Progress of environmental effects on MS especially vitamin D

A/Prof Robyn Lucas presents Progress of environmental effects on MS especially vitamin D

Transcript of Presentation
 

As Jeremy said, I was the coordinator of the Aus immune study, which was a multi centre study. That means it was in four centres, so Brisbane, Newcastle, Geelong and Tasmania – the whole island of Tasmania.

It was a case controlled study so we had people who had had their very first diagnosis of central nervous system demyelination, so they didn’t have a diagnosis of MS, we wanted to get people really early in their disease process, because the question we were asking them about were about exposure to environmental factors, our work is not so much about cure but more about prevention. On the other hand prevention might be able to give us some clues to cure.

So we wanted to get these people right at the very beginning of their disease, before they changed their behaviour. So you can imagine with sun exposure we wanted to find out from people how much sun exposure they had, and whether our case group; the people with first demyelinating events, were any different from our control group. If we waited till they actually had MS, then they might have changed their behaviour and they were different, but that was different because they had MS, low sun exposure was causing the MS.

So that study went on, we recruited people from 2004 to the end of 2006 and we ended up with 282 people across the four centres who’d had a first diagnosis of central nervous system demyelination – horrible words they have, and 558 people randomly selected from the Australian electoral role, who were the same age and sex as a case. So each person had two or three controls matched to them.

We have an enormous amount of data, those people have been followed, also, for 2 to 3 years in the first instance, and now we’ve got the Aus longitudinal study, which was funded by NHMRC, following those people out to 5 years from the first time they participated in the Ausimmune study. And we are particularly interested, there about, in environmental factors that influence people who have a first demyelinating event – who goes on to have MS and who doesn’t, because some people won’t.

So our exciting… If we think about… we are mainly interested in environmental effects on developing MS, but we also have a lot of genetic data, and we have a lot of blood stored so we there are a lot of things that we can explore beyond environmental effects.

So the three really- the environmental influences on MS that are - where there is really strong evidence, where there’s consistent evidence, there’s lots of things that people bring up but they haven’t been confirmed in other studies, are smoking, vitamin D or sun exposure and Epstein Barr virus, those are the things.

So I’ll just quickly deal with the smoking. So lots of people have shown a dose response effect in smoking, so the more you smoke and the longer you smoke for, the higher your risk. They’ve shown that that risk persists up until 5 years after you stop smoking. We haven’t looked in detail at our smoking data – that’s the next cab off the rank for us, so it’s a ‘watch this space’.

The work that Jeremy referred to, I’m sure people have heard about latitudinal gradience in multiple sclerosis, Liz mentioned them. We also found that these first demyelinating events were much more common in Tasmania than Brisbane, and really along the latitude gradient, so really a pretty nice straight line for incidence of those events.

And then we started to look at – we started to investigate why that latitude gradient was there and of course one of the things that – lots of research has been done on vitamin D and on sun exposure. And people in the past have shown that higher vitamin D levels decrease your risks of getting multiple sclerosis, or flip it the other way round, so low vitamin D levels increase your risk.

What we found in our study, we found the same thing. There was a modest vitamin D effect, people with low vitamin D certainly did have a higher risk of being a case in the study, so of having central nervous system demyelination. But the other thing we found that nobody had ever shown before was that even if you took vitamin D out of the equation – sun exposure itself was also important. So several studies have shown in the past that higher levels of sun exposure decrease the risk of MS, but studies have either had sun exposure or they’ve had vitamin D, they’ve haven’t had both.

So people have just said with the sun exposure, “oh that’s a vitamin D effect” and they’ve just assumed that it’s a vitamin D effect. But of the sun rays that hit earth, the vitamin D effect of rays make up only a tiny amount of that UV, ultra violet radiation, that hits earth. So our studies show for the first time, that sun exposure itself had an effect, that wasn’t a vitamin D effect, that there was something else happening there. More work is required obviously to work that out. But what it does mean. Is that as we go forward thinking about vitamin D prevention trials we also have to account of how much sun exposure people are having.

And now Jeremy doesn’t know about this, but I’ll talk very briefly about Epstein Barr virus, coz we have a publication coming out in July in neurology, that you don’t know about yet. So, again, lots of studies have shown that people with MS report a past history of glandular fever more often. Obviously everybody who has glandular fever doesn’t go on to have MS, but if you have MS, a lot more people have had glandular fever than people who haven’t had MS.

If you look at the virus that causes glandular fever is Epstein Barr virus, and you can look at the antibody levels that people have. And 99 to 100% of people with multiple sclerosis have got antibodies to Epstein Barr virus, which means that they have been in contact with it at some time in their past. In the normal population, most of the rest of us have also been in contact with it. So about 95, 96%, but there is that difference.

What we’ve done in, with the samples from the Ausimmune study, is that, we could only afford to look at half the sample unfortunately, so our numbers are a little low, but we’ve actually looked at, the Epstein Barr virus is a very nifty virus, it actually inserts itself into the B-lymphocyte, so you heard about T-cells before, these are B-cells, and it stays there. And it immortalises those B-cells so they live forever, they don’t sort of die and get destroyed, so each of us that have been in contact with Epstein Barr virus, we’ve got a little bit of this virus, very small amounts and they just circulate around with our B-cells. And when those b-cells split and make new b-cells, it just goes with them it’s got a very nifty way where it makes sure it stays with our DNA, and it gets carried along to all those daughter cells.

So we measured the actual levels of Epstein Barr virus DNA in, within the blood. In our control population the people who had higher vitamin D levels had lower levels of Epstein Barr virus DNA, and that’s what we expect, because we know that vitamin D….when viruses invade the cell that people, vitamin D forms this antimicrobial thing called Cathelicidin and that attacks the virus and kills it. So, so that all makes sense. If you have a higher Vitamin D you have lower levels of this circulating Epstein Barr Virus.

But in our cases, if you had just a higher level of Epstein Barr virus DNA you didn’t have an increased risk of having MS. But in the cases who had both higher Vitamin D and higher levels of Epstein Barr virus DNA you had a very high risk of having MS. And you go well, how does that make sense? Because if you have vitamin D you should have lower viral DNA anyway, and if you have high vitamin D then you should have a decreased risk of MS.

And our interpretation of this is that if you have a high viral load, more viral DNA in the blood, even though you have a high vitamin d then what’s happening is that the T cells that should be controlling, keeping the, that level of the viral DNA and the b-cells very low, the T-cells are not working properly.

And, so this is our new paper that’s coming out from the aus immune study, again a lot of our stuff is an indication to other researchers then to actually get the basic science people to actually look at those t-cells and interaction with Epstein Barr virus and so forth. So we sort of highlight these things.

If we had…what I would like to do is to be able to expand and measure the Epstein Barr viral load on the rest of our samples, so that we had another data set that we could corroborate the findings that we’d found, but also a bigger data set, so we could actually look with bigger numbers. Um, I might leave it there Jeremy.