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Multiple Sclerosis Discovery: The Podcast of the MS Discovery Forum

Your independent source of news and information on research in multiple sclerosis and related diseases.
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Now displaying: March, 2015
Mar 23, 2015

[intro music]

 

Hello, and welcome to Episode Thirty-Five of Multiple Sclerosis Discovery, the podcast of the MS Discovery Forum. I’m your host, Dan Keller.

 

This week’s podcast features an interview with Daniel Reich, an expert in MS neuroradiology. But to begin, here’s a brief summary of some of the latest developments on the MS Discovery Forum at msdiscovery.org.

 

Every week somewhere between 30 and 100 scientific papers related to MS are published in the peer-reviewed literature. And every Friday MSDF lists them all. You can find this week’s list, as well as three years’ worth of past lists by clicking on the Papers tab at the top of every MSDF page. In addition to listing the new papers, we also have a section containing classic papers in the field, along with commentary about what makes them classic. We’d love it if you’d like to suggest a classic paper we haven’t yet listed, and we’d love it even more if you’d like to contribute commentary. Please send your suggestions to editor at msdiscovery.org.

 

In addition to detailed original reports on new research, MSDF also curates MS-related news from around the Internet in a series of news briefs we call Research Roundups. In our latest Research Roundup, we reported on a second case of progressive multifocal leukoencephalopathy in a patient taking fingolimod. We mentioned a new trial of mesenchymal stem cells that will soon begin recruiting people in Canada with relapsing or progressive MS. And we pointed out that while scientific research was a favorite choice of America’s 50 biggest philanthropists last year, no neurological disease benefitted directly from the $1.6 billion they contributed. If you happen to have one of those folks on speed dial, we hope you’ll put in a good word for MS research. You can find our Research Roundups by clicking on News and Future Directions and then on News Briefs.

 

If you enjoy this podcast and find MSDF helpful, please consider supporting us with a donation, even if you’re not a billionaire. MSDF is run by a small team of reporters and editors. We are devoted to bridging the gaps between scientific disciplines to speed the flow of information from the lab bench to the bedside. Our ultimate goal is to facilitate the discovery of a cure. We believe one of the best ways to do that is to bring independent, research-focused news to a professional audience on a platform that fosters discussions and discourse. Help keep us going by visiting our website and clicking on the green “Support MSDF” button next to the “Research Resources” tab on the top right of our screen.

 

[transition music]

 

Now to the interview. Dr. Daniel Reich directs the Translational Neuroradiology Unit in the National Institute of Neurological Disorders and Stroke, part of NIH. In his practice as a neuroradiologist, he cares for patients with multiple sclerosis and other neurological diseases, and he also leads several clinical studies. Research in Dr. Reich’s lab focuses on the use of advanced MRI techniques to understand the sources of disability in multiple sclerosis and on ways of adapting those techniques for use in research trials and patient care. Dr. Reich is also a member of MSDF’s scientific advisory board. Science Journalist Carol Morton caught up with Dr. Reich at the recent Keystone meeting on Neuroinflammation in Diseases of the Central Nervous System in Taos, New Mexico.

 

Interviewer – Carol Morton

Can you tell us the value of MRI in multiple sclerosis?

 

Interviewee – Daniel Reich

The way I see it, MRI has tremendous value in multiple sclerosis in three major ways. One is in the clinic, one is in clinical trials, and the third is really for understanding the biology of the disease; it’s an incredibly powerful tool for that. And in my own evolution as a clinician and researcher in multiple sclerosis, I’ve really moved my thinking a lot from kind of using MRI diagnostically or thinking about how we might develop markers of the disease to look at in clinical trials to really the third part, which is trying to understand the disease using the MRI, or sometimes as I call it, the MRIcroscope.

 

Because really it is, in a way, a scientific tool to look at aspects of the disease that we can’t access either because we can’t study the brain tissue or the spinal cord tissue directly, and because it’s really much more sensitive than doing clinical evaluations in neurology. So one of the interesting things that came out from early MRI studies in the 1990s, many of them done at the NIH long before I got there where they started doing MRIs every month on people even before the era of disease-modifying therapy, was that new plaques that appeared in the brain occurred roughly ten times more frequently than new symptoms appeared in the form of relapses.

