Why Are Women More Likely to Develop MS? New Proteomics Study Finds Clues

Knowing that women are diagnosed with multiple sclerosis (MS) at three times the rate of men, particularly during their 30s and 40s, scientists in the CU Anschutz lab of Kimberley Bruce, PhD, recently took that window of opportunity and ran with it.

Seeking clues behind the disparity, the researchers compared the cerebral spinal fluid of women between the ages of 30 and 49 seen at the Rocky Mountain MS Center on campus either for MS or for headache (HA) alone.

The published study involved analyses of over 120 proteins using advanced proteomics technologies. The researchers found higher immune cell activity and lower neuronal function in the MS group compared to the HA group and identified potential new therapeutic targets.

Experts know MS, an autoimmune disease characterized by wide-ranging and often sporadic symptoms, causes the destruction of the myelin sheath, the protective coating surrounding the nerves of the brain and spinal cord. The damage short-circuits neural pathways within the central nervous system, affecting bodily functions from vision and mobility to cognition and bladder control.

Did you know? The Rocky Mountain MS Center at CU Anschutz is home to one of the largest MS research programs in the world, with a biorepository and tissue bank that holds thousands of samples. The center sees over 4,500 patients a year.

“By identifying specific protein changes in the fluid around the brain and spinal cord, the study improves our understanding of how MS progresses – especially in females,” said Bruce, an associate professor of endocrinology, metabolism and diabetes at the CU Anschutz School of Medicine. “It also highlights possible signals doctors or researchers could use to track disease activity or test new therapies.”

Bruce, whose lab focuses on women’s health and neurological diseases, shared more about the study’s highlights in the following Q&A.

What motivates your work and your focus on sex differences?

Many neurological and neurodegenerative diseases show sex differences. Some of them, like Alzheimer's disease and multiple sclerosis, are more common in women, whereas Parkinson's disease is more common in males. So, we can probably learn a lot about the underlying mechanisms driving these diseases, if we understand sex differences in more detail.

What are the chief theories as to why women with MS outnumber men?

Lots of different things may play into the increased risk of MS in women. It could be lifestyle factors, body weight or hormones. But one of the things that we're starting to understand more is the role of the immune system. In some instances, women’s immune systems are more reactive or heightened. In multiple sclerosis, we think that the brain’s main immune cells – microglia and macrophages – are driving the disease process.

Glossary:

Myelin sheath – The protective fatty layer surrounding nerve fibers.

Autoimmune disease – A condition in which the immune system mistakenly attacks the body’s own tissues.

Microglia – Immune cells in the brain and spinal cord that help maintain neural tissue.

Neurogenesis – The process of forming new neurons, or nerve cells.

Proteomics – The large-scale study of proteins, analyzing their structure and function.

Your recent study supports that heighted immune system in women theory, correct?

Yes, we found the women with MS had higher levels of proteins in their cerebrospinal fluid linked to activated microglia and macrophages, which suggests increased inflammation. We also found lower levels of proteins involved in neurogenesis and neuron function in the MS group, which suggests reduced repair processes in the women with MS.

How does that track with what scientists understand about the disease process in MS?

Multiple sclerosis is a neurodegenerative autoimmune disorder characterized by muscle weakness and loss of function. In MS, the fatty coating of our neurons (myelin sheath) is damaged and doesn't get rebuilt properly. Microglia, as key immune cells in the brain, are really important in making sure that this myelin is recycled, so that new myelin can be made.

My lab is very interested in understanding what makes microglia more reactive and less efficient at recycling fat and myelin. We are also trying to find new ways to target microglia, to improve how they recycle fat and myelin, and eventually improve outcomes for multiple sclerosis.

Key points:

Women are diagnosed with multiple sclerosis at about three times the rate of men, especially in their 30s and 40s.

A study analyzing proteins in cerebral spinal fluid showed heightened immune cell activity, suggesting a stronger inflammatory response, in women with MS compared to women with headache only.

MS samples also showed reduced neuron function and repair in women compared with headache samples.

Proteins such as FABP5, APOC3 and CD99 were highlighted as possible targets for future MS treatments.

What else might be playing a role in this MS sex gap in the 30s-and-40s age range?

Hormones are a big component of this. This is a transitional time for women regarding hormone fluctuations. In women, these immune cells are quite different with age, whereas in men, this difference isn’t as pronounced. So our lab is interested in how hormones affect these cells. In fact, we've previously shown that when we give estrogen to human cells in-vitro, we can see that it improves cell functions, and how the cells use energy.

Estrogen may not be a potential therapeutic per se, but by exploring what protective pathways are downstream of estrogen, we might be able to mimic them and improve cell health and overall disease risk.

Can you talk about your finding related to sex hormone binding globulin (SHBG)?

SHBG wasn't necessarily a target of this study, but we did find an increase in SHBG protein in the women with MS compared with our headache-only subjects. SHBG is a protein that acts a little bit like a sponge. It binds to estrogen, making it less available to tissues and cells.

Although we need to do a lot more work to figure out what this means, it does point to reduced estrogen availability. And if you haven't got neuroprotective estrogen available, this could lead to more activation of the brain’s immune cells.

See related: How Multiple Sclerosis Affects Women During Pregnancy, Periods and Menopause

What is the main takeaway from this work?

Our findings support recently identified therapeutic targets that were higher in the MS group, such as FABP5 (fatty acid-binding protein 5), and highlight novel targets that may predict or promote MS neuropathogenesis in females, such as APOC3 (apolipoprotein C-III) and CD99 (cluster of differentiation 99).

FABP5 is expressed by these microglia, and it binds to lipids, such as lipids in the myelin sheath. So more of this protein in the MS group suggests that this whole process is hyperactive in these women. While there are emerging disease-modifying drugs for MS aiming to reduce inflammation, I don't think there are enough therapies out there that are focused on improving this recycling of myelin lipids.

There are lots of distinct factors that are playing into multiple sclerosis risk. Going forward, we need different therapies that target these varied factors for better and more personalized overall care.

This interview was edited for length and clarity.