International genetic research into MS susceptibility

My little ladybug antenna have been wiggling furiously.  I am starting a new thread as I don’t want to intrude on Myra’s thread Melbourne Treating Doctor for Cpni<.

 

I have become something of a patient activist on this side of the world.  Think of me as an antipodean aphidcatcher, in which the aphids are little pinholes of opportunity to pass on to Very Important People some of that secret, weighty Cpn knowledge...

 

I have not yet had a response from Professor Stewart, leader of the Australian and New Zealand contribution to the recently published International Multiple Sclerosis Genetics Consortium research Genetic risk and a primary role for cell-mediated immunei mechanisms in multiple sclerosis.  I have transcribed the relevant section of the Margaret Throsby interview below and would be really grateful if some of you MS people could give me some feedback before I pursue the matter further with Professor Stewart.

 

 I should explain that Margaret Throsby has a radio show in Australia called The Morning Show in which she interviews interesting people and plays their choice of music.  I love listening to it as she is a fabulous interviewer and her guests are interesting and insightful people.  Professor Stewart is no exception; he comes across as a very decent and compassionate man with a deep interest in improving the lot of his fellow humans.  He is a doctor and researcher for all the right reasons.  I think that there is scope for expansion of his research into the area of infection, Cpn infection in particular, and I am putting together a compelling case for this, which I intend to forward to him.

 

I know nothing about the validity of the connection between sunlight exposure and multiple sclerosis and your ideas on this would be invaluable in preparing my case. 

 

I have added citations to indicate which articles I think Professor Stewart is referring to.  I am assuming that the “Australian data” he refers to is [1].  I have not been able to obtain a copy of that research report as it is not available online.  I have got a copy of [2] and it is a freetext article available from brain dot oxford journals dot org.  I have got a copy of Genetic risk and a primary role for cell-mediated immune mechanisms in multiple sclerosis, The International Multiple Sclerosis Genetics Consortium & The Wellcome Trust Case Control Consortium 2, Nature 476, 214-219, published online 10 August 2011.  It was the publication of this latter article that caused a flurry of interest in multiple sclerosis in Australia, hence Professor Stewart’s presence on Margaret Throsby’s show on 15 August 2011.

 

Hey Mackintosh, bet you’re glad you didn’t hang around for the gene therapy.

 

Here you are, people – please post your thoughts on the transcript which follows.

 

Cheers,

Ladybug

Partial transcript by Ladybug of the Australian Broadcasting Commission (ABC) Morning Interview on 15 August 2011

 

Interviewer:  Margaret Throsby

Interviewee:  Professor Graeme Stewart, consultant physician and immunological pathologist, founding director of the Institute for Immunology and Allergy Research (IIAR), one of the four founding research groups of the Westmead Millennium Institute.

 

The full interview is available here:

http://mpegmedia.abc.net.au/classic/podcast/current/audioonly/mti_20110815.mp3<

 

<Start of partial transcript>

 

Graeme Stewart  We’ve reported in Nature last week 57 genesi.  That’s a lot and we haven’t yet found them all.  It’s certainly not so, that every patient will have the disease-associated variant for all 57 genes.  They won’t.  It’ll be a selection of those out of that number of 57 or more, and that will probably vary with the particular environmental trigger.

 

Margaret Throsby  Do you get them because your mother or father had them?  Is it passed down in families? 

 

GS  It’s not passed down in families in the way that people think of genetic diseasesi, like say cystic fibrosis or Huntington’s, where there’s a single gene, and if you get that gene, you get the disease.  Sometimes you need a double copy of it, like cystic fibrosis.  These are diseases of complex genetics, where you need a whole number of genes to come together, and then be triggered by the environment:  almost all of the major unsolved diseases of humankind actually fall into that category.

 

MS  What in the environment triggers these genes in MS patients?

 

GS  Hm.  Again, despite decades of research I still can’t give you a clear answer on that but I can tell you some hard facts.  We know that the further you live from the equator, the higher your risk of MS.  The best data for that worldwide is the Australian data [1] that shows that if you grew up in Tasmania, you’re about 7 times more likely to develop MS than if you grew up in northern Queensland.