 

MSDF

Ten times?

 

Dr. Reich

Ten times, or maybe even more. But that was with the sensitivity of the techniques that were available then, that was the number that was found. What that’s telling you, of course, is that there’s a lot of subclinical disease activity that’s going on that we can completely miss if we are just doing examinations or asking patients to report their symptoms.

 

MSDF

Have there been eras of MRI use in MS and where are we now with it? And that could be in clinical trials and biology.

 

Dr. Reich

We’ve made a lot of progress, I think, in all three areas. The MRI is absolutely the most important paraclinical tool for making the diagnosis of MS. And since the newest generation of diagnostic criteria were established, the McDonald Criteria, MRI has really formed the centerpiece of those. So in somebody who is having symptoms that may be due to multiple sclerosis, the MRI is absolutely the most important test that can be done. And, in fact, it’s now evolved to the point where the diagnosis can be made based on a single MRI at one time in many cases in somebody who comes in with the appropriate clinical symptoms.

 

MSDF

A new challenge confronts the whole MS community in developing therapies and monitoring outcomes of interventions for progressive MS.

 

Dr. Reich

Yes. So how might MRI play a role in assessing therapies for progressive MS? That is a huge challenge. It’s a challenge I would say the majority of my colleagues in the imaging field in MS are working on; what can you measure with MRI that might be the equivalent of new plaque development for the progressive MS question? And it’s, in my view, quite unresolved. The most studied markers that have behind them the weight of evidence to date is brain volume changes – how much brain is there – which can be assessed with MRI and is being done routinely in clinical trials now. I think how exactly that’s being done, which parts of the brain to look at – grey matter, white matter, specific portions of the brain like the thalamus – remains an open question.

 

What quantitative analysis tools should you use to make the measurements from the images? How you set up the scanner? All of this is still being worked out. That idea of measuring brain volume and seeing whether therapies may slow the rate of brain volume loss appears to be relatively promising. But even with that, proof of concept early trials to see whether a therapy might work are still much larger and much longer than the proof of concept trials that work for assessing new therapies to reduce the number of plaques.

 

MSDF

By how much longer?

 

Dr. Reich

They usually are two years or so at the minimum and they would involve on the order of 100 to 150 patients. Contrast that to four to six months with 10 to 15 patients and you can see how many more therapies can be tested with the shorter, smaller approach. So, in fact, in our lab, one of the things we’ve been thinking about a lot is how we may shorten that. And in the context of progressive multiple sclerosis, I think that’s not clear how to do. However, a lot of the biological processes that are occurring in progressive multiple sclerosis, there’s now a lot of evidence that they also occur very early in the disease, perhaps even before somebody has their first symptoms. So these brain atrophy processes, I think that’s been quite well established.

 

But you can also ask the question of whether brain tissue repair. Parts of the brain that have been demyelinated that requires remyelination that occurs early in the disease and it may be relevant for progressive phases of the disease as well, or for people who have primary progressive MS. And so we’ve been thinking a lot about how to look at these early plaques that develop early in the disease and use imaging of those plaques to see how they repair in order to test new therapies coming down the block that may promote remyelination or protect brain tissue that’s undergoing inflammation and demyelination from more extensive destruction. And we think, based on the some of the work we’ve done that is going to be published next week, that we can design trials that are, again, very short – six months or so with 10 to 20 patients, 15 to 20 patients – that may be able to assess that. And, of course, we’ll need to understand whether success in such a trial would predict whether that therapy would work in larger trials of progressive MS.

 

MSDF

Are there other challenges with MRI and related to multiple sclerosis?

 

Dr. Reich

Sure. From the point of view of doing clinical trials that are generalizable to large groups of patients that are able to be implemented at multiple sites, we need to understand how to standardize our techniques better. I’ve been involved with an effort recently to develop a group of cooperating investigators in North America similar to our older, more venerable brothers and sisters in Europe who have been working together on imaging for 20 years or so in the MAGNIMS Consortium. Our group which is called the North American Imaging in Multiple Sclerosis Cooperative – or NAIMS – is really very interested in trying to understand how we can standardize high-end approaches that may be very effective for testing new therapies that may be useful for assessing tissue or repair. With this consortium, the NAIMS Consortium, we’ve been very interested in developing standardized protocols that could be useful for assessing in a multicenter way, whether new therapies that are designed to repair or protect brain tissue and spinal cord tissue work. So we’ve been working very hard to do that, and we hope that once a study can be done in multiple sites, it can often be done much more efficiently.

