Autoimmune diseases: when the enemy is oneself

Distinguishing between the proper and the foreign is not as simple as it may seem at first glance. At least for our immune system, in charge of our defense, which must decide when to attack and when it is not necessary.

The decision is made thanks to very specific receptors possessed by lymphocytes. There are millions, randomly generated during cell development, and each receptor recognizes a single substance (antigen). Sometimes strange, as in an infection, and others own.

And this is where the crux of the matter lies. Because if the receptors of the lymphocytes are randomly generated and always recognize some antigen (self or foreign), how can one ensure that they do not react aggressively against their own structures?

The importance of building tolerance

In theory it is as simple as making a previous selection. During the development of lymphocytes, the body only allows those that do not react to their own structures to mature and enter the peripheral circulation. This is known as central tolerance.

But in addition, and as a second control point, we have peripheral mechanisms that block any autoreactive lymphocyte that may have escaped the first filter.

The combination of central and peripheral tolerance mechanisms ensures that no cells circulate that could potentially destroy their own structures. If it works, we will only have cells capable of recognizing the strange. But if any of these tolerance mechanisms fail, we inflict damage on ourselves and suffer from autoimmune disease.

The more hygiene, the more autoimmunity?

In developed countries, while infectious diseases plummet, the incidence of autoimmune diseases and allergies continues to rise. For more than 20 years, the option has been considered that it is not a coincidence, and that exposure to certain pathogens (even potentially dangerous) has a protective effect against the development of autoimmunity.

For example, certain strains of mice raised under strictly sterile conditions easily develop diabetes, while this incidence is markedly reduced if the animals are raised under standard conditions, which are already quite hygienic.

In humans, the case of the Karelia region, on the border between Finland and Russia, is striking: with the same environmental and genetic conditions of the population, but great economic and social differences, autoimmune and allergic diseases are much more frequent in the Finnish area .

On the other hand, lately the composition of the microbiota (that is, the beneficial bacteria that we have in the intestine) has been related to certain diseases, including autoimmune diseases. In fact, the administration of probiotics of certain commensal bacteria to achieve a protective microbiota is an emerging field for the management of these pathologies.

Without going any further, when mice that developed diabetes in sterile conditions are given certain bacteria from Russian individuals from Karelia (who hardly suffer from autoimmunity), the problem disappears. In contrast, administration of commensal bacteria from the Finnish area predisposes these animals to autoimmunity.

Can we deduce that microbes are always protective? Absolutely. The suspicions that have accumulated for years that some autoimmune diseases occur after having suffered certain infections are becoming more solid. A recent study, for example, shows a very strong relationship between multiple sclerosis and a previous infection with the Epstein-Barr virus, which causes infectious mononucleosis. The relationship is so close that we could almost say that there would be no multiple sclerosis without this previous infection.

Therefore, there are microorganisms with protective effects and microorganisms that predispose to the development of autoimmune pathologies.

The complex causes of autoimmunity

Only rarely is autoimmunity due to a mutation in one of the genes that control tolerance or the immune response. But in the vast majority of cases, a combination of genetic predisposition with environmental causes and triggering elements is needed.

A clear example of genetic predisposition can be found in ankylopoietic spondylitis: 95% of patients with this disease have the HLA B27 molecule, which is also present in a percentage of the healthy population. Similarly, in the case of type I diabetes, most patients have certain HLA molecules that we can also find in the healthy population.

Therefore, genetics predisposes (sometimes strongly) but is almost never sufficient for the development of autoimmunity.

More autoimmunity in women

The incidence of autoimmune diseases is much higher in women. For example, more than 90% of people with Sjögren’s syndrome or systemic lupus erythematosus are women, although it is true that there are more men with type I diabetes.

The causes of these differences are not completely clear, but it must be remembered that hormones have an important modulatory role in several regulatory pathways of the immune response related to autoimmunity. In addition, hormones also modulate the microbiota, making men and women have a different composition.

One more reminder that, in any biomedical research, sex is a fundamental factor to keep in mind.

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