Antibodies perform two functions: antigen-binding and effector (cause one or another immune response, for example, trigger classic scheme complement activation).
Innate immunity: cells with a greater appetite
In case of infection or inflammation, the number increases significantly, which can be recognized by the doctor in the patient's blood picture. White blood cells are composed of three important subsets: nurse cells, and T and B lymphocytes called T cells and B cells. Feeding cells belong to the innate immune system. Nine weeks after fertilization, the first defense cells can be detected in a human fetus. They react quickly, but nonspecifically, to substances that are foreign to the body. That is, the feeding cells always react equally strongly every time they come into contact with a foreign body.
Antibodies are synthesized by plasma cells, which some B lymphocytes become, in response to the presence of antigens. For each antigen, specialized plasma cells corresponding to it are formed, producing antibodies specific to this antigen. Antibodies recognize antigens by binding to a specific epitope - a characteristic fragment of the surface or linear amino acid chain of the antigen.
For, contrary to what is acquired, the innate immune system is not capable of learning. Figure 1: Feeding cells that target intruders, dissolve them, and present external structures on their surface. Large, moving, feeding cells are also called monocytes. When they migrate into tissues, they develop into macrophages. Unwanted pathogens are phagocytosed by them, that is, they surround the foreign body and dissolve it. In addition, they warn other intruders to the attacker. For this purpose, nutritional cells migrate with prey to the lymph nodes.
Antibodies consist of two light and two heavy chains. In mammals, there are five classes of antibodies (immunoglobulins) - IgG, IgA, IgM, IgD, IgE, which differ in the structure and amino acid composition of the heavy chains and in the effector functions performed.
History of the study
The very first antibody was discovered by Behring and Kitazato in 1890, but at that time nothing definite could be said about the nature of the discovered tetanus antitoxin, other than its specificity and its presence in the serum of an immune animal. Only in 1937, with the research of Tiselius and Kabat, did the study of the molecular nature of antibodies begin. The authors used the method of protein electrophoresis and demonstrated an increase in the gamma globulin fraction of the blood serum of immunized animals. Adsorption of serum by the antigen that was taken for immunization reduced the amount of protein in this fraction to the level of intact animals.
Antigen, i.e. a foreign body recognition sign is placed on the cell surface of the feeding cells and thus fed into special cells. They can then specifically target the pathogen. Figure 2: Feeder cells point T helper cells to pathogens. As a result, helper cells emit messengers, which in turn form B cells.
Loose cells not only eliminate foreign bodies, but also create dead body tissue and cellular debris from the body as bodily garbage collection. Certain attractants released by damaged tissue give giant giant cells a path to the site of inflammation.
Antibody structure
Antibodies are relatively large (~150 kDa - IgG) glycoproteins with a complex structure. Consist of two identical heavy chains (H-chains, in turn consisting of V H, C H 1, hinge, CH 2- and C H 3-domains) and two identical light chains (L-chains, consisting of V L - and C L - domains). Oligosaccharides are covalently attached to the heavy chains. Using papain protease, antibodies can be cleaved into two Fabs. fragment antigen binding- antigen-binding fragment) and one (eng. fragment crystallizable- fragment capable of crystallization). Depending on the class and functions performed, antibodies can exist both in monomeric form (IgG, IgD, IgE, serum IgA) and in oligomeric form (dimer-secretory IgA, pentamer - IgM). In total, there are five types of heavy chains (α-, γ-, δ-, ε- and μ-chains) and two types of light chains (κ-chain and λ-chain).
Figure 3: B cells produce specific antibodies after exposure to pathogens. Much smaller granulocytes also belong to the feeding cells. They contain numerous enzymes that look like granules under a microscope. With the help of these enzymes, they bombard foreign cells and thereby dissolve the cell walls. It is more difficult for the immune system to recognize virus-infected cells and carry viruses instead of its own genome. Natural killer cells, which are also part of the innate immune system, are active against such camouflaged cells in the body.
Heavy chain classification
There are five classes ( isotypes) immunoglobulins, differing:
- amino acid sequence
- molecular weight
- charge
The IgG class is classified into four subclasses (IgG1, IgG2, IgG3, IgG4), the IgA class into two subclasses (IgA1, IgA2). All classes and subclasses make up nine isotypes that are normally present in all individuals. Each isotype is determined by the amino acid sequence of the heavy chain constant region.
Enzymes support immune cells
They also attack bodily cancer cells that degenerate by changing genotype. Fig. 4: Bret cells can more easily recognize and destroy antigen-antibody complexes. In addition to immune cells, enzymes that are part of the so-called complement system can also become active against intruders. Like nurse cells, the complement system is part of the innate immune system, which is immediately apparent against foreign bodies, but acts nonspecifically. The complement system includes about 20 special enzymes.
