Autoimmunity’s XX factor

That second X chromosome is the reason women are more susceptible than men to autoimmune disorders, according to a study published Feb. 1, 2024, in Cell.

In mammals, male sex is typically determined by the presence of single X and Y chromosomes in every cell. Female sex is determined by the presence of two X chromosomes — but that arrangement risks generating twice the number of X-coded proteins per cell, which would be toxic. So, nature devised a clever workaround: X-chromosome inactivation.

Yet, as the researchers found, X-chromosome inactivation, which is achieved by a molecule called Xist, can lead to autoimmune disorders. The gene for Xist is present on all X chromosomes, but Xist is produced only in cells with an XX pair.

Xist, in cahoots with other proteins it recruits, coats the genes of one of the female cell’s two X chromosomes, drastically cutting its output. But, they found, the oddball complexes of proteins and genetic material formed in the inactivation process can trigger a strong immune response. 

This could account for why as many as 4 out of 5 people in the U.S. with autoimmune disease are women, according to lead author, basic life research scientist Diana Dou, PhD, and senior author, genetics professor Howard Chang, MD, PhD.

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