According to a recent study published in the journal Cell, the Xist ribonucleoprotein complex has a significant impact on the prevalence of autoimmune disorders. This complex hosts various autoantigenic components and is responsible for driving sex-biased autoimmunity, which makes females more susceptible to these disorders than males.
Autoimmune disorders are the third most common disease after cancer and cardiovascular disease. Females are more affected by these disorders, with a fourfold higher incidence compared to males. The study highlights gender imbalances in conditions such as Sjögren’s disease and systemic lupus erythematosus. Additionally, individuals with Klinefelter syndrome, who possess XXY sex chromosomes, have a similar risk of autoimmune disorders as females.
Extensive research has been conducted to study the effect of hormonal influences on autoimmune disorders. However, the researchers suggest that the risk of autoimmune diseases is majorly influenced by the dosage of X chromosomes, regardless of hormonal status. Environmental factors also contribute to the genetic predisposition to autoimmune disorders, as evidenced by variations in identical twins. Toll-like receptor 7 (TLR7), which is an X-linked gene, has been implicated in the development of some autoimmune disorders.
To investigate the role of X chromosome dosage compensation in the disproportionate risk of autoimmune diseases in females, Dhou et.al used autoimmune-resistant and autoimmune-prone mouse models. Female mammals, who have two X chromosomes compared to males with the XY genotype, undergo X chromosome inactivation through the Xist ribonucleoprotein complex. This complex epigenetically silences one X chromosome in every cell.
In this study, researchers used non-silencing alleles of Xist that were introduced into autoimmune-resistant and autoimmune-prone mouse strains. By inducing the expression of non-silenced Xist in male mice, they were able to observe the female-specific process in a male background. The analysis involved RNA sequencing, ATAC sequencing, and principal component analysis to evaluate changes in gene expression and chromatin states.
According to Dhou and colleagues, the results of the study demonstrated that inducing the expression of non-silenced Xist in male mice led to the formation of Xist ribonucleoprotein complexes, which produced autoantibodies. In comparison to wild-type mice, autoimmune-prone male mice exhibited more severe multi-organ pathology. The expression of Xist in male mice also reprogrammed chromatin states and immune cell populations to resemble those found in wild-type female mice.
The researchers concluded that the study found significant reactivity against multiple proteins from the Xist ribonucleoprotein complex in serum samples from human patients with systemic lupus erythematosus, dermatomyositis, and scleroderma. The findings suggest the potential use of these proteins as antigens for the early detection and monitoring of autoimmune disorders. The discovery of atypical B cell accumulation due to Xist ribonucleoprotein complex expression opens new avenues for autoimmune disorder therapy.
Reference
Dou DR, Zhao Y, Belk JA, Zhao Y, Casey KM, Chen DC, et al. Xist ribonucleoproteins promote female sex-biased autoimmunity. Cell. 2024 Feb 1;187(3):733-749.e16.