Tuesday, 1 May 2018

Worrying sheep

Mult Scler. 2018 Apr 1:1352458518767327. doi: 10.1177/1352458518767327. [Epub ahead of print]

Evidence of Clostridium perfringens epsilon toxin associated with multiple sclerosis.

Wagley S, Bokori-Brown M, Morcrette H, Malaspina A, D'Arcy C, Gnanapavan S, Lewis N, Popoff MR, Raciborska D, Nicholas R, Turner B, Titball RW.


Abstract

BACKGROUND:

It was recently reported that, using Western blotting, some multiple sclerosis (MS) patients in the United States had antibodies against epsilon toxin (Etx) from Clostridium perfringens, suggesting that the toxin may play a role in the disease.

OBJECTIVE:

We investigated for serum antibodies against Etx in UK patients with clinically definite multiple sclerosis (CDMS) or presenting with clinically isolated syndrome (CIS) or optic neuritis (ON) and in age- and gender-matched controls.

METHODS:

We tested sera from CDMS, CIS or ON patients or controls by Western blotting. We also tested CDMS sera for reactivity with linear overlapping peptides spanning the amino acid sequence (Pepscan) of Etx.

RESULTS:

Using Western blotting, 24% of sera in the combined CDMS, CIS and ON groups ( n = 125) reacted with Etx. In the control group ( n = 125), 10% of the samples reacted. Using Pepscan, 33% of sera tested reacted with at least one peptide, whereas in the control group only 16% of sera reacted. Out of 61 samples, 21 (43%) were positive to one or other testing methodology. Three samples were positive by Western blotting and Pepscan.

CONCLUSION:

Our results broadly support the previous findings and the role of Etx in the aetiology of MS warrants further investigation.

Believe it or not it is illegal in England & Wales to worry sheep - although this generally applies to dogs, and in certain cases to rambling tourists...But are sheep worrying for us humans? According to Wagley and colleagues, getting too close to our fury friends may not be a good idea as it first seems. 

Clostridium perfringens epsilon toxin is a spore-forming toxin that triggers fatal enterotoxaemia in sheep and goats. It is normally present in the soil and healthy gut of these animals, but under certain conditions may rapidly multiply resulting in large quantities of the toxin. The toxin builds up in the kidneys and the brain where it can damage neuronal structures, including oligodendrocytes (myelin forming cells).

Antibodies to epsilon toxin have been previously found in MS cases and may be a potential aetiological source, such as EBV, HERVS and HSV.  Wagley and colleagues studied the occurrence of antibodies to epsilon toxin in the blood of MS, clinically isolated syndrome (CIS; first presentation of MS) and optic neuritis (ON) cases. They found that 24% of MS/CIS/ON groups compared to 10% of controls had antibodies to the epsilon toxin. The presence of antibodies in controls suggests that their occurrence cannot wholly be explained by the over expression of autoantibodies in MS. 

It is not certain what the significant finding here is; the antibody to the toxin in MS or the initial exposure to the toxin. The Telegraph coverage (above) points out that sheep farming is more common in the northern altitudes, as is MS. This may be a leap too far, but the signal warrants more in-depth investigation.

CoI: Prof G, Dr Turner, Dr Raciborska and myself were involved in this work.

19 comments:

  1. I live in Wales so I've been surrounded by sheep for a large part of my life, as have most of my family but I'm the only one with MS.
    I'd be quite interested in seeing more research on this

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  2. "Believe it or not it is illegal in England & Wales to worry sheep..."

    I run up to them shouting "Mint sauce, mint sauce" ;-)

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    1. :) Hopefully they’re not rabid sheep or they’ll be chasing you baa-ing “offal, offal...”

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    2. There's many a nasty slur about us Welsh and sheep. Details withheld to protect the sensitive ;-)

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    3. Thanks MD2 for the laugh out loud moment!
      Simply ages since I've had lamb and mint sauce.

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    4. go prof ndg you are the best

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    5. Thanks for the promotion Sushmita, will get there one day :)

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  3. I was brought up on a sheep farm in the UK, was sheering sheep as a child, and have PPMS. But are you sure the findings are not confused by possible organophosphate sheep dip exposure? (No longer used, but routine when I was a child.)

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    1. So organophosphate exposure has been linked to a number of neurodegenerative conditions, including Parkinson’s and Multiple Sclerosis. So the sheep association may be blurred by this. However, this particular strain of Clostridium is found in ruminant animals and the question is how is it that we’re exposed?

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  4. Can't be that important if the other 76% of the MS group did not have antibodies? Fairly sure it would have been noticed by now if living near sheep made MS more likely?

    How well matched were the groups for 'sheep exposure' eg where people lived, occupation?

    Good point Woolly re organophosphates, dreadful chemicals.


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    1. To a point but 1 in 4 should not be ignored...
      Toxins as a whole are not known to be transmitted from animals to people, type B and D of the Clostridium that produce the Epsilon toxin are rarely seen in humans. So where is this coming from. Most toxins are through food contamination ?in the nearby water ?in the air from the soil.
      Since no one has actually paid attention to previous publications on this it’s not one of the questions which gets commonly asked ie do you have sheep in your back garden? Baring the cities it would probably include most of the countryside, but that’s me guessing.

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    2. Thanks NDG
      When I first read the Telegraph report (forwarded by well-meaning relative) I understood the study had been carried out in Exeter. First thought was that the MS group would likely have come from across Devon (largely rural, including Dartmoor and Exmoor) whereas placebo group could more conveniently have been found locally within Exeter (small city) itself. I may have got that completely wrong (location Exeter) but the groups should surely have been matched for 'sheep exposure' (no Welsh jokes please) ie urban/rural?

      Interesting never the less that people with and without MS have somehow acquired the toxin...


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    3. The cohort was mostly from London, but everyone travels so much these days it's difficult to say where they've all been. The fact that they have been exposed to the toxin at some point in their lives despite this points to this. And you're right, the next step would be in fact pick one of the Northern Islands in Scotland with high prevalence of MS and examine their incidence relative to somewhere with little exposure to ruminant animals.

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    4. Slightly off-topic comment but does anyone know where healthy controls in a study usually found? I've visions of notices pinned up in hospital staffrooms or local Student Unions, good way to earn pocket money? Or healthy people for phase I drug trials? Would hope that better paid! Just wondered ;-)

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  5. http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0076359

    This paper was from 2013...I would not call this recent but anyway, it showed increased ab to ETX in MS patients. ETX is thought to increase the permeability of the BBB which may lead to toxicity and neuroinflammation. Just reinventing the wheel with this paper, imo.

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    1. There is confirmation from two different methodologies in this paper and they also looked at what bit of epsilon was targeted by the antibodies. This is contentious work as anything involving zoonoses should be backed up by solid research.

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  6. What about MS rates in New Zealand?
    On the Southern cross website it mentions higher rates of MS in the New Zealand south islands.
    They do quite a bit of sheep farming in the south Island.

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    1. Yes, this work needs to be done in the same way that the vitamin D studies have been performed, linking to exposure and see if this is a real signal.

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