Many regard vitamin D3 (Vit D) insufficiency as a major modifiable risk factor for multiple sclerosis (MS); however, this correlation is present in white populations and not in other ethnic groups, which suggests a genetic component. A recent study found that the association between Vit D status and MS susceptibility is genotype dependent and suggested that the outcome of Vit D status in MS is determined by gene-by-sex interactions.
aimed to determine whether direct manipulation of Vit D levels would modulate central nervous system (CNS) autoimmune diseases in sex-by-genotype interactions by using a dietary model of Vit D modulation with the autoimmune animal model of MS, experimental autoimmune encephalomyelitis (EAE). In order to evaluate the impact of genotype-by-Vit D interactions on EAE susceptibility, the researchers used a chromosome substitution mouse model (consomic) that involved the genetic diversity of wild-derived PWD/PhJ (PWD) mice.
“[EAE], the principal autoimmune model used to study the pathogenesis of MS, can be induced by immunization with CNS homogenate or specific myelin proteins/peptides, or by transfer of CD4 T cells reactive to these antigens,” the authors explained. “As in MS, autoreactive CD4 T cells enter the CNS to initiate inflammation and pathology, culminating in neurologic disability. Treatment of adult animals with the hormone calcitriol has long been known to suppress EAE in mice.”
The results demonstrated that high Vit D was protective in EAE in female, not male, C57BL/6J (B6) mice, and had no effect in EAE-resistant PWD/PhJ mice. Furthermore, EAE protection was accompanied by sex- and genotype-specific suppression of proinflammatory transcriptional programs in CD4 T effector cells, yet not CD4 regulatory T cells, according to the study.
The researchers observed decreased expression of proinflammatory genes with high Vit D in female CD4 T effector cells, which demonstrates the key role of MHC class II genes, interferon gamma, and Th1 cell-mediated neuroinflammation.
The results also revealed that in the consomic strains, the effects of Vit D on EAE were also sex and genotype dependent, as high Vit D was protective, had no effect, and unexpectedly had disease-exacerbating effects.
“Analysis of expression of key known VitD metabolism genes between B6 and PWD mice revealed that their expression is genetically determined and sex specific and implicated Cyp27b1 and Vdr as candidate genes responsible for differential EAE responses to VitD modulation,” the study noted. “Taken together, our results support the observation that the association between VitD status and MS susceptibility is genotype dependent and suggest that the outcome of VitD status in MS is determined by gene-by-sex interactions.”
The study also explained that the role of Vit D in MS remains unclear and the researchers’ future studies will be aimed at identifying genetic modifiers of the Vit D response in CNS autoimmunity.
Krementsov D, Asarian L, Fang Q, McGill M, Teuscher C. Sex-specific gene-by-vitamin D interactions regulate susceptibility to central nervous system autoimmunity [published online July 17, 2018]. Front Immunol