New Theory Explaining Higher Prevalence of Autoimmunity in Females

February 2, 2024

An article published this week explores a new explanation for the longstanding question of why women are more prone to developing autoimmune disease. Previous theories focus on sex hormones and gene regulation, but this new theory adds complexity by suggesting that a molecular coating found on one of women’s X chromosomes, related to a process called X-chromosome inactivation (which dampens the function of one X chromosome in the majority of XX cells), may trigger immune responses.

The coating consists of long strands of RNA (known as XIST) that wrap around the chromosome and recruit various proteins to form complexes that silence the genes within. However, some genes manage to evade this inactivation and can provoke immune reactions, potentially contributing to autoimmune diseases like lupus and rheumatoid arthritis. It has long been discovered that many proteins interacting with XIST can be targets of autoantibodies, supporting the hypothesis that the XIST molecule itself has the potential to trigger inflammatory immune reactions.

This study demonstrated that male mice, which don’t naturally express XIST, exhibited increased levels of autoantibodies and tissue damage resembling autoimmune diseases when bioengineered to express a form of XIST that did not silence gene expression but did form the characteristic RNA–protein complexes. This study highlights the importance of understanding XIST-related mechanisms to manage autoimmune diseases and potentially improve diagnostic techniques.