— Why do some people suffer from numerous allergies and autoimmune diseases while others don't?
— Some people are inherently prone to developing autoimmune diseases, but this is pretty rare. Such individuals have some congenital defect in their immune system, a genetic anomaly or trait. Everyone's genome is slightly different, with minor errors accumulating over generations, but these errors vary for each person. Occasionally, someone gets unlucky, and their immune system is configured so that the likelihood of developing an autoimmune disease is significantly higher than the population average.
However, autoimmune diseases are widespread and common, posing a significant burden for humanity. The vast majority of these diseases appear to be acquired, not necessarily because someone is particularly predisposed to them.

— Why then?
— We are products of evolution, and our immune system has evolved to enhance our chances of survival and reproduction and possibly to ensure a lifespan long enough to, for example, allow grandparents to care for their grandchildren. The immune system has developed a vast array of different immune receptors to recognise any infection.
These receptors come in millions and billions of variants on the surfaces of T- and B-cells, the cells of adaptive immunity. Thanks to these receptors, lymphocytes can identify almost any pathogen or infection, including highly diverse and constantly evolving viruses, bacteria, and fungi. To recognise new molecules that we haven't encountered before in the process of evolution, adaptive immunity generates hundreds of millions of receptor molecule variants in each of us and many billions, possibly even trillions, at the population level.
Thus, the immune system is designed to recognise the entire universe of potential pathogens theoretically. However, this creates a balance problem: on the one hand, we need a vast diversity of receptors to identify many different pathogens, but on the other hand, with such diversity, the immune system must not attack our own bodies. This is a complex mathematical challenge for the immune system: creating a set of receptor molecules with sufficient variety to recognise almost anything extraneous while ensuring they do not bind to parts of our body.
For this, receptors are first selected to avoid attacking our own tissues. Secondly, especially in the first few weeks and months after birth, but also later, the human immune system gathers information about the molecules we may meet in the world. Our body has many proteins, DNA, and RNA molecules, which are also present in food, the air, and the microbiota –– bacteria that inhabit our intestines. The immune system trains itself by interacting with these substances, recognising them as harmless and storing this information. This helps minimise allergic and autoimmune reactions.
The immune system creates a catalogue of different molecules throughout our lives, which is continually updated and stored. This catalogue includes memories of past infections and tolerance to safe antigens. Additionally, it is crucial not only to recognise pathogen molecules but also to remember how best to activate the immune system: one response is needed for a virus and another for bacteria. In essence, it learns and remembers what to do if we encounter a certain molecule again.

— What happens if a T-cell meets the molecule it was designed to recognise for the first time?
— Most of the diverse T-cell receptors, those billions of dormant keys, will never be needed. However, if one is activated, the lymphocyte carrying it is activated and begins to multiply, producing clone copies with this receptor. These clones travel to the infected tissues to find the pathogen detected by the original lymphocyte. After this initial adaptive immune response, memory T-cell clones are formed, which carry the same receptor. These clones remember the tissues in which they have to be present mostly and how to neutralise the pathogen carrying the activating antigen molecule. T-cells can perceive danger signals from other cells, exchange information, and process and interpret it.
This entire system, capable of handling information about foreign molecules that are dangerous and harmless and making and remembering decisions, is called adaptive immunity.

— So, adaptive immunity is another memory system in our body? Not just a memory but almost like an alternative mind: it’s analysing information, categorizing, and making conclusions?
— Yes, this system analyses information about which antigens were encountered, under what circumstances, and in which tissues. It decides what action to take, remembers the decision, and can reproduce it, though it may forget it over time. As with other types of memory, sometimes it's healthier to forget than to remember.
And indeed, it functions as a form of intelligence — an independent, separate intelligence. On the other hand, the immune system continually interacts with the nervous system through various channels. This intelligence protects us, preventing us from getting seriously ill with the same infections repeatedly.

