About 5% of the world's population suffers from autoimmune diseases, a condition in which own cells The body's immune system, instead of fighting pathogens, destroys normal cells of organs and tissues. In this article, which precedes a special project on autoimmune diseases, we will look at the basic principles of the immune system and show why such sabotage on its part is possible.
With this article we begin a series on autoimmune diseases - diseases in which the body begins to fight itself, producing autoantibodies and/or autoaggressive clones of lymphocytes. We will talk about how the immune system works and why sometimes it starts to “shoot at its own people.” Separate publications will be devoted to some of the most common diseases. To maintain objectivity, we invited Doctor of Biological Sciences, corresponding member to become the curator of the special project. RAS, professor of the Department of Immunology of Moscow State University Dmitry Vladimirovich Kuprash. In addition, each article has its own reviewer, who delves into all the nuances in more detail. The reviewer of this introductory article was Evgeniy Sergeevich Shilov, Candidate of Biological Sciences, researcher at the same department.
Antigens- any substances that the body perceives as foreign and, accordingly, responds to their appearance by activating the immune system. The most important antigens for the immune system are pieces of molecules located on outer surface pathogen. From these pieces you can determine which one the aggressor attacked the body, and ensure the fight against it.
Cytokines - the body's Morse code
In order for immune cells to coordinate their actions in the fight against the enemy, they need a system of signals that tell who and when to enter the battle, or end the battle, or, conversely, resume it, and much, much more. For these purposes, cells produce small protein molecules - cytokines, for example, various interleukins(IL-1, 2, 3, etc.) . It is difficult to assign an unambiguous function to many cytokines, but with some degree of convention they can be divided into five groups: chemokines, growth factors, about inflammatory, against inflammatory and immunoregulatory cytokines.
The above-mentioned classification convention means that a cytokine included in one of the listed groups, under certain conditions in the body, can play a diametrically opposite role - for example, turn from pro-inflammatory to anti-inflammatory.
Without established communication between types of troops, any sophisticated military operation is doomed to failure, so it is very important for the cells of the immune system, by receiving and giving orders in the form of cytokines, to interpret them correctly and act harmoniously. If cytokine signals begin to be produced in very large quantities, then panic sets in in the cell ranks, which can lead to damage to one’s own body. It is called cytokine storm: in response to incoming cytokine signals, cells of the immune system begin to produce more and more of their own cytokines, which, in turn, act on the cells and increase the secretion of themselves. A vicious circle is formed, which leads to the destruction of surrounding cells, and later neighboring tissues.
Pay in order! Immune cells
Just as there are different types of troops in the armed forces, the cells of the immune system can be divided into two large branches - innate and acquired immunity, for the study of which the Nobel Prize was awarded in 2011. Innate immunity- that part of the immune system that is ready to protect the body immediately as soon as a pathogen attack occurs. Acquired same (or adaptive) the immune response at the first contact with the enemy takes longer to unfold, since it requires sophisticated preparation, but after that it can carry out a more complex scenario of protecting the body. Innate immunity is very effective in the fight against isolated saboteurs: it neutralizes them without disturbing specialized elite military units- adaptive immunity. If the threat turns out to be more significant and there is a risk of the pathogen penetrating deeper into the body, the innate immune cells immediately signal about this, and the acquired immune cells enter the battle.
All the body's immune cells are formed in the bone marrow from hematopoietic stem cell, which gives rise to two cells - general myeloid And common lymphoid progenitor, . Acquired immune cells originate from a common lymphoid progenitor and are accordingly called lymphocytes, whereas innate immune cells can originate from both progenitors. The differentiation scheme of immune system cells is shown in Figure 1.
Figure 1. Scheme of differentiation of cells of the immune system. Hematopoietic stem cell gives rise to cells - the precursors of the myeloid and lymphoid lines of differentiation, from which all types of blood cells are further formed.
Innate immunity - regular army
Innate immune cells recognize the pathogen by molecular markers specific to it - the so-called images of pathogenicity. These markers do not allow one to accurately determine whether a pathogen belongs to a particular species, but only signal that the immune system has encountered strangers. For our body, such markers can be fragments of the cell wall and flagella of bacteria, double-stranded RNA and single-stranded DNA of viruses, etc. With the help of special innate immune receptors such as TLR ( Toll-like receptors, Toll-like receptors) and NLR ( Nod-like receptors, Nod-like receptors), cells interact with images of pathogenicity and begin to implement their protective strategy.
Now let's take a closer look at some of the innate immune cells.
In order to understand how the T-cell receptor works, we must first discuss a little another important family of proteins - major histocompatibility complex(MHC, major histocompatibility complex) . These proteins are the body's molecular "passwords", allowing cells of the immune system to distinguish their compatriots from the enemy. In any cell constantly the process is underway protein degradation. Special molecular machine - immunoproteasome- breaks down proteins into short peptides, which can be integrated into the MHC and, like an apple on a plate, presented to the T-lymphocyte. With the help of the TCR, it “sees” the peptide and recognizes whether it belongs to the body’s own proteins or is foreign. At the same time, the TCR checks whether the MHC molecule is familiar to it - this allows it to distinguish its own cells from “neighboring” ones, that is, cells of the same species, but from a different individual. It is the coincidence of MHC molecules that is necessary for the engraftment of transplanted tissues and organs, hence the tricky name: histos in Greek means "cloth". In humans, MHC molecules are also called HLA ( human leukocyte antigen- human leukocyte antigen).
