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Study: ‘Guardian Molecule’ Protects Men from Multiple Sclerosis

Women are twice as likely as men to develop multiple sclerosis, a potentially disabling autoimmune disease of the brain and spinal cord, according to the Mayo Clinic.

Researchers had previously determined that men seem to be better protected from the disease, in part by high levels of testosterone, but the hormone’s role was unclear – until now.  

Studying the disease in mice, Northwestern Medicine scientists identified a so-called “guardian molecule,” triggered by testosterone. When female mice with the disease were treated with this molecule, their symptoms were eliminated, according to a new study published earlier this week in the Proceedings of the National Academy of Sciences

“This discovery could lead to an entirely new kind of therapy for MS, which we greatly need,” said Melissa Brown, lead study author and professor of microbiology and immunology at Northwestern University Feinberg School of Medicine.

In people with multiple sclerosis, the immune system attacks myelin, the protective sheath that covers nerve fibers within the brain and spinal cord. The sheath acts as insulation and assists in sending nerve signals from the brain and spinal cord to the rest of the body. Damage to the sheath interrupts normal nerve conduction and can cause a variety of symptoms, including tremor, vision problems, fatigue, and numbness or weakness of the limbs.

Northwestern scientists showed in their study that testosterone caused mast cells, a specific type of immune cell, to produce the guardian molecule, cytokine IL-33, in male mice. The guardian molecule triggers a cascade of chemicals that prevents the development of another type of immune cell (a Th17 cell) that can directly attack myelin.

In studies, female mice develop more of the disease-causing Th17 cells that attack and destroy myelin than their male counterparts. But that damaging response was reversed in female mice when treated with the guardian molecule.

“Our model has really evolved to predict that testosterone induces production of the cytokine IL-33 (the guardian molecule) in males and that it triggers a cascade of events that turns off the harmful immune response so males don’t get the disease,” Brown said.

Scientists attribute the difference to higher levels of testosterone in men. “In humans, it’s estimated that testosterone is seven to eight times higher in adult males than females,” she said. While women have some testosterone, researchers believe “the levels don’t reach a threshold that’s required to elicit this (guardian molecule) production.”

The discovery grew from an earlier lucky mistake in the lab in which male mice were studied instead of female mice. “In our models, males never got the disease so we never studied them,” Brown said. By accident, a graduate student ran an experiment using male mice – half of which were healthy. The other half had a mutation that induced a multiple sclerosis-like disease. (Brown says it’s “really hard” to determine a mouse pup’s sex when it’s young.)

To researchers’ shock, the experiment yielded results that contradicted years of research. “This actually set us on the path to where we are now with respect to understanding the whole pathway that triggers protection,” Brown said.

In addition to a higher incidence of disease in women, there are also sex-determined differences in age of onset and subtype of the disease. Women generally develop multiple sclerosis at a younger age and usually have a relapsing-remitting course of the disease. In other words, they experience periods of new symptoms followed by remission.

Men are usually diagnosed later in life and have a more progressive form of the disease that doesn’t have periods of relief. “The male disease is much more severe when it does occur,” Brown said. “That is a very difficult thing to treat.”

There is no cure for multiple sclerosis, and treatments are mainly focused on managing symptoms, slowing progression of the disease and speeding recovery from attacks. However, many of the treatments have side effects, including the development of flu-like symptoms, blurred vision, skin irritation, changes in blood pressure and an increased risk of some types of cancer, according to the Mayo Clinic.

While testosterone has been shown to induce the guardian molecule, it’s unlikely it will become a “widespread therapy” because it too has side effects, including masculinization effects, according to Brown. “The major target population for multiple sclerosis – 85 percent of individuals who get diagnosed are in their early 20s at peak childbearing age. We can’t treat women with testosterone, particularly at that time of their life,” she said.

“I think the most important thing is that we know testosterone works. ... So I think what this is really going to allow us to do is bypass the testosterone treatment and really look at some of the pathways or events in the cascade that we have identified and maybe target those.”

Contact Kristen Thometz: @kristenthometz | kthometz@wttw.com | (773) 509-5452


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