A major discovery in biochemistry suggests that it is antibodies directed against proteins involved in controlling the activity of the X chromosome which contribute to ensuring that women are more affected than men by autoimmune diseases.
In Canada, it is estimated that more than two million people are affected by an autoimmune disease, the most common being lupus, rheumatoid arthritis, multiple sclerosis, Crohn’s disease and Sjögren’s syndrome.
A truly striking feature of these diseases is that they disproportionately affect women: globally, eight out of 10 patients with autoimmune diseases are women. A ratio that even reaches nine women for one man in the case of systemic lupus erythematosus and 19 women for one man for Sjögren’s disease.
Extra X chromosome
Since the fundamental difference between women and men is the presence of two X chromosomes in women (XX) versus just one in men (XY), it has long been suspected that this extra X chromosome contributes to the higher incidence autoimmune diseases in women.
This is also suggested by the fact that patients with Klinefelter syndrome (with an XXY genotype) have an autoimmune disease risk equivalent to that of women, even though they have a typically male phenotype and hormonal profile.
Muzzle the X chromosome
The presence of an extra X chromosome in women, however, does not mean that the expression of genes present on this chromosome is twice as high as in men (this would have catastrophic consequences for the cells).
To make the products of these genes roughly equivalent between the two sexes, each cell in a woman’s body inhibits one of the two X chromosomes using a long stretch of non-coding RNA, called Xist , which associates with many proteins to form a kind of “molecular coat” which covers the extra X chromosome and prevents the expression of the genes located there, thus rendering it inactive.
Immune confusion
The Xist complex is produced only from the inactive autoimmune diseases that affect women(1).
Using model systems, researchers showed that adding the Xist complex to males made them significantly more susceptible to developing an autoimmune disease. They also observed that the blood of people with autoimmune diseases had high levels of antibodies against proteins found in Xist complexes.
According to the researchers, it is possible that during the normal elimination of aging cells, Xist complexes are released into the circulation in the form of protein clumps that could destabilize the immune system and make it believe that it is a foreign body.
This immune confusion has serious repercussions, because the production of antibodies against completely normal proteins leads to the establishment of an autoimmune response and the development of one or another of many diseases that results from it.
This major discovery does not mean, however, that all autoimmune diseases are caused by the phenomenon identified in the study. Even if they are less frequently affected, many men develop these diseases and are even in certain cases (type 1 diabetes) even more affected than women.
Nevertheless, the identification of a new biochemical mechanism associated with the development of autoimmunity is very encouraging and could lead in the medium term to better clinical detection of these diseases and the development of new therapeutic approaches.
(1) Dou DR et al. Xist ribonucleoproteins promote female sex-biased autoimmunity. Cell 2024; 187: 733-749.e16.