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Updated: Jun 20, 2026
Modeling Multiple Sclerosis in the Two Sexes: MOG35-55-Induced Experimental Autoimmune Encephalomyelitis
Published on: October 13, 2023
Estrogen controls vitamin D3-mediated resistance to experimental autoimmune encephalomyelitis by controlling vitamin
Faye E Nashold1, Karen M Spach, Justin A Spanier
1Department of Biochemistry, College of Agricultural and Life Sciences, University of Wisconsin-Madison, Madison, WI 53706, USA. hayes@biochem.wisc.edu
Abstract:
Multiple sclerosis (MS) is an autoimmune, neurodegenerative disease with a rapidly increasing female gender bias. MS prevalence decreases with increasing sunlight exposure, supporting our hypothesis that the sunlight-dependent hormone 1,25-dihydroxyvitamin D(3) (1,25-(OH)(2)D(3)) is a natural inhibitor of autoimmune T cell responses in MS. We found that vitamin D(3) inhibited experimental autoimmune encephalomyelitis (EAE) in intact female mice, but not in ovariectomized females or males. To learn whether 17beta-estradiol (E(2)) is essential for vitamin D(3)-mediated protection, ovariectomized female mice were given E(2) or placebo and evaluated for vitamin D(3)-mediated EAE resistance. Diestrus-level E(2) implants alone provided no benefit, but they restored vitamin D(3)-mediated EAE resistance in the ovariectomized females. Synergy between E(2) and vitamin D(3) occurred through vitamin D(3)-mediated enhancement of E(2) synthesis, as well as E(2)-mediated enhancement of vitamin D receptor expression in the inflamed CNS. In males, E(2) implants did not enable vitamin D(3) to inhibit EAE. The finding that vitamin D(3)-mediated protection in EAE is female-specific and E(2)-dependent suggests that declining vitamin D(3) supplies due to sun avoidance might be contributing to the rapidly increasing female gender bias in MS. Moreover, declining E(2) synthesis and vitamin D(3)-mediated protection with increasing age might be contributing to MS disease progression in older women.
Insights
Vitamin D may protect against multiple sclerosis (MS) in females by working with estrogen. This finding could explain the increasing female gender bias in MS prevalence.
Area of Science:
- Immunology
- Neuroscience
- Endocrinology
Background:
- Multiple sclerosis (MS) is an autoimmune neurodegenerative disease with a growing female predominance.
- MS prevalence inversely correlates with sunlight exposure, suggesting a role for vitamin D.
- The sunlight-dependent hormone 1,25-dihydroxyvitamin D(3) (1,25-(OH)(2)D(3)) is hypothesized to inhibit autoimmune T cell responses in MS.
Purpose of the Study:
- To investigate the role of vitamin D(3) in experimental autoimmune encephalomyelitis (EAE), a model for MS.
- To determine if 17beta-estradiol (E(2)) is essential for vitamin D(3)-mediated protection against EAE.
- To elucidate the synergistic mechanisms between E(2) and vitamin D(3) in EAE resistance.
Main Methods:
- Experimental autoimmune encephalomyelitis (EAE) was induced in intact and ovariectomized female mice, and male mice.
- Mice received vitamin D(3) treatment, with ovariectomized females also receiving 17beta-estradiol (E(2)) or placebo implants.
- Vitamin D receptor expression in the central nervous system (CNS) and E(2) synthesis were analyzed.
Main Results:
- Vitamin D(3) inhibited EAE in intact female mice but not in ovariectomized females or males.
- Ovariectomized females receiving E(2) implants regained vitamin D(3)-mediated resistance to EAE.
- Synergy between E(2) and vitamin D(3) involved vitamin D(3)-enhanced E(2) synthesis and E(2)-enhanced vitamin D receptor expression in the inflamed CNS.
Conclusions:
- Vitamin D(3)-mediated protection against EAE is female-specific and estrogen-dependent.
- Declining vitamin D(3) due to sun avoidance may contribute to the increasing female bias in MS.
- Age-related declines in E(2) and vitamin D(3) may influence MS progression in older women.
