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Why does MS affect more women than men?

For multiple sclerosis (MS) awareness month in May, Women’s Health Matters spoke with Dr. Shannon Dunn, a scientist at Women’s College Research Institute and Toronto General Research Institute, about her research into sex differences in MS.

MS is a potentially debilitating disease that affects the central nervous system. It affects more women than men.

“The ratio of women to men affected is about three to one,” says Dr. Dunn.

This sex difference is curious because it has become stronger in recent decades. Over the past 50 years, the per cent of MS patients that are women has increased from 65 to about 75.

“It suggests also that there is something in the environment that’s interacting with sex or gender to increase the risk in women,” says Dr. Dunn. “Genetics can’t change that quickly.”

Some of the key areas researchers are looking at to help explain the sex difference include dietary changes and the effects of vitamin D. Meanwhile, Dr. Dunn is studying the fundamental question of why females may be more susceptible to MS through work in mouse models of this disease.

Her research focuses on the autoimmune aspects of the disease.

“MS is definitely known to be an autoimmune disease,” she says. An autoimmune disease is one in which the body’s own immune system attacks healthy tissue. “MS appears to be mediated primarily by T-cells, a type of immune cell that gets the immune process started.”

When T-cells react against an infection, it’s a good thing. But in MS patients, the T-cells start to attack the myelin sheath – a protective covering of the nerves – which then affects the nervous system.

“We primarily look at things that can influence the activity of the autoreactive T-cells and how they initiate the disease, or how slowing down their function inhibits the disease,” Dr. Dunn says.

They do this by studying the development of an MS-like condition in mice. In the strain of mice used in the research, the female mice are more susceptible to MS, similar to humans. Researchers have identified differences that may be regulated by sex hormones.

“We’ve definitely observed that it’s sex hormone levels that are playing into the sex differences. In the males it seems to be that their higher levels of testosterone or androgens are somehow dampening the autoimmune response so it doesn’t result in as strong a disease.”

Dr. Dunn is currently studying the role of a type of molecule expressed by immune cells: PPARs, or peroxisome proliferator-activated receptors.

PPARs are important in controlling metabolism, but these molecules also have important anti-inflammatory functions in immune cells, which may help protect against autoimmune conditions. They also tend to have a sex-specific effect on the actions of the immune system’s T-cells, which are central to MS.

“We think that somehow they also have this sex difference in expression,” Dr. Dunn says. Male T-cells appear to express more of these PPARs than female T-cells.

The researchers found that two types of PPARs appear to be sensitive to testosterone and androgens.

“So male hormones would be turning on these molecules which appear to be protective against autoimmunity, so it could be one of the ways that sex hormones may be harnessing or altering the autoimmune response,” says Dr. Dunn.

Another of the researchers’ projects looks at the relationship between pubertal onset in females and autoimmune risk.

“Young girls who get their period earlier, who go through puberty earlier, also seem to have double the risk of getting MS,” Dr. Dunn says. “We’ve been investigating the underlying biology of this risk in mice and we have some evidence that it may be that as soon as the girls go through puberty, estrogen has an effect in stimulating the immune response as well. So it’s not just androgens are protecting males, but it could be that estrogens are also enhancing the immune response in women to make this sex difference happen.”

By looking at MS in mice, Dr. Dunn and her fellow researchers are able to test theories about how sex, gender and the immune system interact. They are trying to validate their observations about mice in human blood samples: first in healthy people and then in samples from MS patients.

“I think it’s really important to validate whatever biology we’re observing in the mouse is actually relevant to what’s going on in the human system,” Dr. Dunn says.

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