Immunity: fighting with strangers and... your own

Apollinaria Bogolyubova, "Biomolecule"

With this article, we begin a cycle 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". Separate publications will be devoted to some of the most common diseases. In order to maintain objectivity, we invited Dmitry Vladimirovich Kuprash, Doctor of Biological Sciences, Corresponding Member of the Russian Academy of Sciences, Professor of the Department of Immunology of Moscow State University, to become the curator of the special project. In addition, each article has its own reviewer, who delves into all the nuances in more detail. The reviewer of this introductory article was Evgeny Sergeevich Shilov, Candidate of Biological Sciences, researcher at the same department

About 5% of the world's population suffer from autoimmune diseases – a condition in which the body's own immune system cells, instead of fighting pathogens, destroy normal cells of organs and tissues. In this article, which is a preview of a special project on autoimmune diseases, we will look at the basic principles of the immune system and show why such a diversion is possible on its part.

Immunity is a system of reactions designed to protect the body from the invasion of bacteria, viruses, fungi, protozoa and other harmful agents – the so–called pathogens. If we imagine that our body is a country, then the immune system can be compared with its armed forces. The more coherent and adequate their response to the intervention of pathogens is, the more reliable the protection of the body will be.

There are a great many pathogens in the world, and in order to effectively fight all of them, as a result of long evolution, an intricate system of immune cells has been formed, each of which has its own fighting strategy. The cells of the immune system complement each other: they use different ways to destroy the pathogen, can strengthen or weaken the action of other cells, as well as attract more and more fighters to the battlefield if they themselves can not cope.

Attacking the body, pathogens leave molecular "clues" that "pick up" immune cells. Such evidence is called antigens.

Antigens are any substances that the body perceives as foreign and, accordingly, responds to their appearance by activating immunity. The most important antigens for the immune system are pieces of molecules located on the outer surface of the pathogen. Using these pieces, it is possible to determine which aggressor attacked the body, and to ensure the fight against it.

Cytokines – the Morse code of the body

In order for immune cells to coordinate their actions in the fight against the enemy, they need a system of signals telling who and when to join 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.) [1]. It is difficult to attribute an unambiguous function to many cytokines, but with some degree of conditionality they can be divided into five groups: chemokines, growth factors, pro-inflammatory, anti-inflammatory and immunoregulatory cytokines.

Chemokines give the cell a signal that tells it where to move. It can be an infected place where it is necessary to pull all the combat units of our army, or a certain organ of the immune system, where the cell will continue to be trained in military literacy.
Growth factors help the cell to decide which "military specialty" to choose for itself. By the names of these molecules, as a rule, it is easy to understand for the development of which cells they are responsible. Thus, granulocyte-macrophage colony stimulating factor (GM-CSF, GM-CSF) promotes the appearance of granulocytes and macrophages, and vascular endothelial growth factor (VEGF), as the name implies, is responsible for the formation of new vessels of the circulatory system. (You can read about how a cell chooses its fate in the article "Who to be? How the hematopoietic stem cell chooses a profession" [2]).
Pro-inflammatory, anti-inflammatory and immunoregulatory cytokines are said to "modulate" the immune response. It is these molecules that cells use to "talk" with each other, because any joint business should be strictly regulated so that key players do not get confused about what to do and do not interfere with each other, but effectively perform their functions. Pro-inflammatory cytokines, as the name suggests, contribute to the maintenance of inflammation, which is necessary for an effective immune response in the fight against pathogens, while anti-inflammatory cytokines help the body stop the war and bring the battlefield to a peaceful state. The signals of immunoregulatory cytokines can be decoded by cells in different ways, depending on what kind of cells they are and what other signals they will receive by this time.

The above–mentioned classification convention means that a cytokine belonging to one of the listed groups, under certain conditions in the body, can play a diametrically opposite role - for example, from pro-inflammatory to anti-inflammatory.

Without an established connection between the types of troops, any ingenious military operation is doomed to failure, so it is very important for the cells of the immune system, taking 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 rows, which can lead to damage to one's own body. This is called a cytokine storm: in response to incoming cytokine signals, the 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 off in order! Immune cells

As there are different kinds of troops in the armed forces, so 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 [3, 4, 5]. Innate immunity is that part of the immune system that is ready to protect the body immediately as soon as a pathogen attack has occurred. The acquired (or adaptive) immune response at the first contact with the enemy takes longer to unfold, since it requires ingenious 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 individual saboteurs: it neutralizes them without disturbing specialized elite military units – adaptive immunity. If the threat turned out to be more significant and there is a risk of the pathogen penetrating deeper into the body, the cells of the innate immunity immediately signal this, and the cells of the acquired immunity enter into battle.