— And autoimmune diseases are errors of this intelligence, something like perceptual illusions?
— Yes, the "immune intelligence" makes millions of decisions throughout our lives. Given the system's complexity, it's impossible to eliminate errors completely. In fact, quite a few such errors occur. These aren't the only major mistakes where the immune system attacks our own cells, leading to autoimmune diseases. There are also less obvious errors. For example, the immune system might mistakenly start a response suited for a viral infection when encountering a bacterial one, or it might conflict with beneficial gut bacteria.
The accumulation of such errors leads to excessive immune activity, inflammation, and the death of our own cells. There's a term "inflammaging" which refers to age-related inflammation. This is where the ability to forget would be useful, but our immune system is bad at forgetting these errors. As people age, they not only acquire useful habits but also some harmful ones. The immune system is similar in this respect.
Interestingly, the balance of remembering and forgetting can be different in other animals. We study a long-lived rodent called a blind mole rat, which lives underground and has a long lifespan, similar to the naked mole rat known for its healthy longevity. Although these animals aren't closely related, their evolution has followed parallel paths, as a result of which they get ill rarely and mildly and do not develop age-related inflammation when they get older.

— How long do blind mole rats live?
— While their close relatives live for a couple of years, blind mole rats live for at least twenty years, though the exact lifespan is uncertain. It's quite difficult to measure because when you catch the animal, it appears young. Regardless of their age, they look and behave the same. They stay cheerful, healthy, and enthusiastic about mating throughout their lives.

— What is the blind mole rat’s secret?
— TBlind mole rats live in small family groups underground and apparently don't interact much with others. This may reduce the need for their immune system to protect against epidemics since the likelihood of infection spread is lower. Their adaptive immunity is generally similar to ours, but their immune memory doesn't last as long.
The secret of the blind mole rat is in its forgiving. Its immune system doesn't accumulate memory T-cell clones as it ages or accumulates to a much lesser extent.

— So, the mole rat's balance between vigilance against foes and the risk of harm to friends is different: its immune system is less vigilant but also causes less friendly fire.
— Yes, and the duration of the immune response is crucial here. Allowing the immune system to remember and replicate responses throughout life places a lot of responsibility on it. If it makes a mistake, it can cause long-term problems, potentially forever-problems. Accidental inflammation isn't an issue as it will pass, but a lifelong memory of a mistaken response leads to chronic inflammation. This creates an "inflammatory niche," which can eventually lead to cancer, among other things.
However, it would also be problematic if the immune system forgets everything too quickly. For instance, if T-cells forget how to respond to COVID-19, we'd be vulnerable when it comes again.

— Can we at least partially learn from a blind mole rat's forgetfulness?
— It's difficult. Our bodies accumulate hundreds of thousands of memory clones over time, many of which, perhaps hundreds or thousands, have errors. We'd like to shed this burden and become young again, but it's extremely challenging. If you completely reset the immune memory, you face significant risks. You'd lose your tolerance to your own microbiota, food, and other familiar elements, as well as your protection from viruses and bacteria you've previously encountered. The consequences of a complete reset would be severe. The goal would be to reset it carefully, ideally targeting those clones that are chronically activated even though you live in a generally healthy environment.
There are ideas and developing approaches. There is hope we can learn from the blind mole rat. It has certainly taught me a lot. Studying this animal has been crucial in forming a comprehensive understanding of how the immune system can function correctly and incorrectly. When I saw in the example of the mole rat that the immune system can be configured differently, the puzzle that had long been challenging finally began to come together.

— So, are autoimmune diseases the price humanity pays for having an overly effective defense against infections?
— Autoimmune diseases are essentially errors made and perpetuated by our immune system. The horror and beauty of the situation is that a person can fall seriously ill or even die because a single cell in their body chose to multiply and survive, leading to millions of identical cells that are poised to attack their own tissues.