Video 2. Short-term interactions of T cells with a dendritic cell (indicated green).
T lymphocytes
To activate a T lymphocyte, it needs to receive three signals. The first of these is the interaction of the TCR with the MHC, that is, antigen recognition. The second is the so-called costimulatory signal, transmitted by the antigen-presenting cell through the CD80/86 molecules to CD28 located on the lymphocyte. The third signal is the production of a cocktail of many pro-inflammatory cytokines. If any of these signals break down, it can have serious consequences for the body, such as an autoimmunity reaction.
There are two types of major histocompatibility complex molecules: MHC-I and MHC-II. The first is present on all cells of the body and carries peptides of cellular proteins or proteins of the virus that infected it. A special subtype of T cells - Killer T cells(they are also called CD8+ T-lymphocytes) - interacts with the MHC-I-peptide complex with its receptor. If this interaction is strong enough, it means that the peptide that the T cell sees is not characteristic of the body and, accordingly, may belong to an enemy that has invaded the cell - a virus. It is urgent to neutralize the border violator, and the T-killer copes with this task perfectly. It, like an NK cell, secretes the proteins perforin and granzyme, which leads to lysis of the target cell.
T-cell receptor of another subtype of T-lymphocytes - T helper cells(Th cells, CD4+ T lymphocytes) - interacts with the MHC-II-peptide complex. This complex is not present on all cells of the body, but mainly on immune cells, and the peptides that can be presented by the MHC-II molecule are fragments of pathogens captured from the extracellular space. If the T-cell receptor interacts with the MHC-II-peptide complex, the T-cell begins to produce chemokines and cytokines that help other cells effectively carry out their function - fighting the enemy. That is why these lymphocytes are called helpers - from English helper(assistant). Among them, there are many subtypes that differ in the spectrum of cytokines produced and, therefore, in their role in the immune process. For example, there are Th1 lymphocytes, which are effective in fighting intracellular bacteria and protozoa, Th2 lymphocytes, which help B cells in their work and are therefore important for resisting extracellular bacteria (which we will talk about shortly), Th17 cells, and many others.
Video 3. Movement of T-helper cells ( red) and T-killers ( green) in the lymph node. The video was filmed using intravital two-photon microscopy.
Among CD4+ T cells, there is a special subtype of cells - regulatory T lymphocytes. They can be compared to the military prosecutor's office, restraining the fanaticism of soldiers eager to fight and preventing them from harming civilians. These cells produce cytokines overwhelming immune response, and thus weaken the immune response when the enemy is defeated.
The fact that the T cell recognizes only foreign antigens, and not molecules from its own body, is a consequence of an ingenious process called selection. It occurs in an organ specially created for this purpose - the thymus, where T cells complete their development. The essence of selection is this: the cells surrounding the young, or naive, lymphocyte show (present) to it the peptides of their own proteins. The lymphocyte that recognizes these protein fragments too well or too poorly is destroyed. The surviving cells (and this is less than 1% of all T-lymphocyte precursors that came to the thymus) have an intermediate affinity for the antigen, therefore, they, as a rule, do not consider their own cells to be targets for attack, but have the ability to react to a suitable foreign peptide. Selection in the thymus is the mechanism of the so-called central immunological tolerance.
There is also peripheral immunological tolerance. During the development of infection, a dendritic cell, like any cell of the innate immune system, is affected by images of pathogenicity. Only after this can it mature, begin to express additional molecules on its surface to activate the lymphocyte and effectively present antigens to T lymphocytes. If a T-lymphocyte encounters an immature dendritic cell, it is not activated, but self-destructs or is suppressed. This inactive state of the T cell is called anergy. In this way, the body prevents the pathogenic effect of autoreactive T-lymphocytes, which for one reason or another survived during selection in the thymus.
All of the above applies to αβ-T lymphocytes, however, there is another type of T cells - γδ-T lymphocytes(the name determines the composition of the protein molecules that form the TCR). They are relatively few in number and mainly inhabit the intestinal mucosa and other barrier tissues, playing a critical role in regulating the composition of microbes living there. In γδ T cells, the mechanism of antigen recognition is different from that of αβ T lymphocytes and is independent of the TCR.
B lymphocytes
B lymphocytes carry the B cell receptor on their surface. Upon contact with an antigen, these cells are activated and turn into a special cell subtype - plasma cells, which have the unique ability to secrete their B-cell receptor into the environment - these are the molecules we call antibodies. Thus, both the BCR and the antibody have an affinity for the antigen it recognizes, as if they “stick” to it. This allows antibodies to envelop (opsonize) cells and viral particles coated with antigen molecules, attracting macrophages and other immune cells to destroy the pathogen. Antibodies are also able to activate a special cascade of immunological reactions called complement system which leads to perforation cell membrane pathogen and its death.
