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Hello, and welcome to Episode Forty-Six of Multiple Sclerosis Discovery, the podcast of the MS Discovery Forum. I’m your host, Dan Keller.   This week’s podcast features the first part of a two-part interview with Dr. Hans Lassmann, who discusses biomarkers in multiple sclerosis. But first, here are some of the new items in the MS Discovery Forum.   According to our curated list of the latest scientific articles related to MS, 61 such articles were published last week. To see the list, go to msdiscovery.org and click on Papers. We selected two of those papers as Editors’ Picks. One, on the prevalence of pain in MS, found that around two-thirds of MS patients experience pain, and this symptom is associated with disability, depression, and especially anxiety. The other editor’s pick is a study of a toxin produced by Clostridium perfringens, a common bacterium often found in the gut that produces an MS-like disease in sheep. This epsilon toxin selectively kills oligodendrocytes while preserving all other neural elements.   Our Drug-Development Pipeline includes continually updated information on 44 investigational agents for MS. During the past week we added 2 new trials and 5 other pieces of information. The drugs with important additions are dalfampridine, dimethyl fumarate, and fingolimod. To find information on all 44 compounds, visit msdiscovery.org and click first on Research Resources and then on Drug-Development Pipeline   [transition music]   Now to the interview. Dr. Hans Lassmann of the Medical University of Vienna in Austria, is one of the most prolific and highly respected MS researchers in the world. In this first part of a two part interview, Dr. Lassmann discusses biomarkers in MS and related conditions such as neuromyelitis optica and how the two conditions may differ important for therapy.   Interviewer – Dan Keller Let’s talk about new markers in MS or differentiating conditions from MS. What’s coming along, and what do we know now?   Interviewee – Hans Lassmann Well, there has been a very important development during the last years. And this was the technical development of assays which can really identify pathogenic autoantibodies which can modify the inflammatory process in the central nervous system. The major trick behind was that these assays are, in essence, based on cells which are transfected with the respective antigen, and so they express the respective antigen on the surface of the cell. And one can now identify those autoantibodies which really bind to the surface of the cell and are pathogenic, in comparison to those antibodies which recognize epitopes, for instance, within the cells, which cannot be reached by the antibodies in the in vivo situation, and which, therefore, are not pathogenic.   MSDF Can you give me some examples of these kinds of antibodies?   Dr. Lassmann So the first antibody which was the antibody against aquaporin 4, which has been shown to be associated with neuromyelitis optica, at least with a large fraction of patients with neuromyelitis optica. And this antibody then was very well characterized, and it turned out that it is directed against aquaporin 4, which is a water channel in astrocytes. And when patients have these antibodies on the background of an inflammatory disease in the central nervous system, these antibodies can reach their astrocytic targets and destroy the astrocytes, which then leads to secondary demyelination and neurodegeneration.   Having these antibodies, it was then possible to define the clinical spectrum of the disease, and it turned out that it is very strictly associated with neuromyelitis optica, but that the spectrum of the disease is broader than only affecting the spinal cord and the optic nerve. So these patients actually have also lesions in other regions of the brain. But they are still different from those lesions which you see multiple sclerosis.   It was then also possible to define the clinical spectrum of the disease. And, again, differences to multiple sclerosis became very clear. And, finally, it was also possible to then look in these patients with these aquaporin 4 antibodies how they respond to the current treatment strategies which have been established for multiple sclerosis. And it turned out that several of the key therapies for multiple sclerosis, including interferons but also natalizumab or fingolimod, can actually make the disease worse in patients with neuromyelitis optica.   So that was the first example that a disease which has originally been defined as a disease in the spectrum of multiple sclerosis has emerged as a separate and distinguishable disease which requires also different treatment in the patients.   MSDF It seems like neuromyelitis optica has components of autoimmune disease. So why do these compounds that work in MS potentially make the condition worse in NMO?   Dr. Lassmann This is currently not yet clear. One possibility is that the action of pathogenic antibodies makes the difference. The immune mechanisms are certainly different in a purely T-cell mediated disease, in comparison to disease which is mediated by a combination of T-cells and antibodies. And that could possibly explain why differences are seen.   