 

From a diagnostic point of view, the types of MRIs that are done at all different centers may be equally good for just assessing, for example, whether plaques are present in the brain of somebody who is being worked-up for multiple sclerosis. But if you have to take the next step to quantify that and to submit those results to statistical analysis, then you really need a lot more homogeneity. It’s not actually clear how much homogeneity you need, how much narratization you need, that’s an open question. Does it need to be exactly the same, or does it need to be approximately the same, or really do we need to understand the differences between what is done at one site versus what is done at the other?

 

The last area in which I think MRI is incredibly valuable and offers something that no other technique really can is the ability to study the spatiotemporal dynamics of the disease. MS is, of course, a disease that affects people young and that they carry with them for their entire life, so it can last 40, 50, 60, 70 years in some cases. And I think we all know that the disease changes a lot during that period, and it changes as people are changing and as they age, and you can’t take pieces of the brain or spinal cord and study it under the microscope. I mentioned already that clinical evaluation is less sensitive than the MRI for picking up these changes, so only with the MRI can you understand how things change and where they’re changing in the brain.

 

In that context, I think people have been going along one of two pathways for how to use MRI to understand the biology of the disease. On the one hand, people have been using the physics of MRI to build really complicated models of how different types of tissue changes – demyelination, inflammation, atrophy – could affect the pictures we take, and that’s been a very interesting but quite complicated effort and the results have been a little bit hard to interpret. The other approach is to take advantage of the rapidly evolving technical changes in MRI acquisitions to really just learn how to take higher and higher resolution pictures.

 

And I think that’s the bias that we have in our group, that’s the approach we’re taking where we think that as we begin to hone in on really fine features of structures of the brain, whether it be the cerebral cortex or the spinal cord or the brain stem or the cerebellum, we’ll begin to see things that will help to bridge this divide between what people can do in the lab with really fancy molecular techniques with what they can do in the clinical with MRI. And so that’s really where we’ve been spending a lot of our effort using very powerful MRI machines – 7 Tesla – using very advanced antennas – we call them coils – in MRI to really get high-sensitivity images.

 

Changing the way we tune the magnet to focus on things that we think are interesting. For example, one of the areas we’ve been studying quite intensively recently is inflammation in the meninges in the coverings of the brain, which we think from the pathological data are quite relevant to the disease. We have a way now that we’ve described of assessing at least some of that inflammation in MS, and we’ve been following up on that. So I think the potential of MRI as a biological tool, even after 30 years of work on it, is really largely untapped.

 

MSDF

Are there things that the MRI can’t do right now that you really want it to do?

 

Dr. Reich

Oh, absolutely. You know, MRI is based on the physics of how protons behave in a strong magnetic field and when those protons which are largely in water are aligned when they go into a magnetic field. And we can perturb that alignment, and then it relaxes back into the equilibrium state. And the rates at which that happen depend on where these protons are located, and that’s what allows us to see the tissue. And I go into that because it just illustrates that we’re not looking at T cells and B cells and microglia and axons and oligodendrocytes, we’re looking at the physics of protons in a magnetic field.

 

I would, of course, love to have a technique that combines the exquisite submillimeter spatial resolution of MRI with specificity for these various cell types or biological processes that are going on. And a lot of people have been working on this, but to date that doesn’t really exist. And part of the reason for that is because the biological processes don’t occur in isolation. Lots of different things happen with inflammation – water moves around – and so it may actually not be possible to do that, but people are still working in that. So that’s a great challenge is to figure out how we could specifically assess inflammation, myelination, axonal health with imaging. But I don’t think that precludes us, again, from using the imaging either to help with the diagnosis, to assess new therapies, or to really observe and build stories about how the biology is working in the disease.

 

MSDF

What’s happening in the cutting-edge of MS neuroradiology?

