Kazakh-Russian Medical University

SRS

On the topic: History of the development of immunology. Theory of immunity.

Made by: Sarsenova A.B.
Checked: Associate Professor M.G.Sabirova.
Department: Microbiology, immunology with epidemiology courses.
Faculty:Med.Prof.Case.
Group:202 A

Almaty 2011

Content

Introduction
1. The Birth of Immunology
2. Formation of macrophages and lymphocytes
3. Immune system cell development
4. Barriers against infections
4.1 Mechanisms of the body's immunological defense
5. Inflammation as a mechanism of nonspecific immunity
6. The role of T lymphocytes in the immune response
7. Phagocytosis
8. Humoral and cellular immunity
9. Characteristic features of specific immunity
10. Cellular mechanisms of immunity
11. Effector mechanisms of immunity
12. Immunodeficiency conditions (IDS)
13. How the body protects itself from viruses
14. How does the body protect itself from bacteria?
15. Apoptosis as a means of prevention
conclusions
Conclusion
Bibliography
Application

Jenner E.

Mechnikov I.I.
Introduction

Chapter I. Organs and cells of the immune system
1. The birth of immunology
The beginning of the development of immunology dates back to the end of the 18th century and is associated with the name of E. Jenner, who first used, based only on practical observations, a subsequently theoretically justified method of vaccination against smallpox.
The fact discovered by E. Jenner formed the basis for further experiments by L. Pasteur, which culminated in the formulation of the principle of prevention against infectious diseases - the principle of immunization with weakened or killed pathogens.
The development of immunology for a long time took place within the framework of microbiological science and concerned only the study of the body’s immunity to infectious agents. Along this path, great strides have been made in uncovering the etiology of a number of infectious diseases. A practical achievement was the development of methods for diagnosing, preventing and treating infectious diseases, mainly through the creation of various types of vaccines and serums. Numerous attempts to elucidate the mechanisms that determine the body's resistance against pathogens resulted in the creation of two theories of immunity - phagocytic, formulated in 1887 by I. I. Mechnikov, and humoral, put forward in 1901 by P. Ehrlich.
The beginning of the 20th century was the time of the emergence of another branch of immunological science - non-infectious immunology. Just as the starting point for the development of infectious immunology was the observations of E. Jenner, so for non-infectious immunology was the discovery by J. Bordet and N. Chistovich of the fact of the production of antibodies in the animal’s body in response to the introduction of not only microorganisms, but also foreign agents in general. Non-infectious immunology received its approval and development in the doctrine of cytotoxins - antibodies against certain body tissues, created by I. I. Mechnikov in 1900, and in the discovery of human erythrocyte antigens by K. Landsteiner in 1901.
The results of the work of P. Medawar (1946) expanded the scope and attracted close attention to non-infectious immunology, explaining that the process of rejection of foreign tissues by the body is also based on immunological mechanisms. And it was precisely the further expansion of research in the field of transplantation immunity that attracted the discovery in 1953 of the phenomenon of immunological tolerance - the body’s unresponsiveness to the introduced foreign tissue.
I. I. Mechnikov placed the phagocyte, or cell, at the head of his system. Supporters of “humoral” immunity E. Behring, R. Koch, P. Ehrlich (Nobel Prizes 1901, 1905 and 1908) vehemently opposed this interpretation. The Latin “humor” or “humor” means liquid, in this case it meant blood and lymph. All three believed that the body protects itself from microbes with the help of special substances floating in the humors. They were called “antitoxins” and “antibodies”.
It should be noted the foresight of the members of the Nobel Committee, who back in 1908 tried to reconcile two opposing theories of immunity by awarding I. I. Mechnikov and the German Paul Ehrlich. Then prizes for immunologists began to pour in like from a cornucopia (see Appendix).
Mechnikov's student, the Belgian J. Bordet, discovered a special substance in the blood. It turned out to be a protein that helps antibodies recognize antigen.
Antigens are substances that, when introduced into the body, stimulate the production of antibodies. In turn, antibodies are highly specific proteins. By binding to antigens (for example, bacterial toxins), they neutralize them, preventing them from destroying cells. Antibodies are synthesized in the body by lymphocytes or lymph cells. The Greeks called the clean and clear water of underground springs and springs limfoy. Lymph, unlike blood, is a clear yellowish liquid. Lymphocytes are found not only in lymph, but also in blood. However, the entry of the antigen into the blood is not yet sufficient for the synthesis of antibodies to begin. It is necessary that the antigen be absorbed and processed by a phagocyte, or macrophage. Thus, the Mechnikov macrophage is at the very beginning of the body’s immune response. The outline of this response might look like this:
Antigen - Macrophage - ? - Lymphocyte - Antibodies - Infectious agent
We can say that passions have been boiling around this simple scheme for a century now. Immunology has become a medical theory and an important biological problem. Molecular and cellular biology, genetics, evolution and many other disciplines are tied here. It is not surprising that immunologists have received the lion's share of biomedical Nobel Prizes.

