Throughout the twentieth century, until the early 1990s, scientists conducted research on immunity based on the belief that higher vertebrates, and in particular humans, possess the most advanced immune system. That’s what you should study first. And if something has not yet been “discovered” in the immunology of birds, fish and insects, then this probably does not play a special role in advancing the understanding of the mechanisms of protection against human diseases. Immunology as a science originated 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 to be the great Louis Pasteur, who began to look for a solution to the survival of the human race, despite the regular devastating epidemics of plague, smallpox, cholera, which descend on countries and continents like a punishing sword of fate. Millions, tens of millions of dead. But in towns and villages where funeral teams did not have time to remove corpses from the streets, there were those who coped with the deadly scourge on their own, without the help of healers and sorcerers. As well as those who were completely untouched by the disease. This means that there is a mechanism in the human body that protects it from at least some external intruders. It is called immunity. Pasteur developed ideas about artificial immunity, developing methods for its creation through vaccination, but gradually it became clear that immunity exists in two guises: 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, two theories and two schools, Paul Ehrlich and Ilya Mechnikov, clashed in an acute scientific debate in response to this fundamental question. Ilya Ilyich Mechnikov. “An outstanding Russian naturalist…” — this is how the articles in Soviet encyclopedic publications began. He graduated from the Kharkov University, trained in scientific and educational institutions in Europe, returned to Russia, he taught at Odessa, but “after a collision with the reaction educators” in 1887 he went to Germany, and in the autumn of 1888 at the invitation of L. Pasteur moved to Paris and the rest of his life he worked at the Pasteur Institute, where (is also a quote from the Great medical encyclopedia, 1960 edition) “created the school of Russian and foreign microbiologists, and Parasitologists, immunologists”. Paul Ehrlich has never been to Kharkov or Odessa. He studied at his universities in Breslau (now Breslau) 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 bears his name today. And here it should be recognized that conceptually, Ehrlich has done more for immunology in the entire history of this science than anyone else. Paul Ehrlich (1854-1915) Mechnikov discovered the phenomenon of phagocytosis, the capture and destruction of microbes and other biological particles foreign to the body by special cells — macrophages and neutrophils. This mechanism, he believed, is the main one in the immune system, building lines of defense against invading pathogens. It is the phagocytes that attack, causing an inflammatory reaction, for example, with an injection, splinter, etc. Ehrlich argued the opposite. The main role in protecting against infections belongs not to cells, but to 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. Interestingly, the 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 that time the theoretical and practical successes of Ehrlich and his followers seemed to completely refute Mechnikov’s views. It was even rumored that the prize was awarded to the latter rather on the basis of merit (which is not at all excluded and not shameful: immunology is just one of the fields in which the Russian scientist worked, his contribution to world science is huge). However, even 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, and Mechnikov outlived his opponent by only a year, so the most fundamental scientific dispute developed without the participation of its initiators until the end of the century. In the meantime, everything that happened in immunology over the next decades proved Paul Ehrlich right. It was found that white blood cells, lymphocytes, are divided into two types: B and T (here it should be emphasized that the discovery of T-lymphocytes in the middle of the twentieth century brought the science of acquired immunity to a completely different level — the founders could not have foreseen this). They are the ones who organize protection against viruses, microbes, fungi and generally 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 contribute to the removal of 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 with their own, but degenerated protein in the same way, which becomes dangerous to the body. Unfortunately, this ability, in the event of a malfunction in the configuration of the most complex mechanism of adaptive immunity, can cause autoimmune diseases, when lymphocytes, having lost the ability to distinguish their proteins from others, begin to “shoot at their own”… Charles Janeway (1943-2003) Thus, until the 80s of the twentieth century, immunology mainly developed along the path indicated by Ehrlich, rather than By Mechnikov. Adaptive immunity, incredibly complex and fantastically sophisticated over millions of years of evolution, 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 received antibiotics that could suppress the biological activity of the aggressor, thereby facilitating the work of lymphocytes. True, since many microorganisms are in symbiosis with their host, antibiotics are no less enthusiastic about attacking their allies, weakening and even nullifying their useful 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 to the horizon, because over time questions appeared and accumulated that the prevailing theory found it difficult 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 from 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 there are a lot of organisms in the human microflora that, it would seem, are simply obliged to cause diseases and initiate an immune response. However, this is not happening. There are dozens of similar questions. They remained open for decades.