For the effective meeting of adaptive immune cells with dendritic cells that carry foreign antigens in the MHC and therefore work as “connectors,” there are special immune organs in the body - lymph nodes. Their distribution throughout the body is heterogeneous and depends on how vulnerable a particular boundary is. Most of them are located near the digestive and respiratory tracts, because penetration of the pathogen with food or inhaled air is the most likely method of infection.
Video 4. Movement of T cells (indicated red) by lymph node. The cells that form the structural basis of the lymph node and the walls of blood vessels are labeled with green fluorescent protein. The video was filmed using intravital two-photon microscopy.
The development of an adaptive immune response requires quite a lot of time (from several days to two weeks), and in order for the body to defend itself against an already familiar infection faster, so-called T- and B-cells that participated in past battles are formed. memory cells. They, like veterans, are present in small quantities in the body, and if a pathogen familiar to them appears, they are reactivated, quickly divide, and an entire army comes out to defend the borders.
The logic of the immune response
When the body is attacked by pathogens, the first cells to enter the battle are innate immune cells - neutrophils, basophils and eosinophils. They release the contents of their granules, which can damage the cell wall of bacteria, and also, for example, increase blood flow so that as many cells as possible rush to the site of infection.
At the same time, the dendritic cell that has absorbed the pathogen rushes to the nearest lymph node, where it transmits information about it to the T- and B-lymphocytes located there. They are activated and travel to the location of the pathogen (Fig. 2). The battle heats up: Killer T cells, upon contact with an infected cell, kill it, Helper T cells help macrophages and B lymphocytes carry out their defense mechanisms. As a result, the pathogen dies, and the victorious cells go to rest. Most of them die, but some become memory cells that settle in the bone marrow and wait for the body to need their help again.
Figure 2. Diagram of the immune response. A pathogen that has entered the body is detected by a dendritic cell, which moves to the lymph node and there transmits information about the enemy to T and B cells. They are activated and enter the tissues, where they carry out their protective function: B lymphocytes produce antibodies, T killer cells, with the help of perforin and granzyme B, carry out contact killing of the pathogen, and T helper cells produce cytokines that help other cells of the immune system in the fight against it.
This is what the pattern of any immune response looks like, but it can vary significantly depending on what pathogen has entered the body. If we are dealing with extracellular bacteria, fungi or, say, worms, then the main armed forces in this case will be eosinophils, B cells that produce antibodies, and Th2 lymphocytes that help them in this. If intracellular bacteria have settled in the body, then macrophages, which can absorb the infected cell, and Th1 lymphocytes, which help them in this, are the first to rush to the rescue. Well, in the case of a viral infection, NK cells and T-killers enter the battle, destroying infected cells using the method of contact killing.
As we see, the variety of types of immune cells and their mechanisms of action is not accidental: for each type of pathogen the body has its own effective method struggle (Fig. 3).
Figure 3. Main types of pathogens and the cells involved in their destruction.
And now all the above-described immune vicissitudes are in a short video.
Video 5. The mechanism of the immune response.
Civil war is raging...
Unfortunately, no war is complete without civilian casualties. Long and intense defense can come at a cost to the body if aggressive, highly specialized troops get out of control. Damage to the body's own organs and tissues by the immune system is called autoimmune process. About 5% of humanity suffers from diseases of this type.
The selection of T lymphocytes in the thymus, as well as the removal of autoreactive cells in the periphery (central and peripheral immunological tolerance), which we discussed earlier, cannot completely rid the body of autoreactive T lymphocytes. As for B lymphocytes, the question of how strictly their selection is carried out still remains open. Therefore, in the body of every person there are necessarily many autoreactive lymphocytes, which, in the event of an autoimmune reaction, can damage their own organs and tissues in accordance with their specificity.
Both T and B cells may be responsible for autoimmune lesions in the body. The former directly kill innocent cells carrying the corresponding antigen, and also help autoreactive B cells in the production of antibodies. T-cell autoimmunity has been well studied in rheumatoid arthritis, diabetes mellitus type 1, multiple sclerosis and many other diseases.
B lymphocytes are much more sophisticated. First, autoantibodies can cause cell death by activating the complement system on their surface or attracting macrophages. Secondly, receptors on the cell surface can become targets for antibodies. When such an antibody binds to a receptor, it can either be blocked or activated without an actual hormonal signal. This happens in Graves' disease: B lymphocytes produce antibodies against the receptor for TSH (thyroid-stimulating hormone), mimicking the effect of the hormone and, accordingly, increasing the production of thyroid hormones. In myasthenia gravis, antibodies against the acetylcholine receptor block its action, which leads to impaired neuromuscular conduction. Thirdly, autoantibodies, together with soluble antigens, can form immune complexes that settle in various organs and tissues (for example, in the renal glomeruli, joints, on the vascular endothelium), disrupting their function and causing inflammatory processes.