2. Formation of macrophages and lymphocytes
Anatomically, the immune system appears to be disjointed. Its organs and cells are scattered throughout the body, although in fact they are all connected into a single system by blood and lymphatic vessels. The organs of the immune system are usually divided into central and peripheral. The central organs include Bone marrow And thymus, to peripheral organs - lymph nodes, spleen, lymphoid clusters(of different sizes), located along the intestines, lungs, etc. (Fig. 3).
Bone marrow contains stem (or germinal) cells - the ancestors of all hematopoietic cells ( erythrocytes, platelets, leukocytes, macrophages and lymphocytes). Macrophages and lymphocytes are the main cells of the immune system. Generally and briefly, they are usually called m u n n o c i t a m i . The first stages of development of immunocytes take place in the bone marrow. This is their cradle.
Macrophages, they are phagocytes, - eaters of foreign bodies and the most ancient cells of the immune system. After going through several stages of development (Fig. 4), they leave the bone marrow in the form monocytes(round cells) and circulate in the blood for a certain time. From the bloodstream they penetrate into all organs and tissues, where they change their round shape to a trimmed one. In this form, they become more mobile and capable of sticking to any potential “foreigners”.
Lymphocytes today are considered major figures in immunosurveillance. This is a system of cells with different functional purposes. Already in the bone marrow, lymphocyte precursors are divided into two large branches. One of them - in mammals - completes its development in the bone marrow, and in birds in a specialized lymphoid organ - the bursa (bursa), from the Latin word bursa. Hence these lymphocytes are called bursa-dependent, or B lymphocytes. Another large branch of precursors from the bone marrow moves to another central organ of the lymphoid system - the thymus. This branch of lymphocytes is called thymus-dependent, or T lymphocytes(a general diagram of the development of cells of the immune system is shown in Fig. 4).

3. Development of immune system cells
B lymphocytes, like monocytes, undergo maturation in the bone marrow, from where mature cells enter the bloodstream. B lymphocytes can also leave the bloodstream, settling in the spleen and lymph nodes, and turn into plasma cells.
The most important event in the development of B lymphocytes is the recombination and mutation of genes related to the synthesis of antibodies (proteins from the class of immunoglobulins directed against antigens). As a result of such gene recombination, each B lymphocyte becomes a carrier of an individual gene capable of synthesizing individual antibodies against one antigen. And since the B-population consists of many individual clones (the offspring of these antibody producers), collectively they are able to recognize and destroy the entire set of possible antigens. After the genes have been formed and antibody molecules appear on the cell surface in the form of receptors, B lymphocytes leave the bone marrow. They circulate in the bloodstream for a short time, and then penetrate into peripheral organs, as if in a hurry to fulfill their vital purpose, since the lifespan of these lymphocytes is short, only 7-10 days.
T-lymphocytes during development in the thymus are called thymocytes. The thymus is located in the chest cavity directly behind the sternum and consists of three sections. In them, thymocytes undergo three stages of development and training for immune competence (Fig. 5). In the outer layer (subcapsular zone) aliens from the bone marrow are contained as predecessors, undergo a kind of adaptation here and are still deprived of receptors for recognizing antigens. In the second section (cortical layer) they are under the influence of thymic (growth and differentiating) factors acquire necessary for the T cell population receptors for antigens. After moving to the third section of the thymus (medulla), thymocytes differentiate according to their functional characteristics and become mature T cells (Fig. 6).
Acquired receptors, depending on the biochemical structure of protein macromolecules, determine their functional status. Most of the T lymphocytes become effector cells called T-killers(from the English killer - killer). A smaller part does regulatory function: T helper cells(from the English helper - assistants) enhance immunological reactivity, and T-suppressors, on the contrary, weaken it. Unlike B-lymphocytes, T-lymphocytes (mainly T-helpers), with the help of their receptors, are able to recognize not just someone else’s, but a changed “self”, i.e. the foreign antigen must be presented (usually by macrophages) in combination with the body's own proteins. After completion of development in the thymus, some mature T-lymphocytes remain in the medulla, and most leave it and settle in the spleen and lymph nodes.
For a long time, it remained unclear why more than 90% of early T-cell precursors coming from the bone marrow die in the thymus. The famous Australian immunologist F. Burnet suggests that the death of those lymphocytes that are capable of autoimmune aggression occurs in the thymus. The main reason for such massive death is associated with the selection of cells that are able to react with their own antigens. All lymphocytes that do not pass the specificity control die.

4.1. Mechanisms of the body's immunological defense
Thus, even a brief excursion into the history of the development of immunology allows us to assess the role of this science in solving a number of medical and biological problems. Infectious immunology - the ancestor of general immunology - has now become only its branch.
It became obvious that the body very accurately distinguishes between “self” and “foreign”, and the reactions that arise in it in response to the introduction of foreign agents (regardless of their nature) are based on the same mechanisms. The study of a set of processes and mechanisms aimed at maintaining the constancy of the internal environment of the body from infections and other foreign agents - immunity - lies at the basis of immunological science (V.D. Timakov, 1973).
The second half of the twentieth century was marked by the rapid development of immunology. It was during these years that the selection-clonal theory of immunity was created, and the patterns of functioning of various parts of the lymphoid system as a single and integral immune system were revealed. One of the most important achievements in recent years has been the discovery of two independent effector mechanisms in a specific immune response. One of them is associated with the so-called B-lymphocytes, which carry out a humoral response (synthesis of immunoglobulins), the other - with the system of T-lymphocytes (thymus-dependent cells), the result of which is the cellular response (accumulation of sensitized lymphocytes). It is especially important to obtain evidence of the interaction of these two types of lymphocytes in the immune response.
The research results suggest that the immunological system is an important link in the complex mechanism of adaptation of the human body, and its action is primarily aimed at maintaining antigenic homeostasis, the disruption of which can be caused by the penetration of foreign antigens into the body (infection, transplantation) or spontaneous mutation.
Nezelof imagined a diagram of the mechanisms that carry out immunological protection as follows:

