Betrayal from within

Why does the immune system attack the endocrine system? Interview with Corresponding Member of the Russian Academy of Sciences Ekaterina Troshina

Anastasia Rogacheva, "Scientific Russia"

Nobel Prize-winning immunologist Paul Ehrlich at the beginning of the twentieth century considered the idea that the immune system, designed to protect us from diseases, can attack our own body senseless and implausible. Today, patients and doctors know that autoimmune pathologies are more than real, and some of them are associated with a genetic predisposition. About 80 known diseases affect millions of people around the world. At the same time, among the diseases of the endocrine system, autoimmune pathologies make up a significant part. What is the reason for the immune system attacks on your own body? Why do such diseases affect women more often? How does stress trigger autoimmune reactions? Ekaterina Anatolyevna Troshina, Director of the Institute of Clinical Endocrinology of the Federal State Budgetary Institution "National Medical Research Center of Endocrinology" of the Ministry of Health of the Russian Federation, Doctor of Medical Sciences, Corresponding Member of the Russian Academy of Sciences, tells.

— When they talk about autoimmune diseases, they mention that the immune system attacks its own body. Is this formulation correct?

— Indeed, when we talk about autoimmune diseases, we associate them with the motto "Our own against our own". This is a unique situation when immune agents attack the organs of their own body.

Two ancient systems, endocrine and immune, functioning harmoniously and performing the most important functions (ensuring metabolic control of all processes of development and vital activity and protection from agents threatening the body), suddenly come into conflict. Autoimmune aggression is directed against the endocrine glands. Even previously inaccessible to attacking antibodies, "barrier" organs become objects of their attack. The function of the endocrine glands changes, and hormonal regulation disorders, in turn, affect the immune system, weakening it. The conflict of systems arises, develops and progresses.

Among the diseases of the endocrine system, autoimmune pathologies make up a significant part. The World Health Organization attaches great importance to them. It is no coincidence that the XXI century was declared by the WHO as the "century of autoimmune pathology". The number of people suffering from various autoimmune diseases triples every year.

In my work, I often encounter autoimmune pathologies of the endocrine system. But, of course, in our specialty we encounter complex problems and as doctors, as scientists and researchers, we must comprehensively and comprehensively evaluate a patient who suffers from autoimmune endocrinopathy.

— Are only T cells responsible for autoimmune diseases?

— The T-cell block of immunity is the most studied and described today. Scientists and doctors clearly understand the mechanisms by which the immune response with the participation of T cells is realized. But no less interesting from a scientific and practical point of view is the B-cell link of immunity.

It is known that regulatory B-lymphocytes play an important role in the formation of autoimmune pathology. It is important to mention here such concepts as central and peripheral tolerance, which are key in immunology. Violation of these processes eventually leads to autoimmune aggression. Both T-cell and B-cell links are involved in the process of violation of both central and peripheral tolerance.

If we consider diseases of the endocrine system, then there are many problems associated with disorders in the main histocompatibility complex, the so-called HLA system. This is an individual set of different types of protein molecules located on the cell surface. The set of antigens (HLA status) is unique for each person, but certain genetic predispositions lead to disruption of the functioning of the histocompatibility complex. They trigger a cascade of mechanisms that lead to autoimmune diseases.

For example, there are many different pathologies of the thyroid gland — an organ of great importance in the human body. It regulates, in fact, all metabolic processes, including responsible for the formation of the fetal brain.

In practice, there are autoimmune thyroiditis, Graves' disease — autoimmune diseases of the thyroid gland, which are accompanied by a violation of its function. On the one hand, a person may develop hypothyroidism (decreased thyroid function); on the other hand, thyrotoxicosis (increased thyroid function): the reverse situation, in which antibodies seem to replace the thyroid-stimulating hormone receptor. They "sit down" on this receptor and either begin to stimulate it instead of thyroid-stimulating hormone, or block its function. This causes an increase or decrease in the production of thyroid hormones.

