Autoimmune diseases, such as multiple sclerosis or lupus, occur when the immune system attacks the tissues it should defend. At the moment, there is no cure, but there are treatments, through diet or anti-inflammatory medications, that help control the symptoms. One of the peculiarities of these ailments, the most frequent after cancer and heart diseases, is that, in four out of five cases, those who suffer from them are women, and there are diseases in which the imbalance is even greater. In lupus, a disease that can cause everything from joint pain to fatal kidney failure, for every man who suffers from it there are nine women. In Sjogren’s syndrome, which is identified because it produces dry mouth and eyes, the ratio is 19 to 1. Today, researchers from Stanford University publish an article in the journal Cell in which they point to the X sex chromosome as the origin of the propensity for this type of disorders.
Having two pairs of the In women, when a defect appears in one of the X chromosomes, it is silenced and its function is replaced by the intact region of the other identical chromosome. In men, this possibility does not exist, and this lack of replacement has been associated with lower male life expectancy. Although half of humanity lives perfectly without the Y chromosome, it is impossible to survive without the X, which contains genes with vital functions. However, so that women do not become poisoned by an excess of any of the proteins produced by the X chromosome, it is necessary that one of the pairs be silenced.
Although hormonal characteristics have been pointed to to explain sexual differences in the propensity to suffer autoimmune diseases, the results of the team of scientists led by Howard Chang, from Stanford, reinforce the importance of the X shutdown system. This would explain, for example, What happens with people with Klinefelter syndrome (XXY), who although they look like men and have masculine hormone levels, have a risk of suffering from autoimmune diseases equivalent to women.
The deactivation of one of the two Xs occurs thanks to the Xist gene, which generates a kind of molecular layer that covers one of the chromosomes. This layer is made of a type of RNA, which instead of acting as a messenger of genetic instructions, as is usually the case, is placed in parts of the chromosomes to modulate the expression of some genes. Proteins accumulate around this envelope that can make the immune system react. In a previous study, Chang and her team had identified dozens of these proteins, some related to autoimmune diseases.
To test the role of Xist and the protein complex that forms around this RNA layer, the researchers used genetically modified male mice. Thus, if autoimmunity occurred, it could be attributed to this genetic factor and not to female hormones, and they used two types of modified mice, one that is prone to developing lupus and another that is resistant to the disease. Males, mice or humans, also have Xist on their X chromosome, but the gene only begins to work in the presence of a second , inserted a modified version of this gene into the mice, so that it could be turned on or off at will, and that it did not completely deactivate the only X chromosome in males, something that is lethal.
The researchers observed that males with the activated gene developed lupus, but only when they were injected with an irritant substance that triggers the autoimmune reaction. However, the presence of Xist alone, as shown by the fact that the vast majority of women do not suffer from autoimmune diseases, did not cause the immune reaction; another trigger is needed. They also saw that in mice genetically modified to resist lupus, the activation of Xist did not produce the disease, something that shows that, in addition to the gene, another group of genetic characteristics is necessary.
Ricard Cervera, head of Immunology at the Hospital Clinic of Barcelona, believes that the work published today “is important and contributes another grain of sand to the understanding of the genesis of autoimmune diseases and reinforces the hypothesis of the role of sex chromosomes.” in the predisposition to suffer them.” For Cervera, the work can be useful in the search for markers that help identify this type of ailments early. “In classic studies on US veterans, where they had samples of soldiers from the time they entered the army until they retired, it had already been seen that, in people who developed lupus, years before those manifestations, antinuclear antibodies and specific to lupus,” he says.
Chang’s team observed how the antibodies that attack many of the proteins found in the Xist complex. The ability to identify disease-specific autoantibodies would be a way to diagnose autoimmune diseases before their symptoms manifest.
Luisa Villar, head of Immunology at the Ramón y Cajal University Hospital in Madrid, considers that this study “is very interesting, but it discovers only a part, which will have to be associated with other things.” “It is similar to when it is said that the Epstein Barr virus causes multiple sclerosis, but a good part of the population has had this infection and does not have the disease,” adds Villar, who suggests that it may be the expression levels of Xist that are determine its weight in the autoimmune response. The hormonal factor, which until now has been used to explain the greater female propensity for this type of ailment, does not have to be ruled out. “The difference in these pathologies between men and women equalizes when menopause arrives,” exemplifies Villar. As the authors of the article that she publishes today recognize Cellsuch complex diseases cannot be blamed on the expression of a single gene.