AUTOIMMUNE DISEASES ARE MUCH MUCH MORE IN WOMEN than in men, and much less well-studied, perhaps because historically fewer resources have been devoted to studying women’s health risks. But in recent years, the picture has changed: technologies allow studying what is happening in the human body at a previously inaccessible level, and researchers have finally realized the importance of the problem of autoimmune diseases and their treatment.
It is known that the immunity of a typically female body is ” stronger ” – it is less susceptible to infections and some types of cancer than a typically male body . At the same time, he is more likely to rebel against his own cells. Approximately 80% of people with autoimmune diseases are women , and everything is ambiguous with infections: although the risk of infection in women is considered lower, they are harder to tolerate the same flu ; perhaps the too strong immune response is to blame. The susceptibility of males and females of different species of animals, including macaques, mice, fruit flies, lizards, and to various diseases, and to the effects of drugs and vaccines, is also not the same. This even led to discussions about whether researchers should report the sex of the animals on which certain experiments are carried out. There is still no definite answer to the question of why this is happening.
For a long time, the reasons for the differences were believed to be the effects of hormones and the sensitivity of cells to their effects: for example, estrogens suppressed the reproduction of the influenza virus in the epithelial cells of the nasal epithelium of women, but not men. In another study, male and female mice suffered from influenza in different ways, but when the gonads were removed, these differences disappeared. Hormones do affect the immune system, and the differences between men and women can change depending on age – for example, inflammation is more pronounced in women during the reproductive period, but not before puberty or after menopause.
Sex hormones are one of the clearest differences between typically male and typically female physiology, and it is easy to associate with them the different prevalence of diseases that occur in adulthood. For example, after puberty, men become less at risk of asthma – they are protected by high testosterone levels. It is also known about the direct effect of hormones on certain immune cells. But there are obvious gaps in this approach: for example, juvenile rheumatoid arthritis usually occurs long before puberty, in early childhood, when the levels of estrogens and androgens are low and do not differ much among children of different sexes. This disease develops three times more often in girls. Obviously, there are other factors besides hormones – and they can be internal or external.
The immune system
The immune system components of men and women work differently. For example, mast cells, which are among the first to respond to infection, produce and store more substances that provoke inflammation (histamine, serotonin, proteases) in women . These substances are responsible, in particular, for symptoms such as nasal congestion, migraine headache, feeling of lack of air. The difference in the work of mast cells is genetic; it turned out that more than 4 thousand genes are more active in female mast cells than in male ones. These are the genes that code for proteins involved in the synthesis and storage of inflammatory substances.
Another important element of immunity is the so-called major histocompatibility complex ( MHC ). Its proteins are found in all cells of the body; they recognize foreign molecules, identify them, and can signal to other immune components that it is time to act. Simply put, these are important regulators of immune processes. It is important that MHC proteins are extremely diverse – they can be identical only in identical twins. At the University of Lund, a study was carried out on songbirds, where it turned out that in males the variety of MHC proteins was not large enough, and in females, on the contrary, excessive – theoretically, the immune system of the latter could regard too many molecules as foreign. Since the immune system of different vertebrates is similar , this could be a step towards understanding the differences in its work in men and women.
We have already talked about immune checkpoints – molecules by which cancer cells can suppress the immune response; it was for their discovery that James Allison and Tasuku Honjo received the Nobel Prize. This discovery allowed the creation of radically new cancer drugs, but not only: scientists talk about possible differences in the work of these molecules in men and women, which can also affect the susceptibility to various diseases.
Chromosomes and genes
The different susceptibility to autoimmune processes is partly due to the fact that women have two X chromosomes , which contain many genes associated with the immune system. In a number of studies , mice with XX chromosomes, in contrast to animals with XY, had a higher risk of lupus and autoimmune encephalomyelitis. True, in reality, not all genes of both X chromosomes are active: some of them are “ turned off ” in such a way that the genes inherited from the father and mother work approximately equally. But this is not always the case, and there may be more active genes than necessary. This feature was found in rheumatoid arthritis and autoimmune diseases of the thyroid gland. It is also known that the risk of autoimmune diseases is increased in people with an excess X chromosome (with a set of XXY or XXX).
There are also features not associated with sex chromosomes. Scientists recently discovered the VGLL3 gene encoding the protein of the same name – now it is called the “master switch”, that is, an important regulator of genes associated with immunity. The genes it regulates have been linked to a wide variety of diseases, including lupus, scleroderma, and Sjogren’s syndrome. As it turned out, there is much more VGLL3 in the skin and other tissues of women than in men; it is also abundant in female reproductive tissues.
External factors can also affect the functioning of the immune system in men and women in different ways. This includes nutrition: for example, several studies have concluded that breastfeeding protects girls from respiratory tract infections better than boys. In Tanzania, a study was conducted with nearly a thousand women with HIV infection who received vitamins B, C and E before and after childbirth; among girls born by them, the mortality rate was 32% lower than among boys.
Another factor that is now receiving more and more attention is the composition of the microbiota. For example, in a model in mice with type 1 diabetes mellitus, when the intestinal flora of males was transferred to females, the latter underwent systemic hormonal changes and they were protected from the disease. In humans, many factors affect the microbiota, and gender is one of them ; perhaps in the future, and this will be used to develop new treatments.
What does the placenta have to do with it?
While some scientists are trying to figure out what mechanisms are responsible for immune differences, others have put forward a theory about why this happens at all. In a paper published recently in the journal Trends in Genetics article it says that from an evolutionary point of view of women’s immune system is adapted to frequent pregnancies and childbirth – and since their number has decreased recently, about a hundred years, to re-adjust it still did not have time. According to this theory, the placenta can partially suppress immune function so that the mother’s body does not attack the fetus, but remains protected from infections. When regular pregnancies do not occur, the immune system remains active, often too much.
In the scientific community, the theory was accepted calmly : it does not contradict other possible explanations and, of course, requires research so that it can be confirmed and refuted. If it turns out that in women who have given birth many times, the risk of autoimmune diseases is reduced, it will be possible to think about how to use this for their prevention and treatment. In an interview with Atlantic, one of the authors emphasizes that pregnancy is also associated with health risks, and based on the results of her work, one should not conclude that everyone should be constantly pregnant. It’s just about finding out exactly how the placenta interacts with the immune system, and learning how to influence this interaction.