The Great Immunological Revolution
"Science and Life" No. 9-2010
Corresponding Member of the Russian Academy of Sciences Sergey Nedospasov,
Boris Rudenko, columnist of the magazine
Revolutionary breakthroughs in any field of science occur infrequently, once or twice a century. And in order to realize that the revolution in the knowledge of the surrounding world has really happened, to evaluate its results, the scientific community and society as a whole sometimes takes more than one year or even more than one decade. In immunology, such a revolution happened 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.
Two schools, two theoriesThroughout the twentieth century, up to the beginning of the 1990s, in the research of immunity, scientists proceeded from the belief that the highest vertebrates, and in particular humans, have the most perfect immune system.
That's what you should study first. And if something is still "undiscovered" in the immunology of birds, fish and insects, then it most likely does not play a special role in advancing on the path of understanding 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 great Louis Pasteur is rightfully considered the founding father of immunology, 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 cities 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. And also those who have not been affected by the disease at all. This means that there is a mechanism in the human body that protects it from at least some intrusions from the outside. 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 hypostases: natural (innate) and adaptive (acquired). Which one is more important? Which of them plays a role in successful vaccination? At the beginning of the twentieth century, in response to this fundamental question, two theories, two schools – Paul Ehrlich and Ilya Mechnikov - collided in an acute scientific controversy.
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 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 bears his name today. And here it should be recognized that conceptually, Ehrlich has done more for immunology in the entire history of the existence of this science than anyone else.
Mechnikov discovered the phenomenon of phagocytosis – the capture and destruction of microbes and other biological particles alien to the body by special cells – macrophages and neutrophils. It is this mechanism, he believed, that is the main one in the immune system, building lines of defense against the invasion of pathogens. It is the phagocytes that rush into the attack, causing an inflammatory reaction, for example, with a prick, 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 was called the theory of humoral immunity.
Interestingly, irreconcilable scientific rivals – Mechnikov and Ehrlich – shared the Nobel Prize in Physiology and 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 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 only one of the areas 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, Mechnikov outlived his opponent by only a year, so that 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 the correctness of Paul Ehrlich. 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 transferred the science of acquired immunity to a completely different level – the founders could not have foreseen this). It is they who organize protection against viruses, microbes, fungi and in general from substances hostile to the body. B-lymphocytes produce antibodies that bind a 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 repeated infection. These protective lines are able to deal with their own, but degenerated protein in the same way, which becomes dangerous for the body. Unfortunately, such an ability, in the event of a failure in setting up 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"…
Thus, until the 80s of the twentieth century, immunology mainly developed along the path indicated by Ehrlich, and not by Mechnikov. Incredibly complex, fantastically sophisticated 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 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 the host, antibiotics are equally 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, were moving further and further to 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 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 does not happen.
There are dozens of similar questions. They have remained open for decades.
How revolutions begin
In 1989, the American immunologist Professor Charles Janeway published a work 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, Janway suggested that the receptors would also recognize some "invariant" chemical structures characteristic of a whole class of pathogens. Otherwise, there just 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 protective system, 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 larva, but is also associated with innate immunity. If this gene is damaged in the fly, then when infected with fungi, it dies. Moreover, it will not die from other diseases, for example, of a bacterial nature, but from a fungal one – inevitably. The discovery allowed us to draw three important conclusions. Firstly, the primitive fruit fly is endowed with a 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 able to recognize not any foreign "structure", but only a well-defined one. And 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 incrementally. Ruslan Medzhitov, who graduated from Tashkent University, then 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.
It turned out that we have at least a dozen of them. Everyone specializes in a certain 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 that are 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. I decided that both were right – their theories complemented each other, and I. I. Mechnikov's theory received a new experimental confirmation.
And in fact there was a conceptual revolution. It turned out that for all beings on Earth, innate immunity is the main thing. And only the most "advanced" organisms on the ladder of evolution – higher vertebrates, in addition, have acquired immunity. 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.
"His Excellency's Adjuvant"New views on the interaction of the innate and acquired branches of immunity helped to understand what was still unclear.
How do vaccines work when they work? In general (and very simplified) form, this happens 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 – antibodies, then its material carriers can be purified and transferred into the human blood, simultaneously transferring the protective mechanism. In other cases, a weakened (or killed) pathogen infects or immunizes the person himself, hoping to cause 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, at the end of the XVIII century, for the first time in the history of medicine, vaccinated 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.
(Immunity after vaccination developed in the 20s of the last century and still used by the BCG anti-tuberculosis vaccine is weakening over the years, but with the question of why the article says that there is no such vaccine at all, contact the authors – VM.)
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 for the reason that the mechanism of the main defender – innate immunity – remains undisturbed.
One of the ways to overcome this obstacle was experimentally demonstrated by the American pathologist J. Freund (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, a water–oil suspension, performed a purely mechanical task of slow release of the antigen. And the second component is quite paradoxical at first glance: dried and well–crushed tuberculosis bacteria (Koch sticks). The bacteria are dead, they are not able to cause infection, but the receptors of innate immunity will still immediately recognize them and turn on the defense mechanisms at full capacity. That's when the process of activating the adaptive immune response to the antigen that was mixed with the adjuvant starts.
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 in 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).
Janway also suggested that the innate immune system recognizes bacteria (both live and killed) by the components of the cell walls. Bacteria that live "by themselves" need strong multilayer cell membranes for external protection. Our cells, under the powerful cover of external protective tissues, do not need such shells. And bacterial shells are synthesized with the help of enzymes, which we do not have, and therefore the components of bacterial walls are just those chemical structures, ideal signaling agents of the threat of infection, for which the body has made identification 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 the other. 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 of the classes. For humans – harmful, neutral and even useful, they live in the soil, water, saliva, intestines – anywhere. Our protective receptors are able to selectively identify both, including appropriate protection against dangerous ones for their carrier. And Gram's 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, tubercle 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, including non-natural, adjuvants for immunizations and vaccinations. This new direction of biological science is of enormous importance for medicine.
Turn on-turn off the desired geneModern technologies make it possible to turn off ("knock out") a single gene in an experimental mouse that encodes one of the receptors of innate immunity.
For example, responsible for the recognition of the same gram-negative bacteria. Then the mouse loses the ability to provide its protection and, being infected, dies, although all other components of its immunity are not violated. This is how the work of immune systems at the molecular level is being 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, there have been examples when in some families, genera and even tribes, the mortality rate of children at an early age from absolutely certain 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, will 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 just have to transfer a "healthy" gene, without mutation. In mice, scientists are able not only to turn off the gene, but also to turn it on. In humans, this is much more difficult.
About the benefits of yogurtIt is worth remembering another foresight of I. I. Mechnikov.
A hundred years ago, he associated 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 here 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 believed. 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 the 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 oncological diseases of the intestinal tract.
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Twenty years since the last (is it the last?) revolutions in immunology are too short a time for the wide 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 is developing 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) – will inevitably lead to significant progress in medicine. There is no need to doubt this. It should only wait a little.
But here's where procrastination is extremely undesirable, so it's 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.
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Sergey Arturovich Nedospasov – Head of the Department of Immunology of the Faculty of Biology of Lomonosov Moscow State University, Head of the Laboratory of the V. A. Engelhardt Institute of Molecular Biology of the Russian Academy of Sciences, Head of the Department of the A. N. Belozersky Institute of Physico-Chemical Biology.
Portal "Eternal youth" http://vechnayamolodost.ru10.09.2010