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Published: April 25, 2016, 10:01 p.m.

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Host \u2013 Dan Keller

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Hello, and welcome to Episode Seventy-four of Multiple Sclerosis\nDiscovery, the podcast of the MS Discovery Forum. I\u2019m Dan\nKeller.

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Today's interview features Dr. Markus Reindl, an Associate\nProfessor of Neuroscience at Innsbruck Medical University in\nInnsbruck, Austria. We discuss autoantibodies to myelin\noligodendrocyte glycoprotein, or MOG, a protein component of\nmyelin. These anti-MOG antibodies are particularly important in\npediatric demyelinating diseases.

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Interviewer \u2013 Dan Keller

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First of all, why don't you define MOG for our audience.

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Interviewee \u2013 Markus Reindl

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MOG is myelin oligodendrocyte glycoprotein, and it's a myelin\nprotein which was discovered about 30 years ago. It is of enormous\ninterest to people working in neuroimmunology, because it's one of\nthe main autoantigens used in experimental models for multiple\nsclerosis. And about 20 to 30 years ago, a lot of people started to\nwork on autoantibodies against MOG in the field of MS because it\nwas suspected to be a key autoantigen. And at that time, there were\na lot of papers published with somewhat contradictory results.

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About five years, six years ago, the interest of MOG was\nrediscovered again when people developed more specific assays to\ndetect these antibodies. And surprisingly, it was found that\nthey're not present in classical multiple sclerosis but rather in\npediatric demyelinating diseases, such as acute disseminated\nencephalomyelitis, ADEM, or neuromyelitis spectrum disorders.

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MSDF

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And what does finding anti-MOG antibodies tell you?

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Dr. Reindl

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At the moment, it just tells you that if you have these\nantibodies the risk that you develop MS is minor. So it points to\nthe direction of a different demyelinating disease, which is in\nmost cases monophasic with a good outcome. Or if it's recurrent,\nit's often recurrent optic neuritis on multiphasic ADEM.\nAltogether, all this with a good recovery from relapse. Severe\ndisease causes are rare.

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MSDF

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So in the early stages of MS \u2013 something like clinically\nisolated syndrome \u2013 does MOG tell you which direction to go in if\nyou find it?

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Dr. Reindl

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Usually if you have a clinically isolated syndrome that fulfills\nthe current criteria for multiple sclerosis, looking at the MRI or\nat the cerebrospinal fluid, it will typically be negative for MOG\nand autoantibodies, so it's just an exclusion criteria. If you look\nat the CIS [clinically isolated syndrome], whether it could go to\nthe direction of multiple sclerosis or not, if MOG antibodies are\npresent, the answer would be rather not.

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MSDF

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Does it fit into neuromyelitis optica, especially seronegative,\nwhere there's no anti-aquaporin-4 antibodies?

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Dr. Reindl

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Yes, it can also be observed in cases with neuromyelitis optica\nthat are aquaporin-4 antibodies negative, particularly in pediatric\ncases, and often in cases that present with simultaneous optic\nneuritis and transverse myelitis at onset. So the classical\ndescription of neuromyelitis optica by Devic back in the 19th\ncentury would rather have been a MOG antibody positive case than an\naquaporin-4 antibody positive case. And the pathology of both\ndiseases is entirely different. So in aquaporin-4 mediated\nneuromyelitis optica, you have an astrocytopathy under high risk of\nfuture relapses and disease deterioration. Whereas in the case of\nMOG antibodies, it's often monophasic, and the recovery is much\nbetter.

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MSDF

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So it sounds like anti-MOG antibodies are not just a marker, but\nthey're actually pathognomonic or pathogenic of the disease.

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Dr. Reindl

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This is currently under investigation. So what we know from\nneuropathology there are currently five cases \u2013 if I'm correct, or\nas far as I know \u2013 that have been analyzed for neuropathology.\nThese were in most biopsies/autopsies where MOG antibodies were\npresent. And their pathology was in multiple sclerosis type II\npathology, which points to the direction of antibody-mediated\npathology. So from a neuropathological point of view, looks like\nMS. If you look at the clinical criteria that are currently valid\nfor multiple sclerosis, it's clearly not MS.

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If you look at the pathogenesis, this is currently under\ninvestigation. From the in vitro studies, we know that\nthese antibodies can, of course, activate compliment. They also\nhave an affect on oligodendrocyte cell function. In vivo\nmodels are currently ongoing, and I expect there to be more results\nby next year on this.

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MSDF

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What is the clinical utility at this point? Is it ready for\nclinical use, or what more needs to be done?

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Dr. Reindl

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I think particular people working in the pediatric field are\nusing it more and more. Because if you look, for an example, at\nADEM, earlier this year we published a study that children with\nADEM that are positive for MOG antibodies they have certain\nfeatures in neuroradiology but also in their clinical presentation\nand their clinical recovery, which could aid the clinician. In\nparticular, in the European countries, many laboratories are now\nsetting up assays for MOG antibodies and using it in clinical\nroutine. What has to be done now is better development of the\nassay, a comparison of the assays like it has been done for\naquaporin-4 antibodies, like international validation experiments.\nWe're currently setting up such an experiment for next year,\ntogether with the people in Oxford and other centers. But, my\nexpectation would be that this antibody would have a similar use\nlike aquaporin-4 antibody has. Also, aquaporin-4 antibodies are\nmore specific for a specific type of disease.