— Is there a way to halt this army of clones?
— This is the goal of our research. We must somehow disrupt these specific lymphocyte clones carrying receptors that react to our own molecules. They must be found, and then we must target, destroy, or suppress them. But finding them is not easy.
On the other hand, we can engineer cells that suppress immune responses to particular antigens, known as regulatory T-cells. Researchers are developing a vaccine to present to the immune system molecules it mistakenly identifies as threats and “explain” to it that these are “good molecules.” We are also exploring this possibility now. Then, the immune system itself will begin to produce clones of regulatory T-cells. To make such a vaccine, it is not even necessary to know what the desired lymphocyte clone looks like—you just need to know the molecule to which it is responding erroneously. Such a vaccine will bring to life populations of lymphocyte clones that will also recognise this antigen and calm the immune system that is defending itself in vain against it.

— It turns out that this is the complete opposite of conventional vaccines that help the body recognise the pathogen on time and protect itself…
— Yes, such a vaccine, on the contrary, antigen-specifically blocks the immune system. Such vaccines, designed for a group of specific antigens, can be relatively universal and suitable for many people suffering from autoimmune diseases.
Another approach is a drug we created for the treatment of ankylosing spondylitis, Seniprutug. It passed the second phase of clinical trials and was registered in April this year and is now due to appear on the market. This is an antibody, a protein that sticks to lymphocytes that carry the error that causes ankylosing spondylitis. And the cells covered with antibodies are eaten by macrophages and natural killers. These immune cells in the body follow a simple principle: if something is covered with antibodies, it means it’s something bad, it must be killed.

— And do these harmful lymphocytes continue to be produced throughout a person's lifetime? And must medication be taken continuously to ensure that macrophages consume them?
— This is a complicated question. T-cells originate from the thymus (hence the "T" in their name), an organ located just above the heart. The activity of the thymus diminishes significantly with age. Even if new clones of harmful lymphocytes are reproduced, there's no guarantee they will make the same mistake.
However, there is a risk of their proliferation. Moreover, completely eliminating all cells from such clones with this medication is quite challenging. Some cells may hide and survive. Therefore, our patients receive treatment 2-3 times a year in clinical trials. We are not yet certain, but perhaps in a few years, it might be possible to discontinue therapy, and these clones will not reemerge. Time will tell, we have not yet accumulated enough experience.

— What happened with the COVID-19 vaccines, and why did multiple vaccinations fail to provide absolute protection?
— The virus evolves rapidly, adapting to our immune systems. This complicates vaccine development because the virus may have already mutated by the time a vaccine is developed. The process was further accelerated by the creation of populations where half were vaccinated, and half were not — a perfect environment for the virus to generate new variants among the unvaccinated and try to infect the vaccinated whenever possible. Essentially, the virus is constantly seeking ways to overcome the vaccine. While this challenge was predicted, it could not be resolved.

— And a vaccine against flu that would protect once and for all still hasn’t been created.
— Dealing with the flu virus is even more challenging because it infects not only humans but also a vast variety of other mammals and birds. Different strains of the flu virus constantly exchange genetic material, making it difficult to predict the nature of the upcoming flu season.
A flu vaccine should have antibodies capable of recognising various strains of the virus. However, developing antibodies that can effectively target multiple strains is difficult. Different infections have conservative regions associated with their most basic functions. But the virus “does not like” that its structure contains such conservative regions, unchanged in all strains. After all, they can be recognised by the same antibody. Such strains are easily detected by the immune system and eventually die out. To evade this recognition, viruses intentionally present our immune system with diverse, attractive regions that vary among strains. As a result, the immune system does not form broad-spectrum antibodies to the flu virus.
However, it is possible to make an artificial vaccine that would present the conservative areas that are the same in different strains of the flu virus to our immune system. Theoretically, this is possible, but there is no such vaccine yet.

— Let's go back to the beginning of our conversation. I still haven't fully grasped why some people develop autoimmune diseases while others do not.
— To a large extent, it's often just a matter of chance. One twin may develop an autoimmune disease while the other may not. Susceptibility to autoimmune diseases can also be influenced by the types of infections and stresses encountered at different stages of life. Infections sometimes confuse the immune system, making it more prone to errors. It's possible, therefore, that infections themselves can trigger autoimmune diseases. Moreover, autoimmune diseases can arise simply because certain viral molecules resemble molecules in our own cells, leading the immune system to attack our own tissues mistakenly.