 

Dr. Reich

I think the most exciting development in MRI and multiple sclerosis is the ability to look with greater and greater precision at what’s going on in the brain and spinal cord, and how that changes over time. And that is being made possible by really rapid advances in the technology. I think that will no doubt translate into the ability to better assess the course of an individual person’s disease, whether they’re responding to therapies, either immunomodulatory therapies that current exist or the reparative or protective therapies that will hopefully come online soon. And I think that’s tremendously exciting.

 

MSDF

Do you also collaborate with people in other specialty areas in the course of your work?

 

Dr. Reich

Yeah. Personally, I have many collaborations. I have collaborations with pathologists, I have collaborations with immunologists, with clinicians, with virologists, with other imagers. So for my work which really depends on understanding the intersection between the imaging we do and the biology of the disease, those collaborations are critical. Through our NAIMS Cooperative, the imaging group in North America that we’ve recently started, we’re hoping really to develop very powerful interactions among groups that have a lot of expertise in how to do imaging in multiple sclerosis.

 

So in addition to the standardization work, we’re very much hoping to be able to share techniques that we develop. And we’ve established a platform in which that is happening. We’re also hoping to use this cooperative group to sort of cross-pollinate the various labs to use it as a training forum so that the next generation of people interested in imaging and MS will, number one, get to know each other, but also learn from labs in which they don’t spend all their time. So it has a multipartite mission which hopefully will really drive the field forward.

 

MSDF

Well, thank you for sharing your thoughts on MRI and MS with MSDF.

 

Dr. Reich

It’s my pleasure.

 

[transition music]

 

Thank you for listening to Episode Thirty-Five 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]

Mar 10, 2015

 [intro music]

 

Hello, and welcome to Episode Thirty-Four of Multiple Sclerosis Discovery, the podcast of the MS Discovery Forum. I’m your host, Dan Keller.

 

This week’s podcast features a follow-up interview from last week’s episode with Dr. Pierre-Antoine Gourraud. This week, we interview Dr. Jill Hollenbach about killer immunoglobulin-like receptors – or KIR – and their relationship with human leukocyte antigen and MS. But to begin, here’s a brief summary of some of the latest developments on the MS Discovery Forum at msdiscovery.org.

 

Take some time to check out our most recent data visualization on our website. Under the research resources tab, you can find a series of interactive data visualizations useful for MS researchers. Our most recent one organizes 142 ongoing clinical trials into an interactive bubble chart. We have another visualization on the natural history of MS symptoms. The interactive bar chart allows you to see the change of various symptom severity in MS over a 30-year period.

 

If you enjoy this podcast and find MSDF helpful, please consider supporting us with a donation. MSDF is run by a small team of full-time employees and a few regular contributors. We are devoted to bridging the gaps between scientific disciplines to speed the flow of information from the lab bench to the bedside. Our ultimate goal is to facilitate the discovery of a cure. We believe one of the best ways to do that is to bring independent, research-focused news to a professional audience on a platform that fosters discussion and discourse. Help keep us going by visiting our website and clicking on the green “Support MSDF” button next to the “Research Resources” tab on the top right of our screen.

 

[transition music]

 

Now to the interview. Dr. Jill Hollenbach is an assistant professor in the department of neurology at the University of California, San Francisco. She met with science journalist Cynthia McKelvey, to talk about KIR in MS.

 

Interviewer – Cynthia McKelvey

Why don’t we start by introducing what KIR is, how it’s different from the potassium channel and what its relationship is to HLA.

 

Interviewee – Jill Hollenbach

Well, KIR is an acronym, it stands for killer immunoglobulin-like receptor. These are receptors on the surface on the surface of natural killer cells. They use generally, not in every case, but use HLA as their ligand and they have either an activating or inhibitory effect on natural killer cells.

 

MSDF

You mentioned in your talk earlier today at UCSF that they are difficult to study. Why is that?

 

Dr. Hollenbach

Just in terms of their genetic architecture. KIR occupy a complex on chromosome 19, it’s a multigene complex. And so on any individual haplotype that’s one chromosome, an individual can have between 4 and 14 KIR genes. These genes are really recently evolved, and so they’ve kind of arisen in humans as a result of repeated events of recombination and gene duplication. So what that means is that one KIR gene often at the nucleotide level looks an awful lot like another KIR gene. And so we’ve had a lot of issues. A lot of the methodologies that are available right now in terms of sequencing, part of this has to do with a lack of human genome reference alignments, but there has been a lot of difficulty in examining these genes because they look so much like one another.