All immune cells of the body are formed in the bone marrow from a hematopoietic stem cell, which gives rise to two cells – common myeloid and common lymphoid precursors [2, 6]. Cells of acquired immunity originate from a common lymphoid precursor and, accordingly, are called lymphocytes, whereas cells of innate immunity can originate from both precursors. The scheme of differentiation of cells of the immune system is shown in Figure 1.

The scheme of differentiation of cells of the immune system

Figure 1. The scheme of differentiation of cells of the immune system. The hematopoietic stem cell gives rise to progenitor cells of myeloid and lymphoid differentiation lines, from which all types of blood cells are further formed. Drawing from the website opentextbc.ca , adapted.

Innate Immunity – Regular Army

Innate immune cells recognize a pathogen by its specific molecular markers – the so-called pathogenicity images [7]. These markers do not allow us to accurately determine whether the pathogen belongs to a particular species, but only signal that the immune system has encountered strangers. Fragments of the cell wall and flagella of bacteria, double-stranded RNA and single-stranded DNA of viruses, etc. can serve as such markers for our body. With the help of special innate immunity receptors, such as TLR (Toll-like receptors, Toll-like receptors) and NLR (Nod-like receptors, Nod-like receptors), cells interact with pathogenicity images and begin to implement their protective strategy.

Now let's take a closer look at some cells of innate immunity.

Macrophages and dendritic cells absorb (phagocytize) the pathogen, and already inside themselves, with the help of the contents of vacuoles, dissolve it. This method of destroying the enemy is very convenient: the cell that carried it out can not only continue to function actively, but also gets the opportunity to preserve fragments of the pathogen – antigens, which, if necessary, will serve as an activation signal for adaptive immunity cells. Dendritic cells cope best with this – they are the ones who work as communicators between the two branches of the immune system, which is necessary for the successful suppression of infection.

Neutrophils – the most numerous immune cells in the human blood – travel through the body for most of their lives. When they encounter a pathogen, they absorb and digest it, but after a "hearty lunch" they usually die. Neutrophils are kamikaze cells, and death is the main mechanism of their action. At the moment of neutrophil death, the contents of the granules contained in them are released – substances with an antibiotic effect – and in addition, a network of the cell's own DNA (NETs, neutrophil extracellular traces) is scattered, into which nearby bacteria fall – now they become even more noticeable to macrophages.

Video 1. Neutrophils (indicated in green) come to the site of tissue damage. The video was shot using lifetime two-photon microscopy.

Eosinophils, basophils and mast cells secrete the contents of their granules into the surrounding tissue – chemical protection against large pathogens, for example, parasitic worms. However, as it often happens, civilians can also be poisoned by chemicals, and these cells are widely known not so much for their direct physiological role as for their involvement in the development of an allergic reaction.

In addition to the above–mentioned myeloid cells, lymphoid cells also work in innate immunity, which are called lymphoid cells of innate immunity. They produce cytokines and, accordingly, regulate the behavior of other cells in the body.

One of the types of these cells is the so–called natural killers (or NK cells). They are infantry in the armed forces of the body: they fight infected cells one–on-one, engaging them in hand-to-hand combat. NK cells secrete proteins perforin and granzyme B. The first, as the name implies, perforates the cell membrane of the target, embedding into it, and the second, like buckshot, penetrates through these gaps and triggers cell death, splitting the proteins that form it.

Surprisingly, at different stages of their development, some cells of the immune system can perform functions that are opposite to each other. Thus, a heterogeneous group of precursors of various immune cells of innate immunity is isolated, which in such an immature form suppress the immune response. That's what they were called: myeloid suppressor cells. Their number increases in the body in response to the appearance of a chronic infection or cancer. The role of such cells is very important, because they do not allow other soldiers of the army of immunity to fight the enemy too much, thereby damaging the civilian population – innocent cells located nearby.

Adaptive immunity – special forces of the armed forces of the body

Adaptive immunity cells – T- and B-lymphocytes – can be compared with special purpose units. The fact is that they are able to recognize many individual pathogen antigens due to specialized receptors on their surface. These receptors are called T-cell (TCR, T-cell receptor) and B-cell (BCR, B-cell receptor), respectively. Thanks to the ingenious process of TCR and BCR formation, each B- or T-lymphocyte carries its own unique receptor for a specific, unique antigen. (This is described in detail in the article "Analysis of individual repertoire of T-cell receptors" [8]).

