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9 February, 2024The statistics are clear. Women suffer more autoimmune diseases than men. A study published in the journal Cell points to the silencing of one of the X chromosomes as a factor that, although necessary for the adequate production of proteins, seems to be behind these disorders
When a person suffers a autoimmune disorder, it is your own defenses that attack healthy cells by mistake. The latest data from Spain, made public in 2019, indicate that more than 4 million individuals suffer from lumbar osteoarthritis, gout about 880.000, rheumatoid arthritis almost 300.000, psoriatic arthritis around 215.000 and systemic lupus erythematosus just over 75.000.
Despite its high prevalence and great impact, They are still quite unknown diseases. In Spain there is no data on women and men with these pathologies separately, but in the United States it has been seen that, of the 24 to 50 million affected in the country, up to 4 out of 5 are women.
Rheumatoid arthritis, multiple sclerosis, and scleroderma are characterized by an unequal they-to-them ratio. In the case of lupus, it becomes 9 to 1
Eg rheumatoid arthritis, multiple sclerosis and scleroderma are characterized by an unequal ratio between them and them. In the case of lupus, it becomes 9 to 1; and in the Sjogren's syndrome, from 19 to 1.
Based on these marked differences, a team from Stanford University (USA) has led the search for the main characteristic that differentiates biologically female mammals from male ones, which could facilitate the prediction of this type of pathology before that they develop. The results are published this week in the journal Cell.
“Every day I see many patients with lupus and scleroderma, since these autoimmune disorders manifest themselves in the skin,” he explains. Howard Chang, professor of Dermatology and Genetics and lead author of the study, “and the vast majority are women.”
The answer is in the second X
In mammals, biological sex is determined by the presence of two A mammal can survive without at least one copy of the X chromosome, which contains hundreds of active genes that produce proteins.
Even so, having two X chromosomes carries the risk that each female cell will make twice as many of these proteins, which would be lethal. To avoid this, the call is given X chromosome inactivation, thanks to a molecule called Hist. In this way, the same amount is created in both a female and a male cell.
The researchers discovered that the inactivation of one of the X chromosomes triggers more susceptibility to this type of disease, which does not happen to men..
And that is where the key to the great difference between men and women in autoimmune disorders seems to lie. As the researchers discovered, this inactivation by Xist triggers more susceptibility in them to this type of diseases, which does not happen to them.
In any case, the results reveal that the inactivation of the X chromosome can cause autoimmune diseases, but also other factors, which is why men sometimes develop them.
As explained to SINC Tarek Salman, spokesperson for the Spanish Society of Rheumatology and rheumatologist at the Hospital del Mar in Barcelona, who does not participate in the study, "these results make a lot of sense since we have known for a long time that disorders such as lupus were closely linked to the X chromosome."
“This finding may facilitate the discovery of ways to develop drugs and gene therapy that cure the disease, not just mitigate the symptoms. But this news must be taken with caution because the expressions of rheumatic disorders are polygenic, which is why modifying just one gene is not so important,” he adds. “Of course, it is a great advance and one more step towards finding molecules that improve the pathology.”
What if males made Xist?
In 2015, Chang's group identified nearly 100 proteins that bind to Xist, allowing this molecule to anchor along gene-specifying regions of the X chromosome. With this, the experts observed that many of these proteins were known to be associated with autoimmune disorders.
In the new study, they 'stitched' the Xist gene in the genomes of two different strains of mice laboratory male. One strain was quite susceptible to symptoms that mimic lupus, females being more susceptible than males. The other is resistant.
«This finding may facilitate the discovery of ways to develop drugs and gene therapy that cure these disorders. Although it is a great advance, this news must be taken with caution” Tarek Salman, SER
The inserted Xist gene had been modified in two ways. It could be activated or deactivated by chemical means, pumping out Xist only when scientists wanted it. The Xist gene was also slightly modified so that its RNA product no longer silenced genes on the chromosome. male mouse in which it had been inserted.
Simply inserting that modified Xist gene had no noticeable effect on the mice. But the Xist produced from the inserted gene, once that gene was activated, continued to form characteristic complexes with almost all the proteins previously found to work closely with Xist.
What's more, by injecting an irritant known to induce a lupus-like autoimmune disease into the susceptible strain of mice, males in which the Xist gene was activated developed the disorder at a rate similar to that of females, and considerably more so than males. non-bioengineered males.
Other decisive factors
The absence of autoimmunity in some female or male mice activated by Xist in the susceptible strain demonstrated that not only such activation is necessary, but also some type of Stress that damages the tissues (caused, in this case, by the injection of the irritant) so that the disorders begin to occur.
For autoimmunity to develop, not only does Xist act, but an adequate genetic basis is also necessary..
For its part, in the resistant strain, the activation of Xist in bioengineered male mice was not sufficient to induce autoimmunity. This suggests that, for this to develop, not only the activation of Xist is necessary, but also a adequate genetic base.
“These limitations are very positive, because if they did not exist, all women could be more susceptible to developing immunity,” concludes Chang.
Source: SINC Agency