 

MSDF

How does that relate to why they haven’t really seen them on genome-wide association studies?

 

Dr. Hollenbach

There’s a couple of reasons why we don’t see them on genome-wide association studies. One is that, as I mentioned, there haven’t been a lot of good reference alignments, so as a result we don’t actually see a lot of SNP markers on most of the common platforms that are used for genome-wide association studies. And then the markers that are there are often lost to quality control, because we have a lot of gene content variation, which is kind of like a copy number variant. And so if we only see a result for one chromosome, for example, for a given SNP, that is not going to pass general quality control thresholds. And, of course, you have to recognize that when you’re doing these GWAS studies, you’re looking at a hundred thousand, five hundred thousand, a million markers, two and a half million markers, so you’re not going one-by-one and saying, well this KIR-1, we expect to only see one copy or that sort of thing. So it just gets thrown out in the mix with things that don’t pass QC.

 

MSDF

How does KIR relate to multiple sclerosis specifically?

 

Dr. Hollenbach

Well, we’re trying to figure that out. So there’s been a small number of studies examining KIR in multiple sclerosis, and what seems clear is that variation in the KIR does play a role in susceptibility to multiple sclerosis. It may play a role in progression; we’re just not sure. There’s not been enough work done to say definitely what’s going on, but there’s enough evidence to say that something is going on. And some of the work that I talked about in my talk today, an analysis of KIR variation along with HLA in an African-American MS cohort, a very large study population, it seems clear that there is some association of KIR variation with susceptibility or protection for multiple sclerosis.

 

MSDF

Why study the African-American cohort? What does that tell us about MS in general?

 

Dr. Hollenbach

We want to study them because they’re different from one another; so an African-American population is going to look very different genetically with respect to KIR and HLA from a European-American population. So we want to know two things. We want to know is there something different going on with these genes with respect to disease in these different populations, OR at the same time we want to know is something the same going on? And so we can learn something both from these commonalities and differences, and both can be really important in genetics. So if there’s something that is important that’s specific in the African-American population, we want to know that, and we can only find out by looking at a number of different ethnic groups.

 

MSDF

Let’s talk a little bit more about interaction between KIR and the HLA ligand, and how that plays in with Bw4. And if we can define all of those things, too, that would be great.

 

Dr. Hollenbach

Okay. Well, so KIR molecules, as I mentioned before, need to see something, they need to have a ligand on their target cell. We have both inhibitory receptors and activating receptors. The job of the NK cell is to perform immune surveillance. So NK cells kind of wander around the body, and what they’re looking for are cells that don’t look healthy. So what does that look like and what is an unhealthy cell? It’s a cell that is virally infected, it’s a tumor cell. Those are the two main things that NK cells are looking for. And it’s a really important function because they’re part of what we refer to as the innate immune system; it’s the first line of defense against these kind of unhealthy events.

 

And so what does an unhealthy cell look like? Well, one of the things that happens in both viral infection and tumors is downregulation of MHC class I. That’s what the KIR are looking for. So when an NK cell encounters a healthy cell, it will see HLA class I, it immediately recognizes this is self, this is healthy cell at least in terms of what I’m able to see as an NK cell, and it will move on and it won’t cause any damage to the cell after making contact between the KIR and that ligand.

 

On the other hand, if the KIR doesn’t see this HLA ligand, the inhibitory KIR, an activating KIR – and we’re still not completely sure what the activating KIR ligands are – but the activating KIR is also bound to something on the surface of this cell. If the activating KIR is bound but the inhibitory KIR is not, what happens is the NK cell is going to lyse that cell which is presumably unhealthy in some ways – tumor or viral infected.

