Multiple Sclerosis Discovery -- Episode 33 with Dr. Pierre-Antoine Gourraud

[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.   [transition music]   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. 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