A gene on the X-chromosome may help explain why more women than men develop autoimmune diseases, including multiple sclerosis (MS). Researchers found that a gene known as Kdm6a was expressed more in the immune cells of women compared to men, and female mice compared to males. Additionally, when the Kdm6a gene was eliminated in mice specially bred to mimic a disease like MS, they had improved symptoms, reduced inflammation and less damage to their spinal cords.
Women are known to have about a threefold higher risk of developing MS than men, and also to have stronger immune responses in general. Previous research has suggested that this gender difference may be due to sex hormone and/or chromosome differences between men and women. Since women have two X-chromosomes, they get a “double dose” of genes on the X-chromosome; despite a natural mechanism to silence the extra genes, some genes elude this inactivation. The current study set out to determine which X-chromosome genes may “slip by” and show increased expression in females’ immune systems, and whether they may underlie the increased female susceptibility to autoimmune disease.
The team first used RNA sequencing to determine which X-chromosome genes were expressed more in the T cells of female vs. male immune systems. After finding that a gene known as Kdm6a showed the greatest sex difference, the team bred mice that lacked it—mice that were from a strain destined to develop an MS-like autoimmune disease. The specially bred mice without the Kdm6a gene had reduced clinical symptoms of the disease, compared to their counterparts who had intact Kdm6a.
The researchers next inspected the animals’ spinal cords to assess damage that’s characteristic of MS. In mice lacking the Kdm6a gene, there was evidence of reduced autoimmune activity in spinal cord cells, reduced damage to the cells’ axons (the long extensions through which neural communication occurs, and which undergo deterioration in MS), and greater numbers of intact axons. The results suggest that deleting the Kdm6a gene has protective effects.
Finally, the team was also able to identify the molecular changes that are triggered by the deletion of the gene. In mice lacking Kdm6a, they found evidence of increased activity of multiple genes involved in healthy immune activity, and reduced activity of genes involved in neuroinflammation.
The results help explain why females are more prone to developing autoimmune disease, and suggest that modulating the activity Kdm6a in T cells might be a potential therapeutic target for MS, and other autoimmune diseases. The findings suggest that drugs like metformin, a diabetes treatment that has been shown to alter Kdm6a activity, might also deserve further study.
Yuichiro Itoh, of the department of neurology at the David Geffen School of Medicine at UCLA, is the study’s first author. Rhonda R. Voskuhl is the study’s senior author. Other UCLA-affiliated authors are Lisa Golden, Noriko Itoh, Macy Akiyo Matsukawa, Emily Ren, Vincent Tse, and Arthur P. Arnold.
The study was published in the Journal of Clinical Investigation.
The work was funded by NIH grants RO1NS096748, RO1NS109670 and HL131182; Conrad N. Hilton Foundation grants 20130232 50 and 20150232; the Tom Sherak MS Hope Foundation; the Yvette and Eric Edidin Foundation; and the Rhoda Goetz Foundation for MS.
The authors report no conflicts of interest.