 

Now HLA class I – actually all HLA molecules – have another primary really important role which is antigen presentation to T cells. Class I molecules present antigen to the CD8-positive T cells, and so that’s how these T cells perform their role in terms of the active immune response. KIRs see a different part of the HLA molecule than the T cell receptors, and so they see kind of this piece of the HLA class I molecule that’s kind of on the side of where the T cell receptors sit. And the variation that they see on that HLA class I molecule can kind of be defined by these broad categories based on the particular amino acid residues. And it’s generally just from two to four amino acid residues that determine whether or not a given KIR can see a given HLA class I molecule.

 

So one of these epitopes, as we call them – and if they were originally defined on a serological basis because specific antibodies could recognize them – so one of these epitopes is referred to as Bw4; these are epitopes that we mainly see on HLA-B molecules – not all – so depending on the population, human population, may be from 40 to 60 or 70% of HLA-B molecules will have this Bw4 epitope. Some HLA-A molecules also bear the Bw4 epitope. So that’s what some KIR molecules, specifically KIR3DL1, is seeing is Bw4.

 

The results of the study that I talked about today and what we saw is in this African-American multiple sclerosis cohort, individuals that have both 3DL1 and HLA alleles with the Bw4 epitope appear to be protected from multiple sclerosis. And so we see higher frequencies of this combination in our control population relative to patients. So that suggests a protective effect of that combination, 3DL1 plus Bw4.

 

MSDF

Where do you see the research going from here?

 

Dr. Hollenbach

Right now the data that we’re looking at is strictly in terms of carrying frequencies for these particular genes. So these genes are actually highly variable at the allele level, so any given gene like KIR3DL1 has many, many variants that are already known, and likely many variants that we haven’t identified yet because the technology has not been there. The technology is just about now caught up to the point where we are able to examine at the sequence level the variation within these specific KIR genes, and so I think that that’s really the next step. And we’re actually taking steps to start examining this cohort and others in terms of this fine-grained variation in the KIR genes.

 

MSDF

Very good. Thanks.

 

[transition music]

 

Thank you for listening to Episode Thirty-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 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]

Mar 2, 2015

[intro music]

 

Host – Dan Keller

Hello, and welcome to Episode Thirty-Three of Multiple Sclerosis Discovery, the podcast of the MS Discovery Forum. I’m your host, Dan Keller.

 

This week’s podcast features an interview with Dr. Pierre-Antoine Gourraud about the function of human leukocyte antigens and their role in MS. But to begin, here's a brief summary of some of the latest developments on the MS Discovery Forum at msdiscovery.org.

 

Early in January, the journal Nature Reviews Neurology published a highlights issue of research advances in MS in 2014. The milestones included successful phase 2 trials for simvastatin in progressive MS, new clinical phenotype categories, and more. We summarized each of these advances, supplemented with interviews from some of the authors. Go to the “News and Future Directions” section of our website and click on “Top 8 MS Research Advances of 2014” to read it. And please do make use of our comment section, especially if you believe that we – and Nature Reviews Neurology – failed to list any equally important advances.

 

Dimethyl fumarate, also known as Tecfidera, may lower CD8-positive T cells in patients with MS, according to a new study out last week. This news follows an earlier story of a patient who died of complications from the rare brain infection, progressive multifocal leukoencephalopathy, or PML, after taking dimethyl fumarate. The drug is known to lower leukocyte levels, including lymphocytes, but many patients are able to maintain normal white cell counts while on the drug. This study showed that even patients with normal leukocyte counts may have dangerously low levels of CD8-positive T cells. These cells are involved in viral immunity, and lower levels of them may leave the gate open for opportunistic infections, such as JC virus, that causes PML.

 

If you enjoy this podcast and find MSDF helpful, please consider supporting us with a donation. MSDF is run by a small team of three full-time employees and a few regular contributors. We are devoted to bridging the gaps between scientific disciplines to speed the flow of information from the lab bench to the bedside. Our ultimate goal is to facilitate the discovery of a cure. We believe one of the best ways to do that is to bring independent, research-focused news to a professional audience on a platform that fosters discussion and discourse. Help keep us going by visiting our website and clicking on the green “Support MSDF” button next to the “Research Resources” tab on the top right of our screen.

 

[transition music]

 

Now to the interview. Dr. Pierre-Antoine Gourraud is the leader of the translational digital medicine group in the Department of Neurology at the University of California, San Francisco. He’s also a distinguished member of our scientific advisory board. He met with science writer, Cynthia McKelvey, to talk about human leukocyte antigen in MS.

