A gene on the X-chromosome may help explain why more women than men develop autoimmune diseases, including multiple sclerosis (MS). That is according to research published in the Journal of Clinical Investigation.
The research carried out at the University of California Los Angeles (UCLA) showed that a gene known as Kdm6a is expressed more in the immune cells of women than men, and also in female mice compared to male mice. Additionally, when the Kdm6a gene was eliminated in mice specially bred to mimic a disease like MS, these mice had improved symptoms, reduced inflammation and less damage to their spinal cords.
For some time it has been known that women have about a threefold higher risk of developing MS than men, and also that women have stronger immune responses in general. Previous research has suggested this gender difference may be due to sex hormone and/or chromosome differences between women and men. Since women have two X-chromosomes, they get a “double dose” of genes on the X-chromosome and despite a natural mechanism to silence the extra genes, some genes elude inactivation.
The current research set out to determine which X-chromosome genes may elude inactivation and show increased expression in females’ immune systems and whether this explains the increased female susceptibility to autoimmune diseases including MS.
The researchers first used genetic sequencing to determine which X-chromosome genes were expressed more in the T-cells of female compared to male immune systems. After finding that Kdm6a showed the greatest sex difference, the team bred mice from a strain destined to develop an MS-like autoimmune disease that lacked the gene. The specially bred mice without Kdm6a 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 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 a protective effect.
Finally, the team was also able to identify molecular changes 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 suggest that modulating the activity Kdm6a in T-cells might be a potential therapeutic target for MS, and other autoimmune diseases and also that drugs like metformin, a diabetes treatment that has been shown to alter Kdm6a activity, might also deserve further study.
Source: MS-UK 16/08/2019