 

MS  I’ve seen that and I’ve seen the extrapolation from that that therefore, it must be something to do with sunlight.  Is that the only “therefore” that exists in that?

 

GS  The study’s now been done so well that I think we can say, it’s, we can act as if it’s conclusive, that it is sunlight.

 

MT  It’s not some other factor that exists in the northern, near the equator compared with further away?

 

GS  Within Australia, and within countries where we’ve looked at the same genetic populations, no, I think it is sunlight, I think that, that took me a while I think you know I wrote an editorial on this [2] a couple of years ago so I, in the journal Brain, I had to really look very hard at the, at the data [3].  And I think as I said that, the world can now act as if it is sunlight because the, the evidence is very, very conclusive.  In France, for example, it’s odd, and the French are always odd although I love them, their sunlight exposure doesn’t just increase as you get closer to the equator, it also increases from east to west, and the same gradient of MS prevalence goes from east to west...

 

MT  Is that so?

 

GS  ...along with the sunlight.

 

MT  You said - have you identified these 57 genes, are they all identified now?

 

GS  What we’ve actually found is genetic variations in 57 spots along the chromosomes.  For some of those spots we actually don’t know exactly the gene and we’re looking now at doing what’s called fine mapping, to actually work out exactly which gene...

 

MT  And are they – those 57 – solely concerned with MS, or could, do they have, do they have an association with other diseases?

 

GS  I’m glad you asked that, because these discoveries tell us a lot about MS, but they help us, they help to tell us a lot about some other diseases, some of which I’ve mentioned, the autoimmune diseases, such as lupus, rheumatoid arthritis, inflammatory bowel diseasei, type 1 diabetes, psoriasis have genes in common with the, gene risk factors in common with the genetic risk factors for MS.  When you have a list of 57 you can go looking.  Ah, remember, only 4 years ago we only had 2...

 

MT  Really? 

 

GS  ...MS genes. 

 

MT  It’s as quick as that.  So, do I understand you to say that if you’ve got that, those 57 genes, if they’re in your make-up, then that predisposes you perhaps to autoimmune diseases per se, of a variety?

 

GS  In fact some of them do.  Probably no more than a handful.  Some of them predispose humans to autoimmunityi in general.  And then there are others which are quite specific to the individual disease.

 

MT  Is this a pie in the sky question?  Is it possible for you guys to manipulate genes so that they don’t have this... problem?

 

GS  We can do it well in experimental animals, particularly, particularly mice, and I know this isn’t exactly your question but it’s, I think there’s a good point here, we, the gene discoveries we’ve got at the moment ... we can go back to a mouse model of multiple sclerosis – it has the awkward name of experimental encephalitis">i – autoimmune encephalitis – and we can knock out or increase the function of these genes in that mouse model, and we’re, my lab’s already going down that pathway and many labs around the world will now have 57 new genes to, or 50 odd new genes to work on.  And you can see whether that protects or worsens the animal model.  When it comes to humans, gene therapy still has quite a long way to go.

 

MT  Ethically, or literally?

 

GS  No not ethically.  Scientifically.  It’s been applied to some single gene diseases with benefit but the technology’s, getting a safe technology has been difficult.

 

MT  In theory then, would it be easier to manipulate the environment, so that the trigger doesn’t happen?

 

GS  Absolutely, the best example of that is vaccination, isn’t it?  If we’d found a virus for MS we would have vaccinated for it and you and I wouldn’t be talking about MS – it would be a prevented disease.

 

MT  This brings us to this:  when you say “If we’d found a virus for MS then we could vaccinate against it.”  When we look at human disease as a whole – when I was thinking about this, I was thinking well, it can be caused by a virus, it can be caused by – am I right here? – it can be caused by bacteria, disease can, or it can be caused by a malfunction of the immune system.  Is that correct?

 

GS  Or a combination of all of those things.  But the world has looked very hard for a virus that causes MS, and it hasn’t found it.

 

MT  Do you suspect it exists?

 

GS  Ah, there’s good evidence that the glandular fever virus – Epstein-Barr virus is its correct name – is a factor in increasing the risk of MS.

 

MT  So you have an episode of glandular fever...

