Autoimmune diseases like multiple sclerosis or lupus occur when the immune system attacks the tissue it is supposed to defend. At the moment, there is still no cure, only treatments, which focus on diet or the use of anti-inflammatory drugs to help manage symptoms. One of the peculiarities of this category of disease — the most common after cancer and heart disease — is that in four out of five cases, the person affected is a woman. With some autoimmune diseases, this imbalance is even greater. With lupus, a disease that can cause everything from joint pain to lethal kidney failure, nine out of ten people affected are women. With Sjögren’s syndrome, which causes dry mouth and dry eyes, the ratio is 19 to one. This week, researchers at Stanford University have published an article in the journal Cell in which they identify the X sex chromosome as the origin of this propensity for females to develop autoimmune diseases.
Having two X chromosomes in every cell, as females tend to have, instead of the XY combination typical in males, usually serves as a form of protection. In females, when a defect appears in one of the X chromosomes, it is silenced and its function is replaced by the intact part of the other identical chromosome. This is not possible for males, and this inability to replace gene functions has been associated with the shorter life expectancy of men. While half of humanity lives perfectly well without a Y chromosome, it’s impossible to survive without an X chromosome, which contains genes essential to vital functions. But in order for females not to suffer a toxic excess of proteins produced by the X chromosome, one of the pairs must be silenced.
Scientists have already pointed to hormonal characteristics to explain differences in the propensity of males and females to suffer autoimmune diseases, but the new findings of a team led by Howard Chang, of Stanford University, reinforce the importance of the X turn-off system. It would explain, for example, what happens to people with Klinefelter’s syndrome (XXY), who, though they look like men and have male hormone levels, have a risk of suffering autoimmune diseases equivalent to that of women.
The deactivation of one of the two X chromosomes occurs thanks to the Xist gene, which generates a kind of molecular layer covering one of the chromosomes. This coating is made of a type of RNA that, instead of acting as a messenger for genetic instructions, as is usually the case, is placed on parts of the chromosomes to modulate the expression of certain genes. Around that envelope, proteins accumulate that can trigger the immune system to react. In a previous study, Chang and his team identified dozens of these proteins, some of which are associated with autoimmune diseases.
To test the role of Xist and the protein complex that forms around this RNA coating, the researchers used genetically modified male mice. Thus, if autoimmunity occurred, it could be attributed to this genetic factor and not to female hormones. They used two types of modified mice, one prone to developing lupus and one resistant to the disease. Males, mouse or human, also have Xist on their X chromosome, but the gene only starts working in the presence of a second X chromosome. To study what happened in males — that is, to determine if their Xist behaved like that of females — researchers inserted a modified version of the gene into the mice, so that it could be turned on or off at will, and did not completely deactivate the single X chromosome of males, which is lethal.
The scientist observed that males with the activated gene developed lupus, but only when injected with an irritant substance that triggers the autoimmune reaction. However, the presence of Xist alone did not cause the immune reaction, as shown by the fact that the vast majority of females do not suffer from autoimmune diseases; instead another trigger is needed. They also found that in mice genetically modified to resist lupus, activation of Xist did not produce the disease, suggesting that, in addition to the gene, another set of genetic characteristics is required.
Ricard Cervera, head of Immunology at the Hospital Clínic de Barcelona, believes that the study published this week “is important and contributes another grain of sand to our understanding of the genesis of autoimmune diseases, reinforcing the hypothesis that sex chromosomes play an important role in the predisposition to suffer them.” For Cervera, the research may be useful in the search for markers that help in the early identification of these types of ailments. “In classic studies of U.S. veterans, where they had samples of soldiers from the time they entered the army until they retired, we already see how people who develop lupus, years before symptoms manifest, have antinuclear antibodies and lupus-specific antibodies,” he says.
Chang’s team looked at how the Xist protein complex causes changes in immune cells: from defending the body’s tissues to attacking them. In a blood test conducted on human subjects, he also observed that people with various autoimmune diseases had elevated levels of antibodies that attack many of the proteins found in the Xist complex. The ability to identify disease-specific autoantibodies could be one way to diagnose autoimmune diseases before symptoms manifest.
Luisa Villar, head of Immunology at the Ramón y Cajal University Hospital in Madrid, think the new study “is very interesting, but discovers only one part, which will have to be connected to others.” She says that “it’s similar to when people say that the Epstein-Barr Virus causes multiple sclerosis: a large part of the population has had this infection, but does not have the disease.” Villar suggests that it may be the expression levels of Xist that determine its weight in the autoimmune response. The hormonal factor, which until now has been used to explain the greater female propensity to develop this type of ailment, should not be ruled out. “The difference in these pathologies between men and women is equalized when menopause arrives,” Villar says. As the authors of the article published this week in Cell recognize, complex diseases cannot be attributed to the expression of a single gene.
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