Typically, an autoimmune disease occurs suddenly, and it is impossible to determine exactly what caused it. It is believed that almost any stressful situation can serve as a trigger, be it an infection, injury or hypothermia. A significant contribution to the likelihood of an autoimmune disease is made by both a person’s lifestyle and genetic predisposition - the presence of a certain variant of a gene.
Predisposition to a particular autoimmune disease is often associated with certain alleles of MHC genes, which we have already talked about a lot. So, the presence of an allele HLA-B27 may serve as a marker of predisposition to the development of ankylosing spondylitis, juvenile rheumatoid arthritis, psoriatic arthritis and other diseases. Interestingly, the presence in the genome of the same HLA-B27 correlates with effective protection from viruses: for example, carriers of this allele have a reduced chance of becoming infected with HIV or hepatitis C,. This is another reminder that the more aggressively an army fights, the more likely civilian casualties are.
In addition, the development of the disease may be influenced by the level of autoantigen expression in the thymus. For example, insulin production and thus the frequency of presentation of its antigens to T cells varies from person to person. The higher it is, the lower the risk of developing type 1 diabetes, as it removes insulin-specific T lymphocytes.
All autoimmune diseases can be divided into organ-specific And systemic. In organ-specific diseases, individual organs or tissues are affected. For example, in multiple sclerosis - the myelin sheath of neurons, in rheumatoid arthritis - joints, and in type 1 diabetes - the islets of Langerhans in the pancreas. Systemic autoimmune diseases are characterized by damage to many organs and tissues. Such diseases include, for example, systemic lupus erythematosus and primary Sjogren's syndrome, which affect connective tissue. These diseases will be discussed in more detail in other articles of the special project.
Conclusion
As we have already seen, immunity is a complex network of interactions at both the cellular and molecular levels. Even nature was unable to create an ideal system that reliably protects the body from attacks by pathogens and at the same time does not damage its own organs under any circumstances. Autoimmune diseases - by-effect the high specificity of the adaptive immune system, the costs we have to pay for the opportunity to successfully exist in a world teeming with bacteria, viruses and other pathogens.
Medicine - the creation of human hands - cannot fully correct what was created by nature, therefore, to date, none of the autoimmune diseases can be completely cured. Therefore, the goals that modern medicine strives to achieve are timely diagnosis of the disease and effective relief of its symptoms, on which the quality of life of patients directly depends. However, for this to be possible, it is necessary to increase public awareness about autoimmune diseases and their treatments. "Forewarned is forearmed!"- that's the motto public organizations created for this purpose all over the world.
Literature
- Mark D. Turner, Belinda Nedjai, Tara Hurst, Daniel J. Pennington. (2014). Cytokines and chemokines: At the crossroads of cell signaling and inflammatory disease. Biochimica et Biophysica Acta (BBA) - Molecular Cell Research. 1843. Focus on 50 years of B cells. (2015). Nat. Rev. Immun. 15 ;
Reservoir dogs: immunity against the owner January 20th, 2017
Immunity can be dangerous to health, turn young man disabled, deprived of offspring, or even killed. Today I will talk about how the immune system learns to distinguish its own from someone else's and why it, like a mad dog, sometimes rushes at the owner - its own body, causing multiple sclerosis, rheumatoid arthritis, psoriasis and other incurable autoimmune diseases.
Ask yourself: how does the immune system distinguish its cells and tissues from foreign infections? In computer antiviruses, this issue is resolved by daily downloading updated databases with codes of all known viruses. But the immune system does not have Internet access to WHO databases, and our genome does not fit information about all possible infections. In addition, viruses and bacteria quickly mutate and literally during the course of the disease are able to escape from the control of attacking antibodies.
Nature solved this problem in a fundamentally different way than the developers of antivirus programs. Imagine that the master made a billion different keys - each one is at least slightly different from the other. With such a link, you can open almost any lock in the world.
Nature did exactly that. Even in utero, the immune system created billions of lymphocytes, each of which was equipped with a unique receptor. Imagine billions of lymphocytes and each has its own unique receptor - a kind of “key” that fits only in one “lock” intended for it. The lock in this analogy will be almost any protein molecule that nature can come up with when creating viruses, bacteria or humans.
However, such billions of unique receptors cannot be encoded even in an infinitely large genome. Nature, as always, saved money and acted more simply. Our key maker first made a billion copy keys using one template, and then randomly applied slots and holes, making each key unique. By this analogy, the receptor genes are identical in all lymphocytes (as is the entire genome in every cell of the body). But during the maturation of a lymphocyte, individual sections of its receptor genes are cut by enzymes - some parts are thrown away, others change places and are stitched together again, forming a unique code. Then, RNA is synthesized from the already unique gene, which serves as a matrix for the synthesis of a unique receptor in each lymphocyte. The scheme only seems complicated, but in reality everything is stupid and simple:
Thus, even before birth, we have a huge bunch of billions of keys - each of which is different from all the others. Immunologists call this the "immunoglobulin repertoire." You've probably heard about immunoglobulins freely floating in the blood (antibodies) - these are analogues of their receptors secreted by lymphocytes with the same specificity as the receptors for the same antigen. But the antibodies themselves will enter the battlefield only after birth - they are not needed in a sterile womb. In the meantime, we will continue to talk about their analogues - immunoglobulin-like receptors built into the membranes of lymphocytes.