 

GS  Yes, but you see most people do.  Just about everybody with MS has had glandular fever – about 90% of the population has had glandular fever by the time they reach adult life.

 

MT  And not realised it?

 

GS  And often not realised it. 

 

MT  You can have glandular fever – you can have a mild dose of it and not...

 

GS  Absolutely.  Absolutely, it’s just like chicken pox.  Most of us have chicken pox antibodies in our blood don’t remember ever having it.

 

MS  Is that so?  Really?

 

GS  Yes.  Absolutely.

 

MT  You’re telling me stuff I have no idea about.  So most of them, people who have glandular fever and you can have it during childhood or adolescence and not know it, then they have a greater potential for having...  so, if you’re tracking patients who’ve got MS and you take, go backwards in their story, you ask them whether they’ve ever had glandular fever and if they say well no, not that I’m aware of, you still don’t know that they haven’t, do you?

 

GS  Well you can do a blood test to show that they’ve got antibodies.

 

MT  Ah.

 

GS  A footprint remains even after the virus has gone. 

 

MT  And most MS patients have had glandular fever.

 

GS  Yep, yep.  In fact there’s an Australian study called Ausimmune that’s funded by Multiple Sclerosis Research Australia which is doing exactly that – tracking back.

 

MT  So most or all?  Most or all?

 

GS  Almost all.

 

MT  Well then why...

 

GS  There’s occasional people.

 

MT  Well then why wouldn’t you say that MS is caused by a virus that started off as glandular fever and then developed into MS?

 

GS  There’s just no evidence for that.  There’s a, it’s not a unique, or a variant of the glandular fever virus, it’s just...  Glandular fever virus stimulates your immune system quite, in quite an extraordinary way, and in almost everybody you control that and you’re just left with, perfectly healthy, but along the way it stimulates some of the cells of your immune system that could encourage later development of autoimmunity.

 

MT  Hah.  All right.

 

<End of partial transcript>

 

[1]  McLeod JG, Hammond SR, Hallpike JF.  Epidemiology of multiple sclerosis in Australia.  Med J Aust 1994; 160: 117-22.

 

[2]  Stewart G.  Multiple Sclerosis and vitamin Di:  don’t (yet) blame it on the sunshine.  Brain 2009; 132: 1126-1127. (This is a freetext article available from brain dot oxford journals dot org.)

 

[3]  References in the editorial at [2]:

Acheson ED, Bachrach CA, Wright EM. Some comments on the

relationship of the distribution of multiple sclerosis to latitude, solar

radiation, and other variables. Acta Psychiatr Scand Suppl 1960;

147: 132–47.

Ebers GC. Environmental factors and multiple sclerosis. Lancet Neurol

2008; 7: 268–77.

Freedman DM, Dosemeci M, Alavanja MC. Mortality from multiple

sclerosis and exposure to residential and occupational solar radiation:

a case-control study based on death certificates. Occup Environ Med

2000; 57: 418–21.

Islam T, Gauderman WJ, Cozen W, Mack TM. Childhood sun exposure

influences risk of multiple sclerosis in monozygotic twins. Neurology

2007; 69: 381–8.

McLeod JG, Hammond SR, Hallpike JF. Epidemiology of multiple sclerosis

in Australia. Med J Aust 1994; 160: 117–22.

Munger KL, Zhang SM, O’Reilly E, Hernan MA, Olek MJ, Willett WC,

et al. Vitamin D intake and incidence of multiple sclerosis. Neurology

2004; 62: 60–5.

Munger KS, Levin LI, Hollis BW, Howard NS, Ascherio A. Serum

25–hydroxyvitamin D levels and risk of multiple sclerosis. JAMA

2006; 296: 2832–8.

Ramagopalan SV, Maugeri NJ, Handunnetthi L, Lincoln MR, Oroton SM,

Dyment DA, et al. Expression of the multiple sclerosis–associated MHC

class II allele HLA-DRB1*1501 is regulated by vitamin D. PLoS Genet

2009; 5: 1–6.

Smolders J, Damoiseaux J, Menheere P, Hupperts R. Vitamin D as an

immune modulator in multiple sclerosis, a review. J Neuroimmunol

2008; 194: 7–17.