Antibody functions
Immunoglobulins of all isotypes are bifunctional. This means that immunoglobulin of any type
- recognizes and binds antigen, and then
- enhances the destruction and/or removal of immune complexes formed as a result of activation of effector mechanisms.
One region of the antibody molecule (Fab) determines its antigen specificity, and the other (Fc) performs effector functions: binding to receptors that are expressed on body cells (for example, phagocytes); binding to the first component (C1q) of the complement system to initiate the classical pathway of the complement cascade.
Regulatory proteins ensure that enzymes are activated as needed, but are also deactivated again. This prevents the enzymes from being directed against your own body. The system can be alerted in three ways: Enzymes can directly bind to invading antigens as they recognize their structure in a similar way to feeding cells. They can also be activated by an enzyme from the liver and further prevented by antibodies of a specific defense system.
When the enzymes bind to bacteria, other complement enzymes become active again. The complement system can directly kill unwanted cells by degrading their cell walls. In addition, the feeding cells warn off intruders and increase the activity of giant giant cells. This shows how individual immune responses are interconnected and support each other in their work.
Antibody specificity
This means that each lymphocyte synthesizes antibodies of only one specific specificity. And these antibodies are located on the surface of this lymphocyte as receptors.
As experiments show, all cell surface immunoglobulins have the same idiotype: when a soluble antigen, similar to polymerized flagellin, binds to a specific cell, then all cell surface immunoglobulins bind to this antigen and they have the same specificity, that is, the same idiotype.
Defense proteins react quickly
By pressing the feeder cells against the intruder, they release a chemical messenger, interleukin. It stimulates the production of numerous proteins in the liver and macrophages. These immediately produced proteins are referred to as acute phase proteins. In this way, they activate the complement system and appear to also increase the effectiveness of specific immune cell defenses. Acute phase proteins also play a role in the inflammation process: they can promote but also mitigate.
Nonspecific protection is often not enough to completely combat painful diseases. However, it is first necessary to create protection against more powerful specific immunity. The starting cells are lymphocytes, of which healthy person has about 10 trillion. Every day, a billion new lymphocytes are produced to replace the substance consumed. They form similar to feeding cells in the bone marrow, but develop in different places in different forms: In the thymus gland, a small gland behind the breast bone, they become T cells and bone marrow into B cells.
The antigen binds to receptors, then selectively activates the cell to produce large amounts of antibodies. And since the cell synthesizes antibodies of only one specificity, this specificity must coincide with the specificity of the initial surface receptor.
The specificity of the interaction of antibodies with antigens is not absolute; they can cross-react with other antigens to varying degrees. Antiserum raised to one antigen can react with a related antigen that carries one or more of the same or similar determinants. Therefore, each antibody can react not only with the antigen that caused its formation, but also with other, sometimes completely unrelated molecules. The specificity of antibodies is determined by the amino acid sequence of their variable regions.
Ban is as important as support
T cells control the immune response. They specialize into further subgroups: helper and killer cells, the latter also called cytotoxic cells. T helper cells become active when antigens are supplied to them by nutritional cells. This division of labor has its own meaning. For many pathogens, viruses invade the body's cells and can only be controlled by destroying the infected cells.
Envoys control cooperation
Both subgroups produce chemical messengers with different effects. However, this has a negative impact on autoimmune diseases. However, this has so far only been demonstrated in animal experiments. In experiments, researchers found that B cells can activate and inhibit T cells. This once again shows how accurately individual reactions immune system coordinate with each other. Another group of T lymphocytes, killer T cells, recognize cells whose surface has changed viral infection or cancer.
Clonal selection theory:
- Antibodies and lymphocytes with the required specificity already exist in the body before the first contact with the antigen.
- Lymphocytes that participate in the immune response have antigen-specific receptors on the surface of their membrane. B lymphocytes have receptor molecules of the same specificity as the antibodies that the lymphocytes subsequently produce and secrete.
- Any lymphocyte carries receptors of only one specificity on its surface.
- Lymphocytes that have the antigen undergo a proliferation stage and form a large clone of plasma cells. Plasma cells synthesize antibodies only of the specificity for which the precursor lymphocyte was programmed. Signals for proliferation are cytokines, which are released by other cells. Lymphocytes can themselves secrete cytokines.
Antibody variability
Antibodies are extremely variable (up to 10 8 antibody variants can exist in the body of one person). All the diversity of antibodies stems from the variability of both heavy chains and light chains. Antibodies produced by one or another organism in response to certain antigens are distinguished:
They specialize in destroying such infected or degenerated cells. To do this, they release chemicals that dissolve the cell walls of infected body cells and thus kill them. Since immune cells themselves are active in defense, which is mediated by T cells, cellular immunity or cell-mediated immunity is also referred to. B cells arise as T cells from bone marrow stem cells. However, they mature in the bone marrow. With the help of signals from bone marrow cells, each B cell forms a specific receptor, which it carries on the cell surface.