There is another possibility is that some of these drugs actually stimulate the B-cell response or increase the B-cell response in the peripheral blood, and with that possibly also the antibody response. So, in that case, the T-cell mediated inflammation would be suppressed, but the antibody-mediated effects would be enhanced. And that could certainly also play a role. But these are, at the present moment, not proven.   MSDF But even in MS there’s evidence for B-cell trafficking and B-cell participation, but it seems to be less important or am I off base?   Dr. Lassmann No, this is a very interesting question. There is clearly a B-cell component in multiple sclerosis, and it has also been shown that depleting B-cells, for instance, with an antibody against CD20 can actually have a very good therapeutic effect in multiple sclerosis. However, we have to keep in mind that B-cells not only produce antibodies, but they have also other immunological functions. So one function, for instance, is that they help the T-cells, for instance, by very efficient antigen presentation. So by eliminating B-cells, you get also a decrease of the T-cell response. But this is not only one possibility. There are other possibilities that B-lymphocytes actually can also produce cytokines – proinflammatory cytokines – which may directly act on the tissue and damage the tissue independent from antibodies.   MSDF Getting back to NMO, if someone tests negative for antibody, but has clinical signs, does that rule out NMO or are you just not detecting antibodies or is it always required or not?   Dr. Lassmann So it rules out an aquaporin 4 antibody associated form of NMO, but a fraction of NMO patients – it’s around between 10 and 20% – which have a clinical presentation of NMO, but have no antibodies against aquaporin 4. There is currently very much effort to define what is the mechanism in these patients. And it turned out that a fraction of these aquaporin 4 antibody-negative NMO patients actually have antibodies against myelin oligodendrocyte glycoprotein.   And this leads, actually now, to a second type of disease which can be separated from multiple sclerosis. These are patients with high titers of pathogenic antibodies against myelin oligodendrocyte glycoprotein. Now, again, these patients, when you look at them at pathology, you would clearly define the disease as multiple sclerosis because they have inflammation, and they have very selective primary demyelination. And this is different from what you see in NMO where the astrocyte pathology is the earliest event. But in those patients with the MOG antibodies, its demyelination sort of hallmark, actually, of multiple sclerosis…of the disease process in multiple sclerosis.   However, when you now analyze these patients with mock antibodies, clinically you see that the clinical presentation is different from the classical presentation of multiple sclerosis patients. These antibodies are, for instance, frequent in children with inflammatory demyelinating disease of a spectrum of acute disseminated encephalomyelitis or relapsing disseminated encephalomyelitis or even patients with a disease similar to relapsing, remitting multiple sclerosis. This is in children.   In adults, you find these antibodies in a fraction of NMO patients. But there are also other patients who have a disease which is more similar to what is seen in multiple sclerosis, with the exception that they have relatively large and aggressive lesions, and also that they have, relatively frequently, lesions in the brain stem such as, for instance, the pons or the medulla oblongata. And, again, it seems to be that here a new disease entity appears which can be separated from multiple sclerosis.   Regarding therapy of these patients, we don’t have yet the data which we need to have. It can be speculated that the therapeutic response may possibly be more similar to those patients with NMO in comparison to the classical MS patients, but to know that we would have to have much larger cohorts of patients who have been treated with the different regimes.   MSDF Do some of these do worse on the typical MS treatments such as natalizumab or fingolimod?   Dr. Lassmann These data currently are not yet existing. It’s also because, due to these possible problems related to NMO, generally now, patients with mock-antibody-associated diseases are more likely to be treated with global immunosuppression or with rituximab, so the anti-CD20 antibody. And clinicians are very reluctant to use these therapies which have been shown to make disease worse in NMO in these mock patients. So we don’t have the data, currently.   MSDF Are there separate etiologies, does it look like here, the MOG versus classical MS?   Dr. Lassmann This comes to the important question about the etiology of MS in general. We have to admit that we don’t know what is the real etiology of multiple sclerosis. It is thought to be an autoimmune disease, but this is not finally proven. It may also be associated with infections – Epstein-Barr virus infection is, for instance, one possible example. And there are certainly other theories also, which discuss completely different mechanisms of disease pathogenesis in multiple sclerosis. It is clearly that all these diseases, including NMO, mock antibody associated disease, and MS are chronic inflammatory diseases. But what drives the inflammation is currently not yet known.   MSDF Is it possible there’s an initial insult to oligodendrocytes which then sort of precipitate a chain reaction cascade?   