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Why Are Women at a Greater Risk of Autoimmune Disease?

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X-chromosome inactivation

Every cell in the human body has 23 pairs of chromosomes including the 2 “sex chromosomes”, X and Y. Every female cell possesses two X chromosomes, while every male cell possesses an X and a Y.

Historically, the X and Y chromosomes’ roles had been reduced to sex determination. Over recent years, it has become increasingly clear that the X and Y chromosomes can contribute to sex differences in health and disease, including disease susceptibility and severity risk. Largely, this has stemmed from an increased understanding of X-chromosome inactivation.

X-chromosome inactivation is a process where, as its name suggests, one of the X chromosomes is effectively “inactivated”, ensuring that the proteins encoded by the genes on the X chromosome are not expressed twice in the same cell.

X-chromosome inactivation is integral to an organism’s survival, as overexpression of proteins can prove lethal. But as scientists from Stanford University have discovered, it is also a process that contributes to a greater risk of autoimmune diseases in women. The research, led by Dr. Howard Chang, professor of dermatology and genetics, and a Howard Hughes Medical Institute investigator, is published in Cell.

Studying the role of Xist in autoimmune conditions

“As a practicing physician, I see a lot of lupus and scleroderma patients, because those autoimmune disorders manifest in skin,” said Chang. “The great majority of these patients are women.”

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Autoimmune disorders are conditions where the immune system is unable to differentiate between healthy tissue and harmful tissue. As a result, a person’s immune system essentially attacks itself. Systemic sclerosis, rheumatoid arthritis, psoriasis and systemic lupus erythematosus are all examples of autoimmune disorders. Eighty percent of all individuals affected by autoimmune disorders tend to be women.

Chang’s lab has been studying Xist, a long noncoding RNA (lncRNA) molecule that helps to coordinate X-chromosome inactivation, for a number of years.

All chromosomes carry the genes encoding Xist, but it is produced only when the X chromosome it resides on is one of a matched pair, i.e., XX. It is also only active on one member of that pair.

Xist generates the production of some “interesting” molecules, Chang’s research has found.

Previously, his team identified ~100 proteins that are either bound to Xist, or the molecules it produces that help it to stay anchored on the inactive X chromosome. Among this milieu of molecules, Chang recognized some familiar faces – proteins that are also associated with autoimmune disorders.

In the new study, the research team wanted to understand whether the presence of such molecules contributes to the increased risk of autoimmune disorders in females.

To remove compounding factors such as hormonal influences, and the effects of proteins produced by the second X chromosome, they utilized male mice. Specifically, they studied two species of laboratory mice: one strain that is genetically susceptible to conditions that mimic autoimmune disorders in humans, such as lupus, and another that is autoimmune-disease resistant. They genetically engineered both sets of mice to express a modified form of Xist and included healthy male and female mice in their analyses as controls. 

The modified version of Xist could be “turned off” by the application of specific chemicals, meaning the researchers could study its expression in a targeted way. It was also engineered such that its RNA would no longer silence the genes of the male mouse’s chromosome in which it had been inserted.

Xist activation, tissue stress and genetics play a role in autoimmunity

Activation of Xist in the genetically engineered mice led to the formation of the “interesting” molecular complexes that Chang had observed previously.

Simply inserting Xist did not prompt an autoimmune response in the mouse model of autoimmune disorders. But by injecting an irritant that induces a lupus-like condition in the mice, Chang and team could explore whether the irritant, coupled with activation of Xist, had any effect on mice’s likelihood of developing autoimmune symptoms, compared to the same mouse strain that lacked Xist. It did; males expressing Xist developed lupus-like symptoms at a rate similar to that of female mice and much higher than the male mice lacking Xist. This suggests that Xist and some form of molecular stress, such as that which is induced by injecting the irritant, gets the autoimmunity ball rolling.

When studying the autoimmune-resistant mouse strain, Chang and colleagues found that activating Xist was not sufficient to induce autoimmunity-like symptoms. This makes sense – not all women expressing Xist suffer from autoimmune conditions. It suggests that genetic background is also important, given that the other mouse strain studied was genetically predisposed to autoimmune disorders.

Towards better diagnostics for autoimmune conditions  

Chang and colleagues also analyzed blood samples from 100 patients with autoimmune disorders. They discovered autoantibodies against the molecular complexes that are associated with Xist in the samples.

What is an autoantibody?

An antibody that is produced by the immune system and is directed against one of the individual’s own proteins.

While some of the autoantibodies were specific to one autoimmune disorder, others were broader. The authors suggest they could have utility as diagnostic biomarkers, which might help to identify emerging autoimmune disorders before symptoms start to show.

“Every cell in a woman’s body produces Xist,” said Chang. “But for several decades, we’ve used a male cell line as the standard of reference. That male cell line produced no Xist and no Xist/protein/DNA complexes, nor have other cells used since for the test. So, all of a female patient’s anti-Xist-complex antibodies — a huge source of women’s autoimmune susceptibility — go unseen.”

“Future studies with larger numbers and a detailed focus on exactly which Xist-related antigens contribute to female-biased immunity will be valuable,” the authors concluded.

Reference: Dou DR, Zhao Y, Belk JA, et al. Xist ribonucleoproteins promote female sex-biased autoimmunity. Cell. 2024;187(3):733-749.e16. doi: 10.1016/j.cell.2023.12.037 

This article is a rework of a press release issued by Stanford University. Material has been edited for length and content.