WASHINGTON —
Research has revealed that women are at a higher risk of developing autoimmune diseases compared to men. This occurs when the immune system becomes imbalanced and attacks the body’s own cells.
On Thursday, researchers from Stanford University reported that the way the body deals with an additional X chromosome in females may hold important implications for detecting and treating various difficult-to-diagnose diseases.
University of Pennsylvania immunologist E. John Wherry, not involved in the study, stated that this changes our perspective on the entire autoimmunity process, particularly the gender bias between males and females.
According to some calculations, over 24 million people in the United States, potentially even up to 50 million, suffer from an autoimmune condition. These include illnesses like lupus, rheumatoid arthritis, multiple sclerosis, and many others. Interestingly, around 4 out of every 5 patients are female, a phenomenon that has puzzled researchers for many years.
One hypothesis suggests that the X chromosome could be responsible. This is due to the fact that females have two X chromosomes, while males have one X and one Y.
A recent study, released in the publication Cell, reveals that an additional X factor is at play – but in a surprising manner.
This picture, courtesy of the National Institutes of Health (NIH), displays the X and Y chromosomes.
Our genetic material, known as DNA, is contained in every cell in 23 sets of chromosomes. These pairs include the last set, which determines an individual’s biological sex. The X chromosome contains numerous genes, significantly more than the Y chromosome found in males. In order to prevent an excessive amount of these genes, each female cell must deactivate one of its copies of the X chromosome.
Performing that so-called X-chromosome inactivation is a special type of RNA called Xist, pronounced like “exist.” This long stretch of RNA parks itself in spots along a cell’s extra X chromosome, attracts proteins that bind to it in weird clumps, and silences the chromosome.
Dr. Howard Chang, a dermatologist from Stanford, was investigating the mechanisms of Xist function when his team discovered approximately 100 attached proteins. Upon further examination, Chang noted that many of these proteins were associated with autoimmune disorders related to the skin, where patients may produce “autoantibodies” that mistakenly target these healthy proteins.
Chang suggested, “This sparked our curiosity: These are the proteins we are aware of, but what about the remaining ones in Xist?” Perhaps this specific molecule, exclusive to females, “has the ability to arrange proteins in a manner that triggers the immune system.”
If Xist is indeed valid, it alone would not be able to induce autoimmune disorders as all females would be impacted. Researchers have previously believed that a combination of genetic predisposition and a stimulus from the environment, like an infection or injury, is necessary for the immune system to malfunction. For instance, the Epstein-Barr virus has been associated with multiple sclerosis.
The team led by Chang made the decision to genetically modify male laboratory mice to produce Xist artificially. They did not silence their sole X chromosome and observed the outcome.
Scientists specifically bred mice that are prone to developing a lupus-like condition when exposed to a certain chemical irritant.
The team concluded that the mice who generated Xist showed the typical formation of protein clumps and, when activated, experienced lupus-like autoimmune reactions at similar levels as females.
“We believe it is crucial for Xist RNA to be released from the cell so that the immune system can detect it. However, an external trigger is still necessary to initiate the entire process,” stated Chang, who receives compensation from the Howard Hughes Medical Institute, which also provides funding for The Associated Press’ Health and Science Department.
In addition to mice, scientists also investigated the blood samples of 100 patients. They discovered autoantibodies that were targeting proteins associated with Xist, which had not been previously associated with autoimmune diseases. One possible explanation, according to Chang, is that the standard tests for autoimmunity were conducted using male cells.
Penn’s Wherry stated that further research is needed, but the results could potentially lead to a quicker method for diagnosing patients who exhibit varying clinical and immunological characteristics.
Some individuals may have autoantibodies to Protein A, while others may have autoantibodies to Proteins C and D. However, recognizing that these proteins are all part of the Xist complex can help doctors identify disease patterns more effectively. This discovery provides a significant piece of the puzzle in understanding the biological context of the disease.
Chang from Stanford ponders the potential for interrupting the process in the future.
“What is the process of transformation from RNA to abnormal cells? This will be the next stage of the inquiry.”
Source: voanews.com