Spach KM, Nashold EE, Dittel BN, Hayes CE. IL-10 signaling is essential

for 1,25-dihydroxyvitamin D3-mediated inhibition of experimental

autoimmune encephalomyelitis. J Immunol 2006; 177: 6030–7.

van der Mei IAF, Ponsonby A-L, Dwyer T, Blizzard L, Simmons R,

Taylor BV, et al. Past exposure to sun, skin phenotype, and risk of

multiple sclerosis: case-control study. Br Med J 2003; 327: 316–20.

van der Mei IAF, Ponsonby A-L, Dwyer T, Blizzard L, Taylor BV,

Kilpatrick T, et al. Vitamin D levels in people with multiple sclerosis

and community controls in Tasmania, Australia. J Neurol 2007; 254:

581–90.

Maybe Prof Stewart would be interested in this paper.

The sad plight of multiple sclerosisi research (low on fact, high on fiction): critical data to support it being a neurocristopathy.
Behan PO, Chaudhuri A.


Department of Neurology, Institute of Neurological Sciences, Glasgow University, Glasgow, Scotland, UK. pob1w@clinmed.gla.ac.uk<

 PubMed< 

It was the mention of the mouse model that reminded me of this paper...

speedbird

Thanks, speedbird.  All donations gratefully received!  I'll add it to my collection.

Ladybug

FM & chronic myofascial pain 2000; Cpni; EBVi; lead poisoning; CAPi since Jan 2009; Flagyli pulses & Azi M/W/F from Mar 2009; now also Cymbalta; Rivotril; Low Dose Naltrexone; Doxyi.  Pain-free and heading upwards again.

Glandular fever. I have never had it. So I must belong to the group which doesn't know about having this disease. But my blood tests haven't shown any EBVi for 30 years. It was the first blood test which was done when I was diagnosed with MSi. So then I don't know what group I belong to. Probably Cpni group. But this group wasn't mentioned

Sunlight. I can say it was always very difficult for me to spend some time exposing myself to the sunlight. I was often very bad after it. It started in my childhood. In my 30s I went to the seaside 3 times. It was difficult time for me but I went there because of my children. I was extremely tired the first days. I had had MS then for more than 10 years. In the afternoons I slept together with my children and this helped me. The last days of the stay were better and I would stay longer there. The following year I was better and wasn't tired and I was feeling well. 10 years ago and more I couldn't be on the sun at all. After a few minutes I thought I was going to faint. Now after 3 years on the CAPi I enjoy staying on the sun but I am limited by doxyi. When I can I spend at least half an hour on the sun a day in these summer days.

MSi for more than 30 years, WP since July 08, break Jan 09-March 09. NACi 2x600mg, Doxyi 2x100mg, Roxi 2x150mg, Entizol in pulzes, LDNi, supplementsi.Since May 2013 without abxi.

 There are also works that suggest no autoimmunityi with MSi.

http://www.direct-ms.org/pdf/ImmunologyMS/MS_Not_Autoimmune.pdf<

And the note in this work is also very interesting.

NOTE ADDED DURING
FINAL SUBMISSION
At the time of the final submission of
this manuscript, Barnett and
Prineas20 have published pathological
findings of the newly forming demyelinating
lesion in 12 patients who
died with acute MS. Extensive oligodendrocytei<
apoptosisi and microglial
activation with virtual absence of the
lymphocytes or myelin phagocytes
were the changes observed in the developing
lesions, supporting our contention
that the current laboratory
model (EAE) and the autoimmune
hypothesis of MS are both incorrect
and inappropriate. 

http://onlinelibrary.wiley.com/doi/10.1002/ana.20016/abstract<

 

MSi for more than 30 years, WP since July 08, break Jan 09-March 09. NACi 2x600mg, Doxyi 2x100mg, Roxi 2x150mg, Entizol in pulzes, LDNi, supplementsi.Since May 2013 without abxi.

Calling the disease autoimmune is a way of blaming the patient for the disease. Saying that it is genetically caused is an even more emphatic way of blaming the patient for the disease.

