The molecular mechanism of vitamin D’s role in MS

Low vitamin D: chicken or egg? #MSBlog #MSResearch

“Chicken or egg? The study below shows that MS disease activity on IFN-beta is linked to low vD levels and suggest the mechanism is via complex network of gene regulation. What this study does not address is whether the low vD levels are a consequence of MS disease activity; the so called consumptive hypovitaminosis D hypothesis. There is published data showing that proliferating T cell, which are the major players in autoimmunity, consume vD as part of their proliferative response. The only way to sort out association (consumptive hypovitaminosis) from causation (low vD levels cause MS disease activity) is to do a randomised double-blind placebo-controlled trial of vD supplementation in MS. The good news is that there are several clinical trials that are currently underway. The bad news is that I think all of these studies are underpowered and are unlikely to give a definitive answer.”

“The other elephant in the room is that vD is simply a surrogate for lack of sun exposure and it the poor sun exposure that is important. Professor Robyn Lucas, in Canberra, Australia, has been saying for years that it is not simply low vD that is important, but poor sun exposure. As lymphocytes and other immune cells pass through the tiny blood vessels, or capillaries, in the skin they are exposed to ultraviolet (UV)-A and UV-B light that affects their function. Robyn claims that it is the immunomodulatory function of sunlight that is important. You may interested to know that so called light therapy, or heliotherapy, has been around for millennia. If it is light that is important then the vD supplementation trials will be negative. As this topic is so hot at the moment I will invite Robyn to do a guest post on this topic.”

“The following is an old slideshow of mine that tries to capture the complexity of the role vD may, or may not, play in MS. What is clear is that we as a community can’t ignore it anymore. Please note that we actively monitor vD levels in our patients and supplement to a target of >100nmol/L, but less than 250 nmol/L. Why? We do this as part of our bone health and not to modify the course of MS. Unfortunately, we have no data to support the latter. The dose of vD supplementation we recommend is based on the advice of the Vitamin D Council.”

Munger et al. Molecular mechanism underlying the impact of vitamin D on disease activity of MS.  Ann Clin Transl Neurol. 2014 1(8):605-17. d

OBJECTIVE: Some previous studies suggest modest to strong effects of 25-hydroxyvitamin D (25(OH)D) on multiple sclerosis (MS) activity. The objective of this study was to explore the mechanistic rationale that may explain potential clinical effects of 25(OH)D.

METHODS: This study measured serum 25(OH)D levels and global gene expression profiles over a course of up to 2 years in CISers starting treatment with interferon beta-1b (IFNB-1b) after a clinically isolated syndrome. MS disease activity was assessed by the number of gadolinium-enhancing lesions present on repeated magnetic resonance imaging (MRIs).

RESULTS: The number of gadolinium-enhancing lesions was highly significantly associated with 25(OH)D levels. Conducting various systems-level analyses on the molecular level, multiple lines of evidence indicated that 25(OH)D regulates expression dynamics of a large gene-gene interaction system which primarily regulates immune modulatory processes modulating MS activity. The vitamin D response element was significantly enriched in this system, indicating a direct regulation of this gene interaction network through the vitamin D receptor. With increasing 25(OH)D levels, resulting regulation of this system was associated with a decrease in MS activity. Within the complex network of genes that are regulated by 25(OH)D, well-described targets of IFNB-1b and a regulator of sphingosine-1-phosphate bioavailability were found. The 25(OH)D effects on MS activity were additively enhanced by IFNB-1b.

INTERPRETATION: Here, we provide mechanistic evidence that an unbalanced 25(OH)D gene expression system may affect MS activity. Our findings support a potential benefit of monitoring and managing vitamin D levels (e.g., through supplementation) in early MS patients treated with IFN-beta-1b.

About the author

Prof G

Professor of Neurology, Barts & The London. MS & Preventive Neurology thinker, blogger, runner, vegetable gardener, husband, father, cook and wine & food lover.


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  • I've been taking D3 5000 iu consistently every morning for 15 years plus come rain, snow or sun I walk an average of 7-8 miles every day (a dog helps), sometimes at weekends much more, and blood tests show I have quite a high level:-) . I have a very mild course of MS -so far – and this may be one of the reasons, it's not DMTs as I can't get 'em.

  • For me it's more the sun that does the trick – if I've got vertigo and go out to sit in the sun for 30 min. the vertigo vanishes almost completely.

    I supplement during winter with 1000 iu daily (sometimes double as much) but my blood levels stay low throughout.

    I worry a bit about clogging your arteries with vit d which transfers to calcium if one takes high doses of vit d.

    • 5000 iu D3 is dosage recommended by the Vitamin D council. This does not cause vitamin D to 'clog' your arteries, quite the opposite. I have had no adverse effects whatsoever. I agree that sunlight is best and that's why I get outside as much as possible. But as you get older, it becomes more difficult to absorb enough vit D from the sun, so diets rich in high vit D food sources and Vitamin D3 as a supplement are important.

    • The fear of overdose comes from the 1950s when they tried giving people huge doses. There are no recorded cases of toxicity at 10,000IU a day although there have been a few with sustained doses (6 months) of 40,000IU a day. Vitamin d cannot clog the arteries. Some of the vitamin d in the body, 1,25(OH)D in the blood, along with the parathyroid hormones control blood calcium levels. If the 1,25(OH)D level in the blood is high or the parathyroid is hyperactive then calcium levels rise and is deposited in the body. The rest of the vitamin d is stored in the blood as 25(OH)D which is inactive. The 25(OH)D is converted into the active form when needed, this can happen in most cells. Low levels of 25(OH)D can cause the blood calcium levels to rise, known as secondary parathyroidism. From now until April you will make no vitamin d from sunlight.

    • It should be clear enough to everyone that vertigo that disappears after 30 min of sun exposure has nothing to do with vitD related immune responses. It' the heat and the resulting muscle relaxation that does the trick. The exact way is an exercise to inquiring minds.

  • Dear Professor Giovannoni,
    I really liked the presentation, thank you very much!
    Unfortunately, I couldnt hear what you were saying when presenting slide 46 (Meier et al., 2010). There, it looks like disease activity was higher when sunshine was more? I thought it would be the opposite (high disease activity in winter, low in summer). I can't get my head round this bit of data, just after the summer months (June, July, August), the rate of new lesions peaked in September (maybe August) when vitamin-D levels should be at their best during the year. What are your thoughts on this?

    • The hypothesis is that there is a lag phase of 3-6 months; low vitamin D levels at the end of winter say in Feb-Mar will only manifest in Jun-Jul-Aug as disease activity. The high vitamin D levels at the end of summer will have their greatest impact over winter. Does this make sense?

    • It does!

      Thanks for quick reply!

      Given that data, I would suggest to a patient with MS to move as quickly as possible home to a region close to the equator!

      I would like to do a study, 40 patients on UV-B (narrowband) and 40 without the specific wavelength as a control.

      Do you think people would hesitate since UV-B can cause cancer?

  • Description of phase3 copaxone+high/low dose Vitamin D3 trial:
    'Further, a vitamin D response element was recently identified in the promoter region of HLA-DRB1*15, the gene believed to be critical to initiating the autoimmune response in MS, and 1, 25-dihydroxyvitamin D3 increases the expression of the gene in vitro, suggesting that vitamin D supplementation could even be harmful in established MS.'
    What is the best decision? Copax + 5000 IU of vitamin D, or Copax + 600 IU of vitamin D

By Prof G



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