Autoimmune diseases such as multiple sclerosis disproportionately affect women more than men. To find out why, scientists are investigating estrogen and testosterone and the role these sex hormones play in MS, in hopes of developing better treatments.
One tantalizing clue: Women with MS report fewer symptoms during pregnancy, a time when hormone levels increase dramatically. It turns out, perhaps counterintuitively, that estrogen plays a protective role in MS, meaning that it slows or halts symptoms and disease progression.
Researchers (pictured above) in the lab of Halina Offner, Dr. Med., professor of neurology and anesthesiology and perioperative medicine, OHSU School of Medicine, and other scientists demonstrated this finding in animal studies. But they didn’t know the cellular mechanism behind it – how exactly it happens. Uncovering the mechanism could lead to better targeted drugs for MS that are not as broadly immunosuppressive as most current treatments, said Dr. Offner.
Her team set out to find the answer. The resulting study, “Estrogen-induced compensatory mechanisms protect IL-10-deficient mice from developing EAE” published in the Journal of Neuroinflammation was selected as the School of Medicine’s Paper of the Month.
A test, with surprising results
The Offner lab utilizes a mouse model of MS called experimental autoimmune encephalomyelitis (EAE). Previously, the team was among the first to demonstrate that low-dose estrogen can protect mice from developing paralytic signs of EAE when administered seven days prior to disease induction.
The researchers surmised that B cells – a type of white blood cell that produces antibodies to fight infection when activated – play a role in estrogen-mediated protection. They focused on a regulatory subset of B cells that secretes small cytokine proteins called Interleukin-10 or IL-10.
IL-10 aids in cell communication during immune responses. It seemed plausible, the team theorized, that IL-10 mediates the pathway that allows estrogen to raise a defense response against MS.
To test their theory, the team gave an estrogen pretreatment to mice which lacked IL-10. Surprisingly, the mice didn’t develop EAE; the estrogen continued to protect them.
“This indicated that IL-10 was not necessary for estrogen-induced protection from EAE,” said Dr. Offner.
Not one, but three
What, then, is the cellular pathway that gives the mice protection? It turns out there’s not one but three possibilities, the team determined.
“The first pathway is an up regulation of the checkpoint inhibitor ligands PD-L1 and PD-L2 on macrophages in the periphery and an increase in PD-L2 in the central nervous system,” explained Dr. Offner. “Second is the increase in the immune checkpoint mediator CD73 on subsets of regulatory B cells and in the CNS. CD73 can increase the anti-inflammatory molecule adenosine. Third is the decrease in peripheral regulatory T cells that likely migrate to the CNS, as the CNS of IL-10 knockout mice have increased infiltrating T cells but do not develop EAE.”
How did the researchers identify these changes? They observed a decrease in pro-inflammatory cytokines and chemokines in the central nervous system of IL-10 knockout mice when compared to estrogen-treated wild-type mice with EAE.
The results, explained Dr. Offner, implicate those regulatory immune mechanisms as key players in protecting the central nervous system from destructive, myelin-specific T cells that induce EAE in the absence of IL-10.
“What I found compelling about this paper was how it gives us increasing precision in understanding the interactions between gonadal hormones and neuroimmune interactions,” said Mary Heinricher, Ph.D., associate dean for research, OHSU School of Medicine.
“Not only do these findings identify the protective mechanisms, but they also suggest that the presence of IL-10 in wild type mice may actually inhibit expression of such markers,” said Dr. Offner. The team already submitted an R21 NIH grant to delve deeper. A complete understanding of the interactions could one day could lead to more effective drug therapies for people with MS.
Seifert, H.A., G. Gerstner, G. Kent, A.A. Vandenbark and H. Offner (2019). “Estrogen-induced compensatory mechanisms protect IL-10-deficient mice from developing EAE.” J Neuroinflammation 16(1): 195 doi: 10.1186/s12974-019-1588-z.
Hilary A. Seifert, Grant Gerstner, Gail Kent, Arthur A. Vandenbark, and Halina Offner