Dr. Lassmann This is also one of the theories which is put forward, but one has to say that with a bit caution, because there are experimental models where you can actually destroy oligodendrocytes in the central nervous system which do not lead to an autoimmune disease which is somehow related or similar to multiple sclerosis.   MSDF Anything interesting or important to add on the subject, in this context?   Dr. Lassmann I think what is now of interesting new research line is to search for additional autoantibodies in the population of multiple sclerosis patients. There are indications from pathology that there are certainly more patients who may have pathogenic autoantibodies, in comparison to those patients which now can be identified as NMO or mock-autoantibody-associated disease. There is a relatively recent study suggesting that another channel, a potassium channel on oligodendrocytes and astrocytes, the KIR4.1 channel, may also be a target for pathogenic autoantibodies in multiple sclerosis. Here, however, we are still in the very early stage because the test systems are not yet fully reproducible. And we will see in the future whether this antibody association with the KIR4.1 antibody really holds true in MS patients. And if that’s the case, what patients are they and whether they differ in any way in their clinical presentation or also response to therapy.   MSDF Is there a way to survey patients and essentially see what commonalities they have in antibody reactivity, and zero in on it that way, looking at a wide array of antibodies in various patients and seeing if they have reactivities in common?   Dr. Lassmann I think this is valid as a second step. But there is another alternative strategy which is now very well established also for other diseases, including paraneoplastic diseases or other autoimmune diseases. In that case, one can actually take the sera of the patients, and there are now new technologies developed where you can put these sera, for instance, on brain sections – normal brain sections – of either humans or animals and test whether they bind to specific structures.   This has been tried for nearly 30 years now, but only recently, new technologies became available which make that in a much more specific way. And this has been very successful in identifying new diseases which are associated with antibodies against a variety of neurotransmitter receptors or ion channels. So they certainly, in general, have not the spectrum of multiple sclerosis. They may have epilepsy. They may have psychosis. They may have motor neuron diseases, other things. But, on the other hand, the same technique can also be used to identify in multiple sclerosis patients whether some of them have actually antibodies which bind to brain tissue. And when that is established, one can actually then isolate the specific protein with the antibodies out of the brain tissue, and then, with modern molecular biology technology, can identify the antigen.   This is a strategy which has very nicely and very successfully shown for other diseases. And this was also, in principle, the strategy how people found evidence for these, for instance, KIR4.1 antibodies and also for the NMO antibodies.   MSDF Finally, do you envision being able to develop specific treatments if you find out specific autoantibodies or causes of some of these conditions?   Dr. Lassmann It may very well be. I think there are two dimensions on that. The one dimension is that such patients have pathogenic autoantibodies, and that certainly will have implications for therapy. That means that you will try to block the pathogenic action of the antibodies in general. In that case, it doesn’t make a difference whether the antibody is now directed against a neuron or against an astrocyte or against an oligodendrocyte. And this is a strategy which is actually now already approached in many different conditions, and neuromyelitis optica certainly is a disease where this is relatively advanced in this respect.   Now, the other possibility would be to try to find therapies which are then counteracting specifically the destruction of the particular cells which contain the antigen. So it can very well be that, for instance, an antibody against a neurotransmitter receptor will have a different implication on neuronal function, in comparison to an antibody against an astrocyte or an oligodendrocyte. Here, if these are just blocking antibodies and not antibodies which destroy the tissue, one can actually then try also symptomatic therapies with interfering with these channels directly.   MSDF Is there any thought towards trying to induce tolerance or clonal deletion of the pathogenic clones?   Dr. Lassmann This is obviously the dream of immunologists, and it would be extremely attractive. And it works extremely well in inbred mouse models with a very well-defined disease induction process. The strategy is very dangerous in a genetically heterogeneous population and also in a disease process which may be induced by different mechanisms. So, in that case, the big danger is that this tolerizing strategy in certain patients, for instance, with a certain histocompatibility genetics, actually is counterproductive and increases the immune response. And this is actually a problem which is very, very difficult to solve, in the aim of translating this mouse data into humans.   [transition music]   Thank you for listening to Episode Forty-six 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 Robert Finn. 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.   [outro music]    

