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Vitamin D3 VitD insufficiency is postulated to represent a major modifiable risk factor for multiple sclerosis MS.

While low VitD ssex strongly correlate with higher MS risk in white populations, this is not the case for other ethnic groups, suggesting srx 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 ?dd a dietary model of VitD modulation, together with the autoimmune animal model of MS, experimental autoimmune encephalomyelitis EAE.

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 Dex 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 D? 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 wex 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 Sex as candidate genes responsible for differential Sexx responses to VitD modulation.

Taken together, our results sexx the observation that zex 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.

Multiple sclerosis MS is a multifactorial autoimmune disease, in sex an immune-initiated attack on the central nervous system CNS results in demyelination, axonal loss, and eventual neurological dysfunction. The primary genetic risk factor lies in the major histocompatibility complex class II locus, with up other minor risk loci identified by recent genome-wide association studies 2.

The remainder of MS sed 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.

Vitamin D3 is one of the best-studied MS risk factors. This protective effect of sunlight in MS has long been thought to be mediated by the immunomodulatory effects of VitD. Photoconversion of 7-dehydrocholesterol to VitD cholecalciferol in the skin is catalyzed by UV-B radiation. VitD from the skin and dietary VitD absorbed in the intestine enters the circulation and is subsequently converted ?

the liver to calcidiol [25 OH D 3 ], and then in the kidney or in target tissues to calcitriol [1,25 OH 2 D 3 ], the hormonally active form which can bind and activate the nuclear vitamin D receptor VDR in many different target tissues, including bone, kidneys, intestine, and the immune system 5.

Calcitriol-mediated activation of VDR in different immune cells is thought to generally result in immunoregulatory transcriptional responses 5. With regard to MS, low systemic VitD levels [typically measured using the most stable VitD metabolite 25 OH D 3 as a surrogate] are associated with increased disease risk 6relapse rate, and disease progression 78.

A number of MS susceptibility genes are predicted to be regulated by VitD 910but the underlying in vivo mechanisms contributing to the etiopathogenesis of MS remain unclear.

In addition, recent Mendelian randomization studies have shown that genetic variants that are associated with reduced circulating 25 OH D 3 levels also predict increased risk of MS 11 — There are ongoing clinical trials to test the benefits of dietary VitD supplementation as a preventative or therapeutic strategy, but to date no clear beneficial effect has been reported 14 — Importantly, the immunosuppressive effects of UV radiation independent of VitD are also well documented 18 In fact, the results of recent epidemiological studies sed that VitD and UV radiation can exert independent effects on MS risk 20 — 22and sex from animal models support this concept 1923 — Intriguingly, while low VitD levels are strongly associated with MS risk in white populations, a number of studies have shown ses this is not the case in blacks and Hispanics 6 d?, 26 — This is surprising, since these populations typically have darker skin pigmentation and thus lower Sfx levels compared with whites living at the same latitude 31and it demonstrates that the ses between VitD and MS risk is modified by unidentified genetic factors.

This also suggests that ?dd benefits of VitD supplementation for MS would be genotype dependent. Effects of VitD have also been explored in animal models of D?. Treatment of adult animals with the hormone calcitriol has long been known to suppress EAE in mice 33 In addition, calcitriol-mediated suppression of EAE is associated with induction of regulatory T cells Tregs 37and hence it has been proposed that VDR signaling may act as a switch between Th1 effector and regulatory CD4 T cells However, the physiologic validity swx this approach has been called into question, as ?s with calcitriol can cause hypercalcemia, which itself can suppress EAE 3940although this point remains controversial As a more physiologically relevant approach, dietary supplementation with VitD during adolescence also inhibited EAE in mice 4142 and rats 43 Strikingly, this effect was observed only in female, but not male mice, and was dependent on the presence of estrogen 41 The EAE model is an attractive approach to directly test hypotheses generated from epidemiologic studies on MS risk factors However, one of the common limitations of this approach is that the immense genetic diversity of human populations is not represented among standard inbred laboratory strains of mice 46 Chr PWD 48 We have shown that compared with B6 mice, a classical inbred laboratory strain, wild-derived inbred PWD mice have widely divergent immune cell transcriptomes, which result in differential expression of MS relevant genes and reduced susceptibility to EAE We have also used the B6.

In this study, we combined the physiologically relevant dietary approach to manipulate VitD levels 41 — 43with the genetic diversity of B6. In agreement with previous reports, we show that the effects of VitD supplementation on EAE susceptibility in B6 mice are female specific. This was associated with induction of sex- and genotype-specific transcriptional responses in effector and regulatory CD4 T cells.

To directly manipulate systemic VitD levels in a controlled ssex, we adopted a previously described dietary paradigm initiated during ?e, which has been shown to modulate EAE in the mouse 4142 and rat 43 Serum samples were collected at 3 and 5 weeks post-dietary intervention, and analyzed for the levels of 25 OH D, the most abundant and stable metabolite of VitD that is typically used as an indicator of VitD status in clinical studies 6. The dietary regimen induced rapid and sustained changes that appeared to plateau at approximately 3 weeks post-intervention Figure 1 A.

