Host – Dan Keller
Hello, and welcome to Episode Seventy-four of Multiple Sclerosis
Discovery, the podcast of the MS Discovery Forum. I’m Dan
Today's interview features Dr. Markus Reindl, an Associate
Professor of Neuroscience at Innsbruck Medical University in
Innsbruck, Austria. We discuss autoantibodies to myelin
oligodendrocyte glycoprotein, or MOG, a protein component of
myelin. These anti-MOG antibodies are particularly important in
pediatric demyelinating diseases.
Interviewer – Dan Keller
First of all, why don't you define MOG for our audience.
Interviewee – Markus Reindl
MOG is myelin oligodendrocyte glycoprotein, and it's a myelin
protein which was discovered about 30 years ago. It is of enormous
interest to people working in neuroimmunology, because it's one of
the main autoantigens used in experimental models for multiple
sclerosis. And about 20 to 30 years ago, a lot of people started to
work on autoantibodies against MOG in the field of MS because it
was suspected to be a key autoantigen. And at that time, there were
a lot of papers published with somewhat contradictory results.
About five years, six years ago, the interest of MOG was
rediscovered again when people developed more specific assays to
detect these antibodies. And surprisingly, it was found that
they're not present in classical multiple sclerosis but rather in
pediatric demyelinating diseases, such as acute disseminated
encephalomyelitis, ADEM, or neuromyelitis spectrum disorders.
And what does finding anti-MOG antibodies tell you?
At the moment, it just tells you that if you have these
antibodies the risk that you develop MS is minor. So it points to
the direction of a different demyelinating disease, which is in
most cases monophasic with a good outcome. Or if it's recurrent,
it's often recurrent optic neuritis on multiphasic ADEM.
Altogether, all this with a good recovery from relapse. Severe
disease causes are rare.
So in the early stages of MS – something like clinically
isolated syndrome – does MOG tell you which direction to go in if
you find it?
Usually if you have a clinically isolated syndrome that fulfills
the current criteria for multiple sclerosis, looking at the MRI or
at the cerebrospinal fluid, it will typically be negative for MOG
and autoantibodies, so it's just an exclusion criteria. If you look
at the CIS [clinically isolated syndrome], whether it could go to
the direction of multiple sclerosis or not, if MOG antibodies are
present, the answer would be rather not.
Does it fit into neuromyelitis optica, especially seronegative,
where there's no anti-aquaporin-4 antibodies?
Yes, it can also be observed in cases with neuromyelitis optica
that are aquaporin-4 antibodies negative, particularly in pediatric
cases, and often in cases that present with simultaneous optic
neuritis and transverse myelitis at onset. So the classical
description of neuromyelitis optica by Devic back in the 19th
century would rather have been a MOG antibody positive case than an
aquaporin-4 antibody positive case. And the pathology of both
diseases is entirely different. So in aquaporin-4 mediated
neuromyelitis optica, you have an astrocytopathy under high risk of
future relapses and disease deterioration. Whereas in the case of
MOG antibodies, it's often monophasic, and the recovery is much
So it sounds like anti-MOG antibodies are not just a marker, but
they're actually pathognomonic or pathogenic of the disease.
This is currently under investigation. So what we know from
neuropathology there are currently five cases – if I'm correct, or
as far as I know – that have been analyzed for neuropathology.
These were in most biopsies/autopsies where MOG antibodies were
present. And their pathology was in multiple sclerosis type II
pathology, which points to the direction of antibody-mediated
pathology. So from a neuropathological point of view, looks like
MS. If you look at the clinical criteria that are currently valid
for multiple sclerosis, it's clearly not MS.
If you look at the pathogenesis, this is currently under
investigation. From the in vitro studies, we know that
these antibodies can, of course, activate compliment. They also
have an affect on oligodendrocyte cell function. In vivo
models are currently ongoing, and I expect there to be more results
by next year on this.
What is the clinical utility at this point? Is it ready for
clinical use, or what more needs to be done?