The immune system at this stage is still completely blind. He has not yet encountered infections, but the body’s own tissues contain a huge variety of “lock” proteins, to which lymphocytes continually try to find their individual “key” receptors. And since their repertoire is very diverse, many lymphocytes (as many different proteins in the body) manage to contact proteins of their own body, which immunologists call autoantigens (auto - one's own). However, without humoral support (as happens in an adult body), lymphocytes that bind to autoantigens are not activated, but die immediately. 
Thus, the repertoire is reduced - all lymphocytes capable of recognizing something with their receptor die. And this “something” in the sterile conditions of intrauterine life can only be autoantigens. For example, if hepatitis virus antigens are introduced into an embryo, all the lymphocytes that bind it will die, and after birth such a person will not develop an immune response against this infection or to the vaccine. Immunologists call this process “negative selection”, thanks to which you were born without lymphocytes capable of attacking proteins in your own body. If we continue the analogy with keys, then those keys that fit into their locks, when turned, break off forever, eliminating the possibility of opening the door.
However, why do autoimmune diseases become possible? One of the reasons for the immune system to attack the host is that some proteins of the body are first synthesized after birth, when the negative selection of lymphocytes is already completed. Thus, in our body there are lymphocytes capable of binding self-antigens and damaging cells and tissues, causing serious illnesses.
For example, the protein myelin, which accelerates signal transmission in the nervous system, is formed in the central nervous system after birth, so lymphocytes specific to it safely survive negative selection. In adulthood, as a result of a violation of the blood-brain barrier, these lymphocytes and their antibodies penetrate the central nervous system and damage the myelin sheaths of the fibers - multiple sclerosis develops. 
Fine motor skills require stable feedback that continuously transmits information about the position of the limbs and tongue muscles in space. Feedback ensures correction of all nuances of movements. The slower the feedback, the less often movement correction occurs - fingers tremble and make mistakes, and speech is distorted. These are some of the symptoms of multiple sclerosis.
Another example of such proteins is the receptor on the surface of the sperm that allows it to penetrate the egg. This receptor appears with the onset of puberty. When the blood-testis barrier is disrupted, sperm-specific lymphocytes and their antibodies mistake them for microbes. Sperm bound by antibodies stick together with their heads and lose the ability to fertilize. 
There are also examples of the pathogenesis of autoimmune diseases when the holy of holies DNA becomes the target for lymphocytes. Yes, DNA is present in the body from the very conception, but the embryo’s immune system does not have access to the contents of the cell nucleus, so lymphocytes capable of binding DNA successfully survive negative selection. An example of such a disease is psoriasis, in which DNA from destroyed skin cells becomes available for recognition by lymphocytes. Here it is necessary to clarify that lymphocytes do not bind antigens directly, but through intermediaries - phagocytes, which first absorb the antigen, then intracellularly bind it with an HLA molecule and bring this complex to its surface. Only in combination with HLA antigen (in this case, autoantigen - DNA) can be recognized by a lymphocyte. 
However, why does this process not start with ordinary injuries, when DNA is released from destroyed cells, but is possible with psoriasis? This may be due to the genetic makeup of people with psoriasis. More than half of them are carriers of a gene variant that encodes the structure of the HLA molecule, which precisely “transfers” antigens to lymphocytes for binding. At the same time, this gene variant is practically not found in people without psoriasis. According to the hypothesis, HLA molecules in healthy people are not able to bind DNA and transfer them to lymphocytes for recognition, but the variant of the HLA molecule in patients with psoriasis copes with this “excellently.”
Another example of the pathogenesis of an autoimmune disease is observed in rheumatoid arthritis, in which immunity is stimulated by proteins of the connective tissues of the joints, which, like DNA, are present in the earliest stages of embryogenesis. Moreover, lymphocytes specific to them die safely due to negative selection. However, these proteins become slightly denatured during inflammation, and this “slightly” is enough for recognition of the altered protein by other lymphocytes, which have a “slightly” different receptor, unlike their colleagues who died in the womb. In rheumatoid arthritis, the proteins of the connective tissue of the joint convert the amino acid arginine into the amino acid citrulline, which is not one of the 20 amino acids in the body. 
An even more cunning type of pathogenesis is when a virus or bacterium has proteins similar to those of the body. This is called antigenic mimicry, which allows the microorganism to reduce attention from the immune system. For example, streptococcus has a protein on its surface similar to the protein of cardiac muscle cells. However, slight differences in the structure of the bacterial protein from those in the body protein are sometimes enough to activate lymphocytes against it. Activated lymphocytes under conditions of inflammation can nonspecifically bind other similar proteins of their own body - in this case, the protein of heart cells. This example pathogenesis can be compared with those rare cases when you can open your door with someone else’s key, but very similar to your own.