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MSDF

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You've discussed anti-MOG antibodies in terms of diagnosis. You\nmentioned prognosis, better course. Can they be useful for\nfollowing therapy? Do the antibodies actually disappear with\nimmunosuppression, or are they always present?

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Dr. Reindl

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The point is in the monophasic cases the antibodies disappear\nanyway. So, I guess in 70% to 80% of all patients \u2013 particular the\npediatric patients \u2013 they have these antibodies at disease onset at\nhigh titers, and with time they disappear. They only are persistent\nif there is a bad recovery or if there's a recurrent disease cause,\nlike recurrent optic neuritis would be an excellent example for\nthis. If you look at therapies, of course, therapies like plasma\nexchange or corticosteroid used at high doses will lead to a\ndisappearance or a drop of antibody titers. I think we have no\nreally long-term experience, at the moment, because these\nantibodies were just discovered a few years ago, until long-term\nstudies are ongoing.

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MSDF

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Is there any work on what triggers these antibodies; whether\nthere's exposure of antigens, what agents may be\ninvolved\u2014environmental, genetic, viral?

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Dr. Reindl

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This is the $100 million question. Of course, we would be happy\nto know it. It's the similar situation like with aquaporin-4\nantibodies. Also there we still don't know it. What is particular\ninteresting is that this is most frequently observed in children at\nthe age under 10 years. These are children that are frequently\nexposed to infections \u2013 the respiratory infections and other\ninfection \u2013 therefore it's highly likely that the underlying cause\nis infectious. But at the moment, as far as I know, there were a\ncouple of studies, at least, but no real systematic study using a\nlot of patients and with a good epidemiological setup.

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MSDF

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If there's an infectious agent, is it that it is causing damage\nto myelin, which is exposing antigens, or there's some\ncrossreactivity with the infecting agent itself?

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Dr. Reindl

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Both things I think could be possible. The animal models tell us\na lot of this. This is work published by Hartmut Wekerle\u2019s group\nthree years ago where they discovered that in transgenic animals \u2013\nanimals that are transgenic for MOG T cells \u2013 gut bacteria activate\nthese T cells that go into the brain, and then MOG is released,\ntransported out by dendritic cells to the cervical lymph nodes. And\nat this stage, the antibodies are induced and built. So it's a\nrather secondary phenomenon, which is caused by T-cell damage and\nT-cell destruction. I could imagine that a similar phenomenon could\nalso help in the human situation, particularly if you consider\nADEM, which has large lesions, a lot of inflammation going on\nthere. I think it's highly likely that antigen is released, and MOG\nis one of the most antigenic components of the central nervous\nsystem.

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MSDF

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So what are the big lines of research right now \u2013 two or three\nof them \u2013 or the big questions that people are approaching?

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Dr. Reindl

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At the moment, of course, a better developmental definition of\nthe assay\u2014I guess this is one of the most important\u2014is we're\nworking together \u2013 a lot of laboratories, a couple of groups \u2013 to\nimprove our assays to come to a common standard and to develop an\nassay which could be used by different laboratories in the\nworld.

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The second is, of course, to better define the clinical and\nneuropathological diagnosis of the patients presenting with these\nantibodies. Because at the moment, it's rather diffuse. You have\nchildren with ADEM, you have children with optic neuritis, children\nwith myelitis. You have adults with NMO-like symptoms. And to put\nthis together in a better way is, of course, highly challenging,\nand this is work ongoing at the moment. I think we will have more\nresults of this by the next year.

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And of course, the third thing is just to look better at the\nlong-term prognosis of these patients. How these antibodies fits in\ntheir long-term prognosis, if they are rather beneficial or not.\nAnd this is also work that only can be clarified using larger\ncohorts of patients and international studies.

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MSDF

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So is it fairly rare to find anti-MOG antibodies?

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Dr. Reindl

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In adults, yes. In children, no. So if you look at children\npresenting with demyelinating syndromes, from our own ongoing study\ncohort in Germany and Austria\u2014we know it's about a third of all\nchildren presenting with demyelinating syndromes\u2014more than a third\nhave these antibodies. If you look at adults, it's much more rare.\nI guess it's about 5% or less.

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MSDF

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Well, thank you very much.

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Dr. Reindl

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You're most welcome.

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MSDF

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Thank you for listening to Episode Seventy-four of Multiple\nSclerosis Discovery. This podcast was produced by the MS Discovery\nForum, MSDF, the premier source of independent news and information\non MS research. MSDF\u2019s executive editor is Carol Cruzan Morton.\nMsdiscovery.org is part of the non-profit Accelerated Cure Project\nfor Multiple Sclerosis. Robert McBurney is our President and CEO,\nand Hollie Schmidt is vice president of scientific operations.

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Msdiscovery.org aims to focus attention on what is known and not\nyet known about the causes of MS and related conditions, their\npathological mechanisms, and potential ways to intervene. By\ncommunicating this information in a way that builds bridges among\ndifferent disciplines, we hope to open new routes toward\nsignificant clinical advances.

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We\u2019re interested in your opinions. Please join the discussion on\none of our online forums or send comments, criticisms, and\nsuggestions to editor@msdiscovery.org.

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For Multiple Sclerosis Discovery, I'm Dan Keller.

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