clear that this was not the only reason.
If this article deals with the immune aspects of cancer, then the work “There are no more terrible claws in the world...” You can read about the features of cancer metabolism. - Ed.
It turned out that the interaction of cancer cells with the immune system is much more diverse. The tumor does not just “hide” from attacks, it can actively suppress the local immune response and reprogram immune cells, forcing them to serve their own malignant needs.
The “dialogue” between a degenerated cell, out of control, with its offspring (that is, a future tumor) and the body develops in several stages, and if at first the initiative is almost entirely on the side of the body’s defenses, then at the end (in the event of the development of a disease) - goes to the side of the tumor. Several years ago, cancer immunologists formulated the concept of “immunoediting” ( immunoediting), describing the main stages of this process (Fig. 1).
Figure 1. Immunoediting (immunoediting) during the development of a malignant tumor.
The first stage of immunoediting is the process of elimination ( elimination). Under the influence of external carcinogenic factors or as a result of mutations, a normal cell is “transformed” - it acquires the ability to divide indefinitely and not respond to the body’s regulatory signals. But at the same time, as a rule, it begins to synthesize special “tumor antigens” and “danger signals” on its surface. These signals attract cells of the immune system, primarily macrophages, natural killer cells, and T cells. In most cases, they successfully destroy “spoiled” cells, interrupting the development of the tumor. However, sometimes among these “precancerous” cells there are several whose immunoreactivity - the ability to cause an immune response - is weakened for some reason, they synthesize fewer tumor antigens, are less recognized by the immune system and, having survived the first wave of the immune response, continue to divide.
In this case, the interaction of the tumor with the body enters the second stage, the equilibrium stage ( equilibrium). Here the immune system can no longer completely destroy the tumor, but is still able to effectively limit its growth. In such an “equilibrium” (and undetectable by conventional diagnostic methods) state, microtumors can exist in the body for years. However, such latent tumors are not static - the properties of the cells that make them up gradually change under the influence of mutations and subsequent selection: among the dividing tumor cells, those that are better able to resist the immune system receive an advantage, and eventually cells appear in the tumor - immunosuppressants. They are able not only to passively avoid destruction, but also to actively suppress the immune response. Essentially this is evolutionary process, in which the body involuntarily “removes” the exact type of cancer that will kill it.
This dramatic moment marks the transition of the tumor to the third stage of development - avoidance ( escape), - in which the tumor is already insensitive to the activity of cells of the immune system, moreover, it turns their activity to its benefit. It begins to grow and metastasize. It is this kind of tumor that is usually diagnosed by doctors and studied by scientists - the two previous stages occur hidden, and our ideas about them are based mainly on the interpretation of a number of indirect data.
Dualism of the immune response and its significance in carcinogenesis
There are many scientific articles describing how the immune system fights tumor cells, but an equally large number of publications demonstrate that the presence of immune system cells in the immediate tumor environment is a negative factor that correlates with accelerated cancer growth and metastasis. Within the framework of the concept of immunoediting, which describes how the nature of the immune response changes as the tumor develops, such dual behavior of our defenders finally received its explanation.
We will look at some of the mechanisms of how this happens, using macrophages as an example. The tumor uses similar techniques to deceive other cells of the innate and acquired immunity.
Macrophages - “warrior cells” and “healing cells”
Macrophages are perhaps the most famous cells innate immunity - it was with the study of their abilities for phagocytosis that Metchnikoff began classical cellular immunology. In the mammalian body, macrophages are the combat vanguard: being the first to detect the enemy, they not only try to destroy it on our own, but also attract other cells of the immune system to the battlefield, activating them. And after the destruction of foreign agents, they begin to actively participate in eliminating the damage caused, developing factors that promote wound healing. Tumors use this dual nature of macrophages to their advantage.
Depending on the predominant activity, two groups of macrophages are distinguished: M1 and M2. M1 macrophages (they are also called classically activated macrophages) - “warriors” - are responsible for the destruction of foreign agents (including tumor cells), both directly and by attracting and activating other cells of the immune system (for example, T-killer cells ). M2 macrophages - “healers” - accelerate tissue regeneration and ensure wound healing.
The presence of a large number of M1 macrophages in the tumor inhibits its growth, and in some cases can even cause almost complete remission(destruction). And vice versa: M2 macrophages secrete molecules - growth factors, which additionally stimulate the division of tumor cells, that is, they favor the development malignant formation. It has been experimentally shown that M2 cells (“healers”) usually predominate in the tumor environment. Worse yet: under the influence of substances secreted by tumor cells, active M1 macrophages are “reprogrammed” into the M2 type, stop synthesizing antitumor cytokines, such as interleukin-12 (IL12) or tumor necrosis factor (TNF) and begin to secrete environment molecules that accelerate tumor growth and the germination of blood vessels that will provide its nutrition, such as tumor growth factor (TGFb) and vascular growth factor (VGF). They stop attracting and initiating other cells of the immune system and begin to block the local (antitumor) immune response (Fig. 2).
Figure 2. M1 and M2 macrophages: their interaction with the tumor and other cells of the immune system.
Proteins of the NF-kB family play a key role in this reprogramming. These proteins are transcription factors that control the activity of multiple genes required for M1 activation of macrophages. The most important members of this family are p65 and p50, which together form the p65/p50 heterodimer, which in macrophages activates many genes associated with the acute inflammatory response, such as TNF, many interleukins, chemokines and cytokines. The expression of these genes attracts more and more immune cells, “highlighting” the area of inflammation for them. At the same time, another homodimer of the NF-kB family - p50/p50 - has the opposite activity: by binding to the same promoters, it blocks their expression, reducing the degree of inflammation.
Both activities of NF-kB transcription factors are very important, but the balance between them is even more important. It has been shown that tumors specifically release substances that disrupt p65 protein synthesis in macrophages and stimulate the accumulation of the p50/p50 inhibitory complex. In this way (in addition to a number of others), the tumor turns aggressive M1-macrophages into unwitting accomplices of its own development: M2-type macrophages, perceiving the tumor as a damaged area of tissue, turn on the restoration program, but the growth factors they secrete only add resources for tumor growth. This completes the cycle - the growing tumor attracts new macrophages, which are reprogrammed and stimulate its growth instead of destruction.
Reactivation of the immune response is a current direction in anticancer therapy
Thus, in the immediate environment of tumors there is a complex mixture of molecules, both activating and inhibiting the immune response. The prospects for the development of a tumor (and therefore the prospects for the survival of the organism) depend on the balance of the ingredients of this “cocktail”. If immunoactivators predominate, it means that the tumor has not coped with the task and will be destroyed or its growth will be greatly inhibited. If immunosuppressive molecules predominate, this means that the tumor was able to pick up the key and will begin to progress rapidly. By understanding the mechanisms that allow tumors to suppress our immune system, we can develop countermeasures and shift the balance toward eliminating tumors.
Experiments show that the “reprogramming” of macrophages (and other cells of the immune system) is reversible. Therefore one of promising directions Onco-immunology today is the idea of “reactivating” the patient’s own immune system cells in order to enhance the effectiveness of other treatment methods. For some types of tumors (for example, melanomas) this allows achieving impressive results. Another example discovered by Medzhitov's group is the common lactate, a molecule that is produced when there is a lack of oxygen in fast-growing tumors due to the Warburg effect. This simple molecule stimulates the reprogramming of macrophages, causing them to support tumor growth. Lactate is transported into macrophages through membrane channels, and potential therapy is to block these channels.