Thus, there are three reasons for the immune system to attack its own body, but in all cases the problem is not the rabid dog, but most often the owner:
1) separation in time of negative selection and the moment of the beginning of protein biosynthesis;
2) mutations of HLA genes, which tease the immune system with molecules unfamiliar to it;
3) denaturation of protein molecules, after which they become “foreign” to the immune system;
4) mimicry of viruses and bacteria.
For these reasons, immunologists call the central nervous system, testicles, joints, eyes and a number of other organs immunoprivileged - immune processes in them are suppressed by the body different ways. For example, one of the mechanisms of tolerance of the immune system to these organs is their constant hypothermia, which reduces the binding strength of antibodies and lymphocyte receptors to their own proteins. I previously described in detail how cooling and . Be sure to read it if you are afraid of multiple sclerosis and infertility.
I have deliberately omitted many details in favor of a better understanding of such a complex topic. If something requires clarification, ask and I will clarify the text! It is important for me that the material is understandable to any reader, since I am already preparing the next series of “Reservoir Dogs”, in which I will talk about the further development and behavior of the immune system in allergies, asthma and infectious diseases. In order not to miss out, Subscribe to the most read blog about medicine! If you don't have a LiveJournal account, subscribe to updates on
The immune system protects us 24 hours a day, however, with certain violations it begins to attack its own body.
How the immune system works
You don’t notice it, but inside you there is a constant struggle with alien conquerors. Millions of bacteria, viruses and so they strive to settle on everything that is ready, and conduct their hectic life activity at your own expense. That's why defense mechanisms The body must constantly be on alert, and in case of danger, react immediately. The immune system is a kind of ministry of defense that mercilessly destroys microscopic “occupiers” and “illegal migrants.” Whatever you do, whatever you do, a large army of immune cells is ready to fight the enemy. Moreover, for each specific type of foreign pathogen (antigen), specific “hired killers” (antibodies) are produced. Even during sleep, every cell of the human body is reliably protected.
The question arises: How does the immune system destroy “everything foreign”, while its own tissues and organs remain unharmed? The thing is that on the surface of every cell in the body there are special proteins - something like an identity card. The immune system is able to recognize these proteins as its own. Thus, a healthy cell, having presented its “crust” to the immune system, calmly goes about its business, without fear of violent action. This phenomenon is known as "immunological tolerance."
As soon as immune cells meet strangers without “documents,” an operation to neutralize the enemy immediately begins.
Immunologist
The process of formation of autoantibodies occurs constantly, but there is a system of resistance (tolerance) to these antibodies. When tolerance breaks down, the disease begins. This can affect the skin, blood vessels, joints and all internal organs individually or in combinations. The insidiousness of these ailments is that they often cannot be distinguished from infectious or somatic diseases, and the presence of an autoimmune disease can only be confirmed in a laboratory.
When the reaction is excessive
Today, everyone is mostly puzzled by how to strengthen the immune system. Every now and then, at every opportunity, we try with all our might to improve our health by taking foods of plant or synthetic origin. Unfortunately, except immunodeficiency problems, there is also a danger of skewing in the other direction. Certain malfunctions in the body lead to the fact that the immune system, our Ministry of Defense, begins to fight its own body, not distinguishing “us” from “strangers”. And thus the faithful defender becomes a terrible monster, devouring everything in its path. The so-called occurs, which leads to serious illnesses. Rheumatoid arthritis, systemic lupus, (thyroid damage), glomerulonephritis (kidney damage), multiple sclerosis- this is not the entire list of these diseases.
For a long time it was not possible to understand the cause of these diseases. Local or general anti-inflammatory drugs were used as treatment options, which naturally turned out to be ineffective.
And only half a century ago, medicine slowly began to come to the solution to autoimmune diseases. Although this category of diseases is still fraught with many mysterious and incomprehensible things. For example, relatively recently it became clear that the presence in the body of auto-aggressive antibodies (damaging the cells of one’s own body) is not a pathology at all!
A natural question arises: why did nature create a system in our body that is directed against us? It turns out that autoantibodies perform a very important function in cleansing the body of obsolete cells. After all, throughout our lives we are literally reborn several times, new cells take the place of old cells, etc.
The causes of these diseases can be both genetic and factors environment. However, we often have to talk about their combination, because heredity may not be realized. Among the causes of disruption of the autoimmune process, it is worth highlighting the following:
- nutrition;
- human psychology;
- chronic infections;
- stress;
- medications;
- irradiation.
However, it is worth keeping in mind that each patient will have his own set of the above factors.
Difficulties of treatment
Search effective treatment Autoimmune diseases are being investigated in several directions. IN Lately Scientists are even thinking about using gene therapy, thanks to which it will be possible to replace the defective gene. However, this treatment method will not come into practice any time soon; moreover, mutations in the genome are not always the cause of a particular disease.
Today, treatment protocols mainly include drugs that suppress the immune system or alter the immune response. Depending on the specific case, hormones, immunosuppressants, and drugs based on monoclonal antibodies may be used. In our country, plasmapheresis is also used (blood sampling followed by plasma separation).
