Phagocytic theory of immunity. What future awaits the phagocytic theory in the 21st century? The author of the phagocytic theory, the main provisions of this theory

Pasteur

In the second half of the 19th century, many hypotheses were put forward about how vaccines work. For example, Pasteur and his followers proposed the theory of “exhaustion.” The implication was that the introduced microbe absorbs “something” in the body until its reserves are exhausted, after which the microbe dies.

The "noxious obstacle" theory suggested that introduced microbes produced certain substances that interfered with their own development. But both theories were based on the same false premise: that the body plays no role in the vaccine’s work and passively watches from the sidelines as the microbes dig their own hole.

Both theories were forgotten with the advent of new data and new vaccines, and soon the epoch-making work of two scientists not only allowed for a new understanding of this process, but also created a new field of scientific activity and brought both of them the Nobel Prize in 1908.

Ilya Mechnikov: discovery of the immune system

The origins of the epoch-making insight of the Russian microbiologist Ilya Mechnikov dates back to 1882, when he conducted a groundbreaking experiment in which he noted that some cells had the ability to migrate through tissue in response to irritation or injury.

Moreover, these cells are able to surround, absorb and digest other substances. Mechnikov called this process phagocytosis, and the cells - phagocytes(from Greek phagos “devourer” + cytos “cell”).

Initially, a version was put forward that the function of phagocytosis is to provide cells with nutrients. However Ilya Mechnikov I suspected that these cells were not just gathering for a Sunday picnic. His suspicion was confirmed during a debate with Robert Koch, who in 1876, observing anthrax, interpreted what he saw as the invasion of white blood cells by pathogens.

Metchnikoff looked at this process differently and suggested that it was not the anthrax bacteria that invaded the white blood cells, but rather that the cells surrounded and engulfed the bacteria.

Mechnikov realized that phagocytosis- a defense tool, a way to capture and destroy an invader. Simply put, he discovered the cornerstone of the organism's greatest mystery - its immune system providing protection against diseases.

In 1887, Mechnikov classified phagocytes into macrophages And microphages and, no less important, formulated the basic principle of the immune system.

To function properly when faced with unfamiliar phenomena in the body, the immune system asks a very simple, but at the same time extremely important question: “one’s own” or “not one’s”?

If it’s “not your own” (which means there’s a variola virus, anthrax bacterium or diphtheria toxin ahead), the immune system begins an attack.

Paul Ehrlich's theory reveals the mystery of immunity

Paul Ehrlich's breakthrough discovery was, like many others, associated with the development of technology, which allowed the world to see what had previously been a secret. For Ehrlich, dyes became such a means - chemical compositions for staining cells and tissues, which made it possible to discover new details of their structure and functioning.

In 1878, when Ehrlich was only 24 years old, he was able to use them to describe several types of immune system cells, including different types white blood cells. In 1885, these and other discoveries prompted the young scientist to think about a new theory of cell nutrition.

Paul Ehrlich proposed that "side chains" on the outside of cells - today we call them cell receptors - could attach to certain substances and carry them into the cell.

Having become interested in immunology, Paul Ehrlich wondered whether the receptor theory could explain the principle of operation of serums against diphtheria and tetanus. As we already know, Bering and Kitasato discovered that an animal infected with diphtheria bacteria begins to produce an antitoxin and this can be isolated and used as a defense against the disease for other organisms.

It turned out that these "antitoxins" are actually antibodies - specific proteins that cells produce to find and neutralize diphtheria toxin.

During his pioneering experiments with antibodies, Ehrlich wondered whether receptor theory could explain the mechanism of action of antibodies. And soon he came to an epoch-making insight.

Initially, as part of his side chain theory, Ehrlich proposed that the cell has a large variety of external receptors, each of which attaches to a specific nutrient. He later developed this idea and suggested that harmful substances - bacteria and viruses - can imitate nutrients and also attach to specific receptors. What happens next, according to Ehrlich's hypothesis, explains how cells produce antibodies against a foreign microorganism.

When a harmful substance attaches to the desired receptor, the cell is able to determine its key characteristics and begins to produce a large number of new receptors identical to the one attached to the invader. These receptors are then separated from the cell and become antibodies - highly specific proteins that can search for harmful substances, attach to and deactivate them.

Ehrlich's theory finally explained how specific foreign substances, once entering the body, are recognized by cells and provoke them to produce specific antibodies that pursue and destroy the invader.

The beauty of this theory is that it explains how the body produces antibodies against specific diseases and whether they are produced in response to a previous disease, variolation, or vaccination.

