A new paper explains why females are more susceptible to autoimmune diseases

A new paper explains why females are more susceptible to autoimmune diseases

Cartoon drawing of two X-shaped chromosomes.

Eighty percent of patients with autoimmune diseases are female. These diseases are one of the ten leading causes of death for women under the age of 65, and their incidence increases annually throughout the world. There is evidence to suggest that it is the double complement of X chromosomes in females that puts them at increased risk of developing autoimmune diseases. Female cells have two X chromosomes, while males have one X and one Y chromosome (at least in mammals).

Turn off X

Different animals compensate for this type of asymmetry in different ways. Male fly cells produce twice the amount of proteins encoded by the single X chromosome, so they end up producing the same amount as female cells. Vermis hermaphrodite cells reduce the production of proteins encoded by each of their X chromosomes by half, so they end up with the same amount as male cells.

Mammals use X inactivation, where each female cell turns off one of its X chromosomes and uses only the other. Which X chromosome is turned off (inherited from the father or inherited from the mother) is random and independent within each cell. So women are all genetic mosaics: their cells don’t all make the same proteins because some of their cells use one X chromosome and some of their cells use the other.

X is inactivated by a complex of proteins and RNA called Xist. The inactivated X chromosome creates a Xist, which creates an X inactivation center on that chromosome. It then recruits proteins to bind to it, and these eventually cover the entire chromosome so that it cannot be used. Since male cells do not contain a second X chromosome, they do not make Xist.

One suggestion as to why women are more susceptible to autoimmune diseases is the load compensation hypothesis, which posits that women’s immune systems must be hypervigilant to deal with potentially dangerous foreign bodies that have been implanted in them on a regular and repeated basis throughout human history ( placenta). and fetuses). Now, women have access to birth control and don’t spend most of their lives pregnant, but their overactive immune systems haven’t yet learned to calibrate, the idea goes, so they attack the body’s own tissues.

The presence of autoimmunity

To examine the role that Xist may play in autoimmune diseases, a group of researchers at Stanford University inserted the Xist gene into the cells of male mice. The Xist they used is mutated. It does not have the gene silencing function that regular Xist has because that would shut down the chromosome and kill the mice. But it is still bound to almost all of its protein partners.

Most male mice expressing Zest developed autoimmune disease (lupus was the specific model they used) and achieved “female-level severe disease,” which included multi-organ autoimmune disease along with abnormal B cells and cells. B cells are what make autoantibodies, and the B cells in these male mice mimicked those in females with autoimmune diseases, in that they were hyperproliferative and hyperinflammatory. The T cells showed the same profile and made fewer molecules that normally help T cells regulate self-tolerance and immune modulation.

Thirty Xist-related proteins have already been reported to be antibody targets in human autoimmune diseases, which is what motivated this study in the first place. These researchers also identified 28 new Xist-related proteins that the autoimmune sera specifically reacted to.

Doctors and scientists have long known that (1) women develop autoimmune diseases more often than men; (2) dosage compensation of the second X chromosome in female cells likely played some role; (3) RNA-protein complexes are often targeted by autoantibodies; and (4) Xist is part of an RNA-protein complex involved in X inactivation. However, no one has ever looked to see whether Zist itself might be the reason behind women’s greater tendency to develop autoimmune diseases. Finally, someone put all these logical pieces together and discovered that it was. We hope that this research will reveal some new and effective targets for diagnosing, monitoring, stratifying and treating this group of diseases.

Cell, 2024. DOI: 10.1016/j.cell.2023.12.037

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