- Isotypic variability - manifested in the presence of classes of antibodies (isotypes), differing in the structure of heavy chains and oligomerity, produced by all organisms of a given species;
- Allotypic variability - manifests itself at the individual level within a given species in the form of variability of immunoglobulin alleles - is a genetically determined difference between a given organism and another;
- Idiotypic variability - manifests itself in differences in the amino acid composition of the antigen-binding site. This applies to the variable and hypervariable domains of the heavy and light chains that are in direct contact with the antigen.
Control of proliferation
The most effective control mechanism is that the reaction product simultaneously serves as its inhibitor. This type of negative feedback occurs during the formation of antibodies. The effect of antibodies cannot be explained simply by neutralization of the antigen, because whole IgG molecules suppress antibody synthesis much more effectively than F(ab")2 fragments. It is assumed that the blockade of the productive phase of the T-dependent B-cell response occurs as a result of the formation of cross-links between the antigen , IgG and Fc receptors on the surface of B cells. Injection of IgM enhances the immune response. Since antibodies of this particular isotype appear first after the introduction of an antigen, they are credited with an enhancing role at the early stage of the immune response.
Each receptor recognizes and binds a very specific external structure. If a suitable intruder arrives at the receptor, the B cell divides again and again within a very short time and moves into the plasma cell. This plasma cell can produce huge amounts of appropriate antibodies. Antibodies are nothing more than a soluble form of a specific B cell receptor. A single B cell can deliver more than 10 million antibodies per hour and produce more than 100 million different antibodies.
Antibodies attract nutritional cells and enzymes
Since antibodies float freely in the blood, this protection is also called humoral immunity, from English humor = fluid. Antibodies are applied to the corresponding antigen, neutralizing it or facilitating its degradation. Antibodies themselves can only mark and contain pathogens. Eliminate other immune system factors. Thus, the complement system as well as the feeding cells are bracketed by the antigen-antibody complex. Although both of them work regardless of the specific protection.
What kind of plasma cells are these that produce antibodies, and can a plasma cell be considered the most important cell of the immune system?
What are these plasma cells that produce antibodies? Did they already know about them in Mechnikov’s time or is this a later discovery?
Antibodies
Of course, later. These are the achievements of new immunology. Swedish researcher Astrid Fagreus proposed in 1948 that antibodies are produced by plasma cells. This was finally proven by the famous American immunologist Albert Coons just 20 years ago, in 1956.
However, when antibodies stick to the intruder, the complement system and nutritional cells react much faster. Today there are five different classes of antibodies, also called immunoglobulins. Class M immunoglobulins play a special role in the first defense against pathogens. Antibodies of this class are most often found in the blood.
This protects the unborn baby from infections already in the mother's body. This likely serves to stimulate the production of additional antibodies. They bind to mast cells and stimulate them to release inflammatory mediators such as histamine. Antibodies are mainly caused by pathogens outside the body's cells, such as bacteria in the blood or other body fluids. T cells, on the other hand, fight pathogens that invade the body's cells, Viruses or some bacteria, such as the tubercle bacilli.
- No, you can’t. Chief cells were recognized even later.
- What kind of cells are these?
- These are lymphocytes.
If you do not take into account red blood cells that carry oxygen, then all other blood cells have white. They are called leukocytes, that is, white cells. Of all white cells, 30 percent are lymphocytes. Lymphocyte translated into Russian means “lymph cell.”
Some T and B cells also become circulating cells circulating in the blood and lymphatic system. They store all the information from pathogens that the body had to protect. If the same pathogen is detected again, the memory cells ensure that the appropriate antibodies are immediately produced. The intruder can then be disabled before causing any discomfort. When our bodies are already suffering from diseases such as measles, rubella or chickenpox, we usually do not notice that pathogens have taken up residence again.
A healthy body can protect itself from most pathogens. Therefore, it is worth doing something to ensure a stable and intact immune system. Osteomyelosclerosis or myelosclerosis is a disease of the bone marrow that results in severe deficiency of blood cells, especially red blood cells.
In addition to blood, lymph circulates in all tissues of our body. Through the lymphatic vessels it enters the lymph nodes, and from there it is collected into one large vessel - the thoracic duct, which flows into the bloodstream near the heart. There are no red blood cells in lymph. Only lymphocytes.
Exactly three hundred years ago, the famous Dutchman Antonie Leeuwenhoek created his “microscope”. The first objects of his observations were a drop of rainwater and a drop of blood. He discovered red blood cells - red blood cells, which make up the bulk of blood cells. Less than a hundred years later, white blood cells were discovered. There are almost a thousand times fewer of them than red blood cells, but still a lot. A gram of blood contains 4-5 billion red blood cells and 6-8 million leukocytes.