Of course, Ehrlich was wrong about some things. For example, it was later discovered that not all cells are able to attach to invaders and produce antibodies. This important task is performed by only one type of white blood cell - B lymphocytes. Moreover, it will take decades of research to understand the complex roles of B cells and the many other cells and substances of the immune system.

And today, the complementary breakthrough discoveries of Ilya Mechnikov and Paul Ehrlich are considered two cornerstones of immunology and provide a long-awaited answer to the question of how vaccines work.

Nowadays, few people remember that the word “gerontology” - that is, the science of old age and ways to overcome it - was introduced into scientific use by Ilya Ilyich Mechnikov.

Mechnikov was a curious person. The son of a guards officer and the daughter of a famous Jewish publicist, he made a rapid scientific career and won the Nobel Prize in 1908.

Mechnikov's contribution to gerontology is significant, but controversial. He was one of the authors of the scientific theory of aging, according to which old age is caused by poisons that poison the body. Namely: decrepitude stems from toxins secreted by microbes of the large intestine.

By the way, they really release toxins; another question is that aging is now explained by other reasons. But at the time, the “ass theory” seemed pretty convincing.

For example, Leo Tolstoy, having become familiar with the newfangled teaching, wrote in his diary: “Mechnikov is coming up with a way to neutralize old age and death by cutting out the intestines and picking the ass.”

To say “old age is not joy” does not exhaust our attitude to this topic. In addition, mentioning this life stage is often ignored and taboo in society. Old age is considered in close proximity to death. Since this is the final stage of life, the issue of old age and aging will always have its significance.

Mechnikov's theory of aging: saturation of life and death, instinct

The beginning of the scientific study of old age was laid by Mechnikov in the 19th century. He developed the theory of orthobiosis, in which he analyzed the problem of natural, physiological and premature, pathological aging. The scientist was interested in life and the mechanisms of the aging process, which he described in his book “The Teaching of Optimism” and “Human Nature”.

Metchnikoff is often credited with saying that age is a disease. In fact, he said that most people die from disease, not from old age per se. The degree of aging is distinguished depending on the intensity of life.

He comes to an interesting conclusion about the meaning and purpose of life in old age.

"People, especially those who lived for a long time, do not ask themselves the question why a person lives in the world. The reason for this is the instinctive desire to live, which is associated, at the same time, with the strongest fear of death,” the scientist said.

Theory of the first half of the twentieth century

In the first half of the twentieth century, a number of theories of aging emerged. Firstly, the molecular theory of aging was developed by A. Pictet, V. Alpatov, O. Nastyukova, K. Parhon and other scientists. In this group, the theory of aging is considered as a consequence of the accumulation with age of optical isomers of proteins unfavorable for metabolism.

The second theory considers aging to be the result of changes in the genetic apparatus of cells.
The third theory of automatic intoxication is the destruction of immune properties and tissue control in the body.

Aging and stress theory

We cannot ignore the theory of the famous scientist Hans Selye - the father of stress. Selye believed that stress represents the rate of wear and tear of the human body in the process of life and corresponds to the intensity of life. According to Selye, aging is strongly related to adaptation mechanisms. “Flexibility is one of the most outstanding features of life,” he said.

Thus, stress is a mechanism of adaptation to the environment, but as long as there is no wear and tear on the internal human resource. There are limits not only to the individual, but also to the adaptability of species. Many scientists agree with Hans Selye's findings that the sharp increase in cardiovascular disease and cancer is the result of adaptation exhaustion.

Adaptive-normative theory of aging

In the eighties of the twentieth century, the deep processes of aging began to be studied. Scientists have made fairly optimistic predictions about slowing down aging and increasing the lifespan of species. The predictions were made essentially at the end of the twentieth century (plus another twenty years). The dominant position was occupied by the adaptive-normative theory of aging, developed by V. Frolkis and his school.

According to this theory, aging is a natural stage in the existence of a living organism. That is, the right to look at the period that begins as the aging process was laid down at the level of the embryo. Every living system is self-regulating, so that the species is able to adapt to changing conditions

Adaptation controller is characterized by the author as anti-aging. Vitaukta is what determines the stability and duration of a living system and helps maintain adaptability. From a theoretical point of view human life cannot be associated with the speed and rate of destruction of the body, its aging, as was previously assumed.

Average life expectancy, according to Frolkis, is more correct to distinguish between mechanisms for maintaining the reliability of the body, the ability to compensate for disturbances.

Aging is primarily a biological process. But a person ages not only biologically. Man is the only living being who is aware of his mortality. To study old age, it is necessary to take into account the socio-cultural component associated with the perception of old age in culture.

