Autoimmune conditions linked to reactivated X chromosome genes

Female mammals have a higher risk of developing autoimmune conditions such as lupus because extra copies of genes that are supposed to be permanently turned off get reactivated as they grow older, a study of mice suggests.

The findings are likely to apply to all mammals, including humans, says Céline Morey at the Paris Cité University in France, and could explain why older women are more likely to develop conditions such as rheumatoid arthritis.

Whereas male mammals usually have one X and one Y chromosome, most female mammals have two copies of the X chromosome. If all the genes on both X chromosomes were active, females would get a double dose of the gene products compared with males.

Instead, soon after embryos start developing, most of the genes on one of the two copies of the X chromosome get turned off, a phenomenon known as X inactivation.

Morey and her colleagues set out to study this process by creating mice that lack one of the genes involved in X inactivation. This deletion doesn’t prevent X inactivation entirely – that would be fatal – but it does diminish its strength.

At first, the mice appeared normal. “We had to wait for the mice to grow old to finally see something wrong, because otherwise they were happy,” says Morey.

In older age, the mice developed symptoms resembling those of lupus, such as an enlarged spleen.

The team found that several key genes on the inactivated X chromosome in their immune cells were becoming reactivated as the mice got older. These genes regulate the immune system and one of them, called TLR7, is already known to affect the risk of people developing lupus.

It has been suspected that higher doses of genes such as TLR7 make people with two X chromosomes more resistant to many infectious diseases but also more prone to autoimmune conditions. The new study provides the strongest evidence so far that higher doses could come about because of the failure to maintain X inactivation.

Morey hopes the findings could lead to better treatments for autoimmune conditions such as rheumatoid arthritis, which are more common in older age and in women compared with men.

“If we identify the genes that are involved, we could maybe design some treatments that are targeting specific key factors,” says Morey.

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