2024-07-24 04:00:04
Why do autoimmune diseases like lupus preferentially affect women? In an article published in the journal Science Advancesscientists show that in female mice, the second X chromosome, when it is not completely inactivated, causes the appearance of signs of autoimmunity. This discovery could allow the development of new therapeutic strategies targeting regulators of the inactivation of chromosome X.
In mammals, female immunity is stronger than male immunity. This enhanced immunity has several advantages, including better resistance to different types of pathogens (viruses, bacteria, etc.) or a better vaccine response. However, it can become harmful when not properly controlled. The immune system then becomes overreactive and attacks the body’s cells, which manifests itself in the form of autoimmune diseases.
Most of these diseases, such as lupus, mainly affect women. Understanding the origin of this sexual difference is therefore a key issue in order to better treat these diseases.
Genes on the X chromosome play a role in regulating immunity
One hypothesis being studied is the involvement of the X chromosome, which is particularly rich in genes related to immune functions. Abnormalities in the expression of some of these genes, such as the genes of the Toll-like receptor (TLR) family, are responsible for the onset of autoimmune diseases.
One might then think that the presence of two X chromosomes in females and only one in males is sufficient to explain this difference in immunity. However, during the early stages of development of female mammals, one of the X chromosomes is repressed. This inactivation is maintained throughout adult life, which rebalances the expression of X genes between the sexes.
A link between X chromosome inactivation defects and autoimmune diseases
This is why scientists investigated the link between abnormal X chromosome inactivation and the onset of autoimmune symptoms. Using a line of mouse presenting inactivation defects, they notably observed an overexpression of TLR genes associated with signs ofinflammation typical of lupus. These genes normally partially escape repression by the rest of the X chromosome, which contributes to the better natural immunity of females. However, when X chromosome inactivation is disrupted, this escape is exacerbated and immune system cells are activated even in the absence of pathogens.
Female mice have a better immune response than male mice which is associated with the low level expression of TLR signaling pathway genes (Tlr7, Tlr8, Tasl) from the inactive X chromosome in addition to their expression from the active X (Xa). When X chromosome inactivation is impaired, these genes are strongly reactivated leading to the spontaneous appearance of signs of inflammation and autoimmune manifestations.
© Huret et al.
These results suggest that there is a direct link between autoimmune diseases and incomplete inactivation of the X chromosome. This discovery could lead to the development of new therapeutic strategies specifically targeting certain genes on the X chromosome or regulators of X chromosome inactivation. These strategies could be considered for treating lupus, but also other autoimmune diseases that preferentially affect women.
Réferences:
Huret C., Ferrayé L., David A., Mohamed M., Valentin N., Charlotte F., Savignac M., Goodhardt M., Guéry JC., Rougeulle C. and Morey C. (2024)
Altered X-chromosome inactivation predisposes to autoimmunity. Science Advances, 10: eadn6537.
DOI: 10.1126/sciadv.adn6537
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