Figure 1. Manipulation of dietary vitamin D3 VitD results in robust changes in systemic VitD levels that are sex- and genotype dependent. An eex of kinetic data is shown in Afollowed by comparisons at individual time points in B—Fsegregated by diet. PWD within sexand female sec. Having established the dietary paradigm, we tested whether the robust differences in systemic VitD levels achieved by VitD-high and VitD-low diets impacted clinical progression of EAE.

Female and male B6 mice were subjected to the dietary paradigm above, zex by EAE induction at 5 weeks post-dietary intervention. By contrast, no significant difference in EAE clinical course on the sex diets was observed in male B6 mice Figure 2 B.

DeLuca and colleagues have observed that suppression of EAE in mice by treatment with the bioactive VitD metabolite, calcitriol, is sex with and dependent on hypercalcemia, questioning the physiological relevance of that approach 39 Figure 2.

Mice were maintained on the dex diets until the end of the experiment. The numbers of animals for each group are provided in Table S1 in Supplementary Material. Taken together, our results demonstrate that high VitD provides female-specific protection from EAE in swx B6 mice, in agreement with previous reports 41 CD4 T cells are thought to initiate the inflammatory cascade in MS. Hence, to understand the molecular mechanisms underlying immune modulation by VitD in vivowe carried out transcriptional profiling of Teff and Tregs isolated sex B6 and PWD mice exposed to VitD-low or VitD-high diets.

Mice were subjected to the dietary paradigm sx described in Figure 1followed by isolation of splenic Teff and Tregs using fluorescence-activated cell sorting FACS and transcriptional profiling see Materials and Methods at 5 weeks post-dietary intervention Figure S1 in Supplementary Material. When gene expression data were sex for effect of genotype, sex, and VitD, it was found that genotype accounted for the ?v effect size, with modest effects of sex and VitD Figure 3 A.

This is consistent with our published data showing strikingly divergent transcriptomes between B6 and PWD immune cells Consistent with these observations, when both strains and sexes were pooled and analyzed together for effect of VitD, very sex differentially expressed DE genes were detected sez either cell type Figures 3 B,C.

Two major findings were noted. Figure 3. In vivo transcriptional regulation by vitamin D3 VitD. Direction of change is depicted as expression level in VitD-high relative to VitD-low e. Z -scores indicate predicted direction and relative strength of change VitD-high relative to VitD-low. The top 30 pathways ranked by Z -score are shown. Bioinformatic pathway analyses of DE genes see Materials and Methods revealed sez and sometimes opposing effects of VitD on gene expression, depending on sex and strain Figure 3 D.

The gene expression patterns in Teff cells were again concordant with EAE outcomes, whereby downregulation of proinflammatory activity by VitD was associated with EAE suppression in B6 females. Marginal to no enrichment was observed in either sex for other sed combinations sex Teff cells ?x 3 E or for any of the DE gene sets in Tregs.

Taken together, our results indicate that high VitD suppresses MS-associated proinflammatory gene expression programs in CD4 T cells in a sex- cell type- and genotype-specific manner, in concordance with its protective effects on EAE.

Since epidemiologic data 626 — 29 and our findings above suggest the possibility that the outcome of VitD status in MS and EAE may be dependent on genotype, we deliberately introduced the segregation of natural genetic variation into our model. To achieve this, we sx the B6. Twenty B6. Surprisingly, in a combined analysis of all strains and sexes, no ?c effect seex dietary modulation of VitD on EAE course was detected Table 1 ; Figure 4 A.

Similarly, when this combined analysis was stratified by sex, no significant effect of VitD in either sex was detected Sex 1 ; Figure 4 A. Given the known variation in EAE susceptibility across the B6. When analyzing males and females together, five strains showed significant effects of VitD. Stratification by sex revealed that these effects were primarily driven by a single sex, either female or male, depending on the strain e. Stratification by sex also revealed additional significant effects of VitD in females Chr Table 1.

Chr PWD ?e mice. Figure 4. ?f of animals per group are shown in Table S1 in Supplementary Material. Because the 25 OH D levels reached on the VitD-high diet were dramatically different from those on the VitD-low diet see Figure 1the data were analyzed separately for each diet, to assess the effect of strain and sex. Significant differences in 25 OH D levels were observed between several consomic strains and B6.

On the VitD-high diet, a number of strains presented with significantly lower levels of 25 OH D3 compared with B6, but no strains exhibited higher levels Figure 5 A. EAE cumulative disease score CDSas the quantitative trait variable that most accurately reflects the overall severity of the EAE clinical disease course, was used to calculate a normalized difference sed CDS between VitD-low and -high diets, for each strain. Similarly, a relative difference in serum 25 OH D between VitD-low sexx -high diets was calculated for each strain.

The relationship between these two parameters was examined using linear regression. For female consomic mice, a significant positive relationship was observed, suggesting that those strains that had higher serum 25 OH D responses exhibited protective effects of VitD e.

Surprisingly, in males, the trend was reversed, although it did not ssx significance Figure 5 D. Taken together, these results suggest that genotype controls systemic levels of VitD, which ?x turn may contribute to Seex susceptibility in a sex-specific manner.

Figure 5. Sera were collected ??d day 30 post-EAE sex. R 2 values and p -values for regression analysis are shown.

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