Vitamin D and auto-immune disease

Vitamin D has a clear role in regulating the immune/inflammatory response and association studies have demonstrated a link between vitamin D deficiency and autoimmune diseases. However, supplementation is complicated by the lack of universal agreement about the levels that are ‘normal’ and ‘deficient’, says Professor Martin Hewison.

Vitamin D acts in both the innate and adaptive arms of the immune system. In the innate arm it promotes non-specific antibacterial and antiviral responses to infection. In the adaptive arm vitamin D appears to act on T-cells to suppress the normal inflammatory responses to an infection.  The inflammatory response to infection is normal but a problem arises when there is a sustained and inappropriate inflammatory response that persists after the initial infection has abated and can damage tissues.

Professor Hewison explains:

“That’s where vitamin D has its … second function which is to dampen down inappropriate inflammatory responses and it does this by suppressing the T-cells that are known to be associated with this. These are Th1 (T helper type 1) and T helper 17 T-cells. It dampens them down but also importantly increases [the] expression of cells which are known as regulatory T-cells or T-regs and they … adapt the immune system and calm it down quite a bit. So, it’s promoting the good guys in inflammation and dampening down the bad guys – and in this way vitamin D could be quite an important factor in terms of just generally keeping your inflammation down and potentially protecting against this inappropriate response that can lead to autoimmune disease”.

Thus, if 25D levels are low, then less is available to macrophages, dendritic cells and T-cells, which, in turn, are able to make less activated 1,25-dihydroxyvitamin D (1,25D) and suppression of inflammation by the adaptive immune system is reduced.

To date, evidence for a link between vitamin D and autoimmune disease has come from association studies where people have looked at the levels of vitamin D in healthy individuals and compared them to levels in individuals who’ve got various autoimmune diseases, such as type 1 diabetes, Crohn’s disease or multiple sclerosis – and found that those individuals tend to have lower levels of 25D. Such associations are not necessarily evidence of causality.

It has been difficult to demonstrate a causal effect for vitamin D deficiency in autoimmune disease, Professor Hewison acknowledges.  “Essentially what you have to have is a randomized, controlled trial in which people are receiving higher levels of vitamin D to correct that vitamin D deficiency and then look to see whether they’re going to develop autoimmune disease – which is not easy to do given that it can take many years to develop something like multiple sclerosis or type 1 diabetes”, he explains.

What is a normal vitamin D level?

Much of this work hinges on achieving a normal vitamin D (25D) level. However, this is not straightforward because different levels of 25D are accepted as ‘normal’. Furthermore, there can be some confusion over the units that are used; some centres use nanomoles per litre (nmol/L) and others using nanograms per ml (ng/ml).

A large study by the National Academy of Medicine in North America in 2010 recommended a level of 50nmol/L (20ng/ml), but this was based exclusively on the effects of vitamin D on bone health and protection against rickets. If this were used as the threshold level (i.e. above 50nmol/L – healthy; below 50nmol/L – unhealthy) most people in the UK would be classified as vitamin D deficient, says Professor Hewison. The Science Advisory Council on Nutrition (SACN) in the UK therefore recommended that vitamin D levels should not fall below 25 nmol/L or 10 ng/ml.  However, many clinicians in North America, would say that neither of those two levels is really optimal – we should be aiming for an optimal level which would be higher than 75 nmol/L.  “Really, it’s unclear what is the best approach to take and certainly it’s very difficult when you’re carrying out randomised, controlled supplementation trials”, he says.  In many trials that are carried out in North America, participants often have baseline levels of vitamin D as high as 75 nm/L and supplementation studies take the levels higher still. A similar trial in the UK would start from a lower baseline level.

Mendelian randomisation studies might throw more light on this. Professor Hewison explains:

“I think there are some interesting studies that just come out recently which have involved something called Mendelian randomisation. Without going into greater detail, this is a way of saying that, …. as well as sunlight access and various foods, everybody has a genetic component to their vitamin D levels.  That’s genetic variations in the enzymes that metabolise vitamin D, the proteins that carry it around and so on…….. Some people will always be predisposed to having slightly higher vitamin D than others and if you use this tool on a wide range of people – hundreds of thousands of individuals – you can begin to link that genetic level of vitamin D to diseases and get some idea of the sort of level where you get better health effects. ……It seems very likely that 50 nmol/ml 25-hydroxyvitamin D is a threshold level for vitamin D. Really, I think we should be trying to get everybody above 50nmol/L.  Whether you need to go higher – I think that’s a matter for discussion, but certainly people less than 50 nmol/L – they do appear to be more strongly linked with disease risk than people who are over 50 nmol/L.”

Two recent studies have used a non-linear approach based on the notion that being supplemented with vitamin D means much more to somebody who’s deficient than it does to somebody who’s already got sufficient. “If you’re already at 75 nmol/L going up to 100, which is what some of the U.S trials have done, doesn’t give you a great advantage but if you’re down at 10 nmol/L and you go up to 35 that’s a big improvement. ….. I think that’s something we really need to get over – is the idea that the major beneficiaries of any vitamin D will be people who are deficient and there are plenty of them in the UK”, says Professor Hewison.

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