Xist lncRNA identified as key trigger in female-biased autoimmune diseases

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In a recent study published in the journal Dr cellA team of scientists, mainly from Stanford University, discovered that sex-biased autoimmunity, where women are more affected by autoimmune disorders than men, is primarily driven by the Xist ribonucleoprotein complex that contains various autoantigenic components.

Study: Xist ribonucleoproteins promote sex-biased autoimmunity in women.  Image credit: Kateryna Kon/ShutterstockStudy: Xist ribonucleoproteins promote female sex-biased autoimmunityy Image credit: Kateryna Kon/Shutterstock

Background

After cancer and cardiovascular disease, autoimmune disorders are the most prevalent category of disease, with women four times more likely to develop autoimmune diseases than men. The prevalence of Sjögren’s disease is 19 to one female to male, while the sex ratio of patients with systemic lupus erythematosus is 9:1 female to male. Furthermore, patients with Klinefelter syndrome who have an XXY sex chromosome and are phenotypically male with a biologically male hormone pattern are at risk of developing autoimmune disorders similar to females.

Although the role of hormones in autoimmune disorders has been extensively studied, research indicates that X chromosome dosage appears to be one of the main drivers of autoimmune disease risk, regardless of hormonal status and gender. In addition, studies in identical twins indicate that the penetrance of autoimmune diseases may also vary, suggesting that environmental factors may influence the genetic predisposition for autoimmune disorders. X-linked genes such as Toll-like receptor 7 (TLR7) are thought to contribute to the development of some autoimmune diseases.

About the study

In the current study, the researchers used autoimmune-resistant and autoimmune-prone mouse models, C57BL/6J and SJL/J, respectively, to understand the role of X chromosome dosage compensation in determining the disproportionate risk of autoimmune disease in females.

Since mammals have two copies of a female-coding ribonucleic acid (lncRNA) called Xist. Xist is not expressed in males, and only the inactive X chromosome transcribes this lncRNA in females.

Studies of mouse embryonic stem cells have shown that X chromosome inactivation is established when Xist forms a ribonucleoprotein complex with 81 binding proteins that are unique to this complex. Xist binds to 10 of these binding proteins directly by RNA-protein interactions and indirectly by protein-protein interactions to the remaining 71. Several of these binding proteins have previously been identified as autoantigens and are thought to activate innate immune system pathways through Toll-like receptors.

Here, the researchers used non-silencing alleles of Xist that were inducible and introduced them into the autosomes of autoimmune-resistant and autoimmune-prone mouse strains. Induction of Xist ribonucleoprotein complex formation in male mice in a chemically induced systemic lupus erythematosus mouse model allowed this female-specific process to be observed in a male background.

RNA sequencing and assay of transposase-accessible chromatin by ATAC-sequencing or sequencing were used to assess gene expression changes and potential transcriptional regulatory changes in splenic CD4+ T cells. Principal component analysis was also used to determine similarity between male mice expressing the induced Xist allele.

Serum samples from treated mice were also evaluated for antigens against scleroderma and systemic lupus erythematosus. In addition, serum samples obtained from human patients with systemic lupus erythematosus, dermatomyositis, and scleroderma were tested for reactivity against proteins from the Xist ribonucleoprotein complex.

result

The results reported that induction of transgenic expression of non-silenced Xist in male mice produced Xist ribonucleoprotein complexes and led to the production of autoantibodies. Male autoimmune-prone mouse models show multi-organ pathology of pristane-induced systemic lupus erythematosus that is more severe than wild-type mice. Moreover, expression of Xist in male mice reprogrammed the chromatic state and B and T cell populations to more closely resemble wild-type female mice.

Reactivity against multiple proteins from the Xist ribonucleoprotein complex has also been shown to be significant in serum samples obtained from patients with human systemic lupus erythematosus, dermatomyositis, and scleroderma.

The findings highlight the potential of using 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 Xist ribonucleoprotein complex expression also provides a potential area of ​​research for autoimmune disorder therapy.

Conclusion

Overall, the results indicate that the Xist ribonucleoprotein complex is selectively expressed in females and drives sex-biased autoimmunity involving X chromosome dosage compensation. Patients with autoimmune conditions such as scleroderma and systemic lupus erythematosus have high reactivity against proteins from the Xist ribonucleoprotein complex, highlighting the potential use of these proteins as antigens for screening and early detection of autoimmune disorders.

Journal Reference:

  • 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, & Fiorentino, DF (2024). Xist ribonucleoproteins promote female sex-biased autoimmunity. cell187(3), 733-749.e16, 10.1016/j.cell.2023.12.037, https://www.cell.com/cell/fulltext/S0092-8674(24)00002-3



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