[intro music]   Host – Dan Keller Hello, and welcome to Episode Nineteen of Multiple Sclerosis Discovery, the podcast of the MS Discovery Forum. I’m your host, Dan Keller.   This week’s podcast features the second half of an interview with Dr. Samuel Ludwin. This time Dr. Ludwin and I discuss the implications of treating multiple sclerosis subtypes. But to begin, here is a brief summary of some of the latest developments on the MS Discovery Forum at msdiscovery.org.   This week we reported some good news: a large case-controlled study showed that there is no causal link between vaccines and multiple sclerosis. However, the study came with the caveat that there is some increased risk for developing MS in younger patients who receive vaccines. This increased risk is likely due to the vaccines triggering a pre-existing asymptomatic condition, the researchers said. The study, which was published in the journal JAMA Neurology, was most concerned with the role that vaccines for hepatitis B and human papillomavirus play in the long-term risk for developing MS.   We also reported on a new iPad app that will allow clinicians and MS patients to track their disease course. The app, called Bioscreen, is currently in beta-testing at the University of California, San Francisco. The developers, including Pierre-Antoine Gourraud who is on MSDF’s scientific advisory board, assert that Bioscreen has the potential to be a powerful tool for researchers, clinicians, and patients. At the core of the app is a dataset of around 600 patients who have been participating in a data collection survey for the past 10 years. Physicians can compare their patient’s disease course with other confirmed MS cases and use that information to influence their recommendations. The researchers also believe that patients’ ability to visualize their own disease in this way will improve adherence to medical recommendations and ultimately strengthen the bond between patient and physician.   Every week we publish at least one “Research Roundup” where we curate stories from around the web related to multiple sclerosis. Recently we published roundups about advances in spinal cord injury treatment, the recipe for selling the perfect bogus drug, and the report of a rare brain infection in a patient taking dimethyl fumarate, trade name Tecfidera. To view Research Roundups, go to the “News Briefs” section of the “News and Future Directions” tab at msdiscovery.org. Look for the blue Research Roundup logo and stay up-to-date with all the latest MS news.   [transition music]   Now to the interview with Dr. Samuel Ludwin, a neuropathologist who is currently a visiting scientist at the Montreal Neurological Institute. Last week we aired an interview with Dr. Ludwin in which he discussed remyelination therapies. This week he speaks with MSDF about MS subtypes.   Interviewer – Dan Keller Welcome, Dr. Ludwin. Let’s talk about some of the subgroups of multiple sclerosis, as has been proposed by Professor Hans Lassmann, and you wrote an editorial some time ago about it. First of all, can you tell me what subgroups he identified and what progress there has been made since then?   Interviewee – Samuel Ludwin This is a very groundbreaking paper, very controversial, and over the years many people who have followed this particular pattern, others who’ve not been able to reproduce it and believe that the conclusions are not valid. However, what Claudia Lucchinetti and Hans Lassmann showed in a mammoth first-time examination of very acute lesions; they had access to a particularly unique group of specimens that are from both the Mayo Clinic and other areas, where very early lesions were examined. And in looking at this, they looked at patterns of tissue breakdown and the mechanisms of tissue breakdown, and essentially came up with four different categories. The two most important ones are very important to discuss because in the one, the features were very, very consistent with the kind of immune injury that one finds in experimental allergic encephalomyelitis where we know the damage has been caused by the injection of the antigen with a subsequent immune reaction to that antigen. And the other main group was one where there appeared to be a primary damage of some sort to the oligodendrocyte and then a subsequent immune reaction.   Now this is important for a couple of reasons, and the first is that there is a big debate going on in the multiple sclerosis literature or research as to whether the disease starts from the outside peripheral activation of immune cells and then homes in on the brain because they are cross-antigens or cross-antibodies or cross-cells, or whether the process actually starts with damage to something in the brain which subsequently sets off the – and this is called the “inside-out” or “outside-in” controversy at the same time. What this might mean, according to the way they have done the study – which was a very good one – was they suggested that there might be multiple mechanisms towards the end result of damage to oligodendrocytes and myelin, and subsequently the physical appearance of multiple sclerosis lesions.   