United States: Researchers at Stanford University are working on a problem, that has been unresolved for a long time, namely, women having higher chances of different autoimmune diseases like multiple sclerosis, lupus, and rheumatoid arthritis, and they might now be one step further to get the solution. 

However, the way the female body handles its pair of extra X chromosomes (the male body has just one plus a Y chromosome) may be the clue that clarifies why the impact of the long-term type of diseases arising from diabetes is more impactful and noticeable in women, a recent study introduced. 

Almost all of the long-term diseases are characterized as being caused by an improper immune system that is overwhelmed by reacting to its own cells and tissues, reported CNN Health. 

The recent studies that performed experiments on mice pointed out that the cause of the disease may be interference with genes. 

However, further investigation of this subject will be necessary to come up with new diagnostic and treatment strategies, said Dr. Howard Chang, the senior author of the paper published in the Journal Cell on February 1. 

Chang, the professor of dermatology and genetics at Stanford School of Medicine who led the research, was attracted to this subject because the symptoms of some autoimmune diseases like lupus and scleroderma show up on the skin as rashes. 

According to CNN Health, Chang said, “Many of these diseases that show up in our clinics, especially the immune-related diseases, show this really striking female bias. And so I’ve always wondered about that from my own clinical practice,” 

Prevalence of Autoimmune disease in the US 

There are over 80 autoimmune diseases prevalent in the United States, and the estimate shows around 24 million people being affected. 

The autoimmune disorders happen when a person’s immune system triggers a foreign body response against itself, mistaking itself as a hostile body, as mentioned by Montserrat Anguera, an associate professor in the Department of Biomedical Sciences at the University of Pennsylvania School of Veterinary Medicine. 

Anguera, who wasn’t involved in the research stated, “The same sort of players that are acting in response to a virus or bacteria (are the ones) that are acting in immune disease but in autoimmune disease the ‘infection’ isn’t being cleared, it’s persisting and with persistence, it’s getting magnified and it’s causing damage to tissues, depending on the autoimmune disease,” reported CNN Health. 

Added further, “Some of them affect the whole body and other ones are localized to a particular organ.” 

Other researchers had theorized about the disorders‘ “female bias” by investigating the role of the sex hormones or chromosome counts. 

Instead of focusing on the role of the molecule named Xist, which is absent in the male cells, Chang concentrated on the fact that it is present in the X-shaped chromosomes. 

What is the role of Xist? 

Visual Representation – X chromosome in Female Embryos.

The primary function of the Xist molecule is deactivating the second X chromosome in female embryos. This ensures that no one will experience the toxic mixed messages that would arise from the over-expression of the body’s cells with the high dose level of the gene products of the X chromosome. 

Chang said, “Xist is a very long RNA, 17,000 nucleotides long, or letters, and it associates with approximately almost 100 proteins,” as CNN Health reported. 

Xist molecules function together with other proteins to inactivate the second X chromosome gene expression. 

Chang came up with an idea while taking an exam to renew his license in medicine 9 years ago. He noticed that many of the proteins Xist works with to bind to and silence the X chromosome had a connection to skin-related autoimmune disorders – The autoantibodies, which in these diseases are supposed to attack the usual protein, reported CNN Health. 

Chang questioned if the aggregations of protein molecules that can occur following the attachment of Xist to the X chromosome may be the reason for autoimmune disease. 

Chang’s findings come from the experiments he has conducted over the years. He decided that Xist, which only produces female placenta cells, would function differently if they were placed in male mice. This was possible because of genetic engineering. 

According to him, this would clear the path for the elimination of alternate explanations for the genetic basis of autoimmunity in females like the presence of sex hormones or proteins produced by a certain X-chromosome that was not properly switched off. 

When mice were genetically modified to produce the Xist gene, an experiment with substances mimicking lupus was done with the primary goal of checking whether autoimmune symptoms similar to female mice could be caused by male mice. 

Surprisingly, this turned out to be true, and male mice developed autoantibodies at a rate almost equal to that of female mice, thus confirming the ability of the studies had no targets thought to show in the animals whether autoimmune disease would be caused by Xist or the related proteins. 

Chang and his co-authors additionally did investigations of blood serum samples from individuals with lupus, dermatomyositis, and systemic sclerosis while these samples were compared to those from healthy people who didn’t have autoimmune disease, as CNN Health reported. 

Blood samples from patients with autoimmune disease revealed higher levels of autoantibodies produced from Xist in reaction to the proteins, the researchers added. 

Altogether, the data pointed to a “significant role” for Xist as a driver for autoimmunity that might explain why autoimmune disease skews females, according to the study. 

The study has found a piece of the complex puzzle- Experts 

The results of this study indicated that the inactive X chromosome machinery was of importance and should be seen as a contributor to autoimmune disease female predisposition according to Montserrat. 

She also pointed out that the latest finding was surely just one corner piece in a very complex puzzle — a “coral reef” in a big ocean. Whether the proteins associated with the Xist gene are in fact inducing disease is not clear at this point. It is, likewise, a fact that environmental conditions contribute greatly to the high incidence percentage of autoimmune diseases. 

Anguera said “It’s not just an individual’s genetics … there’s a whole other aspect which is interactions with the environment,” and, “So these are diet, microbiome, and then behaviors like smoking,” CNN Health reported. 

Additionally, diagnosis of autoimmune diseases may be particularly complicated and require years for accurate results. Chang hoped the research would help expedite the process that is aimed at coming up with remedies for the currently incurable diseases. 

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