Women’s “inactive” second X chromosome may have a lot to answer for

In humans, female cells possess two X chromosomes, one inactive. The inactive chromosome looks different, and it’s called the Barr body. Male cells possess one active X chromosome and one active Y chromosome.

Autoimmune conditions in which the immune system mistakenly attacks the body’s cells are four times more common in females. For the past 40 or 50 years, researchers have searched for the trigger behind sex-biased autoimmunity. New research suggests that the silent X chromosomes could hold the answer.

How is the extra X chromosome silenced? A piece of noncoding RNA, a complex made of the X-inactive specific transcript (XIST), in conjunction with about 80 proteins bound to it, silences the inactive X chromosome. The hypothesis was that the XIST RNA-protein complex might be behind the autoimmunity female bias since XIST isn’t expressed in males.

Using mice and genetic engineering, it was found that Xist expression in male mice altered antibodies and another aspect of the immune system,  adaptive immune cells. Among these changes, the levels of proteins that regulate autoantibody-producing B cells and suppress autoimmunity dropped in male mice with Xist, and several proteins that tame T cell reactivity were suppressed. Suppressing proteins that preempt autoimmunity may create B and T cells that are more trigger-happy toward the body’s own proteins.
In humans, higher levels of autoantibodies against 40 XIST-associated proteins in people with autoimmune conditions suggest that the XIST RNA-protein complex may also trigger autoimmunity in humans.

Clinicians struggle to diagnose autoimmune disorders because distinct conditions often share similar symptoms.  Autoantibody markers that help narrow the diagnosis could better equip doctors to treat their patients. However “basic” the science is, eventually, it clarifies the mechanisms of illness and opens possible solutions and cures. Let’s be grateful for science!

References

Dou DR, et al. Xist ribonucleoproteins promote female sex-biased autoimmunity. bioRxiv. 2023. https://doi.org/10.1101/2022.11.05.515306. Note: this is a pre-print, before it can be published it will have to go through peer review.