— I’ve seen a research in which babies were exposed to various common allergens, like peanut butter, as a result they developed fewer allergies.
— Yes, there is substantial evidence suggesting that early exposure to different antigens in the first months and years of life is crucial for the immune system to know the environment. This exposure helps train memory cells that learn to recognise harmless and normal substances so they don't have to do anything about them –– don’t have to attack them.

— This immediately suggests a particular educational approach...
— "Try this, try that"? I believe it first prompts us to reconsider the overly sterile handling of children. In the modern world, we have a unique opportunity that never existed before — to surround children with nearly sterile environments. We may think we're protecting them from infections, and our instinct to maintain cleanliness is commendable and important. However, everything should be balanced. Opting for a sensible and healthy approach would involve letting children know their environment, especially in the early months after birth. Of course, this doesn't mean exposing them to dirt or every possible infection immediately.
As the first few months pass, the immune system transitions to a more robust defense mode, becoming more reactive to potential threats. This might explain why some vaccines are less effective in newborns: their immune systems are still very tolerant of new stimuli. Therefore, infancy is a delicate period where caution is warranted, but a reasonable introduction to food and airborne allergens is crucial during this time. Studies show that children raised in rural areas tend to have significantly fewer allergies than their urban counterparts.

— I really appreciated the metaphor comparing adaptive immunity to a cognitive system, another form of memory, or even intellect that makes decisions. But does this "mind" interact with our nervous system? For instance, asthma appears to involve an autoimmune component but often arises following stress or trauma. How does this connection occur?
— This area is still poorly understood. It's known that regulatory lymphocytes reside directly on neuronal endings, suggesting they can interact and exchange information. Autoimmune diseases may correlate with certain psychiatric symptoms; for example, depression is often associated with multiple sclerosis. Conversely, a medication for psoriatic arthritis has antidepressant effects.
Yet, there's much left to understand. What's clear is that there's undoubtedly an interaction between the immune and nervous systems. This interaction occurs bidirectionally: the nervous system influences the behaviour of immune cells, and immune cells, in turn, communicate with our nervous system in some manner.

— What do immunologists dream of? What can we hope for in 20 years?
— I believe that immunotherapy will advance methods to reset these age-old immune system errors over the next two decades essentially rejuvenating it. This could alleviate the burden of inflammatory processes in the body and potentially reduce cancer incidence, as inflammation is often at its core.

— And what about the burden of aging? At least to some extent.
— To a significant degree, yes. There are two distinct causes of aging in our bodies. One is our predetermined lifespan, which spans our maturation, development, and eventual decline — roughly around 110 years. If our immune system didn't make mistakes, we might all live to around 110 years, healthy like mole rats, and peacefully pass away without suffering.
Evolution hasn't yet equipped us with such an immune system, but perhaps it has made us immunologists for this very purpose.

— The Wikipedia page about you starts by noting that you are not just a scientist but also a children's author. How did that come about?
— Quite unexpectedly. I was reading Gerald Durrell's The Talking Parcel to my daughter. This is a delightful fantasy book for children. The book turned out to be very cool.
She eagerly asked, "What happens next?" But there is no sequel. That's when the idea struck me to write one myself, thinking I could finish it in about two months.
However, it took me four years. Writing a children's book, even a short one, was incredibly challenging. I meticulously crafted every sentence, aiming to capture the essence of Durrell's storytelling as if he himself were writing the continuation.
During those years, my daughter grew older... She remained interested, but she was definitely stretching her patience. It's still a book for very young children.

— How do you find being a professor at Skoltech? What do you think is lacking here?
— I've been teaching at Skoltech for 7 or 8 years, but I still don't feel like a professor. I often feel more like a young graduate student or a lab head. Teaching students here brings me immense joy.
As for what's lacking, student dormitories are needed for a better student experience, although I hear they are under construction. Parking spaces for professors are also limited and mainly allocated to administrative staff. Overall, I sincerely hope Skoltech will continue thriving as a hub for international collaboration and global scientific advancement.