But, as research in recent years has shown, the division of immunity into humoral and cellular is very arbitrary. Indeed, the influence of the antigen on the lymphocyte and reticular cell is carried out with the help of micro- and macrophages that process immunological information. At the same time, the phagocytosis reaction, as a rule, involves humoral factors, and the basis of humoral immunity is made up of cells that produce specific immunoglobulins. Mechanisms aimed at eliminating a foreign agent are extremely diverse. In this case, two concepts can be distinguished - “immunological reactivity” and “nonspecific protective factors”. The first refers to specific reactions to antigens, due to the highly specific ability of the body to respond to foreign molecules. However, the body’s protection from infections also depends on the degree of permeability of the skin and mucous membranes to pathogenic microorganisms, and the presence of bactericidal substances in their secretions, the acidity of gastric contents, and the presence of enzyme systems such as lysozyme in the body’s biological fluids. All these mechanisms belong to nonspecific protective factors, since there is no special response and they all exist regardless of the presence or absence of the pathogen. Some special positions are occupied by phagocytes and the complement system. This is due to the fact that, despite the nonspecificity of phagocytosis, macrophages participate in the processing of antigen and in the cooperation of T and B lymphocytes during the immune response, that is, they participate in specific forms of response to foreign substances. Similarly, complement production is not a specific response to an antigen, but the complement system itself is involved in specific antigen-antibody reactions.

5. Inflammation as a mechanism of nonspecific immunity
Inflammation is the body’s reaction to foreign microorganisms and tissue decay products. This is the main mechanism of natural congenital, or nonspecific) immunity, as well as the initial and final stages of immunity when acquired. Like any defensive reaction, it must combine the ability to recognize a particle foreign to the body with an effective way to neutralize it and remove it from the body. A classic example is inflammation caused by a splinter that has passed under the skin and is contaminated with bacteria.
Normally, the walls of blood vessels are impermeable to blood components - plasma and formed elements (erythrocytes and leukocytes). Increased permeability to blood plasma is a consequence of changes in the walls of blood vessels, the formation of “gaps” between endothelial cells tightly adjacent to each other. In the area of ​​the splinter, inhibition of the movement of red blood cells and leukocytes (white blood cells) is observed, which begin to stick to the walls of the capillaries, forming “plugs”. Two types of leukocytes - monocytes and neutrophils - begin to actively “squeeze” from the blood into the surrounding tissue between the endothelial cells in the area of ​​developing inflammation.
Monocytes and neutrophils are designed for phagocytosis - the absorption and destruction of foreign particles. Purposeful active movement to the source of inflammation is called x e m o t a x i s a. Arriving at the site of inflammation, monocytes turn into macrophages. These are cells with tissue localization, actively phagocytic, with a “sticky” surface, mobile, as if feeling everything that is in the immediate environment. Neutrophils also come to the site of inflammation, and their phagocytic activity increases. Phagocytic cells accumulate, actively engulf and destroy (intracellularly) bacteria and cell debris.
Activation of the three main systems involved in inflammation determines the composition and dynamics of the “actors.” They include the education system kinins, system complement and system activated phagocytic cells.

6. The role of T lymphocytes in the immune response

7. Phagocytosis
The enormous role of phagocytosis not only in innate, but also in acquired immunity is becoming increasingly obvious thanks to the work of the last decade. Phagocytosis begins with the accumulation of phagocytes at the site of inflammation. Monocytes and neutrophils play the main role in this process. Monocytes, having arrived at the site of inflammation, turn into macrophages - tissue phagocytic cells. Phagocytes, interacting with bacteria, are activated, their membrane becomes “sticky,” and granules filled with powerful proteases accumulate in the cytoplasm. Oxygen uptake and generation of reactive oxygen species (oxygen explosion) increase, including hydrogen peroxide and hypochlorite, as well as
etc.................

In the early 1880s Mechnikov in Messina, Italy, after sending his family to watch a circus performance, he calmly examined a transparent starfish larva under a microscope. He saw how mobile cells surrounded a foreign particle that had entered the body of the larva. The phenomenon of absorption was observed before Mechnikov, but it was generally believed that this was simply preparation for the transport of particles by blood. Suddenly, Mechnikov had an idea: what if this is not a mechanism of transport, but of protection? Mechnikov immediately introduced pieces of thorns from the tangerine tree, which he had prepared instead of a New Year tree for his children, into the body of the larva. The moving cells again surrounded the foreign bodies and absorbed them.

If the mobile cells of the larva, he thought, protect the body, they should also absorb bacteria. And this assumption was confirmed. Mechnikov had previously observed more than once how white blood cells - leukocytes - also gather around a foreign particle that has entered the body, forming a focus of inflammation. In addition, after many years of work in the field of comparative embryology, he knew that these motile cells in the larval body and human leukocytes originate from the same germ layer - the mesoderm. It turned out that all organisms possessing blood or its precursor - hemolymph, have a single defense mechanism - the absorption of foreign particles by blood cells. Thus, a fundamental mechanism was discovered by which the body protects itself from the penetration of foreign substances and microbes. At the suggestion of Professor Klaus from Vienna, to whom Mechnikov told about his discovery, the protective cells were called phagocytes, and the phenomenon itself was called phagocytosis. The mechanism of phagocytosis has been confirmed in humans and higher animals. Human leukocytes surround microbes that have entered the body and, like amoebas, form protrusions, cover the foreign particle from all sides and digest it.