In 1989, the American immunologist Professor Charles Janeway published a paper that was very soon recognized as visionary, although, like Mechnikov’s theory, it had and still has serious, erudite opponents. Janeway suggested that there are special receptors on human cells responsible for immunity that recognize some structural components of pathogens (bacteria, viruses, fungi) and trigger a response mechanism. Since there are innumerable potential pathogens in the sublunary world, Janeway assumed that the receptors would recognize some kind of “invariant” chemical structures characteristic of a whole class of pathogens. Otherwise, there simply won’t be enough genes! Jules Hoffmann 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 protective system that was previously misunderstood and unappreciated. It turned out that this fruit fly has a special gene that is not only important for the development of the larva, but is also associated with innate immunity. If this gene is corrupted in a fly, it will die when infected with fungi. Moreover, he will not die from other diseases, for example, bacterial ones, but from fungal ones – inevitably. The discovery allowed us to draw three important conclusions. Firstly, the primitive fruit fly is endowed with powerful and effective innate immunity. Secondly, its cells have receptors that recognize infections. Thirdly, the receptor is specific to a certain class of infections, that is, it is not able to recognize any foreign “structure”, but only a well-defined one. But this receptor does not protect against another “structure”. It is these two events — an almost speculative theory and the first unexpected experimental result — that should be considered the beginning of the great immunological revolution. Then, as happens in science, events developed incrementally. Ruslan Medzhitov, who graduated from Tashkent University, then completed postgraduate studies at Moscow State University, and later became a professor at Yale University (USA) and a rising star of world immunology, was the first to discover these receptors on human cells. Ruslan Medzhitov It turned out that we have at least a dozen of them. Everyone specializes in a specific class of pathogens. To put it simply, one recognizes gram—negative infections, the other gram—positive, the third fungal, the fourth proteins of unicellular parasites, the fifth viruses, and so on. The receptors are located on many types of cells and even on skin and epithelial cells. But first of all, on those responsible for innate immunity, phagocytes. Similar receptors have been found in amphibians, fish, other animals, and even plants (although the mechanisms of innate immunity function differently in the latter). So, after almost a hundred years, the long-standing theoretical dispute of the great scientific rivals was finally resolved. He decided that both were right — their theories complemented each other, and I. I. Mechnikov’s theory received a new experimental confirmation. In fact, a conceptual revolution has taken place. It turned out that innate immunity is the main thing for all beings on Earth. And only the most “advanced” organisms on the ladder of evolution, the higher vertebrates, have acquired immunity in addition. However, it is innate who directs its launch and subsequent work, although many details of how all this is regulated have yet to be established.

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 a general (and very simplified) way, it goes something like this. A weakened pathogen (usually a virus or bacterium) 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, such as antibodies, then its material carriers can be purified and transferred into human blood, while simultaneously transferring the protective mechanism. In other cases, a weakened (or killed) pathogen infects or immunizes the person himself, hoping to trigger an immune reaction that can protect against the real causative agent of the disease and even gain a foothold in cellular memory for many years. This is how Edward Jenner vaccinated against smallpox for the first time in the history of medicine at the end of the 18th century. 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, there is no response to many simple chemical compounds or proteins that are foreign to the body and would simply have to initiate an immune system response! And this often happens because the mechanism of the main defender — innate immunity — remains undetected. The drosophila, mutated by the Toll gene, overgrown with fungi and died because it does not have immune receptors that recognize fungal infections. 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 a hostile antigen is mixed with an adjuvant. The adjuvant is a kind of mediator, an assistant in immunization, in Freund’s experiments it consisted of two components. The first one, a water—oil suspension— performed the purely mechanical task of slowly releasing the antigen. And the second component is, at first glance, rather paradoxical: dried and well—crushed tuberculosis bacteria (Koch’s bacilli). The bacteria are dead, they are not capable of causing infection, but the receptors of the innate immune system will immediately recognize them anyway and turn on the protective mechanisms at full capacity. That’s when the process of activating the adaptive immune response to the antigen that has been mixed with the adjuvant begins. Freund’s discovery was purely experimental and therefore may seem private. But Janeway caught a moment of general significance in it. Moreover, he even called the inability to induce a full-fledged immune response to a foreign protein in experimental animals or humans “a dirty little secret of immunologists” (hinting that this can only be done in the presence of an adjuvant, and no one understands how an adjuvant works). Janeway suggested that the innate immune system recognizes bacteria (both live and killed) by the components of the cell walls. Bacteria that live “on their own” need strong, multi-layered cell membranes for external protection. Our cells, however, do not need such shells under the powerful cover of external protective tissues. And bacterial membranes are synthesized with the help of enzymes that we do not have, and therefore the components of the bacterial walls are precisely those chemical structures, ideal signals of the threat of infection, for which the body has produced recognition receptors in the process of evolution.

