Sex hormones, and genes in the two sex chromosomes, impact the risk of multiple sclerosis (MS) in men and women differently, and lead to differences in the course of the disease between the sexes, according to two studies.
Two speakers at the ACTRIMS 2017 Forum highlighted the role of sex hormones and chromosomes in MS during a Feb. 24 session titled “Hormones, Sex Chromosomes and MS: Risk Factors, Biomarkers and Therapeutic Targets.”
The findings advance our understanding of why women develop MS more often, but men have a worse disease course. The forum runs from Feb. 23-25.
Dr. Rhonda Voskuhl of the University of California, Los Angeles (UCLA) spoke about intricate experiments in mice that demonstrated the influence on the brain of genes residing in sex chromosomes, as opposed to the immune system.
Voskuhl said that while studies of sex hormones are common, few researchers have focused on how sex chromosomes impact the risk of someone getting MS and the manifestations of the disease. Her talk was titled “The Influence of Sex Chromosomes on MS Susceptibility and Clinical Course.”
Chromosome impacts without hormones
Studying the impact of sex chromosomes — XX in females and XY in men — is challenging. Sex chromosomes are obviously linked to the production of male and female sex hormones, so how is it possible to look at effects beyond hormonal impact?
Voskuhl uses a model that has gained increasing popularity in recent years. The four core genotype model involves engineering XX and XY mice with testes, and XX and XY mice with ovaries. This makes it possible to study the impact of other genes related to sex.
The research team did much of its work with a mouse model of experimental autoimmune encephalomyelitis (EAE) — that is, a mouse model of human MS.
One finding was that in female mice with a higher disease risk, two X chromosomes, rather than hormones, promoted the disease. Immune responses in XX mice were also more pronounced that in XY mice, independent of hormones.
Based on the findings, the team is now working to identify specific genes in the X chromosome that impact immune responses.
Immune system versus brain
When the researchers realized that genes in the female XX chromosome influence immune reactions, another set of questions arose. Do sex chromosomes play additional roles in disability progression? Do male and female brains react differently to injury?
To answer these questions, the research team created bone marrow chimeric mice. The mice shared the same immune system, but had male and female chromosomes. This meant that their brains worked under the influence of the associated genes.
It turned out that mice with male chromosomes had more severe EAE symptoms, and worse damage in their spinal cord and cerebellum. Again, researchers are searching for the particular genes involved in these differences in central nervous system damage.
The results suggested that genes residing in the X and Y chromosomes have different effects on the immune system and brain.
But what about hormones?
Dr. Emmanuelle Waubant of the University of California, San Francisco (UCSF) took a different approach from Voskhul in studying sex differences in MS. Her talk, “Effect of puberty on MS risk and course,” covered differences in disease risk in children before, during, and after puberty.
Studies show that the risk of developing childhood MS peaks around age 15. Among children who fall ill before age 10, boys and girls are equally affected. At age 11, the ratio between the sexes starts changing, and in teenagers, girls are twice as likely to develop MS than boys.
Researchers have also noted that most girls develop MS two years after their first period. Girls who fall ill before their initial period have more frequent relapses before their menstrual cycling begins than after their first period. These observations suggest a tight connection between MS and hormonal changes.
In children who fall ill before they turn 10, brain scans and analyses of cerebrospinal fluid differ from those seen in older children with MS.
Together, the findings suggest that hormones play a role in the risk of developing MS and in disease activity.
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