Autoimmune diseases, the third most prevalent disease category globally, are characterized by the immune system attacking the body’s own tissues. Surpassing only cancer and heart disease in prevalence, autoimmune diseases disproportionately affect females, with four out of five patients being women.
The disproportionate prevalence is evident in diseases like systemic lupus erythematosus (SLE) and Sjögren’s disease, where female-to-male ratios are 9:1 and 19:1, respectively. While hormonal factors have been extensively studied, recent research suggests that the dosage of the X chromosome plays a significant role in autoimmune risk, regardless of sex or hormonal status in humans and mice.
In a breakthrough study, researchers investigated the role of X chromosome-related factors in autoimmune diseases. Klinefelter syndrome (XXY), a condition where individuals are phenotypically male but have an extra X chromosome, was found to have an elevated risk of autoimmune diseases comparable to females.
Specific X-linked genes, including TLR7, escaping X inactivation, have been identified as potential contributors to autoimmune diseases. However, the genetic risk from the second X chromosome remains unclear, and environmental factors are believed to interact with genetic predisposition, triggering autoimmune disease development.
The study focused on X chromosome inactivation (XCI), a process where every cell in a female’s body epigenetically silences one of the two X chromosomes. The long non-coding RNA (lncRNA) Xist plays a crucial role in this process. Xist is transcribed only from the inactive X chromosome, coating it entirely. Previous studies identified Xist binding proteins as autoantigens, and it was discovered that XIST RNP (ribonucleoprotein) complexes share similarities with nucleic acid-autoantigen immune complexes.
To examine the impact of XIST RNP in autoimmune predisposition independent of sex or hormonal background, researchers introduced an inducible Xist allele into an autosome in autoimmune-resistant and autoimmune-prone mouse strains. The study utilized a chemically induced SLE model and observed increased disease severity and autoreactive lymphocyte pathway signatures in mice with Xist RNP induction.
The discussion delves into the implications of Xist RNP complexes as antigenic triggers in female-biased autoimmunity. The study suggests that every cell in a woman’s body, through XIST, presents a unique antigen array, and exposure of XIST RNPs to the immune system may contribute to the greater prevalence of autoimmune diseases in females. The findings open avenues for disease diagnosis and therapy, with the identification of seropositivity toward XIST-associating proteins in autoimmune patients. This discovery introduces a potential antigen set for enhancing disease detection and monitoring.
With over 100 known autoimmune diseases affecting around 50 million Americans, understanding the risk factors and drivers of autoimmunity is crucial for developing targeted therapies and sensitive diagnostics. The study’s identification of atypical B cells as a consequence of Xist RNP expression suggests potential pathogenic leukocyte targets for future research and therapeutic development. The research underscores the need for further studies to explore the contribution of atypical B cells and other cell types evoked by Xist RNP in promoting autoimmunity, offering hope for more effective and specific treatments for autoimmune diseases in the future.
Journal Reference
Diana R. Dou, Yanding Zhao et al. Xist ribonucleoproteins promote female sex-biased autoimmunity, Cell, Volume 187, Issue 3, 2024, Pages 733-749.e16.
