Why do autoimmune diseases like lupus erythematosus always affect women?

Autoimmune diseases are the third most common disease category, after cancer and heart disease. It is interesting to note that 80% of patients with autoimmune diseases are women. For example, in systemic lupus erythematosus (SLE), the ratio of women to men is 9:1, and in Sjögren's disease, the ratio of women to men is as high as 19:1.

The core difference between males and females is the difference in sex chromosomes, with females having two X chromosomes (XX) and males having one chromosome and a Y chromosome paired with it (XY). Patients with Crohn's syndrome (XXY) are males by virtue of having a Y chromosome and in fact exhibit male phenotypes and hormonal patterns, but have the same risk of autoimmune disease as females, which suggests to us that the number of X chromosomes appears to be the primary driver of autoimmune disease risk, regardless of sex or hormonal status. In addition, identical twins show different rates of autoimmune disease, suggesting that, in addition to genetic susceptibility, environmental factors may also be drivers of autoimmune disease development.

A long-stranded noncoding RNA (lncRNA) in the X chromosome, Xist, is expressed only in female cells to randomly inactivate one of the two X chromosomes in females to ensure that the number of genes in female and male cells is roughly the same. Because Xist is expressed only in human and female mammalian cells, it drives sex-biased autoimmunity.

On February 1, 2024, a team of Stanford University researchers published a research paper in the journal Cell entitled "Xist ribonucleoproteins promote female sex-biased autoimmunity".

The study shows that Xist binds to a variety of RNA-binding proteins to form XIST-RNP, a package with properties similar to nucleic acid-autoantigen immune complexes that lead to autoimmunity.

To investigate the effects of XIST RNP in autoimmune predisposition independent of sex chromosome or hormonal background, the team introduced inducible and non-silencing alleles of XIST into autosomes in autoimmune-resistant C57BL/6J mice and autoimmune-prone SJL/J mice. Transgenic Xist RNP formation was induced in male mice using a SLE model induced by the chemical inducer Pristane, and this female-specific lncRNA was studied in a male background.

The results showed that male SJL/J mice expressing the transgene Xist exhibited more severe multiorgan pathology than wild-type male mice. Xist expression in male mice reprogrammed T and B cell populations as well as chromatin status to be more similar to wild-type female mice. The team also designed an antigen array to test the serum activity of XIST RNP in autoimmune patients and detected significant reactivity to multiple components of XIST RNP.

The results of these experiments indicate that the sex-specific lncRNA, Xist, which is expressed only in the inactivated X chromosome, binds multiple RNA-binding proteins to form XIST RNP, and that multiple of its protein components belong to autoantigens that lead to the production of significant autoantibodies that drive sex-biased immune responses. Since X chromosome inactivation (XCI) and Xist expression are normally present only in cells from females, this leads to autoimmune diseases mostly in females.antigen array

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