In a recent study published in the journal Cell, a team of scientists, predominantly from Stanford University, discovered that gender-specific autoimmunity, in which women are more affected by autoimmune diseases than men, is primarily caused by the Xist ribonucleoprotein complex which contains various autoantigenic components.
Following cancer and cardiovascular diseases, autoimmune diseases represent the most prevalent category of illness, with women being four times more likely than men to suffer from autoimmune diseases. The prevalence of Sjögren’s disease is 19 to 1 in women compared to men, while the gender ratio in patients with systemic lupus erythematosus is 9:1 for women and men. In addition, patients with Klinefelter Syndrome, who have an XXY sex chromosome and phenotypically male and hormonal patterns of a biological male, have the same risk for autoimmune diseases as women.
While the role of hormones in relation to autoimmune diseases has been extensively researched, research results indicate that X-chromosome dosing appears to be one of the main factors for the risk of autoimmune diseases independent of hormonal status and gender. Moreover, studies on identical twins suggest that the penetrance of autoimmune diseases can also vary, indicating that environmental factors may influence the genetic predisposition for autoimmune diseases. X-chromosomal genes such as the Toll-like receptor 7 (TLR7) are believed to contribute to the onset of certain autoimmune diseases.
About the Study
In the present study, the researchers used autoimmune-resistant and autoimmune-prone mouse models, C57BL/6J and SJL/J, to understand the role of X-chromosome dosage compensation in determining the disproportionate risk of autoimmune diseases in women.
Given that female mammals have two copies of the X chromosome compared to male mammals, who have an XY genotype, one of the X chromosomes encodes a ribonucleic acid (lncRNA) called Xist. Xist is not expressed in males, and only the inactive X chromosome transcribes this lncRNA in females.
Studies in mouse embryonic stem cells have shown that X chromosome inactivation occurs when Xist forms a ribonucleoprotein complex with 81 binding proteins that are unique to this complex. Xist directly binds to 10 of these binding proteins through RNA-protein interactions, and the remaining 71 indirectly through protein-protein interactions. Several of these binding proteins have already been identified as autoantigens and are believed to activate the innate immune system’s signaling pathways via Toll-like receptors.
Here, the researchers used non-silencing alleles of Xist, which were inducible, and introduced them into the autosomes of the autoimmune-resistant and autoimmune-prone mouse strains. The induction of Xist ribonucleoprotein complex formation in male mice of a chemically induced systemic lupus erythematosus mouse model allowed observation of this female-specific process against a male background.
RNA sequencing and ATAC sequencing, or Assay for Transposase-Accessible Chromatin using sequencing, were used to assess changes in gene expression in spleen CD4+ T cells and potential changes in transcriptional regulation. Principal component analysis was also used to determine similarities between male mice expressing the induced Xist allele.
Serum samples from treated mice were also examined for antigens against scleroderma and systemic lupus erythematosus. Additionally, serum samples from human patients with systemic lupus erythematosus, dermatomyositis, and scleroderma were tested for reactivity to proteins from the Xist ribonucleoprotein complex.
The results showed that induction of the transgenic expression of non-silenced Xist in male mice formed Xist ribonucleoprotein complexes and led to the production of autoantibodies. Male, prone-to-autoimmune-disease mouse models with pristane-induced systemic lupus erythematosus showed multi-organ pathology that was more severe than in wild-type mice. Furthermore, reactivity to several proteins from the Xist ribonucleoprotein complex in serum samples from human patients with systemic lupus erythematosus, dermatomyositis, and scleroderma was significant.
The results underscore the potential use of these Xist ribonucleoprotein complex-associated proteins as novel antigens for the detection and monitoring of autoimmune diseases. The discovery of atypical B cell accumulation due to the expression of the Xist ribonucleoprotein complex also provides a potential area of research for the therapy of autoimmune diseases.
Overall, the results suggest that the Xist ribonucleoprotein complex, which is selectively expressed in women and involved in X-chromosome dosage compensation, promotes gender-specific autoimmunity. Patients with autoimmune diseases such as scleroderma and systemic lupus erythematosus have a higher reactivity to proteins from the Xist ribonucleoprotein complex, highlighting the potential use of these proteins as antigens for screening and early detection of autoimmune diseases.
- Dou, DR, Zhao, Y., Belk, JA, Zhao, Y., Casey, KM, Chen, DC, Li, R., Yu, B., Srinivasan, S., Abe, BT, Kraft, K., Hellström, C., Sjöberg, R., Chang, S., Feng, A., Goldman, DW, Shah, AA, Petri, M., Chung, LS und Fiorentino, DF (2024). Xist-Ribonukleoproteine fördern die geschlechtsabhängige Autoimmunität von Frauen. Zelle187(3), 733-749.e16, 10.1016/j.cell.2023.12.037, https://www.cell.com/cell/fulltext/S0092-8674(24)00002-3