Fog Lifting in MS Gender Enigma

Recent discoveries in the laboratory have provided strong clues to the reasons why multiple sclerosis now afflicts mainly women, two prominent MS researchers said.

Differences in how the female and male immune systems are “tuned” are the most striking among these findings, but not the only ones, according to Shannon Dunn, PhD, of the University of Toronto, and Lawrence Steinman, MD, of Stanford University, in a “Viewpoint” article published online in JAMA Neurology.

“These discoveries illuminate the pathogenesis of MS, with applications and benefits for both men and women,” the authors wrote. “These breakthroughs potentially allow for the repurposing of certain approved drugs for potential use as treatments of MS.”

Currently, close to three-quarters of new MS cases occur in women. The biological basis for the gender imbalance has been one of the stubborn mysteries surrounding the disease — in no small part because it is of relatively recent origin. When MS was first described in the late 19th century, about as many men as women had the condition.

“Over the past 50 years, [the female:male] ratio has been steadily increasing,” Dunn and Steinman wrote.

Fewer and later pregnancies, vitamin D3 and sunlight, and the female sex hormone estradiol are other notable factors in understanding how the autoimmune disease works and impacts three times as many women as men, the authors said.

“Something in the environment” must be at work besides genetic changes, then authors explained, because the 50-year trend of increasing female preponderance in MS is not enough time for mutations to present, they said.

Because pregnancy is a known “major protective factor” against MS relapses, fewer pregnancies and a later age for pregnancy and childbearing might allow the hormones involved in MS pathogenesis to flourish.

Vitamin D3 and sunlight — or lack of them — are other suspects in the rapid increase in MS among women. Vitamin D3 has been effective in reducing proinflammatory Th1 immune activity in MS, the authors wrote.

A sterol, vitamin D3 thwarts interleukin-17. It and similar cytokines are involved in molecular inflammation in MS. Vitamin D regulates the inflammation by eliminating those cells that attack myelin, the protein coating that protects nerve fibers. Demyelination is the root pathology in MS.

“Surprisingly, vitamin D3 has a greater modulatory effect in women with MS than in men with MS, where it inhibits both Th1 and Th17 pathways to a greater extent,” the authors wrote. “This may be due in part to a deficiency in females of the inactivating enzyme, CYP24A1 for vitamin D3, leading to accumulation of more vitamin D3 in target cells.”

In experimental autoimmune encephalomyelitis (EAE), the standard animal model of MS, vitamin D3 reduced paralysis in females, “again to a much greater extent than in males,” they said.

Estradiol, the authors said, has a great impact on the immune system and is naturally more prevalent in women. The authors cited earlier studies that showed estradiol protects against EAE. Much interest is focused on mediating B cells, “a major target of interest in MS therapy,” Dunn and Steinman wrote.

A phase II clinical trial with estriol is now active with an aim to preserve cognition, they wrote.

Another influence of sex hormones is on peroxisome proliferator–activated receptors (PPARs), which in turn control Th1 responses as well as levels of fatty acids and lipids that play roles in MS.