Immunity is a protective-adaptive reaction of the body against various pathogenic agents. In the usual understanding, this means immunity to infectious diseases. The science that studies immunity is called immunology, and the reactions that accompany the development of immunity are called immunological reactions. I.I. Mechnikov defined immunity as follows: “By immunity to infectious diseases we must understand the general system of phenomena due to which the body can withstand the attack of pathogenic microbes.”

There are specific and acquired immunity. Species immunity is a property of a given animal species and is inherited. For example, animals do not suffer from measles, typhus and some other diseases, and humans do not suffer from many infections that affect animals (cattle plague, canine plague, etc.).

Species immunity can be absolute or relative.

Possessing absolute immunity, neither an animal nor a person will, under any circumstances, become ill with this disease. So, dogs never get measles and other infections observed in humans. However, birds, which under normal conditions do not get sick with anthrax, can get sick with it when the body weakens as a result of cooling, starvation and other reasons. Consequently, they are relatively immune to anthrax.

In the development of relative immunity, favorable social conditions are of great importance, as well as the acquired properties of the organism that have developed in it through interaction with environment(for example, hardening the body with physical education).

Acquired immunity is developed in a person during his life, usually after any infectious disease.

In the fall of 1882, Mechnikov, together with his wife Olga Nikolaevna Belokopytova, a friend and assistant in all matters, left for Messina, where he made his most famous discovery.

Once, when Mechnikov observed under a microscope the moving cells (amebocytes) of a starfish larva, the idea occurred to him that these cells, which capture and digest organic particles, not only participate in digestion, but also perform a protective function in the body. Mechnikov confirmed this assumption with a simple and convincing experiment. Having inserted a rose thorn into the body of the transparent larva, after a while he saw that amebocytes had accumulated around the splinter. Cells that either engulfed or encased foreign bodies("harmful agents") that entered the body, Mechnikov called phagocytes, and the phenomenon itself - phagocytosis. The following year, 1883, Mechnikov made a report at the congress of naturalists and doctors in Odessa “On healing powers body." He devoted the next 25 years of his life to the development of the phagocytic theory of immunity. To do this, he turned to the study of inflammatory processes, infectious diseases and their causative agents - pathogenic microorganisms. "Before that, a zoologist - I immediately became a pathologist," Mechnikov wrote. Working on the phagocytic theory, Mechnikov, at the same time, in 1884 and 1885, carried out a number of studies on comparative embryology, which are considered classic.

Before Mechnikov, the prevailing idea was that microbes and other foreign bodies played a leading role in immunity.

In numerous experiments, Mechnikov discovered the enormous, sometimes leading role of the microorganism in its fight against infections. He conducted numerous experiments to study the process of the emergence of immunity in rabbits to the swine cholera microbe, to the causative agent of rubella in pigs, to the causative agent of anthrax in pigeons and rats, to the Mechnikov vibrio in guinea pigs, etc. In all cases, the decisive importance of phagocytosis was proven in the process of freeing the body from microbes that have penetrated it.

Thus, the scientist convincingly showed that active cells of the body - leukocytes, as a result of their interaction with microbes or with their products - toxins or, finally, with other non-living foreign bodies, specifically change the nature and direction of their activity, “change their reactivity”. Figuratively speaking, they mobilize their forces and change the level of tension and activity in accordance with the characteristics and strength of the “enemy attack”. “The reaction of phagocytic cells,” Mechnikov wrote, “is accomplished as a result of their sensitivity.” From his friend A.O. Kovalevsky Mechnikov saw dull daphnia in the aquarium of the laboratory. Upon examination, it turned out that they were filled with spores of the fungus Monospora bicuspidata.

Mechnikov organized an experimental reproduction of this fact and observed how needle-shaped fungal spores, like needles, pass through the walls digestive tract and penetrate into the body cavity of daphnia.

How will a wounded daphnia “defend itself” against enemies that have penetrated it?

The microscope makes it possible to observe how “dramatic events” play out in the body of the daphnia crustacean. First of all, leukocytes circulating in large quantities in the body of daphnia, they make a “stormy” attack on “uninvited guests”. Around each fungal spore, as before around a splinter in a starfish larva, leukocytes accumulate. They envelop and isolate each spore. But this is not enough. After all, fungal spores are not glass. Daphnia leukocytes swallow them through intracellular digestion, and not a trace remains of the spores. The battlefield has been cleared. There is no need to remove the corpses of enemies, in the witty expression of Mechnikov’s student and successor, Bezredok.

Daphnia “defeated” the fungal spores, although it is also microscopic. Previously cloudy, it brightens and “lives” again until the next infection. But this happy outcome for daphnia does not always happen. If there are more enemy forces (in this case, fungal spores) than the leukocytes formed in the body of daphnia can overcome, then those spores that are not swallowed by leukocytes have time to germinate into fungi, and general infection leads to the death of daphnia.

