Autoimmune diseases associated with reactivated X chromosome genes

Female mammals are at higher risk of developing autoimmune diseases like lupus because extra copies of genes that should be permanently turned off become reactivated as they age, a study in mice shows.

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

While male mammals generally have one X and one Y chromosome, most female mammals have the majority have two copies of the X chromosome. If all genes on both X chromosomes were active, women would receive a double dose of the gene products compared to men.

Instead, shortly after embryo development begins, most genes on one of the two copies of the X chromosome are turned off, a phenomenon known as X inactivation.

Morey and her colleagues set out to study this process by breeding mice lacking one of the genes involved in X inactivation. This deletion does not completely prevent the inactivation of X – that would be fatal – but it does reduce its strength.

At first the mice appeared normal. “We had to wait until the mice got old to finally realize something was wrong, because otherwise they were happy,” says Morey.

As they got older, the mice developed symptoms similar to those of lupus, such as an enlarged spleen.

The team found that several key genes on the inactivated X chromosome in their immune cells became reactivated as the mice aged. These genes regulate the immune system and one of them, called TLR7is beautiful are known to influence the risk of developing lupus.

It has been suggested that higher doses of genes such as TLR7 make people with two X chromosomes more resistant to many infectious diseases but also more susceptible to autoimmune diseases. The new study provides the strongest evidence yet that higher doses may occur because X inactivation cannot be maintained.

Morey hopes the findings could lead to better treatments for autoimmune diseases such as rheumatoid arthritis, which occur at older ages and are more common in women than men.

“If we identify the genes involved, we might be able to develop some treatments that target certain key factors,” says Morey.