Brain Receptor More Common to Women May Explain Sex Disparity in Multiple Sclerosis

For years, clinicians and patients could only notice and accept the fact that four times more women than men are diagnosed with multiple sclerosis. Now, a group of researchers from Washington University School of Medicine in St. Louis are uncovering a potential reason for the disparity, and they recently published a paper in The Journal of Clinical Investigation that describes a sex-related difference in the brain.

Experimental autoimmune encephalomyelitis (EAE) is a mouse model of multiple sclerosis in which females are affected more often than males. The team of researchers used EAE mice to probe gene activity in the brains of male and female mice, and 20 genes were found to be active at different levels in damaged regions of the female brain. One of these genes, S1PR2, showed increased activity, which was of interest because sphingosine-1-phophate receptors (S1PRs) regulate vascular permeability.

Probing further, the team found S1PR2 was intimately related to opening the blood-brain-barrier. “It was a ‘Bingo!’ moment–our genetic studies led us right to this receptor,” said senior author Robyn Klein, MD, PhD, in a press release. “When we looked at [S1PR2’s] function in mice, we found that it can determine whether immune cells cross blood vessels into the brain. These cells cause the inflammation that leads to multiple sclerosis.” Inflammation in the brain damages the myelin sheath around nerve cells in the brain and spinal column. When myelin is damaged, nerve cell communication suffers and the symptoms of multiple sclerosis become apparent.

The team found that not only did female EAE mice have higher S1PR2 than male mice, but also more multiple sclerosis patients have S1PR2 than unaffected individuals. Female patients have more S1PR2 than male patients, and the highest levels were seen in two female patients with irregular symptom flare-ups.

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Dr. Klein hopes to bring these findings to the clinic in the form of a tracer that monitors S1PR2 levels in the brain. She is collaborating with chemists to make this possible with goals of increasing the knowledge of how S1PR2 contributes to multiple sclerosis. It is not yet possible to block the action of S1PR2 using drugs, as the investigational multiple sclerosis drug in clinical trials to block other types of S1PRs is not effective against S1PR2. However, this study “is an exciting first step in resolving the mystery of why multiple sclerosis rates are dramatically higher in women and in finding better ways to reduce the incidence of this disorder and control symptoms,” said Dr. Klein.