Genetic predisposition does not mean that a person is immediately born with a disease, but at some stage of life something happens that becomes a trigger. Most often, a viral infection or stress is responsible for this. Large-scale studies conducted after World War II showed a surge in autoimmune thyroid diseases caused by severe stress. By the way, pregnancy can become such a "trigger" for women. This does not mean that you do not need to get pregnant. It is necessary, but desirable, to know about diseases that have occurred in close relatives, because many genetic aspects are inherited, including a predisposition to autoimmune diseases.

— So autoimmune diseases can be considered hereditary?

- yes. Very often, patients with one autoimmune disease, most often the thyroid gland, or type I diabetes mellitus, come to our Institute of Clinical Endocrinology. These are the most common autoimmune problems in endocrinology. Examining these patients, we begin to identify the so-called latent forms of other autoimmune pathologies.

There are two large blocks of diseases that belong to autoimmune polyglandular syndromes. We are talking about a situation when several organs are affected by an autoimmune attack at once. For example, autoimmune polyglandular syndrome type I is determined by a clear genetic predisposition. In this case, there is a "breakdown" in a single gene of the autoimmune regulator - AIRE.

Autoimmune polyglandular syndrome type II affects the HLA system. Because of this, autoimmune pathology of the thyroid gland, autoimmune insufficiency of the adrenal glands, autoimmune gastritis, autoimmune diabetes mellitus appear sequentially during a person's life.

— Continuing the conversation about type I diabetes, I can't help but ask about the mechanisms. Some studies suggest that beta cells of people with diabetes produce an increased number of molecules that T cells responsible for autoimmune reactions consider targets. What do you think about this theory? Are similar studies being conducted in Russia?

— Of course, such studies are conducted in our country. As I have already said, almost all links of immunity are involved in the pathogenesis of type I diabetes mellitus. There is a situation in which the cells forming the islet of Langerhans, that is, the beta cells of the pancreas, suffer. If earlier we thought that type I diabetes mellitus proceeds according to the same laws, now we are sure that this disease is partly heterogeneous. Today we see a variety of forms of type I diabetes.

— It is known that out of five cases, four are almost always women. Why do autoimmune diseases affect women more often than men?

— It really is. Women, unlike men, get pregnant and give birth to children. And, as we have already said, this is a powerful trigger factor that can trigger autoimmune processes. Moreover, today there is an interesting theory of fetal microchimerism. When a child is in the fetal stage, the blood supply to both him and the mother, in fact, is realized in one system. There is a constant interchange of certain substances between them. After birth, the substances remaining in the mother's bloodstream are called microchimers. These residual elements may be responsible for trigger processes in relation to autoimmune pathologies in the mother. Indeed, there are studies that indicate that autoimmune diseases are more common in mothers with many children. Again, this does not mean that you do not need to have many children! The positive protective mechanisms that pregnancy provides to a woman are indisputable. It is necessary to get pregnant, give birth, it is really good for a woman's health. But it is necessary to keep in mind some aspects, especially with a certain heredity.

There are so-called nuclear families, when several people in the family suffer from the same disease. And this is characteristic of multifactorial damage to the endocrine glands in autoimmune polyglandular syndromes. Therefore, a modern person should know his pedigree. This is extremely important, especially at the stages of family planning. Both a man and a woman should be aware of the risks lurking in their genetics. And if these risks are present, it is necessary to take measures. Today there are opportunities for the birth of a healthy child.

Modern science makes it possible to minimize risks, in some cases — by conducting preimplantation diagnostics. So, future parents can ensure the birth of an absolutely healthy child who will not transmit genetic predispositions to other generations.

— What other reasons, besides stress, can trigger an autoimmune reaction?

— The realities of recent years have clearly shown these reasons. Unfortunately, today, against the background of a pandemic of a new coronavirus infection, the number of people with autoimmune pathology is growing. During the peak of morbidity in Russia, our center was also redesigned. The whole building was reorganized into a red zone, where patients with COVID-19 were treated.