A small digression in the context of the main topic

There was 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, but not another. Those that turned pink are now called gram—positive in honor of the scientist, and those that remained colorless are gram-negative. There are millions of different bacteria in each class. Harmful, neutral, and even beneficial to humans, they live in soil, water, saliva, intestines, and anywhere. Our protective receptors are able to selectively identify both, including appropriate protection against those that are dangerous to their host. And Gram’s dye could distinguish them by binding (or not binding) to the same “invariant” components of the bacterial walls.

It turned out that the walls of mycobacteria — namely, tuberculosis bacilli — are particularly complex and are recognized by several receptors at once. That’s probably why they have excellent adjuvant properties. So, the point of using an adjuvant is to deceive the immune system, to send it a false signal that the body is infected with a dangerous pathogen. Make them react. But in fact, there is no such pathogen in the vaccine at all or it is not so dangerous. There is no doubt that it will be possible to find other adjuvants, including non-natural ones, for immunizations and vaccinations. This new field of biological science is of great importance for medicine.

Modern technologies make it possible to turn off (“knock out”) the only gene in an experimental mouse that encodes one of the innate immunity receptors. For example, it is responsible for recognizing the same gram-negative bacteria. Then the mouse loses its ability to provide protection and, being infected, dies, although all other components of its immunity are not impaired. This is how the work of immune systems at the molecular level is being experimentally studied today (we have already discussed the example of a fruit fly). At the same time, clinicians are learning to link people’s lack of immunity to certain infectious diseases with mutations in specific genes. For hundreds of years, there have been examples where in some families, clans, and even tribes, the mortality rate of children at an early age from very specific diseases was extremely high. Now it becomes clear that in some cases the cause is a mutation of some component of innate immunity. The gene is turned off — partially or completely. Since most of our genes are in two copies, we need to make sure that both copies are corrupted. This can be “achieved” as a result of closely related 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 defect of immunity is purposefully protected from a dangerous infection until the age of 2-3, then with the completion of the formation of the immune system, the mortal danger for him may pass. Even without one level of protection, he will be able to cope with the threat and, perhaps, live a full life. The danger will remain, but its level will decrease significantly. There is still hope that someday gene therapy will enter into everyday practice. Then the patient will simply need to transfer the “healthy” gene, without mutation. In a mouse, scientists can not only turn off a gene, but also turn it on. It’s much more difficult for humans.

It is worth remembering another foresight of I. I. Mechnikov. A hundred years ago, he linked the activity of the 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, recent studies have 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 digestive 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 the receptors of innate immunity, bacteria send certain “tonic” signals to the body, 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 intestine, in particular from the abuse of antibiotics), then this is one of the factors for the possible development of cancers of the intestinal tract. *** Twenty years have passed since the last (is it the last?) Revolutions in immunology are too short a time for the widespread practical application of new ideas and theories. Although there is hardly a single serious pharmaceutical company left in the world that develops 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 (do not forget that they must act together — friendship has won) — it will inevitably lead to significant progress in medicine. There is no doubt about it. You just have to wait a bit. But where procrastination is highly undesirable is in educating the population, as well as in changing stereotypes in teaching immunology. Otherwise, our pharmacies will continue to be full of homegrown medicines that supposedly universally enhance immunity. Author: Sergey Nedospasov, Corresponding Member of the Russian Academy of Sciences Boris Rudenko, columnist for the Nauka i Zhizn magazine, Nauka i Zhizn, No. 9, 2010