Abstract
Vitamin D3 (VitD) insufficiency is postulated to represent a major modifiable risk factor for multiple sclerosis (MS). While low VitD levels strongly correlate with higher MS risk in white populations, this is not the case for other ethnic groups, suggesting the existence of a genetic component. Moreover, VitD supplementation studies in MS so far have not shown a consistent benefit. We sought to determine whether direct manipulation of VitD levels modulates central nervous system autoimmune disease in a sex-by-genotype-dependent manner. To this end, we used a dietary model of VitD modulation, together with the autoimmune animal model of MS, experimental autoimmune encephalomyelitis (EAE). To assess the impact of genotype-by-VitD interactions on EAE susceptibility, we utilized a chromosome substitution (consomic) mouse model that incorporates the genetic diversity of wild-derived PWD/PhJ mice. High VitD was protective in EAE in female, but not male C57BL/6J (B6) mice, and had no effect in EAE-resistant PWD/PhJ (PWD) mice. EAE protection was accompanied by sex- and genotype-specific suppression of proinflammatory transcriptional programs in CD4 T effector cells, but not CD4 regulatory T cells. Decreased expression of proinflammatory genes was observed with high VitD in female CD4 T effector cells, specifically implicating a key role of MHC class II genes, interferon gamma, and Th1 cell-mediated neuroinflammation. In consomic strains, effects of VitD on EAE were also sex- and genotype dependent, whereby high VitD: (1) was protective, (2) had no effect, and (3) unexpectedly had disease-exacerbating effects. Systemic levels of 25(OH)D differed across consomic strains, with higher levels associated with EAE protection only in females. 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. 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.
Highlights
Multiple sclerosis (MS) is a multifactorial autoimmune disease, in which an immune-initiated attack on the central nervous system (CNS) results in demyelination, axonal loss, and eventual neurological dysfunction
To directly manipulate systemic vitamin D3 (VitD) levels in a controlled fashion, we adopted a previously described dietary paradigm initiated during adolescence, which has been shown to modulate EAE in the mouse [41, 42] and rat [43, 44]
Part of the difficulty in identifying such interactions is the inability to clearly define over time the presence/absence/level of environmental variables/exposures and possible confounding variables [57]
Summary
Multiple sclerosis (MS) is a multifactorial autoimmune disease, in which an immune-initiated attack on the central nervous system (CNS) results in demyelination, axonal loss, and eventual neurological dysfunction. Genetics contribute to a significant portion of MS risk, with estimates ranging from 20 to 30% [1]. The primary genetic risk factor lies in the major histocompatibility complex class II locus, with up 200 other minor risk loci identified by recent genome-wide association studies [2]. The remainder of MS risk is thought to come from environmental factors or gene-by-environment interactions. A number of different environmental risk factors have been associated with MS susceptibility. Over the past 100 years, MS incidence has remained stable in men, but has tripled in women, suggesting the existence of sex/gender-specific risk factors and/or behavioral changes [3]
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