Now we are analyzing our own experience and observing people who have been ill. The results show that the number of people with diabetes mellitus and thyroid pathology is increasing among them. There are patients who, due to a coronavirus infection, have impaired adrenal function. We have yet to study the phenomenon of initiation of autoimmune endocrinopathies associated with the "cytokine storm" suffered by many patients — in fact, a protective reaction of the body aimed at destroying a harmful agent. But in the fight against the virus, cytokines begin to destroy everything in their path, including healthy cells of a number of organs. We are again faced with the situation of "friends against friends" and see the risks of developing cytokine-induced thyroiditis, adrenalitis, pituitary, etc.

— Have you heard about the problem associated with doctors' distrust of patients with unusual symptoms?

— You need to remember that people go to the doctor when they are really worried about something. Therefore, the doctor should always respond to the patient's treatment not with distrust, but with attention. After all, a person does not come to the doctor just like that, he turns for help, looking for answers to his questions when he feels bad. And even if a person came up with something and came to the doctor, it means that he has a certain concern and the duty of the doctor is to help him. V.M. Bekhterev once said: "If the patient does not feel better after talking to the doctor, then this is a bad doctor." The doctor should always evaluate not only the symptoms characteristic of a particular disease, but also the psychological status of a person. It is important that the patient trusts the specialist. Often facial expressions, intonation, behavior, appearance can tell a lot to the doctor. Thus, behavioral changes, including emotional lability and excitability, or inhibition and lethargy, certain skin changes may indicate the development of an autoimmune disease.

For example, a person suddenly has a local swelling of the back surface of the lower leg that looks like an orange peel, which does not hurt at the same time. In this case, a person will most likely turn to a dermatologist, get some recommendations, but in some cases the prescribed treatment will not help. Then the person begins to "walk in circles" in search of answers. And finally, at some stage he will reach the endocrinologist, who will see in the symptoms a manifestation of an autoimmune combined disease - pretibial myxedema, which may accompany Graves' disease (thyroid pathology). It would seem, where is the thyroid gland and where is the shin? But these are links in the development of the same pathological autoimmune process. An endocrinologist will immediately understand that such a patient has a high risk of developing another autoimmune disease — endocrine ophthalmopathy, or "bug-eyed". It should be understood that any component can become the debut of a combined autoimmune pathology. Patients who have become ill with endocrine ophthalmopathy for the first time, as a rule, at the beginning of their journey come to an ophthalmologist with complaints of photophobia, lacrimation, redness of the eyes. They have been treated for conjunctivitis for some time. They are prescribed local treatment, eye drops, but soon the eyes begin to literally fall out of their orbits. It becomes painful for a person to rotate the eyeballs — this is a characteristic symptom of endocrine ophthalmopathy, which in 50% of cases accompanies Graves' disease.

Another example: a person suddenly begins to feel constant weakness. He blames it on vitamin deficiency and stress, fatigue and lack of sleep. The doctor prescribes a course of taking vitamins when applying and advises to rest. However, the person is getting worse and worse. Muscle weakness is forming and growing. And at some point, against the background of this weakness, his skin suddenly begins to darken, his body weight decreases, nausea and cravings for salty food appear. All this is a manifestation of insufficient adrenal function — Addison's disease. This is a dangerous disease that can lead to death if a person is not prescribed replacement therapy in time. In 50-70% of cases, the cause of primary adrenal insufficiency is autoimmune. In the practice of an endocrinologist, there are many unusual, interesting symptoms, and, as a rule, they are really associated with autoimmune pathology of the endocrine system.

— Do autoimmune diseases have a connection with primary immunodeficiency, which are accompanied by similar reactions?

— This connection partly exists. And, of course, research in this direction has been conducted and is being conducted at the moment. There is also evidence that autoimmune diseases of the endocrine organs are indeed more often detected in people with primary immunodeficiency.

— You have told about a lot of frightening symptoms. How effectively are autoimmune diseases cured?

