Autoimmunity’s XX factor

Molecule can set off immune response in women

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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.

Read the full story here.

Ep. 4: Health Compass Podcast

Why are women at a greater risk for autoimmune diseases? Hear from podcast host Maya Adam in conversation with basic life research scientist Diana Dou and genetics professor Howard Chang.

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Bruce Goldman

Bruce Goldman is a science writer in the Office of Communications. Email him at goldmanb@stanford.edu.

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