Prevention of decreased immunity
The real problem in the treatment of autoimmune diseases is that often the known methods do not act on the cause of the disease, but on the entire body as a whole. In addition to suppressing the activity of autoimmune processes, medications significantly reduce the normal protective functions of the body. Of course, this situation cannot suit anyone, so active development work is underway effective means treatment. And one of the encouraging methods was T cell vaccination. The essence of the method is that a vaccine is prepared from aggressive immune cells, and when it is introduced into the body, the immune system, willy-nilly, begins to fight the aggressor. Currently, T-cell vaccination is used in the treatment of multiple sclerosis and rheumatoid arthritis.
The immune system is the real defense of our body; it protects the human body from attacks by viruses, fungi, bacteria and other pathogenic organisms and substances. The immune system is capable of destroying body cells if they have degenerated into a malignant tumor. But sometimes the immune system cannot cope with a malignant tumor, for example, it may be a genetic reason, and the tumor begins to grow. A large tumor can affect the immune system in such a way that it stops responding to a malignant tumor. In this case, the tumor can affect the “protective” cells, and they begin to destroy the host body. If doctors can understand how tumors suppress the immune system, this will be a breakthrough in the treatment of cancer.
Immunity and tumor
For a long time, doctors believed that the immune system reacts poorly to cancer cells. Because the latter are very similar to normal cells. The immune system best resists malignant tumors that are of viral origin; the incidence of viral tumors increases in people with immunodeficiency. After some time, it became clear to doctors that not only the “similarity” of cells is the reason for the poor fight of the immune system against cancerous tumors.
It turned out that malignant tumors not only suppress the immune cells next to them, but also reprogram them, the immune cells begin to “serve” the cancer. The degeneration of an immune cell has several stages: at first it actively fights cancer, but then, dividing, it becomes part of the tumor. Scientists call this process “immunoediting.”
The first stage of immunoediting is the elimination process. External carcinogenic factors or mutations affect a normal cell, and it begins to “transform.” The cell gains the ability to divide unlimitedly, but it stops responding to regulatory signals that come from the body. The cell begins to synthesize “tumor antigens” on its surface and then sends “danger signals.”
Macrophages and T cells respond to these signals. The body’s “messengers” effectively destroy transformed cells, and tumor development is interrupted. But it happens that “precancerous” cells trigger an immune response. The transformed cell is weak and synthesizes fewer tumor antigens. Such cells are poorly recognized by the immune system; “traitor” cells survive the first immune response and then continue to divide.
The second stage of interaction between the body and the tumor begins. Which is called the “equilibrium stage”. The immune system can no longer completely destroy the tumor, but limits its growth. In this state, tumors “live” in the body for years; they are not detected during routine diagnostics.
Microtumors are not static; the properties of the cells they consist of gradually change as a result of the effects of mutations. Next comes selection; those cells that can most strongly resist the effects of the immune system remain to exist. Immunopresor cells appear. These cells passively avoid destruction and suppress the immune response. As a result, this evolutionary process leads to the fact that the body begins to die from cancer.
The third stage begins, which is called the “avoidance stage.” The tumor becomes practically insensitive to the effects of the immune system; the tumor begins to turn the activity of immune cells to its benefit. The tumor metastasizes and grows, there comes a time when doctors can diagnose the tumor. The previous stages proceed unnoticed; ideas about them are only an interpretation of several indirect data.
The significance of the dual behavior of the immune response in carcinogenesis
Today you can find many scientific articles that describe the fight of the immune system against malignant tumors. Almost the same amount of scientific material describes Negative influence the presence of immune cells in the tumor, which provoke its growth and the appearance of metastases. The concept of immunoediting explained the change in behavior of cells of the immune system.
Cells of the immune system are very plastic, so they can reorient themselves to the side of the tumor. The immune response, in our understanding, is the body’s fight, but in addition to the fight, the body must also spend energy on eliminating the damage that remains after the destruction of harmful cells. Cancer affects the body in such a way that white blood cells begin to perceive cancer cells as if they need help and begin to treat them.
Take for example macrophages, which are called “war cells” or “healing cells.” The tumor “deceives” macrophages in much the same way as leukocytes. Macrophages were discovered by Metchnikoff; these cells are capable of absorbing harmful substances. This phenomenon is called "phagocytosis", which became the basis of all immunology. Macrophages detect the “enemy” and rush towards it; in addition, they attract other cells with them that are responsible for protecting the body. After destroying the “intervenors,” macrophages help other cells clear the “battlefield”; they produce substances that promote rapid healing of damage. It is this ability of macrophages that cancer cells use for their own benefit.
There are two groups of macrophages, each group has its own predominant activity. M1 macrophages are “classically activated”, they are responsible for the destruction of foreign objects, including cancer cells. M1 macrophages can also attract other blood cells, such as killer T cells, to destruction. M2 macrophages are “healers”; they are responsible for tissue regeneration (recovery).