 

 

Interviewer – Cynthia McKelvey

Let’s begin by defining the major histocompatibility complex and human leukocyte antigen; what those are and how they relate to multiple sclerosis.

 

Interviewee – Pierre-Antoine Gourraud

So the MHC, the major histocompatibility complex is one of the most important region of the genome. It’s 1000 of the genomes, 3.6 megabase, but it represent about 1% of the total number of genes. So a region that is very dense in genes that are very, very important in neurological functions. It’s also one of the most polymorphic region of the genome, which mean that there are many, many version, many diversity, a lot of alleles, as we call these different forms of a given gene for that particular region of the genome. Basically, it’s encode for or identity or genetic identity, and it has been studied a lot for transmutation. So for multiple sclerosis, since 1972 has been recognized that something in that region had to do with multiple sclerosis risks or the susceptibility; why people are getting multiple sclerosis whatever or not. So back in 1972, researchers realized that people carrying an HLA-DR2 type were actually more susceptible to multiple sclerosis. So doing that in a very simple and comparative manner, we took a bunch of people that have MS, a bunch of people that don’t have MS, and you just see that people that have MS tends to have more HLA-DR2. At that time, the HLAs so the genes that bears the immunity identity of [?] – very important for transmutation again – they were typed by serological techniques. So we were using antibodies to distinguish different types. Over the years, serology has been replaced by PCR-based technique, molecular techniques, and we are now doing HLA typing by sequencing. And for 30 years basically this result has been confirmed, and many additional findings we find the initial association between the MHC region and multiple sclerosis.

 

MSDF

So you’re looking at a cohort of African American MS patients and comparing them to people of European descent with MS. And, you're seeing some differences in the major histocompatibility complexes with these. And how do those relate to MS? What are they telling you about the disease?

 

Dr. Gourraud

You know, if we're stepping back a little bit, it's very important to get very large samples to do genetic studies. The more people we are looking at the easier the findings easy to find alleles. So UCSF and other groups in the world have been organizing to coordinate their effort in structuring the International Multiple Sclerosis Genetic Consortium, IMSGC, and we have been really, really successful in gathering large number of MS patients of European ancestry, as well as controls. Within that consortium, UCSF and Dr. Cree and Dr. Oksenberg, have been pushing an effort to coordinate as well African American cohort of MS patients. So we have been working on that, and for the past two to three years we have done a tremendous effort to actually type the HLA of these patients and these controls. And we have gathered more than about 1600 African American MS patients – and we are still collecting them – and roughly 2000 African American controls to do the comparison.

 

So the first thing we want to do is to see if we are confirming what we see in the European patients – and that is true – we have found  HLA-DRB1 15:01, 15:03 as a specific allele for African American. The HLA-DRB1 03:01 is also to some extent a risk allele in African American. And we also confirm that in the class I HLA-02:01 has a protective effect on MS. So, it's not necessarily obvious, because some of these alleles are actually not found in people of African ancestry, and they also have a much larger diversity. So we are starting to accumulate evidence showing that other alleles that are not present in the Europeans are associated with MS risk. And that’s a very important finding, because now we are in a position where we're going to find structural, functional commonalities between the African American alleles and the European alleles that are both associated to MS.

 

MSDF

And where do you see the research going from here?

 

Dr. Gourraud

So one also very important topic that's being working on both in Europeans and African American is trying not to consider HLA on its own, even if we have really put a lot of samples and money and effort in that, but also consider another very complex family of genes that interact with HLA. These are called KIR (K-I-R), and they are receptor at the cell surface of NK cells, the natural killer cells that have a very important role in immune regulation, and it has been reported that NK cells are actually present in the brain in active MS lesions. So we looked at these two system as potentially interacting to define the risk of MS. So we started typing also for these KIR genes in our African American to be able to study at the same time the MHC or the HLA genes, the KIR genes on a different region of the genome, and also the rest of the genome where we've used a simple marker called SNP.

 

MSDF

That’s great. Thank you very much.

 

Dr. Gourraud

You’re very welcome. Thank you.

 

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Thank you for listening to Episode Thirty-Three 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.

 

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