Other people have challenged this and suggested that maybe it is a question of timing, and the mechanism is the same in all patients, but we’re looking at a different kind of progression and timing. And that controversy is still being discussed, as is the inside-out, outside-in phenomenon. But when you look at some of the things that might be causing these inside-out or their type 3 pattern where the primary damage could be in the oligodendrocyte, there are many reasons that the mechanism could be due to either stroke-like causes such as a lack of oxygen or blood flow that damages the oligodendrocyte, possibly certain infections that may target the oligodendrocyte. And we know that there are many mouse models where you can target oligodendrocytes with certain viruses. And those overlap very significantly with mechanisms of tissue damage in other diseases.   So it is a very important paper because it has set people thinking about multiple mechanisms. The fallout from this is that, in fact, when you have different mechanisms of causing disease, there are potentially different ways of treating it. And if you have a primary immune-based phenomenon from the outside, antiinflammatories as are given on disease-modifying therapies are perhaps the way to go, whereas if you’ve got something that is damaging it from the inside and some other cause, we need to elucidate what that cause is and go straight for that particular cause. In addition, what we are trying to find out is whether we can predict what sort of pattern has caused the disease, either with imaging or with biomarkers, and be able to do this without biopsies and other things so that patients can be treated accordingly. It’s an advance on perhaps what we might call personalized medicine in multiple sclerosis.    MSDF Are there imaging or clinical correlates of these different types of processes? You’re not going to do a biopsy on most people.   Dr. Ludwin No, there isn’t. But in fact, there are some therapeutic differences. For instance, in the type 2 pattern, which is the autoimmune pattern or the outside-in pattern, these patients respond very well to plasmapheresis where one is removing the offending gammaglobulin. And patients with the type 3, which is the main oligodendrocyte-based pattern of the disease, they don’t respond to that well. And that’s perhaps the best clinical differentiation that we know at the moment that helps us. A lot of the data is not clear. They based a lot of the data on the fact that they felt that every patient had a uniform pattern in the lesions. Other people have questioned this and found that there might be a multitude of different kind of patterns in the same patient, and therefore it supported modifications of the same inherent cause.   MSDF Does the efficacy of plasmapheresis correlate with the presence of oligoclonal bands in the CSF, or that’s not a correlation?   Dr. Ludwin There doesn’t seem to be a correlation, leastwise I know. Certainly plasmapheresis where we know that there is antibody, such as in neuromyelitis optica is more effective as a treatment early for diseases where we know that there is circulating antibody, but patients will have oligoclonal banding, I think, in both patterns.   MSDF You’d alluded to damage to the oligodendrocyte in one of these forms as the primary dysfunction or lesion. Does that imply that something is being exposed, an antigen that might be reacted to, or how is that leading to damage?   Dr. Ludwin Absolutely, that if you get damage to a tissue, various proteins are being broken down and antigenic epitopes are being exposed, which then are transported back to the peripheral lymphoid tissue for reactions to take place. I mean, there are counter-arguments to this. One can ask why, with a lot of trauma injury, a lot of stroke injury which is far more common than MS, why you don’t get a secondary immune response to that, even though we know many people with the genetic makeup makes them susceptible to MS or exist in the normal population, and almost certainly some of them have strokes. So there are questions on both sides and arguments. And we know from other experiments that you can induce circulating antigens with tissue destruction of any cause, and potentially these are circulating to be able to produce reactive antibodies in the periphery.   MSDF I think Lassmann showed that even in healthy people you can find CNS antigens in the cervical draining lymph nodes, which raises the same question you just brought up; why do some people have a reaction and some not?   Dr. Ludwin Absolutely, and there are now all sorts of theories coming out of the genetics that there are multiple genes, each having a small effect, but in totality may be adding up to a genetic defect that will allow some of these circulating cells to suddenly start having an effect.   MSDF Now it seems, in terms of thinking of personalized medicine, so much of it is empiric – what works works, and you try something else if it doesn’t. Is there a possibility of any harm from these treatments to people for whom it doesn’t work? Do you have to be very concerned about also first not do harm, especially considering you can’t tell the difference among these types from the start?   Dr. Ludwin Yeah, I think that it’s too early to apply personalized medicine to patients in this particular area in the different types. If you’re looking at personalized medicine that, you know, we treat patients as individuals, or we should, because a lot of the therapy is based on empiric choice and anecdotal experience sometimes with the clinician, and there’s no absolute algorithm that everybody uses to treat a patient. So in that sense, we already do practice it. But you’re quite right, a lot of that is anecdotal or empirical rather than mechanistic.   