If the tumor contains big number M1-macrophages, then this makes it grow poorly, and as a result, complete remission may occur. M2 macrophages, on the contrary, secrete growth factors that promote the division of cancer cells. Experiments have shown that there are always many M2 cells around the tumor. Under the influence of M2 macrophages, M1 macrophages are reprogrammed and turn into the former. The “killers” can no longer cause damage or synthesize antitumor cytokines, but begin to release substances that promote tumor growth.
Proteins of the NF-kB family are the leading “programmers”; they control many genes that are so necessary for the activation of M1 macrophages. Important members of the family are p50 and p65, which form a p65/p50 heterodimer that influences gene activation in M1 macrophages. The p65/p50 heterodimer activates TNF in M1 macrophages, which responds to the acute inflammatory process, chemokines, interleukins, and cytokines. Excitation of these genes in M1 attracts to the focus a large number of immune cells. The NF-kB family homodimer or p50/p50 binds to promoters and blocks excitation. The degree of inflammation decreases. It is very important that there is a balance between heterodimer and homodimer in the body. Scientists have proven that the tumor disrupts the synthesis of p65 in M1 and promotes the accumulation of the p50/p50 complex.
Reactivation of the immune response
It turns out that there are cells around the tumor that destroy it, etc. who restore it. The future of cancer will depend on where the proportion shifts.
Experiments in modern medicine have shown that the process of “reprogramming” is reversible. Today, the most promising direction in onco-immunology is considered to be the development of an idea that can reactivate M1 macrophages.
Some types of tumors, such as melanoma, are perfectly treated with reactivation. The lactate molecule appears in tumors when there is a lack of oxygen due to rapid growth. Lactate enters the membrane channels of M1 macrophages. After this, the macrophage changes; oncological therapy will consist of blocking the M1 channels.
If scientists learn to control the immune response the way tumors control it, then the time will come when a person will be able to defeat cancer.
Scientists hope to find the causes of autoimmune diseases at the molecular genetic level.
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The immune system is designed to protect the body. But in some situations, its functioning is disrupted, and immune defense factors become aggressors in relation to the body’s own tissues. Treatment of such autoimmune diseases is very difficult: the main goal of therapy is the balance between reducing the activity of the immune system against its own body and preserving immunity.
One such disease is systemic lupus erythematosus. This is a severe systemic connective tissue disease that affects various internal organs. The disease has been known since ancient times, and received its name because of the characteristic rash on the bridge of the nose and cheeks, reminiscent of wolf bites. 90% of patients are women aged 20–40 years. In Russia, the number of patients with systemic lupus erythematosus increases annually and is already approaching 80 thousand, and in 40 thousand the disease steadily progresses and leads to early disability and death.
The cause of lupus is unknown. In developed countries, on average 3.5 years after diagnosis, 40% of patients are forced to stop working. Patients experience damage to the skin, joints, muscles, mucous membranes, heart, lungs, nervous system, more than half have kidney damage. Periods of exacerbation are followed by remission, but an active, constantly progressive course also occurs.
A conference held at the Research Institute of Rheumatology of the Russian Academy of Medical Sciences in Moscow was devoted to the problems of systemic lupus erythematosus.
The molecular genetic basis of the disease is poorly understood, so until recently there was no specific treatment. Academician of the Russian Academy of Medical Sciences Evgeniy Nasonov, director of the Research Institute of Rheumatology of the Russian Academy of Medical Sciences, emphasized that the entire arsenal of drugs used in rheumatology is used to treat systemic lupus erythematosus medicines, including non-steroidal anti-inflammatory drugs, hormones, anti-cell division agents, anti-malarial drugs and even extracorporeal blood purification methods. Most of them are used for systemic lupus erythematosus for off-label indications.
Understanding of the need to improve the pharmacotherapy of systemic lupus erythematosus has become an incentive to conduct large-scale clinical studies of various drugs. And first of all – genetically engineered biological drugs.
Immunological control over pathogenetic mechanisms became possible with the discovery of a molecular pathway that, by acting on it, can to some extent inhibit the development of systemic lupus erythematosus. This pathway involves a protein called B-lymphocyte stimulator (BLyS), from the tumor necrosis factor family. It has been found that suppressing BLyS can somewhat contain the runaway immune system.
The researchers, wanting to specifically block BLyS, relied on a human monoclonal antibody called belimumab. Against the background of its use, a decrease in the overall frequency of exacerbations and severe exacerbations of the disease was observed.
Academician Evgeniy Nasonov noted that in clinical trial Russian rheumatology centers in Moscow, St. Petersburg and Yaroslavl took part in the study of the monoclonal antibody belimumab. Its development is inextricably linked with progress basic research in the field of immunopathology of human diseases and is a striking example of the practical implementation of the concept of translational medicine. We can say that a new era is opening in the treatment of systemic lupus erythematosus, associated with the beginning of the widespread use of genetically engineered biological agents and the creation of a new class of drugs - BLyS inhibitors, which may have important therapeutic potential not only for systemic lupus erythematosus, but also for a wide range of human autoimmune diseases.