— As a rule, autoimmune pathology of any endocrine organ can lead to both insufficient and excessive function. Therefore, the main task of an endocrinologist is either to make up for hormone deficiency or to suppress their excess. Today, the schemes of such therapy are well developed, we really help our patients. Research is being actively conducted on targeted treatment, which in principle does not allow the development of autoimmune disease in people with a predisposition to it. To do this, it is necessary to identify the problem before the possible "launch" of an autoimmune reaction. Since autoimmune diseases of the endocrine system at the beginning of their development can be almost asymptomatic, a person turns to a doctor only when the clinical picture has already become vivid and certain manifestations of the disease have appeared that cause him concern. At this stage, it is no longer possible to reverse the process.

Nevertheless, understanding the mechanisms of development and the role of the genetic component, we are looking forward to research in the field of genome editing, which in the future will help patients with autoimmune pathologies. Such developments are also being carried out within the walls of the National Medical Research Center of Endocrinology.

— The opinion is also spreading among experts that our immune system is now being insufficiently affected by the outside world and therefore overreacts even to relatively harmless molecules from the outside. How much can we agree with this?

"That's what immunity is for, to react. Immunity is a guardian and protector. Another question is that organs called "barrier", to which biologically antibodies should not be produced, suddenly become available for these antibodies. This is how autoimmune pathology is triggered.

But by itself, immunity is perhaps the oldest adaptation of human biological defense. We encounter both microbes and viruses on a daily basis. This allows the body to form an immune defense. But immunity needs to be helped and vaccinated. There is a National Vaccination Calendar, which is constantly being modified and supplemented. Those who say: "I have a weak immune system, so I'm afraid to get vaccinated are deeply mistaken." This is a delusion that becomes dangerous ignorance if a person does not listen to the advice of specialists. On the contrary, if the immunity is really weak, it is necessary to be vaccinated. Including coronavirus infection. This is the only way to protect your body from numerous problems, in some cases to save your own and your children's lives.

— What do you associate with the rapid increase in the spread of autoimmune diseases?

— The living conditions of modern man have changed dramatically. People began to consume more processed foods, transgenic fats, and move less. Life has become more convenient and faster, but you have to pay for it, and in some cases a person pays with his own health.

However, no one cancels the notorious healthy lifestyle. Man remains the biological being he has always been. At the same time, motor activity was replaced by a sedentary lifestyle. Reduced activity, or inactivity, leads to the fact that the muscles work worse. Because of this, they produce less biologically active substances and hormones, which are also involved in the formation of immunity. The more a person sits, the more he "grows" adipose tissue — a significant producer of many negative pro-inflammatory factors that form the basis of vascular wall lesions (endothelium), lesions of the same endocrine glands, fatty liver infiltration, etc. This cascade of biological relationships, of course, reacts to how a person lives, what he eats, whether he smokes, whether he experiences stress. Obese people are a huge risk group for the development of autoimmune pathology.

Everyone's health is their responsibility. The state, of course, should create conditions for effective healthcare, but whether a person will use these conditions is a matter of individual choice and decision. In order for your children to be healthy, it is extremely important to set their own example. All the key habits of a healthy lifestyle, of course, are laid in the family.

— What about the intestinal microbiome? It is assumed that it also affects the likelihood of an autoimmune disease.

— Of course! The microbiome is a huge world that lives inside us. He can be our friend, or he can become an enemy. This connection between us and the world of bacteria is one of the oldest. Therefore, the microbiome reacts very sensitively to how we live, changes depending on this and at some stage begins to affect human life.

Experimental work carried out at the NMIC of Endocrinology, at the Institute of Diabetes Mellitus, is devoted to the problems of type II diabetes mellitus, obesity and the study of the microbiome. Studies show that when a thin person's microbiome is transplanted to an overweight patient, the latter begins to lose weight. That is, certain colonies of microorganisms that are characteristic of a lean person can take their place in the intestines of a full person, begin to multiply there, behave in their own way and stimulate certain metabolic processes that lead to a decrease in body weight. This is a very interesting direction in modern therapy. Today, perhaps, there is no medical specialty left that would not somehow address the issue of the human microbiome.