Paul Ehrlich

A prominent representative of the German school of microbiologists was Paul Ehrlich (1854-1915). Since 1891, Ehrlich has been searching for chemical compounds capable of suppressing the life activity of pathogens. He introduced the treatment of four-day malaria with methylene blue dye and the treatment of syphilis with arsenic.

Starting with work with diphtheria toxin at the Institute of Infectious Diseases. Ehrlich created the theory of humoral immunity (in his terminology, the theory of side chains). According to it, microbes or toxins contain structural units - antigens, which cause the formation of apbodies in the body - special proteins of the globulin class. Antibodies have stereospecificity, that is, a conformation that allows them to bind only those antigens in response to the penetration of which they arose. Thus, Ehrlich subordinated the aptigen-antibody interaction to the laws of stereochemistry. Initially, antibodies exist in the form of special chemical groups (side chains) on the surface of cells (fixed receptors), then some of them are separated from the cell surface and begin to circulate in the blood (freely interfering receptors). When encountering microbes or toxins, antibodies bind to them, immobilize them and prevent their effect on the body. Ehrlich showed that the toxic effect of a toxin and its ability to bind to an antitoxin are different functions and can be affected separately. It was possible to increase the concentration of antibodies by repeated injections of the antigen - this is how Ehrlich solved the problem of obtaining highly effective sera that bothered Behring. Ehrlich introduced a distinction between passive immunity (the introduction of ready-made antibodies) and active immunity (the introduction of antigens to stimulate one’s own antibody production). While studying the plant poison ricin, Ehrlich showed that antibodies do not appear immediately after the antigen is introduced into the blood. He was the first to study the transfer of some immune properties from mother to fetus through the placenta and to the baby through milk.

A long and persistent discussion arose in the press about the “true theory of immunity” between Mechnikov and Ehrlich. As a result, phagocytosis was called cellular immunity, and antibody formation was called humoral immunity. Metchnikoff and Ehrlich shared the 1908 Nobel Prize.

Bering was engaged in the creation of serums by selecting bacterial cultures and toxins, which he injected into animals. One of his greatest achievements is the creation in 1890 of antitetanus serum, which turned out to be very effective in the prevention of tetanus in wounds, although ineffective in a later period, when the disease had already developed.

“Behring wanted the honor of discovering the anti-diphtheria serum to belong to German, not French, scientists. In search of vaccinations for diphtheria-infected animals, Bering made serums from various substances, but the animals died. He once used iodine trichloride for vaccination. True, this time the guinea pigs became seriously ill, but none of them died. Inspired by the first success, Bering, after waiting for the experimental pigs to recover, inoculated them from a broth with diphtheria toxin strained using the Roux method, in which diphtheria bacilli had previously been grown. The animals withstood the vaccination perfectly, despite the fact that they received a huge dose of the toxin. This means that they have acquired immunity against diphtheria; they are not afraid of either bacteria or the poison they secrete. Bering decided to improve his method. He mixed the blood of recovered guinea pigs with a strained liquid containing diphtheria toxin and injected the mixture into healthy guinea pigs - none of them got sick. This means, Bering decided, the blood serum of animals that have acquired immunity contains an antidote to diphtheria poison, some kind of “antitoxin”.

By inoculating healthy animals with serum obtained from recovered animals, Bering became convinced that guinea pigs gained immunity not only when infected with bacteria, but also when they were exposed to a toxin. Later he became convinced that this serum also had a healing effect, that is, if sick animals were vaccinated, they would recover. At the clinic for children's diseases in Berlin, on December 26, 1891, a child dying of diphtheria was inoculated with the serum of a recovered mumps, and the child recovered. Emil Bering and his boss, Robert Koch, won a triumphant victory over the terrible disease. Now Emil Roux has taken up the matter again. By inoculating horses with diphtheria toxin at short intervals, he gradually achieved complete immunization of the animals. Then he took several liters of blood from horses, extracted serum from it, from which he began to vaccinate sick children. Already the first results exceeded all expectations: the mortality rate, which previously reached 60 to 70% for diphtheria, fell to 1–2%.

In 1901, Behring received the Nobel Prize in Physiology or Medicine for his work on serum therapy.

During the second half of the 19th century, doctors and biologists of that time actively studied the role of pathogenic microorganisms in the development of infectious diseases, as well as the possibility of creating artificial immunity to them. These studies have led to the discovery of facts about the body's natural defenses against infections. Pasteur proposed to the scientific community the idea of ​​the so-called “exhausted force.” According to this theory, viral immunity is a condition in which the human body is not a beneficial breeding ground for infectious agents. However, this idea could not explain a number of practical observations.

