Between two and two-and-a-half million people in the world suffer from multiple sclerosis (MS), an autoimmune disease that degrades the protective coverings of nerves, disrupting communication lines between the brain and body. MS wreaks havoc on the central nervous system, and is responsible for the the deaths of about 18,000 people annually.
One of the most unusual features of the disease that could hold the crucial key to a cure is that it manifests in women at about four times the rate it does in men.
It’s a mystery that has plagued researchers—until now. A recent study published in The Proceedings of the National Academy of Sciences highlights a mechanism in female biology that finally accounts for women experiencing higher rates of MS. The secret? Testosterone.
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MS is an autoimmune disease, where immune cells enter the brain and spinal cord and mount an attack on the myelin sheath, the outer membrane that insulates the nerves and helps facilitates proper nerve signal conduction throughout the body. As a result, MS patients suffer from sensory disturbances, problems in cognition, and loss of proper motor control. Scientists have known for some time that females are more susceptible than men to developing MS (and autoimmune disorders in general), but testosterone’s role is only recently becoming apparent.
The finding could help illuminate current treatments, which aim to suppress the immune system right now. Certainly, that provides relief—but it also raises the potential for being unable to fight off infections.
Melissa Brown, an MS researcher at Northwestern University’s Feinberg School of Medicine and a coauthor of the new PNAS study, has been trying to uncover the source of MS’s mysterious gender difference. The breakthrough in the team’s latest findings are actually thanks to a mistake made by a new student in Brown’s lab several years ago. The lab almost exclusively used female mice for its investigations, studying mutations that would prevent MS progression. But when one of Brown’s newest students was tasked with collecting the mice for one of the investigations, she couldn’t correctly discern which were males and which were females—a common mistake for younger students.
The student accidentally pulled up a cohort of male mice, and brought them up for experimentation. “When she got her results, they were completely opposite from what we had seen in females,” says Brown. “The mutation’s protection—in both females and males—makes things much worse.”
That set Brown and her lab on a new path to understand what was going on, and they ended up finding out how the mutation actually prevented the development of a particular immune cell that had just been discovered by others around this time. “If you have this mutation, you don’t have this immune cell, and it turns out that this immune cells is really important in putting the brakes on damages being inflicted on healthy cells in MS,” she said.
The lab hypothesized at the time that males didn’t get the disease unless they had this mutation, so they fell sick. “If males with this mutation get sick, is that also the case with females?” Brown and her colleagues asked themselves.
The research team did some digging and found that the mutation lead to problems in a type of cell responsible for mediating the development of a special group of T helper cells, Th17. Th17 cells naturally partner up with a type of immune cell known as ILC2, or “innate” lymphoid cells, which play an important role in immunity by monitoring inflammation. What this means: When ILC2 cells get dysregulated because of the mutation in Th17 cells, immune systems can fall apart. On a minor level, it can lead to allergies and asthma; on a more serious level, it can lead to autoimmune diseases like MS.
Brown and her team found that males with the mutation had inactive ILC2 cells, which would otherwise lead to Th17 cells going off on their own and launching an immune response against the myelin protecting the nerves. In contrast, ILC2 cells were inactive in females even without the presence of a mutation.
Brown and her team soon identified the culprit: a molecule called IL-33, previously known for its role in allergic reactions, triggered a biochemical process that activated ILC-2, which in turn prevented Th17 cell development, thus keeping the myelin safe from harm.
And what protected these cells from harm? Turns out the production of IL-33 is caused by testosterone.
Men produce between seven and eight times as much testosterone as women do, and rates in males are known to especially increase in inflammatory conditions. Brown and her team believe females aren’t normally able to meet the threshold of testosterone required to activate the IL-33 pathway.
“One of the really exciting observations we made was we could give female mice who had severe MS and not only block the immune response, but also reverse the symptoms [of MS],” Brown said.
“This is really exciting because of how relevant it is to humans,” she added of testosterone’s role in the immune system pathways. “Being able to block the disease along with reversing it is so important.”
So does this mean to prevent and treat MS, we just need to give females injections of testosterone? Unfortunately, it’s not quite that simple.
In the first place, “the protective role of testosterone in MS is nothing new,” Dr. Stefan Gold, an MS researcher based in Berlin who did not participate in the study, but who has previously studied the relationship of testosterone and MS in clinical settings, said. “Indeed, there have been previously successful treatment trials — and several ongoing — with testosterone for men with MS.”
But what Gold finds especially interesting is how the new study points to how we might be able to target IL-33 directly for MS treatment. Side effects make testosterone injections for women far too risky and impractical. YEt finding a way to activate IL-33 production or emulate the pathway that prevents the autoimmune response through a different approach could be a game changer in treating MS in women, and bypass the masculinization effects associated with testosterone, as well as the immunosuppressive effects of current MS treatments.
We’re far from demonstrating any of these potential solutions in a clinical sense. The results are promising, but, “mice aren’t humans,” Brown emphasized. “There are limitations to these kinds of studies.” Brown is hopeful other drug companies or clinical institutions will take up this research and pursue it for humans. For now, Brown is trying to figure out how to get IL-33 produced naturally in females without testosterone, as well as how IL-33 might help males who experience more severe MS complications later in life. That might be what it takes to understand not only the biochemical pathways better but also the path towards a potential cure.
