New Findings Implicate XIST in Female Sex-Based Autoimmunity

Being born female increases risk of autoimmune disease four-fold compared to males. The disproportionate risk females carry has long been recognized, but the cause has not. New research points to flaws in the mechanism that protects females from overexposure to their own X chromosomes.

“There is a striking imbalance between the sexes in autoimmune diseases,” said Montserrat C. Anguera, PhD, Associate Professor of Epigenetics, University of Pennsylvania School of Veterinary Medicine. “This bias was long thought to be related to sex hormones. Now we see the involvement of the X chromosome. The greater the exposure to X chromosome, the greater the risk for autoantibodies and autoimmune disease.”

Dr. Anguera opened the scientific session XIST-ential: Sex-Based Epigenetic Control of Systemic Lupus Erythematosus on Monday, Nov. 18. The session will be available on-demand to all registered ACR Convergence 2024 participants after the meeting through Oct. 10, 2025, by logging into the meeting website.

Having an active X chromosome is essential to cell survival. However, so many immune-related genes are located on the X chromosome that having too many active X chromosomes can be lethal. Female cells protect themselves from excess X chromosome exposure by routinely inactivating one of their two X chromosomes early in development.

But X chromosome inactivation (XCI) is not perfect. Incomplete XCI can increase autoantibody production, leading to systemic lupus erythematosus (SLE) and a host of other autoimmune diseases.

Female mammals, including humans, use a long, noncoding RNA called XIST to deactivate one X chromosome early in fetal development. XIST coats one of the two X chromosomes in every cell, effectively blocking activity.

XCI is a dynamic process in T-cells, Dr. Anguera explained. Stimulated T-cells may have incomplete XCI. Instead of coating the second X chromosome in activated T-cells, XIST is dispersed in the nucleus, exposing some exons. This impaired XCI maintenance is seen in both SLE mouse models and in SLE patient lymphocytes.

XIST is made up of long, repetitive elements with distinct functions that are tethered to the X chromosome by XIST RNA-binding proteins. Activating T-cell receptors activates NF-κB signaling, which regulates XCI maintenance through these binding proteins.

Any defects in XCI maintenance can expose X chromosome exons, many of them immune related, that are intended to be hidden, Dr. Anguera said. XCI maintenance defects can also expose XIST RNA-binding proteins, some of which have been previously identified as autoantibodies.

“We tend to look for disease genes and ignore noncoding DNA and RNA, said Diana R. Dou, PhD, Assistant Professor of Integrative Immunobiology at Duke University. “But if you ignore noncoding areas, you are ignoring 98% of the genome.”

The most important single risk factor for autoimmune disease is female sex, Dr. Dou said. Much of the increased risk appears to be associated with ribonucleoprotein particles (RNP) that bind XIST to X chromosomes.

Working with SLE mouse models, she identified 81 RNPs that act as autoantigens, 21 of them not previously identified.

“The XIST RNP complex promotes female-specific autoimmunity in mice and in humans,” she said. “It acts as a trigger for autoimmunity.”

Knocking out XIST in male mice and inducing SLE with pristane left the male mice with female-like gene and autoantibody expressions. The male mice had increased autoantibody production and more severe organ disease penetrance and severity, mimicking patterns seen in female mice with SLE. Those same autoantibody patterns can be seen in SLE patient tissue samples.

“XIST expression promotes increased autoimmunity in mouse models,” Dr. Dou said. “And SLE patients are seroreactive to multiple components of the XIST RNP. We hope to use these findings to improve therapies and diagnostics.”