— Are there any national peculiarities of the spread of autoimmune diseases that you observe only in Russia?

— Of course, there are national peculiarities. It is known that type I diabetes, for example, is more common for people who live in the north-western regions of our country. And in general, the prevalence of type I diabetes mellitus is growing from east to west, from south to north. St. Petersburg, Karelia and other northern regions of the country are the part of the Russian Federation where type I diabetes mellitus is most common in medical practice. This "geography" of type I diabetes is clearly recorded in the state register of diabetes, which has been maintained by our institution for decades.

But by itself, immunity is perhaps the oldest adaptation of human biological defense. We encounter both microbes and viruses on a daily basis. This allows the body to form an immune defense. But immunity needs to be helped and vaccinated. There is a National Vaccination Calendar, which is constantly being modified and supplemented. Those who say, "I have a weak immune system, so I'm afraid to get vaccinated," are deeply mistaken. This is a delusion that becomes dangerous ignorance if a person does not listen to the advice of specialists. On the contrary, if the immunity is really weak, it is necessary to be vaccinated. Including coronavirus infection. This is the only way to protect your body from numerous problems, in some cases to save your own and your children's lives.

— What do you associate with the rapid increase in the spread of autoimmune diseases?

— The living conditions of modern man have changed dramatically. People began to consume more processed foods, transgenic fats, and move less. Life has become more convenient and faster, but you have to pay for it, and in some cases a person pays with his own health.

However, no one cancels the notorious healthy lifestyle. Man remains the biological being he has always been. At the same time, motor activity was replaced by a sedentary lifestyle. Reduced activity, or inactivity, leads to the fact that the muscles work worse. Because of this, they produce less biologically active substances and hormones, which are also involved in the formation of immunity. The more a person sits, the more he "grows" adipose tissue — a significant producer of many negative pro-inflammatory factors that form the basis of vascular wall lesions (endothelium), lesions of the same endocrine glands, fatty liver infiltration, etc. This cascade of biological relationships, of course, reacts to how a person lives, what he eats, whether he smokes, whether he experiences stress. Obese people are a huge risk group for the development of autoimmune pathology.

Everyone's health is their responsibility. The state, of course, should create conditions for effective healthcare, but whether a person will use these conditions is a matter of individual choice and decision. In order for your children to be healthy, it is extremely important to set their own example. All the key habits of a healthy lifestyle, of course, are laid in the family.

— What about the intestinal microbiome? It is assumed that it also affects the likelihood of an autoimmune disease.

— Of course! The microbiome is a huge world that lives inside us. He can be our friend, or he can become an enemy. This connection between us and the world of bacteria is one of the oldest. Therefore, the microbiome reacts very sensitively to how we live, changes depending on this and at some stage begins to affect human life.

Experimental work carried out at the NMIC of Endocrinology, at the Institute of Diabetes Mellitus, is devoted to the problems of type II diabetes mellitus, obesity and the study of the microbiome. Studies show that when a thin person's microbiome is transplanted to an overweight patient, the latter begins to lose weight. That is, certain colonies of microorganisms that are characteristic of a lean person can take their place in the intestines of a full person, begin to multiply there, behave in their own way and stimulate certain metabolic processes that lead to a decrease in body weight. This is a very interesting direction in modern therapy. Today, perhaps, there is no medical specialty left that would not somehow address the issue of the human microbiome.

— Are there any national peculiarities of the spread of autoimmune diseases that you observe only in Russia?

— Of course, there are national peculiarities. It is known that type I diabetes, for example, is more common for people who live in the north-western regions of our country. And in general, the prevalence of type I diabetes mellitus is growing from east to west, from south to north. St. Petersburg, Karelia and other northern regions of the country are the part of the Russian Federation where type I diabetes mellitus is most common in medical practice. This "geography" of type I diabetes is clearly recorded in the state register of diabetes, which has been maintained by our institution for decades.

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