I think particular people working in the pediatric field are
using it more and more. Because if you look, for an example, at
ADEM, earlier this year we published a study that children with
ADEM that are positive for MOG antibodies they have certain
features in neuroradiology but also in their clinical presentation
and their clinical recovery, which could aid the clinician. In
particular, in the European countries, many laboratories are now
setting up assays for MOG antibodies and using it in clinical
routine. What has to be done now is better development of the
assay, a comparison of the assays like it has been done for
aquaporin-4 antibodies, like international validation experiments.
We're currently setting up such an experiment for next year,
together with the people in Oxford and other centers. But, my
expectation would be that this antibody would have a similar use
like aquaporin-4 antibody has. Also, aquaporin-4 antibodies are
more specific for a specific type of disease.
You've discussed anti-MOG antibodies in terms of diagnosis. You
mentioned prognosis, better course. Can they be useful for
following therapy? Do the antibodies actually disappear with
immunosuppression, or are they always present?
The point is in the monophasic cases the antibodies disappear
anyway. So, I guess in 70% to 80% of all patients – particular the
pediatric patients – they have these antibodies at disease onset at
high titers, and with time they disappear. They only are persistent
if there is a bad recovery or if there's a recurrent disease cause,
like recurrent optic neuritis would be an excellent example for
this. If you look at therapies, of course, therapies like plasma
exchange or corticosteroid used at high doses will lead to a
disappearance or a drop of antibody titers. I think we have no
really long-term experience, at the moment, because these
antibodies were just discovered a few years ago, until long-term
studies are ongoing.
Is there any work on what triggers these antibodies; whether
there's exposure of antigens, what agents may be
involved—environmental, genetic, viral?
This is the $100 million question. Of course, we would be happy
to know it. It's the similar situation like with aquaporin-4
antibodies. Also there we still don't know it. What is particular
interesting is that this is most frequently observed in children at
the age under 10 years. These are children that are frequently
exposed to infections – the respiratory infections and other
infection – therefore it's highly likely that the underlying cause
is infectious. But at the moment, as far as I know, there were a
couple of studies, at least, but no real systematic study using a
lot of patients and with a good epidemiological setup.
If there's an infectious agent, is it that it is causing damage
to myelin, which is exposing antigens, or there's some
crossreactivity with the infecting agent itself?
Both things I think could be possible. The animal models tell us
a lot of this. This is work published by Hartmut Wekerle’s group
three years ago where they discovered that in transgenic animals –
animals that are transgenic for MOG T cells – gut bacteria activate
these T cells that go into the brain, and then MOG is released,
transported out by dendritic cells to the cervical lymph nodes. And
at this stage, the antibodies are induced and built. So it's a
rather secondary phenomenon, which is caused by T-cell damage and
T-cell destruction. I could imagine that a similar phenomenon could
also help in the human situation, particularly if you consider
ADEM, which has large lesions, a lot of inflammation going on
there. I think it's highly likely that antigen is released, and MOG
is one of the most antigenic components of the central nervous
So what are the big lines of research right now – two or three
of them – or the big questions that people are approaching?
At the moment, of course, a better developmental definition of
the assay—I guess this is one of the most important—is we're
working together – a lot of laboratories, a couple of groups – to
improve our assays to come to a common standard and to develop an
assay which could be used by different laboratories in the
The second is, of course, to better define the clinical and
neuropathological diagnosis of the patients presenting with these
antibodies. Because at the moment, it's rather diffuse. You have
children with ADEM, you have children with optic neuritis, children
with myelitis. You have adults with NMO-like symptoms. And to put
this together in a better way is, of course, highly challenging,
and this is work ongoing at the moment. I think we will have more
results of this by the next year.
And of course, the third thing is just to look better at the
long-term prognosis of these patients. How these antibodies fits in
their long-term prognosis, if they are rather beneficial or not.
And this is also work that only can be clarified using larger
cohorts of patients and international studies.
So is it fairly rare to find anti-MOG antibodies?
In adults, yes. In children, no. So if you look at children
presenting with demyelinating syndromes, from our own ongoing study
cohort in Germany and Austria—we know it's about a third of all
children presenting with demyelinating syndromes—more than a third
have these antibodies. If you look at adults, it's much more rare.
I guess it's about 5% or less.
Well, thank you very much.
You're most welcome.
Thank you for listening to Episode Seventy-four of Multiple
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For Multiple Sclerosis Discovery, I'm Dan Keller.