Mechnikov: cellular theory of immunity

This theory appeared in 1883. The creator of the cellular theory of immunity relied on the teachings of Charles Darwin and was based on the study of digestive processes in animals, which are located at various stages of evolutionary development. The author of the new theory discovered some similarities in the intracellular digestion of substances in endoderm cells, amoebas, tissue macrophages and monocytes. Actually, immunity was created by the famous Russian biologist Ilya Mechnikov. His work in this area continued for quite a long time. They began in the Italian city of Messina, where a microbiologist observed the behavior of larvae

The pathologist discovered that the wandering cells of the observed creatures surround and then absorb foreign bodies. In addition, they resorb and then destroy those tissues that the body no longer needs. He put a lot of effort into developing his concept. The creator of the cellular theory of immunity introduced, in fact, the concept of “phagocytes,” derived from the Greek words “phages” - to eat and “kitos” - cell. That is, the new term literally meant the process of eating cells. The scientist came to the idea of ​​such phagocytes a little earlier, when he studied intracellular digestion in various connective tissue cells in invertebrates: sponges, amoebae and others.

In representatives of the higher animal world, the most typical phagocytes can be called white blood cells, that is, leukocytes. Later, the creator of the cellular theory of immunity proposed dividing such cells into macrophages and microphages. The correctness of this division was confirmed by the achievements of the scientist P. Ehrlich, who differentiated different types of leukocytes through staining. In his classic works on the pathology of inflammation, the creator of the cellular theory of immunity was able to prove the role of phagocytic cells in the process of eliminating pathogens. Already in 1901, his fundamental work on immunity to infectious diseases was published. In addition to Ilya Mechnikov himself, a significant contribution to the development and dissemination of the theory of phagocytic immunity was made by I.G. Savchenko, F.Ya. Chistovich, L.A. Tarasevich, A.M. Berezka, V.I. Isaev and a number of other researchers.

Immunity is the body’s defense system from external influences. The term itself comes from a Latin word that translates as “liberation” or “getting rid of something.” Hippocrates called it “the self-healing power of the body,” and Paracelsus called it “healing energy.” First of all, you should understand the terms associated with the main defenders of our body.

Natural and acquired immunity

Even in ancient times, doctors knew that humans were immune to animal diseases. For example, distemper in dogs or chicken cholera. This is called innate immunity. It is given to a person from birth and does not disappear throughout life.

The second appears in a person only after he has suffered from the disease. For example, typhus and scarlet fever are the first infections to which doctors discovered resistance. During the disease process, the body creates antibodies that protect it from certain germs and viruses.

The great importance of immunity is that after recovery the body is ready to face re-infection. This is facilitated by:

• maintaining the antibody pattern for life;
• recognition by the body of a “familiar” disease and rapid organization of defense.

There is a softer way to acquire immunity - a vaccination. There is no need to fully experience the disease. It is enough to introduce a weakened disease into the blood to “teach” the body to fight it. If you want to know what the discovery of immunity gave to humanity, you should first know the chronology of discoveries.

A little history

The first vaccination was done in 1796. Edward Gener was convinced that artificial infection of smallpox from the blood of a cow was the best option for acquiring immunity. And in India and China they infected people with smallpox long before they began to do this in Europe.

Preparations made from the blood of such animals became known as serums. They became the first cure for diseases, which gave humanity the discovery of immunity.

Serum as a last chance

If a person gets sick and cannot cope with the illness on his own, he is injected with serum. It contains ready-made antibodies that the patient’s body, for some reason, cannot produce on its own.

These are extreme measures and are only necessary if the patient's life is in danger. Serum antibodies are obtained from the blood of animals that already have immunity to the disease. They receive it after vaccination.

The most important thing that the discovery of immunity gave humanity was an understanding of the functioning of the body as a whole. Scientists have finally understood how antibodies appear and what they are needed for.

Antibodies - fighters against dangerous toxins

Antitoxin began to be called a substance that neutralizes the waste products of bacteria. It appeared in the blood only if these dangerous compounds were ingested. Then all such substances began to be called a general term - “antibodies”.

Laureate Arne Tiselius experimentally proved that antibodies are ordinary proteins, only with a larger one. And two other scientists - Edelman and Porter - deciphered the structure of several of them. It turned out that the antibody consists of four proteins: two heavy and two light. The molecule itself is shaped like a slingshot.

And later Susumo Tonegawa showed the amazing ability of our genome. The sections of DNA that are responsible for the synthesis of antibodies can change in every cell of the body. And they are always ready, in case of any danger they can change so that the cell begins to produce protective proteins. That is, the body is always ready to produce a variety of different antibodies. This diversity more than covers the number of possible alien influences.

The Importance of Opening Immunity

The very discovery of immunity and all the theories put forward about its action allowed scientists and doctors to better understand the structure of our body, the mechanisms of its reactions to viruses, and this helped defeat such a terrible disease as smallpox. And then vaccines were found for tetanus, measles, tuberculosis, whooping cough and many others.

All these advances in medicine have made it possible to greatly increase the average person and improve the quality of medical care.

In order to better understand what the discovery of immunity gave to humanity, it is enough to read about life in the Middle Ages, when there were no vaccinations and serums. Look how dramatically medicine has changed, and how much better and safer life has become!

Corresponding Member of the Russian Academy of Sciences Sergei Nedospasov, Boris Rudenko, columnist for the journal “Science and Life”.

