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Host – Dan Keller
Hello, and welcome to Episode Seventy-four of Multiple Sclerosis Discovery, the podcast of the MS Discovery Forum. I’m Dan Keller.
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.
MSDF
And what does finding anti-MOG antibodies tell you?
Dr. Reindl
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.
MSDF
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?
Dr. Reindl
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.
MSDF
Does it fit into neuromyelitis optica, especially seronegative, where there's no anti-aquaporin-4 antibodies?
Dr. Reindl
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 better.
MSDF
So it sounds like anti-MOG antibodies are not just a marker, but they're actually pathognomonic or pathogenic of the disease.
Dr. Reindl
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.
MSDF
What is the clinical utility at this point? Is it ready for clinical use, or what more needs to be done?
Dr. Reindl
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.
MSDF
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?
Dr. Reindl
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.
MSDF
Is there any work on what triggers these antibodies; whether there's exposure of antigens, what agents may be involved—environmental, genetic, viral?
Dr. Reindl
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.
MSDF
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?
Dr. Reindl
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 system.
MSDF
So what are the big lines of research right now – two or three of them – or the big questions that people are approaching?
Dr. Reindl
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 world.
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.
MSDF
So is it fairly rare to find anti-MOG antibodies?
Dr. Reindl
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.
MSDF
Well, thank you very much.
Dr. Reindl
You're most welcome.
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MSDF
Thank you for listening to Episode Seventy-four of Multiple Sclerosis Discovery. This podcast was produced by the MS Discovery Forum, MSDF, the premier source of independent news and information on MS research. MSDF’s executive editor is Carol Cruzan Morton. Msdiscovery.org is part of the non-profit Accelerated Cure Project for Multiple Sclerosis. Robert McBurney is our President and CEO, and Hollie Schmidt is vice president of scientific operations.
Msdiscovery.org aims to focus attention on what is known and not yet known about the causes of MS and related conditions, their pathological mechanisms, and potential ways to intervene. By communicating this information in a way that builds bridges among different disciplines, we hope to open new routes toward significant clinical advances.
We’re interested in your opinions. Please join the discussion on one of our online forums or send comments, criticisms, and suggestions to editor@msdiscovery.org.
For Multiple Sclerosis Discovery, I'm Dan Keller.
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