The do no harm is a very interesting point also, because you mustn’t forget that basically multiple sclerosis is an inflammatory disease, and very frequently we tend to look at inflammation as being something that’s bad. But the reason the body mounts an inflammatory infiltrate is usually to cure something or to clean up something that is attacking it from the outside. So in any kind of these interferences, we have to choose a very find balance between stopping an inflammatory infiltrate or reaction that may be doing a lot of good for the patient, while preventing it from its worst excesses.   And here, empiricism comes in quite well at the moment; we know which of these drugs that we give are more likely to give side effects, we know more about side effects than we do about potential for not allowing growth. We will stop a particular cytokine or block a particular protein in its action, but I think we should always be aware that the protein, if it’s a normal one and not abnormal protein, may be there for a reason and the patients will do worse if they don’t have this mess cleaned up, so to speak.   MSDF We’re also finding today that we’re almost living in a proinflammatory environment; it has repercussions in heart disease, dental disease, MS, fat is proinflammatory. So do all these things add to the risk in MS if there’s other inflammatory processes going on?   Dr. Ludwin Well, it’s not only the inflammatory processes that’s going on, it’s the things that are causing them. As you’re right, we are now discovering that things like salt, fast foods, the changes in the microbiota all tend to make us more proinflammatory. And certainly in experimental animals and now some human studies, it has been shown that experimental immune disease is worsened by a high salt intake which leads to increased salt in the tissues, as well as being prevented by some of these diseases. If you change the gut microbiota in many of these diseases from normal commensals into something that may be pathogenic, you will set off inflammatory autoimmune disease. It’s been shown very beautifully in ulcerative colitis and Crohn’s disease, and the same thing is now being looked at very strongly in multiple sclerosis, so certainly a proinflammatory environment.   On the other hand, it should be remembered that there’s certain kind of infections that produce a reaction that may very well be protective, and there’s some evidence that some of the parasites produce a factor and we believe it could be related to a particular type of protective T-cell that will then allow for patients to become resistant to multiple sclerosis. And there’s some very good data from South America that populations who’ve been exposed to parasites and have them are actually more resistant to multiple sclerosis, because the parasite has induced a protective antiinflammatory molecule in the cell as well. So it’s a very complex balance and we’re gradually discovering more and more about where this balance lies.   MSDF Might the prevalence of parasites account, at least in part, for the geographic distribution of MS?   Dr. Ludwin Well, parasites are just one part of it. There is a very strong feeling, and it comes back to also the gut microbiota – but it’s more than just gut microbiota; it’s environment microbiota – that this has a major role. And for many years, it wasn’t just parasites. People in the Third World had a much lower incidence of multiple sclerosis, and this could have been also from genetic reasons or from susceptibility. But it was not just for multiple sclerosis. All autoimmune disease was much lower in frequency in these populations, and the theory was that most of the people who grew up in developing countries were exposed to large numbers of bacteria and they developed robust immune systems, normal-functioning immune systems that could help them deal with it. And the theory is that in developed countries, the over-usage of antibiotics has aborted normal immune responses, and so in response to that autoantibodies are created and we are suffering the consequence of living too clean a life. And so I think if you look at that argument, it’s not just multiple sclerosis, it really has been mooted for the inflammatory bowel disease, juvenile diabetes, rheumatoid arthritis, and other immune diseases as well.   MSDF Thank you, this has been very good.   Dr. Ludwin Pleasure.   [transition music]   Thank you for listening to Episode Nineteen 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 Robert Finn. 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.   [outro music]