Revolutionary breakthroughs in any field of science occur infrequently, once or twice a century. And in order to realize that a revolution in the knowledge of the surrounding world has really occurred, to evaluate its results, the scientific community and society as a whole sometimes require more than one year or even more than one decade. In immunology, such a revolution occurred at the end of the last century. It was prepared by dozens of outstanding scientists who put forward hypotheses, made discoveries and formulated theories, and some of these theories and discoveries were made a hundred years ago.

Paul Ehrlich (1854-1915).

Ilya Mechnikov (1845-1916).

Charles Janeway (1943-2003).

Jules Hoffmann.

Ruslan Medzhitov.

Drosophila, mutant for the Toll gene, became overgrown with fungi and died, since it does not have immune receptors that recognize fungal infections.

Two schools, two theories

Throughout the twentieth century, until the early 1990s, in studies of immunity, scientists proceeded from the belief that higher vertebrates, and in particular humans, have the most perfect immune system. This is what should be studied first. And if something has not yet been “underdiscovered” in the immunology of birds, fish and insects, then this most likely does not play a special role in advancing the understanding of the mechanisms of protection against human diseases.

Immunology as a science emerged a century and a half ago. Although the first vaccination is associated with the name of Jenner, the founding father of immunology is rightfully considered the great Louis Pasteur, who began to look for the answer to the survival of the human race, despite the regular devastating epidemics of plague, smallpox, cholera, falling on countries and continents like the punishing sword of fate. Millions, tens of millions of dead. But in cities and villages where funeral teams did not have time to remove corpses from the streets, there were those who independently, without the help of healers and sorcerers, coped with the deadly scourge. And also those who were not affected by the disease at all. This means that there is a mechanism in the human body that protects it from at least some external invasions. It's called immunity.

Pasteur developed ideas about artificial immunity, developing methods for creating it through vaccination, but it gradually became clear that immunity exists in two forms: natural (innate) and adaptive (acquired). Which one is more important? Which one plays a role in successful vaccination? At the beginning of the twentieth century, in answering this fundamental question, two theories, two schools - those of Paul Ehrlich and Ilya Mechnikov - collided in a heated scientific debate.

Paul Ehrlich has never been to Kharkov or Odessa. He attended his universities in Breslau (Breslau, now Wroclaw) and Strasbourg, worked in Berlin, at the Koch Institute, where he created the world's first serological control station, and then headed the Institute of Experimental Therapy in Frankfurt am Main, which today bears his name. And here it should be recognized that, conceptually, Ehrlich has done more for immunology in the entire history of this science than anyone else.

Mechnikov discovered the phenomenon of phagocytosis - the capture and destruction by special cells - macrophages and neutrophils - of microbes and other biological particles foreign to the body. It is this mechanism, he believed, that is the main one in the immune system, building lines of defense against invading pathogens. It is the phagocytes that rush to attack, causing an inflammatory reaction, for example, with an injection, splinter, etc.

Ehrlich argued the opposite. The main role in protection against infections belongs not to cells, but to the antibodies discovered by them - specific molecules that are formed in the blood serum in response to the introduction of an aggressor. Ehrlich's theory is called the theory of humoral immunity.

It is interesting that irreconcilable scientific rivals - Mechnikov and Ehrlich - shared the Nobel Prize in Physiology or Medicine in 1908 for their work in the field of immunology, although by this time the theoretical and practical successes of Ehrlich and his followers seemed to completely refute the views of Mechnikov. It was even rumored that the prize was awarded to the latter, rather, based on the totality of his merits (which is not at all excluded and not shameful: immunology is only one of the areas in which the Russian scientist worked, his contribution to world science is enormous). However, even if so, the members of the Nobel Committee, as it turned out, were much more right than they themselves believed, although confirmation of this came only a century later.

Ehrlich died in 1915, Mechnikov outlived his opponent by only a year, so the most fundamental scientific dispute developed until the end of the century without the participation of its initiators. In the meantime, everything that happened in immunology over the next decades confirmed that Paul Ehrlich was right. It was found that white blood cells, lymphocytes, are divided into two types: B and T (here it must be emphasized that the discovery of T lymphocytes in the mid-twentieth century took the science of acquired immunity to a completely different level - the founders could not have foreseen this). They are the ones who organize protection from viruses, microbes, fungi and, in general, from substances hostile to the body. B lymphocytes produce antibodies that bind the foreign protein, neutralizing its activity. And T-lymphocytes destroy infected cells and help remove the pathogen from the body in other ways, and in both cases a “memory” of the pathogen is formed, so that it is much easier for the body to fight re-infection. These protective lines are able to deal in the same way with their own, but degenerated protein, which becomes dangerous for the body. Unfortunately, such an ability, in the event of a failure in setting up the complex mechanism of adaptive immunity, can become the cause of autoimmune diseases, when lymphocytes, having lost the ability to distinguish their own proteins from foreign ones, begin to “shoot at their own”...

Thus, until the 80s of the twentieth century, immunology mainly developed along the path indicated by Ehrlich, and not by Metchnikoff. Incredibly complex, fantastically sophisticated over millions of years of evolution, adaptive immunity gradually revealed its mysteries. Scientists created vaccines and serums that were supposed to help the body organize an immune response to infection as quickly and efficiently as possible, and obtained antibiotics that could suppress the biological activity of the aggressor, thereby facilitating the work of lymphocytes. True, since many microorganisms are in symbiosis with the host, antibiotics attack their allies with no less enthusiasm, weakening and even negating their beneficial functions, but medicine noticed this and sounded the alarm much, much later...

