Women have long been known to be more susceptible to autoimmune diseases than men, but the reason behind this disparity has remained a mystery. However, a recent study published in Cell has shed light on a potential cause: a molecular coating found on half of a woman’s X chromosomes. This coating, made up of RNA and proteins, is involved in a process called X-chromosome inactivation. While previous research had implicated sex hormones and flawed gene regulation on the X chromosome as factors in the autoimmune disparity, this new discovery adds another layer of complexity.
The study found that proteins central to X-chromosome inactivation can trigger immune responses, which could explain why women are more prone to autoimmune diseases. Laura Carrel, a geneticist at the Pennsylvania State College of Medicine, describes this finding as a “new mechanistic twist.” The researchers believe that this discovery could lead to new diagnostic and therapeutic opportunities for autoimmune diseases.
Autoimmune diseases encompass a range of conditions, including lupus and rheumatoid arthritis, and women account for approximately 80% of all cases. This sex bias has puzzled immunologists and rheumatologists for decades. The X chromosome has long been considered a prime suspect, as males typically have only one copy of the X chromosome, while females have two.
X-chromosome inactivation is a process that silences one X chromosome in most XX cells, equalizing the dosage of X-linked genes with XY cells found in males. This process involves the XIST molecule, which coils around the chromosome and attracts proteins to form complexes that silence genes. However, some genes manage to escape this silencing process and are believed to contribute to autoimmune conditions. Additionally, the XIST molecule itself can initiate inflammatory immune responses.
Howard Chang, a dermatologist and molecular geneticist at Stanford University School of Medicine, noticed that many of the proteins that interact with XIST were targeted by autoantibodies. These rogue molecules can attack tissues and organs, leading to chronic inflammation and damage seen in autoimmune diseases. Since XIST is normally expressed only in XX cells, it was logical to assume that these autoantibodies would pose a greater problem for women.
To test this hypothesis, Chang and his colleagues engineered male mice to produce a form of XIST that did not silence gene expression but still formed RNA-protein complexes. They induced a lupus-like disease in these mice and found that those expressing XIST had higher levels of autoantibodies, heightened immune response, and more extensive tissue damage.
Furthermore, the same autoantibodies were found in blood samples from individuals with lupus, scleroderma, and dermatomyositis, providing evidence that XIST and its associated proteins play a role in human autoimmune conditions. This has implications for disease management, as diagnostics targeting these autoantibodies could aid in the detection and monitoring of various autoimmune disorders.
Montserrat Anguera, a geneticist at the University of Pennsylvania, sees this study as a promising start and believes that using this information to expedite diagnosis would be incredible. The discovery of the molecular coating on X chromosomes as a potential cause of autoimmune disease disparity in women opens up new avenues for understanding and treating these conditions. With further research, scientists hope to develop targeted therapies and improve the lives of individuals affected by autoimmune diseases.