Vitamin D3 Insufficiency Increases MS Susceptibility in a Gene and Sex-dependent Manner

Vitamin D3 insufficiency increases multiple sclerosis (MS) susceptibility in a gene and sex-dependent manner, a mouse study suggests.

The study with that finding, “Sex-Specific Gene-by-Vitamin D Interactions Regulate Susceptibility to Central Nervous System Autoimmunity,” by researchers at the University of Vermont, was published in the journal Frontiers in Immunology.

MS is a progressive, neurodegenerative, autoimmune disease. Previous studies have estimated that genetic factors account for a significant portion of MS risk, ranging from 20 to 30 percent, while the remaining risk factors are either environmental or a combination of gene-environment interactions.

There are several environmental risk factors thought to be associated with MS susceptibility, including Epstein-Barr virus (EBV) infection, low sunlight/ultraviolet (UV) radiation exposure, vitamin D3 deficiency, and smoking.

Vitamin D3 (VitD) insufficiency is one of the most-studied environmental MS risk factors. Interestingly, while previous studies reported a strong correlation between low VitD levels and higher MS risk in caucasian populations, this was not the case for blacks and hispanics, suggesting the involvement of a genetic component.

Indeed, several MS susceptibility genes are thought to be regulated by VitD, but the underlying mechanisms involved in the process are still unknown.

These effects also have been studied in animal models of MS. Dietary supplementation with VitD in younger mice and rat models of MS prevented these animals from developing experimental autoimmune encephalomyelitis (EAE), a condition that mimics the key pathological features of MS in humans.

Curiously, in these animals, VitD effects were observed only in females and seemed to require the presence of estrogen, suggesting the involvement of a sex-dependent mechanism.

However, ongoing clinical trials testing dietary VitD supplementation as a preventive or therapeutic strategy for MS in humans have failed, so far, to show a consistent benefit.

Now, researchers tested whether VitD levels can regulate the central nervous system autoimmune response in a gene and sex-dependent manner.

To this end, investigators used EAE mice, a well-established animal model of MS, and fed the animals with low or high VitD diets immediately after weaning. In addition, to study the impact of genetic factors related to VitD on MS susceptibility, the team used a different mouse model harboring a chromosome substitution that incorporates the genetic diversity found in wild-derived mice (PWD mice). These animals often are used in genetic studies.

Results showed that a high VitD diet protected EAE female mice, but not males, against EAE development. This genetic and sex-dependent VitD protective effect was accompanied by a decrease in the expression of proinflammatory genes in CD4 T effector cells — the killer cells of our immune system — including MHC class II genes, interferon gamma, and other genes involved in neuroinflammation.

In PWD mice, researchers found that the effects of high VitD diet on EAE could be either protective, have no apparent effect, or cause disease aggravation, depending on the genetic background and sex of the animals.

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Investigators also measured the levels of calcidiol [25(OH)D] — the hormone precursor of VitD produced in the liver — and discovered that it varied significantly across several PWD mice strains, with higher levels found in EAE-protected females.

In addition, the expression levels of known VitD metabolism genes between EAE and PWD mice also differed depending on the genetic background and sex of the animals, and hinted at CYP27B1 and VDR as potential gene candidates responsible for different effects of VitD on EAE.

The findings suggest that the association between VitD and MS susceptibility in a mouse model of the disease is highly dependent on both the genetic background and sex of the animals.

“In this study, we have applied a well-defined dietary paradigm to intentionally modulate systemic VitD levels, while at the same time introducing controlled genetic variation. This approach revealed that the effects of VitD in a mouse model of MS are regulated by sex and genotype [genetic background],” the researchers wrote.

“Our future studies will be aimed at identifying genetic modifiers of the VitD response in CNS [central nervous system] autoimmunity. This information will help inform future VitD supplementation trials, as well as the use of VitD status as a prognostic,” they added.