However, the frontiers of complete victory over diseases, which at first seemed so achievable, moved further and further towards the horizon, because over time, questions appeared and accumulated that the prevailing theory found it difficult to answer or could not answer at all. And the creation of vaccines did not go as smoothly as expected.

It is known that 98% of creatures living on Earth are generally devoid of adaptive immunity (in evolution, it appears only at the level of jawed fish). But they all also have their own enemies in the biological microcosm, their own diseases and even epidemics, which, however, the populations cope with quite successfully. It is also known that the human microflora contains a lot of organisms that, it would seem, are simply obliged to cause diseases and initiate an immune response. However, this does not happen.

There are dozens of similar questions. For decades they remained open.

How revolutions begin

In 1989, the American immunologist Professor Charles Janeway published a work that was very quickly recognized as visionary, although, like Metchnikoff’s theory, it had and still has serious, erudite opponents. Janeway suggested that on human cells responsible for immunity, there are special receptors that recognize some structural components of pathogens (bacteria, viruses, fungi) and trigger a response mechanism. Since there are an innumerable number of potential pathogens in the sublunar world, Janeway suggested that the receptors would also recognize some “invariant” chemical structures characteristic of a whole class of pathogens. Otherwise there simply won’t be enough genes!

A few years later, Professor Jules Hoffmann (who later became president of the French Academy of Sciences) discovered that the fruit fly - an almost indispensable participant in the most important discoveries in genetics - has a defense system that was until then misunderstood and unappreciated. It turned out that this fruit fly has a special gene that is not only important for the development of the larvae, but is also associated with innate immunity. If this gene is spoiled in a fly, then it dies when infected with fungi. Moreover, it will not die from other diseases, for example, of a bacterial nature, but inevitably from a fungal one. The discovery allowed us to draw three important conclusions. First, the primitive fruit fly is endowed with a powerful and effective innate immune system. Secondly, its cells have receptors that recognize infections. Thirdly, the receptor is specific to a certain class of infections, that is, it is capable of recognizing not any foreign “structure,” but only a very specific one. But this receptor does not protect against another “structure”.

These two events - an almost speculative theory and the first unexpected experimental result - should be considered the beginning of the great immunological revolution. Then, as happens in science, events developed progressively. Ruslan Medzhitov, who graduated from Tashkent University, then graduate school at Moscow State University, and later became a professor at Yale University (USA) and a rising star in world immunology, was the first to discover these receptors on human cells.

Thus, almost a hundred years later, the long-standing theoretical dispute between the great scientific rivals was finally resolved. I decided that both were right - their theories complemented each other, and I. I. Mechnikov’s theory received new experimental confirmation.

In fact, a conceptual revolution took place. It turned out that for everyone on Earth, innate immunity is the main one. And only the most “advanced” organisms on the ladder of evolution - higher vertebrates - acquire acquired immunity in addition. However, it is the innate that directs its initiation and subsequent operation, although many of the details of how all this is regulated have yet to be established.

"His Excellency's adjuvant"

New views on the interaction of the innate and acquired branches of immunity have helped to understand what was previously unclear.

How do vaccines work when they work? In general (and very simplified) form, it goes something like this. A weakened pathogen (usually a virus or bacteria) is injected into the blood of a donor animal, such as a horse, cow, rabbit, etc. The animal's immune system produces a protective response. If the protective response is associated with humoral factors - antibodies, then its material carriers can be purified and transferred into the human blood, simultaneously transferring the protective mechanism. In other cases, the person himself is infected or immunized with a weakened (or killed) pathogen, hoping to provoke an immune response that can protect against the real pathogen and even become entrenched in cellular memory for many years. This is how Edward Jenner, at the end of the 18th century, was the first in the history of medicine to vaccinate against smallpox.

However, this technique does not always work. It is no coincidence that there are still no vaccines against AIDS, tuberculosis and malaria - the three most dangerous diseases on a global scale. Moreover, many simple chemical compounds or proteins that are foreign to the body and would simply have to initiate a response from the immune system do not respond! And this often happens for the reason that the mechanism of the main defender - innate immunity - remains unawakened.

One of the ways to overcome this obstacle was experimentally demonstrated by the American pathologist J. Freund. The immune system will work in full force if the hostile antigen is mixed with an adjuvant. An adjuvant is a kind of intermediary, an assistant during immunization; in Freund’s experiments it consisted of two components. The first - a water-oil suspension - performed a purely mechanical task of slow release of the antigen. And the second component is, at first glance, quite paradoxical: dried and well-crushed tuberculosis bacteria (Koch bacilli). The bacteria are dead, they are not capable of causing infection, but the innate immune receptors will still immediately recognize them and turn on their defense mechanisms at full capacity. This is when the process of activation of the adaptive immune response to the antigen that was mixed with the adjuvant begins.

Freund's discovery was purely experimental and therefore may seem private. But Janeway sensed in it a moment of general significance. Moreover, he even called the inability to induce a full-fledged immune response to a foreign protein in experimental animals or in humans “the dirty little secret of immunologists” (hinting that this can only be done in the presence of an adjuvant, and no one understands how the adjuvant works).