Both of these are easy ways for a doctor to excuse his own failures: he can say, in effect, "It's your own fault that you're sick" -- a message that patients would naturally revolt against, but which they usually accept when it comes clothed in scientific jargon.

Norman you expressed it exactly how I have felt it since I was diagnosed with MSi more than 30 years ago. That's why no "scientific" theory has never persuaded me. Since now there is an evidence of the cause of MS every research should aim to prove it or shoot it down or just accept it. The way of any created theories in these days when there is an evidence is just wasting time, energy and money and can help MSers in no way. That's my opinion.

MSi for more than 30 years, WP since July 08, break Jan 09-March 09. NACi 2x600mg, Doxyi 2x100mg, Roxi 2x150mg, Entizol in pulzes, LDNi, supplementsi.Since May 2013 without abxi.

Evita, thank you so much for your reply.  Clearly, the reason Cpni wasn’t mentioned is that Professor Stewart doesn’t know about Cpn and doesn’t know about the Vanderbilt work.  So I am going to draw his attention to it.

 

Clearly, sunlight sensitivity has played a role in your case.  Light sensitivity was a factor in the case of Hannelore Kohl, who committed suicide in 2001 after years of struggling with illness: http://www.independent.co.uk/news/world/europe/the-tortured-life-of-mrs-helmut-kohl-2299308.html<.

 

Professor Stewart correctly identifies that there is a correlation between MS and living in an area with less exposure to sunlight.  But his extrapolation that sunlight (or lack of it) is the trigger for MS intrigues me.  That’s a mighty big conclusion to draw.  Professor Paul Ewald’s conclusion of increased winter respiratory infectionsi< leading to greater MS prevalence is a much more rational conclusion, in my book.  Unfortunately, I’m not a professor, and Professor Stewart is not reading from the same book as me, but I intend to make sure he knows about Professor Ewald’s book.

 

Thank you for directing me to the Chaudhuri paper; I will have a good look at it.

 

Norman, thank you for your comment.  I don’t believe in autoimmunityi.  I do believe in opportunistic infections with atypical organisms.

 

Thanks for your input, guys – all comments gratefully received.

Ladybug

FM & chronic myofascial pain 2000; Cpni; EBVi; lead poisoning; CAPi since Jan 2009; Flagyli pulses & Azi M/W/F from Mar 2009; now also Cymbalta; Rivotril; Low Dose Naltrexone; Doxyi.  Pain-free and heading upwards again.

The theory that lack of Vitamin Di from the sunlight may be one of the MSi trigger is known and widely accepted by the authorities.

I think you should ask prof. Stewart to contact Dr. Wheldon. D.W. is here on the site and he is an expert in the treatment of MS with abxi - he is author of WP/Wheldon Protocol. All replies you get here are rather amateur and are from people who try to cure from MS.

MSi for more than 30 years, WP since July 08, break Jan 09-March 09. NACi 2x600mg, Doxyi 2x100mg, Roxi 2x150mg, Entizol in pulzes, LDNi, supplementsi.Since May 2013 without abxi.

Thanks, evita.  The problem with asking Prof Stewart to contact Dr Wheldon is that he (Prof Stewart) won't do it.  I have already passed on to him Dr Wheldon's and Dr Stratton's contact details and Prof Stewart has not replied to me, so I doubt he will have contacted the experts.  I do find that some people are very knowledgeable about their own illnesses after years of personal research.  By addressing my thread to folks here I have already got two interesting research papers.  It is only by throwing some medical research papers at Prof Stewart that he will be inclined to listen to me at all.

Ladybug 

FM & chronic myofascial pain 2000; Cpni; EBVi; lead poisoning; CAPi since Jan 2009; Flagyli pulses & Azi M/W/F from Mar 2009; now also Cymbalta; Rivotril; Low Dose Naltrexone; Doxyi.  Pain-free and heading upwards again.

It's a shame. I think experts all over the world should cooperate not compete. This is the message from MSi sufferer.

MSi for more than 30 years, WP since July 08, break Jan 09-March 09. NACi 2x600mg, Doxyi 2x100mg, Roxi 2x150mg, Entizol in pulzes, LDNi, supplementsi.Since May 2013 without abxi.

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