This is a figurative retelling, close to the presentation of Mechnikov himself and his closest successors about several interesting experimental episodes. But it was precisely these episodes that helped Mechnikov reveal the course of the processes underlying his immortal doctrine of phagocytosis. The deeply fruitful significance of the phagocytic theory lies primarily in the fact that the patterns we examined in the two previous experiments are confirmed in their main features in higher animals and in humans.

The importance of this theory in medicine is great. It reveals in a new way the essence of inflammatory processes as protective devices of the body, underlies the fight against infections, explains the resorption of tissues during regeneration phenomena, etc.

In Stockholm in 1908, Mechnikov received the Nobel Prize for his discoveries in the field of immunity. Mechnikov shared the prize for the phagocytic theory of immunity with the outstanding German scientist Ehrlich, who developed the humoral theory of immunity. This seemed to emphasize that both theories complement each other.

Mechnikov, mentally looking back on the years of grueling struggle that he had to wage “in conditions of mistrust and harsh criticism,” sarcastically said that memories of Bipinnaria with a splinter surrounded on all sides by moving cells, and of Daphnia with blood balls devouring the spiny spores of infectious microbes, supported his hope that his ideas would avoid defeat. History brilliantly justified his hopes. The doctrine of phagocytosis has entered the golden fund of science.

Modern research on the role of viral factors in the development of malignant tumors obliges us to pay great attention to this valuable idea of ​​a scientist brilliant in his insight.

Identification of the role of pathogenic microorganisms in the development of infectious diseases, the possibility of artificially creating immunity prompted studying the body's defense factors against infectious agents.

Pasteur offered theory exhausted strength ; According to this theory, “immunity” represents a state in which the human body (as a nutrient medium) does not support the development of microbes.

However, the author quickly realized that his theory cannot explain a number of observations. In particular, Pasteur showed that if you infect a chicken with anthrax and keep its legs in cold water, then she develops a disease (under normal conditions, chickens are immune to anthrax). Development of the phenomenon caused a decrease in body temperature by 1-2 °C, that is, there could be no talk of any depletion of the nutrient medium in the body.

Phagocytic theory of immunity. I.I. Mechnikov

In 1883 the theory of immunity appeared, based on the evolutionary teachings of Charles Darwin and based on the study of digestion in animals located at different stages of biological development. The author of the new theory, I.I. Mechnikov, discovered the similarity of intracellular digestion of substances in amoebas, endoderm cells of coelenterates and some cells of mesenchymal origin (blood monocytes, tissue macrophages). Mechnikov introduced the term “phagocytes”] from the Greek. phages, eat, + kytos, cell], and later proposed dividing them into microphages and macrophages. This division was also facilitated by the achievements of P. Ehrlich, who differentiated several types of leukocytes through staining. In classical works on comparative pathology of inflammation, I.I. Mechnikov proved the role of phagocytic cells in the elimination of pathogens. In 1901, his monumental final work “Immunity in Infectious Diseases” was published in Paris.

Significant contribution to distribution phagocytic theory contributed works by E. Ru and students of I.I. Mechnikov (A.M. Bezredka, I.G. Savchenko, L.A. Tarasevich, F.Ya. Chistovich, V.I. Isaev).

Mechnikov's theory.

This famous bacteriologist was of the opinion that aging occurs from disharmony in the constitution of the body, that is, from imperfect adaptation of any organ to the urgent needs of life. And as an example he cites the large intestine, an organ of dubious usefulness, and also dangerous, due to the fact that it is a breeding ground for putrefactive microbes that produce toxins that contribute to the weakening and degeneration of the noble cells of the body (brain, muscles, glands, etc.). ). On the contrary, mesodermal elements (leukocytes, connective tissue, etc.) show themselves to be almost completely invulnerable to these bacterial toxins and not only do not reduce functional or reproductive activity, but also multiply rapidly.

The ancestral line of these poorly differentiated cells, designated phagocytes (macrophages and microphages), far from resigning itself to general decline, turns into aggressive, devouring noble elements (phagocytosis). Such aggressiveness is absent in young and mature age, that is, during the period of physiological growth of muscle, nerve and glandular cells, due to the fact that they produce and release some kind of protective substance that repels microphages and macrophages. This protective secretion ceases or greatly decreases during old age; in this regard, phagocytes and connective tissue, without a restraining brake, attack and destroy the mentioned aristocratic and highly differentiated elements.