Janeway suggested that the innate immune system recognizes bacteria (both live and dead) by the components of their cell walls. Bacteria that live “on their own” need strong multilayer cell walls for external protection. Our cells, under a powerful cover of external protective tissues, do not need such shells. And bacterial membranes are synthesized with the help of enzymes that we do not have, and therefore the components of bacterial walls are precisely those chemical structures, ideal indicators of the threat of infection, for which the body, in the process of evolution, has produced recognition receptors.

A small digression in the context of the main topic.

There lived a Danish bacteriologist Christian Joachim Gram (1853-1938), who was engaged in the systematization of bacterial infections. He found a substance that stained bacteria of one class and not another. Those that turned pink are now called gram-positive in honor of the scientist, and those that remained colorless are gram-negative. Each class contains millions of different bacteria. For humans - harmful, neutral and even beneficial, they live in soil, water, saliva, intestines - anywhere. Our protective receptors are able to selectively recognize both, including appropriate protection against those dangerous to their carrier. And the Gram dye could distinguish them by binding (or not binding) to the same “invariant” components of bacterial walls.

It turned out that the walls of mycobacteria - namely, tuberculosis bacilli - are particularly complex and are recognized by several receptors at once. This is probably why they have excellent adjuvant properties. So, the point of using an adjuvant is to deceive the immune system, sending it a false signal that the body is infected with a dangerous pathogen. Force a reaction. But in fact, the vaccine does not contain such a pathogen at all or it is not so dangerous.

There is no doubt that it will be possible to find other, including non-natural, adjuvants for immunizations and vaccinations. This new direction of biological science is of enormous importance for medicine.

Turn on/off the desired gene

Modern technologies make it possible to turn off (“knockout”) the only gene in an experimental mouse that encodes one of the innate immune receptors. For example, responsible for recognizing the same gram-negative bacteria. Then the mouse loses the ability to provide its defense and, being infected, dies, although all other components of its immunity are not impaired. This is exactly how the work of immune systems at the molecular level is studied experimentally today (we have already discussed the example of a fruit fly). In parallel, clinicians are learning to link people's lack of immunity to certain infectious diseases with mutations in specific genes. For hundreds of years, examples have been known when in some families, clans and even tribes there was an extremely high mortality rate of children at an early age from very specific diseases. It now becomes clear that in some cases the cause is a mutation of some component of the innate immune system. The gene is turned off - partially or completely. Since most of our genes are in two copies, we must make special efforts to ensure that both copies are damaged. This can be “achieved” as a result of consanguineous marriages or incest. Although it would be a mistake to think that this explains all cases of hereditary diseases of the immune system.

In any case, if the reason is known, there is a chance to find a way to avoid the irreparable, at least in the future. If a child with a diagnosed congenital immune defect is purposefully protected from a dangerous infection until the age of 2-3 years, then with the completion of the formation of the immune system, the mortal danger for him may pass. Even without one layer of protection, he will be able to cope with the threat and possibly live a full life. The danger will remain, but its level will decrease significantly. There is still hope that one day gene therapy will become part of everyday practice. Then the patient will simply need to transfer the “healthy” gene, without mutation. In mice, scientists can not only turn off a gene, but also turn it on. In humans it is much more difficult.

About the benefits of curdled milk

It is worth remembering one more foresight of I.I. Mechnikov. A hundred years ago, he connected the activity of phagocytes he discovered with human nutrition. It is well known that in the last years of his life he actively consumed and promoted yogurt and other fermented milk products, arguing that maintaining the necessary bacterial environment in the stomach and intestines is extremely important for both immunity and life expectancy. And then he was right again.

Indeed, research in recent years has shown that the symbiosis of intestinal bacteria and the human body is much deeper and more complex than previously thought. Bacteria not only help the digestion process. Since they contain all the characteristic chemical structures of microbes, even the most beneficial bacteria must be recognized by the innate immune system on intestinal cells. It turned out that through innate immune receptors, bacteria send the body some “tonic” signals, the meaning of which has not yet been fully established. But it is already known that the level of these signals is very important and if it is reduced (for example, there are not enough bacteria in the intestines, in particular from the abuse of antibiotics), then this is one of the factors in the possible development of oncological diseases of the intestinal tract.

Twenty years that have passed since the last (is it the last?) revolution in immunology is too short a period for the widespread practical application of new ideas and theories. Although it is unlikely that there is at least one serious pharmaceutical company left in the world that conducts development without taking into account new knowledge about the mechanisms of innate immunity. And some practical successes have already been achieved, in particular in the development of new adjuvants for vaccines.

And a deeper understanding of the molecular mechanisms of immunity - both innate and acquired (we must not forget that they must act together - friendship won) - will inevitably lead to significant progress in medicine. There is no need to doubt this. You just have to wait a little.

But where delay is extremely undesirable is in educating the population, as well as in changing stereotypes in the teaching of immunology. Otherwise, our pharmacies will continue to be filled with home-grown drugs that supposedly universally enhance immunity.

Sergey Arturovich Nedospasov - Head of the Department of Immunology, Faculty of Biology, Moscow State University. M. V. Lomonosova, head of the laboratory of the Institute of Molecular Biology named after. V. A. Engelhardt RAS, head of department of the Institute of Physical and Chemical Biology named after. A. N. Belozersky.

“Science and Life” about immunity:

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Mate J. Man from the point of view of an immunologist. - 1990, No. 8.

Tchaikovsky Yu. Anniversary of Lamarck-Darwin and the revolution in immunology. - 2009, no.