In order to understand how the T-cell receptor works, we must first discuss another important family of proteins – the major histocompatibility complex (MHC, major histocompatibility complex) [9]. These proteins are the molecular "passwords" of the body, allowing the cells of the immune system to distinguish their compatriots from the enemy. In any cell, there is a constant process of protein degradation. A special molecular machine, the immunoproteasome, breaks down proteins into short peptides that can be embedded in the MHC and, like an apple on a plate, presented to the T-lymphocyte. With the help of TCR, he "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 "neighbors", that is, cells of the same species, but of a different individual. It is the coincidence of MHC molecules that is necessary for the engraftment of transplanted tissues and organs, hence such a tricky name: histos in Greek means "tissue". 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 in green). The video was shot using lifetime two-photon microscopy. T-lymphocytes

There are two types of molecules of the main histocompatibility complex: MHC-I and MHC-II. The first one 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 - T–killers (they are also called CD8+ T-lymphocytes) - interacts with the complex "MHC-I–peptide" 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 urgently necessary to neutralize the trespasser, 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.

The T-cell receptor of another subtype of T-lymphocytes – T-helper cells (Th cells, CD4+ T-lymphocytes) - interacts with the complex "MHC-II–peptide". This complex does not exist on all cells of the body, but mainly on immune cells, and 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, then the T-cell begins to produce chemokines and cytokines that help other cells effectively carry out their function – fighting the enemy. That's why these lymphocytes are called helpers - from the English helper (assistant). Among them, there are many subtypes that differ in the spectrum of cytokines produced and, consequently, their role in the immune process. For example, there are Th1 lymphocytes that are effective in fighting intracellular bacteria and protozoa, Th2 lymphocytes that help B cells work and are therefore important for resisting extracellular bacteria (which we will talk about soon), Th17 cells and many others.

Video 3. Movement of T-helpers (red) and T-killers (green) in the lymph node. The video was shot using lifetime 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 rushing into battle and preventing them from harming civilians. These cells produce cytokines that suppress the immune response, and thus weaken the immune response when the enemy is defeated.

The fact that the T-lymphocyte recognizes only foreign antigens, and not the molecules of its own body, is a consequence of a clever process called selection. It occurs in a specially created organ for this purpose – the thymus, where T cells complete their development. The essence of selection is as follows: the cells surrounding a young, or naive, lymphocyte show (present) he needs peptides of his 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 have come to the thymus) have an intermediate affinity for the antigen, therefore, they, as a rule, do not consider their own cells targets for attack, but have the ability to react to a suitable foreign peptide. Selection in the thymus is a mechanism of the so–called central immunological tolerance.

There is also peripheral immunological tolerance. With the development of infection, images of pathogenicity act on the dendritic cell, as well as on any cell of innate immunity. Only after that, it can mature, begin to express additional molecules on its surface to activate the lymphocyte and effectively present antigens to T-lymphocytes. If the T-lymphocyte meets with an immature dendritic cell, then it is not activated, but self-destructs or suppressed. This inactive state of the T cell is called anergy. In this way, the pathogenic effect of autoreactive T-lymphocytes, which for one reason or another survived during selection in the thymus, is prevented in the body. (You can read about the life cycle of T cells in the article "T-lymphocytes: travelers and stay-at-home people" [10]).

All of the above applies to αß-T-lymphocytes, however, there is another type of T-cells – γδ-T-lymphocytes (the name determines the composition of protein molecules forming TCR) [11]. They are relatively small in number and mainly inhabit the intestinal mucosa and other barrier tissues, playing a crucial role in regulating the composition of microbes living there. In γδ-T cells, the mechanism of antigen recognition differs from αß-T-lymphocytic and does not depend on TCR [12].

B-lymphocytes

B-lymphocytes carry a B-cell receptor on their surface [13]. Upon contact with the antigen, these cells are activated and transformed into a special cellular subtype – plasma cells with a 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 it "sticks" to it. This makes it possible for 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 the complement system, which leads to perforation of the pathogen's cell membrane and its death.

For an effective meeting of adaptive immunity cells with dendritic cells that carry foreign antigens in the MHC and therefore work as "connected", there are special immune organs in the body – lymph nodes. Their distribution throughout the body is heterogeneous and depends on how vulnerable a particular border is. Most of them are located near the digestive and respiratory tracts, because the penetration of the pathogen with food or inhaled air is the most likely way of infection.

