Why Are Autoimmune Diseases More Common in Women? The X Chromosome Offers Clues

              Why Are Autoimmune Diseases More Common in Women? The X Chromosome Offers Clues

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China Science Daily (by Wen Lele)

Abstract

Why are women more susceptible to autoimmune diseases than men? A new study published in Cell on February 1st, as reported by Nature, provides a novel explanation: the molecular coating typically found on one of women’s X chromosomes may trigger unnecessary immune responses. This coating, a complex of RNA and Proteins central to X chromosome inactivation, involves the long non-coding RNA XIST and associated Proteins. Research shows that autoAntibodies targeting these XIST-related Proteins—more prevalent in females due to XIST’s exclusive expression in XX cells—could drive higher autoimmune disease rates in women (who account for ~80% of cases). Experiments in mice engineered to produce XIST revealed elevated autoAntibodies, heightened immune alertness, and greater tissue damage, mirroring findings in patients with lupus, scleroderma, and dermatomyositis. This mechanism offers new insights for diagnosis and treatment.

Content

Why Are Autoimmune Diseases More Common in Women? The X Chromosome Offers Clues

Why do women develop autoimmune diseases more frequently than men? A new explanation for this disparity has emerged: the molecular coating typically found on one of the two X chromosomes in women may trigger unnecessary immune responses. As reported by Nature, the findings were published in Cell on February 1st.

This coating, composed of RNA and Proteins, is central to the process of X chromosome inactivation. Researchers previously suspected sex hormones and defective gene regulation on the X chromosome as drivers of autoimmune differences. Now, the discovery that the core Proteins involved in X chromosome inactivation themselves can trigger immune alerts adds complexity to the issue—and may open new avenues for diagnosis and treatment.

“This really proposes a new mechanism,” says Laura Carrel, a geneticist at Pennsylvania State College of Medicine.

Women account for approximately 80% of all autoimmune disease cases, including conditions like lupus and rheumatoid arthritis. However, explaining this gender disparity has long been a mystery, puzzling scientists for the past six to seven decades.

A primary suspect has been the X chromosome. In most mammals, including humans, male cells typically have one X chromosome, while female cells usually carry two copies.

X chromosome inactivation silences most of the genes on one X chromosome in XX cells, equalizing the “dosage” of X-linked genes with that in male XY cells. This process is highly physical: a long RNA molecule called XIST wraps around the chromosome, attracting dozens of proteins to form a complex that effectively shuts down the chromosome’s genes.

Not all genes are silenced, though. Genes that escape X chromosome inactivation are thought to underpin some autoimmune diseases. Additionally, researchers reported in 2023 that the XIST molecule itself can trigger inflammatory immune responses—but this is not the full story.

Around a decade ago, Howard Chang, a molecular geneticist at Stanford University School of Medicine and one of the paper’s authors, noticed that many proteins interacting with XIST are targets of misguided immune molecules called autoAntibodies.

These autoAntibodies attack tissues and organs, causing the chronic inflammation and damage characteristic of autoimmune diseases. Since XIST is usually only expressed in XX cells, it logically follows that autoAntibodies targeting XIST-related proteins might affect women more than men.

To test this idea, Chang and his colleagues studied male mice, which normally do not express XIST. The researchers genetically engineered the mice to produce a version of XIST that does not silence gene expression but still forms the characteristic RNA-protein complex.

The team induced a lupus-like disease in the mice and found that animals expressing XIST had higher levels of autoantibodies than those that did not. Their immune cells were also in a state of higher alert—signaling susceptibility to autoimmune attacks—and they suffered more extensive tissue damage.

Notably, the same autoantibodies were found in blood samples from patients with lupus, scleroderma, and dermatomyositis. “This suggests that XIST and its associated proteins are something the human immune system has a hard time ignoring,” says Allison Billi, a dermatologist at the University of Michigan Medical School.

Montserrat Anguera, a geneticist at the University of Pennsylvania, notes that human data indicates the XIST-related mechanism observed in mice is directly relevant to human autoimmune conditions, with implications for disease management. For example, diagnostics targeting these autoantibodies could help clinicians detect and monitor various autoimmune diseases.