The bone marrow is the place in the body where blood cells typically form and mature in several stages. Stem cells produce red and white blood cells, as well as cells that produce blood platelets. The origin of the disease is a cancerous change in such a blood stem cell. This also applies to chronic myeloid leukemia or polycythemia vera. Osteomyelosclerosis can sometimes resemble these early-stage diseases. However, during the course of the disease, a proliferation of connective tissue rich in fibrous substance occurs, which thus increasingly suppresses the formation of blood in the bone marrow.
Leukocytes are divided into two main groups. The cells of the first group make up about 2/3 and are characterized by having segmented rather than round nuclei. The cells of the second group have absolutely round nuclei that occupy most of the cell. The first are actually leukocytes, and the second are called lymphocytes.
At the end of the last century, Metchnikoff discovered that white blood cells protect the body by devouring foreign particles. In contrast to large tissue phagocytes - macrophages, he called them small phagocytes - microphages. But what lymphocytes do became known only 15 years ago.
How easily we turn the pages of history! Three hundred years ago the first red blood cells were discovered, two hundred years ago - leukocytes, a hundred years ago - lymphocytes. Hard work, research, ingenuity, debate, ten generations of explorers! And we have half a page of printed text.
Inspection
Two million lymphocytes in every gram of blood. What are they doing? Hundreds of researchers have asked themselves this question. Professor James Gowans of Oxford, who has done more than anyone else to discover the functions of these cells, quotes the famous pathologist Arnold Rich: "Lymphocytes are the phlegmatic observers of the vigorous activity of phagocytes." This was one of the common views. Indeed, very small cells, 6-8 microns in diameter, slightly larger than their own nucleus (almost one nucleus!), which do not have active mobility, but almost always accumulate around the inflammatory focus in which phagocytes work, devouring everything foreign or dying.
There was another opinion. Lymphocytes were credited with the function of feeding other cells. They were even called trophocytes - feeding cells.
Many believed that all sorts of other cells arise from lymphocytes - connective tissue, liver, lung, etc. “The old literature,” writes Gowens, “is filled with conflicting evidence that small lymphocytes can turn into erythrocytes, granulocytes, monocytes, fibroblasts, plasma cells cells, etc. A cynic once remarked that all cells, with the exception of cells nervous system, at one time or another were considered to be derivatives of lymphocytes!
The lymphocyte is truly a mysterious cell, since it managed to keep its secret before the insight of science until the 60s of the 20th century! At the beginning of the 1969s, indisputable evidence appeared that all specific immune reactions - the production of antibodies, rejection of transplanted tissues or organs, antiviral protection - are carried out by lymphocytes.
Let's look at this using the example of James Gowens' research. In those years, he had a tiny laboratory at Oxford University. In one of the rooms with old translucent windows, a machine he designed himself stood in the center on the table. The main part of the machine is a plexiglass cylinder. A rat is cleverly secured in the cylinder. There is a cut on the rat's neck. A thin transparent tube goes into the body through the incision. Small white drops keep dripping from the tube.
Dr. Gowens inserted a tube into the main lymphatic vessel - the thoracic duct - and pumped out the lymph. It leaves the rat without lymphocytes. After that, he immunizes her with foreign cells - sheep red blood cells. Antibodies against sheep red blood cells must be developed. He examines the rat's blood once, twice, three times... There are no antibodies! Then he takes another lymphocyte-free rat and puts its lymphocytes back into its blood. Immunizes and detects normal levels of antibodies.
This means that without lymphocytes, antibodies cannot be produced.
Second study. Gowans exposes a rat to X-rays. Many systems suffer after irradiation, including the immune system. The animal does not produce antibodies. The irradiated rat was injected with sheep red blood cells, but there were no antibodies. Another irradiated rat was injected with sheep red blood cells along with lymphocytes from a healthy rat; there are antibodies.
This means that with lymphocytes the ability to produce antibodies can be transferred to another organism. The memory of the antigen is also transferred with lymphocytes. If these cells are taken from an animal that has already been immunized with sheep red blood cells before, then in the irradiated animal they will ensure the production of more antibodies. As if we were immunizing him again.
The third study concerns the mechanism of rejection of transplanted foreign tissue. By the early 60s, it was well known that the first skin graft immunizes the body and the second graft is rejected twice as fast as the first. But why? They thought it was the work of antibodies. However, blood serum from such an animal containing antibodies, if injected into another animal, does not accelerate the rejection of the grafted skin. But lymphocytes accelerate. And exactly twice.
This means that it is lymphocytes that are engaged in the rejection of transplanted foreign tissues! Without the help of antibodies. Themselves, with your own “hands”. Such lymphocytes, which after the first contact with a foreign antigen are specifically targeted against it, are called sensitized lymphocytes. They and antibodies are the two main types of immunity weapons.
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