This study investigated the immunobiology of MOG-induced EAE in the DA rat, an animal model, which reproduces the immunopathology of the type II MS lesion (Lucchinetti et al., 2000). A newly established immunisation protocol results in a highly synchronised biphasic form of EAE, which mimics the disease course of secondary progressive MS, albeit in a strongly abbreviated time course (Figure 3.1.1). This study demonstrates that MOG-specific autoantibodies are responsible for initiating clinical relapse and driving disease progression. On the background of mild, sub-clinical inflammatory activity in the CNS, pathogenic antibodies enter the CNS and mediate demyelination, a process that in turn amplifies the local inflammatory response (Figure 3.1.14 A). It should however be noted that lethal clinical relapses may also occur in the absence of a pathogenic antibody response if an inflammatory lesion develops in a region of the CNS that is particularly sensitive to damage, or where it may perturb vital functions, such as the brain stem. Although antibodies have been shown to amplify the severity of ongoing clinical EAE (Schluesener et al., 1987; Linington et al., 1988; Lassmann et al., 1988), firm evidence for a role in driving relapse and disease progression was missing. This study has now established this principal, which in all probability is relevant to our understanding of the pathogenesis of severe, steroid non-responsive relapses in MS patients. However, this model of EAE is an artificial system, in which the role of antibody is only apparent because of the different kinetics of MOG-specific T and B cell responses. In MS we still have to answer two crucial questions, namely the identity of the autoantigens targeted by the demyelinating antibody response, and the factors that may trigger this response. MOG is the only myelin protein known to initiate a demyelinating antibody response in EAE, and MOG-induced EAE has provided a valuable tool to identify the role of pathogenic autoantibodies in immune mediated demyelination. However, there is a major discrepancy between the proportion of MS patients with pathogenic MOG-specific antibodies in their circulation (5%; Haase et al., 2000) and the frequency of patients with pathological changes suggestive of antibody-mediated pathomechanisms (>50%; Lucchinetti et al., 2000). This discrepancy may in part be accounted for by the absorption of the pathogenic antibodies into the CNS, which will lead to a dramatic reduction of the antibody titre in the periphery, as demonstrated in section 3.1.3.4 of this study. On the other hand, it is unlikely that MOG is the only target autoantigen, which is exposed on the myelin surface and can therefore initiate a demyelinating autoantibody response. The identification of potential targets is a prerequisite to develop diagnostic kits to identify those patients with pathogenic autoantibody responses and then provide an appropriate therapy such as plasma exchange, or immuno-absorption. As demonstrated in this study, DNA vaccination using a plasmid encoding a myelin antigen is one approach to generate high titre autoantibody responses directed against the native protein. The pathogenicity of this antibody response can then be assayed in the same animal by inducing EAE. This method circumvents problems such as purity, yield and denaturation, all of which complicate any study using antigens isolated from the CNS or generated using recombinant technologies. Coupling this approach to a proteomics based analysis of the myelin membrane and reverse genomics to identify candidate gene products provides the means to map out those protein antigens that can be targeted by a demyelinating autoantibody response. The feasibility of this concept is currently being tested in the rat using PLP and MAG as myelin components that may in certain circumstances provoke a pathogenic autoantibody response. Such an analysis will, however, not detect pathogenic antibody responses to glycolipid antigens, which are major target autoantigens in a number of diseases affecting the peripheral nervous system such as Guillain Barré syndrome (GBS). In GBS a pathogenic antibody response to gangliosides appears to be triggered by infections with particular serotypes of Campylobacter jejuni (Fredman, 1998; Willison and O´Hanlon, 1999). In the majority of patients these antibody responses are an acute phenomenon and disappear as the patients recover (Hahn, 1998). It is conceivable that a similar mechanism is responsible for the initiation of severe relapses in some MS patients, if an infection triggers a cross-reactive antibody response to a surface glycolipid epitope. This would induce an episode of acute CNS demyelination that would not be immediately responsive to immunosuppressive therapy, as tissue damage and amplification of the local inflammatory response would be driven by the pre- existing antibody response. Analysis of the autoantibody responses in MS should therefore be extended to examine lipid as well as protein autoantigens. Such studies should also not be restricted to myelin, but also address the question of responses to other structures such as the axon and oligodendrocyte progenitor cells. Such autoantibody responses are however only conditionally pathogenic, in other words their pathogenic potential is only expressed if they can enter the CNS across the blood brain barrier (BBB)(Litzenburger et al., 1998; Bourquin et al., 2000). In EAE the inflammatory insult to the CNS is responsible for the disruption of BBB function and the entry of antibody into the nervous system. MS is characterised by repeated episodes of CNS inflammation but what initiates and maintains this response is unclear. The observation, that DA rats develop a similar, although eventually self-limiting response in the CNS after immunisation with MOG-peptide in CFA provides a model to investigate the immuno-regulatory deficit(s) responsible for chronic CNS inflammation. The disease model is very reproducible with >90% of animals relapsing after peptide immunisation as opposed to