Video 4. Movement of T cells (marked in red) through the lymph node. The cells forming the structural basis of the lymph node and the walls of the vessels are marked with a green fluorescent protein. The video was shot using lifetime two-photon microscopy. The development of an adaptive immune response requires a lot of time (from a few days to two weeks), and in order for the body to be able to defend itself from an already familiar infection faster, so-called memory cells are formed from T and B cells that participated in past battles.

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 go out to defend the borders with an army.

The logic of the immune response

When the body is attacked by pathogens, the cells of innate immunity – neutrophils, basophils and eosinophils - come into battle first of all. They secrete the contents of their granules outside, which can damage the cell wall of bacteria, as well as, for example, increase blood flow so that as many cells as possible rush to the source of infection.

At the same time, the dendritic cell, which 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 rages: T-killers kill it when they come into contact with an infected cell, T-helpers help macrophages and B-lymphocytes to implement their defense mechanisms. As a result, the pathogen dies, and the winning cells are sent to rest. Most of them die, but some become memory cells that settle in the bone marrow and wait for their help to be needed again by the body.

The scheme of the immune response

Figure 2. The scheme of the immune response. The pathogen that has penetrated into the body is detected by a dendritic cell that moves to the lymph node and there transmits information about the enemy to T and B cells. They activate and exit into the tissues, where they realize their protective function: B-lymphocytes produce antibodies, T-killers use perforin and granzyme B to carry out contact killing of the pathogen, and T-helpers produce cytokines that help other cells of the immune system in the fight against it. The scheme is compiled by the author of the article.

This is what the scheme of any immune response looks like, but it can noticeably change depending on which 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 an infected cell, and Th1 lymphocytes, which help them in this, first of all rush to the rescue. Well, in the case of a viral infection, NK cells and T-killers enter the battle, which destroy infected cells by contact killing.

As we can see, the variety of types of immune cells and the mechanisms of their action is not accidental: for each type of pathogen, the body has its own effective way of fighting (Fig. 3).

The main types of pathogens and the cells that destroy them

Figure 3. The main types of pathogens and the cells involved in their destruction. The scheme is compiled by the author of the article.

The civil war is rumbling...

Unfortunately, no war is complete without civilian casualties. Long and intensive defense can cost the body dearly if aggressive highly specialized troops get out of control. Damage to the body's own organs and tissues by the immune system is called an autoimmune process [3]. 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 is still open. Therefore, in the body of every person there is necessarily a lot of autoreactive lymphocytes, which, in the case 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 of the body. The former carry out the direct killing of 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, type I diabetes mellitus, multiple sclerosis and many other diseases.

B-lymphocytes are much more sophisticated. Firstly, autoantibodies can cause cell death by activating a complement system on their surface or by 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 a real hormonal signal. This happens in Graves' disease: B-lymphocytes produce antibodies against the TSH receptor (thyroid-stimulating hormone), mimicking the effect of the hormone and, accordingly, enhancing the production of thyroid hormones [14]. In myasthenia gravis, antibodies against the acetylcholine receptor block its action, which leads to a violation of 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, vascular endothelium), disrupting their work and causing inflammatory processes.

As a rule, 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 for starting, whether it is 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 one or another autoimmune disease is often associated with certain alleles of the MHC genes, which we have already talked about a lot. Thus, the presence of the HLA-B27 allele can serve as a marker of predisposition to the development of Bekhterev's disease, juvenile rheumatoid arthritis, psoriatic arthritis and other diseases. Interestingly, the presence of the same HLA-B27 in the genome correlates with effective protection against viruses: for example, carriers of this allele have a reduced chance of contracting HIV or hepatitis C [15, 16]. This is another reminder that the more aggressively the army fights, the more likely civilian casualties are.

In addition, the level of autoantigen expression in the thymus may affect the development of the disease. For example, the production of insulin and, accordingly, 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 I diabetes mellitus, as this allows you to remove 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, with multiple sclerosis – the myelin sheath of neurons, with rheumatoid arthritis – joints, and with type I diabetes mellitus – 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, affecting connective tissue. More details about these diseases will be described 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 could not create an ideal system that reliably protects the body from pathogen attacks and at the same time does not damage its own organs under any circumstances. Autoimmune diseases are a side effect of the high specificity of the adaptive immunity system, the costs that 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, so today none of the autoimmune diseases is 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, in order for this to be possible, it is necessary to raise public awareness about autoimmune diseases and how to treat them. "Forewarned means armed!" is the motto of public organizations created for this purpose around the world.

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Portal "Eternal youth" http://vechnayamolodost.ru  27.01.2017