New Research Suggests The X Chromosome May Be The Reason Why Women Are Four Times More Likely Than Men To Develop Autoimmune Diseases
Women are actually up to four times as likely as men to develop autoimmune diseases, where the immune system erroneously targets the body’s own cells.
Researchers believe they’ve found the reason behind this higher susceptibility in women, too. It could be linked to the way the body manages its X chromosomes.
Humans possess two kinds of chromosomes, labeled X and Y. Typically, females have a pair of X chromosomes in every cell, whereas males usually have one X and one Y chromosome.
The X chromosome is not only bigger than the Y but also houses a significantly larger number of genes responsible for protein synthesis.
However, in individuals with two X chromosomes, only one is required for the production of proteins to avoid an overload of proteins in the cells.
To manage this, one of the X chromosomes in each cell undergoes a process known as “silencing” during the embryonic development stage in females.
A lengthy RNA molecule, known as Xist, which is closely related to DNA, plays a key role in this silencing process by attaching itself to one of the X chromosomes.
Interestingly, it has been observed that Xist tends to attract many proteins, forming large complexes of RNA and proteins.
This propensity for proteins to bind to Xist could make females more susceptible to autoimmune diseases.
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According to a recent study involving both mice and humans, this occurs because these complexes can trigger an immune response, leading the body to produce antibodies targeting the proteins contained within them.
“So besides Xist’s job in controlling gene activity, there’s really a major immunological imprint that maybe hadn’t been previously recognized,” said Dr. Howard Chang, the study’s co-senior author.
Thus, Chang believes this discovery may pave the way for exploring new treatment options for autoimmune diseases.
Autoimmune diseases impact over 23.5 million people in the United States and result from a mix of genetic factors and environmental influences.
Although researchers have suggested various hypotheses to understand why women are more prone to these disorders, citing factors such as hormones and the microorganisms living in and on their bodies, none of these theories have been definitively proven.
Previous studies conducted by Chang and his team indicated that the Xist complex might contribute to the gender differences observed in autoimmunity, given its ability to bind with numerous proteins linked to autoimmune diseases.
However, to accurately assess Xist’s role, it was necessary to examine it separately, eliminating the influence of other variables like hormones that could obscure its effects.
That’s why the researchers created two genetically modified male mouse strains capable of producing Xist: one predisposed to autoimmune symptoms akin to lupus and another that was resistant, serving as the control group.
After observing that female mice in the lupus-like strain were more susceptible to symptoms than their male counterparts, the team hypothesized that introducing Xist would elevate the disease incidence in males to match that of females.
So, during the study, the team integrated a modified version of the Xist gene into the DNA of male mice, which could be activated without silencing their sole X chromosome.
To induce autoimmune conditions, it was necessary to expose the mice predisposed to lupus to a particular chemical.
After activating Xist and triggering lupus, the researchers observed that male mice expressing Xist exhibited the disease at rates comparable to females and experienced more severe symptoms than those mice not expressing Xist.
However, Chang noted that the necessity for both an environmental chemical trigger and a genetic susceptibility to lupus served as a crucial control measure. This approach enhanced the relevance of the mouse experiments to human conditions.
“If someone is born with a genetic susceptibility, then the presence of Xist has some impact, but also, very importantly, this environmental trigger is necessary,” Chang explained.
Having Xist does not ensure that an individual will develop an autoimmune disease. Rather, the Xist complex might simply explain the differences in disease prevalence between genders.
To support their findings from the mouse studies, the researchers examined blood samples from over 100 individuals with autoimmune diseases, such as lupus, alongside 20 healthy controls without autoimmune conditions.
They found that those with autoimmune diseases had higher levels of Xist autoantibodies in their blood compared to those without autoimmune diseases.
Chang said that the variety and quantity of autoantibodies varied among individuals based on the specific disease, which could aid in diagnosing and treating these conditions in the future.
For instance, analyzing these autoantibody profiles might eventually enable physicians to identify the particular disease affecting a patient or foresee the progression of their illness.
To read the study’s complete findings, which have since been published in Cell, visit the link here.
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