But Mechnikov is not a pessimist. Since aging and death result from the struggle of phagocytes simultaneously with poisoning by intestinal microbial toxins, it is possible, in principle, to weaken the former and delay the latter, although not to abolish them. And he predicts the possibility of reversing the damage, either by inventing serum or other specific substances capable of stimulating the noble cells to develop a defense against phagocytes, or by changing the intestinal flora in favor of an appropriate diet. For this purpose, he offers curdled milk and kefir, commonly used among Bulgarians and Tatars. These and other antidote products include milk coli as an active factor. It is known that among the Bulgarians and Armenians, big consumers of curdled milk, there are many centenarians.

Treatments for old age have been making waves for several years. Large quantities of kefir and yoghurt (fermented special types coli milk), but the enthusiasm has faded and today such remedies are barely used, and even then only for the treatment of certain diseases of the gastrointestinal tract.

Mechnikov's theory lacks universal significance, according to Mino. And there is widespread skepticism about the preventative treatment mentioned. For example, Herter proved that curdled milk does not have a decisive effect on the deadly flora of the colon. And he even doubts that even if it is possible to achieve the predominance of milk coli, then favorable results will be achieved. Such criticism is too harsh because, leaving aside the problem of aging, it is clear that in some patients there is an improvement in intestinal disorders.

Apart from these practical considerations, Mechnikov’s theory loses its fundamental validity. It has been known for many years that phagocytes do not attack either nerve or muscle cells. Studies by numerous authors on aging, especially those of Marinescu and ours 1 , they state this clearly. The brain nerve cells of old people are not consumed by either leukocytes or neuroglial cells.

Typically, functional degradation is objectively expressed in the reduction and wrinkling of the body of neurons and in the increasing deposition of foreign substances in the protoplasm (various types of lipoid substances, calcareous infiltrations, etc.). These substances, deposited in large quantities, interfere with the specific activity of protoplasm, disorganizing neurofibrils and disrupting or destroying Nissl spindles. And yet these degenerative processes, to which we must add in some extreme cases the senile dementia - the Alzheimer's phenomenon, are the effect rather than the cause of general, deeper and more mysterious conditions. Only noble tissues do not deteriorate: even connective tissues degrade and atrophy, starting with bones, which become brittle, followed by cartilage, which tends to calcify, and ending with skin, adipose tissue and even lymph nodes and the spleen - a nursery of leukocytes and phagocytes.

Where are phagocytes located during senile cataracts and deafness, during tooth loss, during degeneration of the heart muscle, and during so many other processes characteristic of the aging and decrepit? How to explain the calcareous infiltration of costal cartilages, intervertebral discs, dying and dead nerve cells? As we have experimentally proven, almost all neurons exposed to traumatic influences attract lime salts. How can you understand that the subcutaneous fat layer is being absorbed and that the dermis of the skin is thinning to such an extent that bones, tendons, veins and even in some cases arteries are visible through it on emaciated arms, legs and faces? Let's dispel the misconception: connective tissue and the mesodermal base in general are also subject to the deadly effects of atrophy and degeneration, which has nothing to do with the aggression of microphages and macrophages, which, when they surround noble cells, young or old, foreshadow their necrobiosis, previously destroyed for unknown reasons .

Regarding neuronophagy (de Sand and other authors), that is, the phenomenon of penetration of satellite cells and even leukocytes into nerve cells, as well as their superficial destruction, described by Marinescu and other scientists, I believe, together with the Bucharest neurologist, that it cannot be considered as a result of the destruction of previously dead nerve cells. In the rare cases where phagocytes act, they work not as killers, but as gravediggers.

As a result: neither macrophages nor microphages attack a living neuroma 2 . Even the numerous satellite cells that are found around neuromas during some processes (for example, rabies) do not originate from blood vessels: on the contrary, they pre-exist, forming a galaxy, in normal nervous organs of humans and animals at a young age. By this we do not exclude the possibility that they will reproduce during old age or due to pathological conditions.

1 Cajal: Manual of pathological anatomy (article "Atrophy", 5th ed.). And our book about degeneration and regeneration nervous system. 2nd volume, 1914

2 Cajal: On the relationship between nerve cells and neuroglial cells. In the Quarterly Journal of Micrography (Spanish, Madrid), No. 1, 1897. A similar study shows the common existence in the brain and cerebellum of satellite cells, incorrectly called phagocytes, some of which belong to the type of ordinary neuroglia. Using neurofibrillary methods, the non-penetration of satellite elements (presumed ordinary phagocytes) into sensitive cells of humans and various mammals was demonstrated (1904 and 1905). Mechnikov confused our satellite cells, permanent and common in all mammals, young and old, with leukocytes (macrophages and microphages).