Father’s X chromosome may yield clues to higher rates of autoimmune disease in women


Father’s X chromosome may yield clues to higher rates of autoimmune disease in women


Scientists from UCLA have discovered a reason that autoimmune diseases are more common in women than in men. Males inherit their mother’s X chromosome and father’s Y chromosome, while females inherit X chromosomes from both parents.

New research has revealed differences in how each of the X chromosomes are regulated, and suggests that the X chromosome females get from their father may help in explaining their more active immune system.

 “It’s been known for many years that women are more susceptible to autoimmune diseases than men are,” said lead study author Dr. Rhonda Voskuhl, a UCLA professor of neurology and director of the UCLA Multiple Sclerosis Program who also holds the Jack H. Skirball Chair in Multiple Sclerosis Research. “Figuring out why can help us develop new drugs to treat these autoimmune diseases.”

Autoimmune diseases, such as multiple sclerosis and rheumatoid arthritis, affect the body’s ability to fight viruses, bacteria, and infections – the immune cells attack the body instead.

Women generally have stronger immune responses than men, and have stronger responses to some vaccinations and infections. The stronger immune response, however, makes women three times more likely than men to develop multiple sclerosis, nine times more likely to develop lupus, and more prone to a range of other autoimmune diseases. The effect of testosterone and estrogen in these differences have been studied at length, but the role of sex chromosomes has been less clear.

In the new work, published in Proceedings of the National Academy of Sciences, Voskuhl and her colleagues aimed to investigate the difference between the X chromosomes inherited from each parent. From analysing mice with XX and XY chromosomes, they discovered that some immune system-related genes were expressed less in the immune system of female mice.

To investigate the differences, the team compared mice with just one X chromosome. They determined the level of methylation in the X chromosomes – methylation is known to reduce or block the expression of genes. The researchers found that more methylation was found on paternal than maternal X chromosomes. They also confirmed that several genes on the X chromosome were expressed less when the X chromosome was of paternal origin, compared to maternal origin.

 “What we’re talking about here is not mutations that affect gene sequences, but instead signals that affect how the same sequence of genes are differentially expressed in females versus males. These differences would be missed in traditional genetic studies,” Voskuhl said.

These findings suggest that the X chromosomes passed from father to daughter may have higher levels of methylation than the X chromosomes passed from mother to her offspring. This methylation dampens the expression of some immune system genes in the females, making their immune activity differ from males.

 “If you can find regulators of methylation that target these differences, you might be able to reduce the immune responses of females to treat autoimmune diseases,” Voskuhl said. “Going forward, when one considers sex as a biologic variable in diseases, it can lead to new treatment strategies.”

Further research is required to determine whether the same results are found in humans, and whether the differences lead to measurable differences in autoimmune disease risk. Voskuhl said that new research is an important step towards a better understanding of sex differences in disease.


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