Who? Why? How? Searching for the Cause of Multiple Sclerosis

North american education program 2010 Who? Why? Why? Who?

The National Multiple Sclerosis Society is a collective H o of passionate individuals, moving together to create a w ? ? world free of MS. Searching for the Cause of Multiple Sclerosis nationalMSsociety.org +1 800 344 4867

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Our mission is to be a leader in finding a cure for multiple sclerosis and enabling people affected by MS to enhance their quality of life. mssociety.ca +1 800 268 7582

© 2010 National Multiple Sclerosis Society © 2010 Multiple Sclerosis Society of Canada On the cover: Kim (left), diagnosed in 1986 AJ (middle), diagnosed in 2000 Beverly (right), diagnosed in 2001 Table of contents

Acknowledgements...... 3

Program Staff...... 4

Preface...... 5

Program Overview...... 6

Program Presenters...... 7

Program Biographies...... 8

What is the Cause of MS?...... 19

The Role of Genetics in the Development of Multiple Sclerosis...... 21

Genetic Susceptibility Among Family Members of People with MS...... 22

New Techniques Help Pinpoint Genetic Factors...... 23

Looking for DNA Markers...... 23

Novel Genetic Variations...... 25

Implications for People with MS...... 25

Epidemiology: Who Develops MS?...... 26

Observations From Epidemiologic Studies...... 27

Recent Research Projects Related to Epidemiology and Possible Infectious Triggers of MS...... 27

Searching for the Cause of MS | 1 Environmental Factors & Multiple Sclerosis...... 29 Geography & Migration Patterns...... 30 ACKNOWLEDGeMENTS Vitamin D & Sunlight...... 31

Smoking...... 32 The National Multiple Sclerosis Society and the Multiple Sclerosis Toxic Substances...... 32

Hormones...... 33 Society of Canada wish to acknowledge the generous support of

Tetanus Vaccine...... 34 Bayer HealthCare Pharmaceuticals, Biogen Idec, Genentech, Clusters & Epidemics...... 34 Genzyme Corporation, and Teva Neuroscience, Inc. for the 2010 Evidence for an Infectious Cause of MS...... 35 North American Education Program — Who? Why? How? — The Epstein-Barr Virus (EBV)...... 37 Searching for the Cause of MS. Non-Specific Immune Reactions in MS...... 38

The Role of Immunology in Multiple Sclerosis...... 39

Research Directed at the Role of the Immune System in MS...... 40

The Roles of T-cells in Multiple Sclerosis...... 41

Chronic Cerebrospinal Venous Insufficiency (CCSVI): A Possible Factor in the Development of Multiple Sclerosis?...... 42

Summary...... 44

Glossary...... 45

2 | Who? Why? How? Searching for the Cause of MS | 3 Program staff preface

John Aden Welcome to the 2010–2011 North American Education Program. Senior Manager, Program Development, National MS Society This program continues the successful collaboration between the Cathy Carlson Senior Director, Research Information National MS Society in the United States and the MS Society of National MS Society Canada to provide the latest information about research and Rosalind Kalb, PhD disease management in multiple sclerosis to thousands of people Vice President, Professional Resource Center, National MS Society on our continent and around the world. Nancy Law, LSW Executive Vice President, Programs and Services Department National MS Society This year, thanks to generous helping us to bring this program sponsorship from Bayer Health- to you. We are delighted that Patricia A. O’Looney, PhD care Pharmaceuticals, Biogen you have chosen to participate Idec, Genentech, Genzyme Vice President of Biomedical Research, National MS Society in our program and hope that Corporation, and Teva Neuro- you find it interesting and science, Inc., our program will Diana M. Schneider, PhD, Editor exciting. Together, we will be focus on finding the cause of MS. learning about how scientists are Consultant, National MS Society You will learn about theories — searching for the cause of MS past and present — and what — research that could some- the future may hold. day lead to a world free of MS. On behalf of our organizations We look forward to sharing this and the program sponsors, we program with you. wish to express our appreciation Nancy Law to our researchers for taking the Executive Vice President time to speak with us and for Programs & Services Department letting us into their labs. In National MS Society addition, we want to thank the staff and volunteers of the Jon Temme National MS Society and MS Senior Vice President, Research & Society of Canada chapters for Programs, MS Society of Canada

4 | Who? Why? How? Searching for the Cause of MS | 5 PROGRAM OVERVIEW Program presenters Welcome to the 2010 North American Education Program,

Who? Why? How? — Searching for the Cause of MS. The National Jeffrey L. Bennett, MD MS Society began offering national education programs in 1988. Professor of Neurology and Ophthalmology University of Colorado — Denver School of Medicine The first national teleconference reached 700 participants in 60 David A. Hafler, MD sites. Since that time, we have utilized a range of technologies to Gilbert H. Glaser Professor of Neurology expand our audience throughout North America. Chairman, Department of Neurology Yale School of Medicine

Paul W. O’Connor, MD, MSC, FRCPC Director, University of Toronto Program in Multiple Sclerosis By archiving our programs on National Scientific and Clinical Advisor, MS Society of Canada the National MS Society web- Near the end of the year the site (nationalMSsociety.org), we program will also be available Patricia A. O’Looney, PhD have made it possible for people on the National MS Society Vice President of BioMedical Research around the world to share the website as part of MS Learn National MS Society information as well. Online (nationalMSsociety.org/ MSLearnOnline) for anyone In an effort to reach the broad- who is unable to participate in Benjamin M. Segal, MD est possible audience, and a program or would like to view Holtom-Garrett Professor of Neurology maintain the flexibility of our or share the program more than Director, Multiple Sclerosis Center programming, we are again once. In the video program, res- University of Michigan providing this year’s program earchers discuss how understanding as a videotaped conference, the causes of MS can provide thus enabling the chapters of Helen Tremlett, PhD hope for future MS treatments the National MS Society and and possibly a world free of MS. Assistant Professor, Department of Neurology the MS Society of Canada University of British Columbia the opportunity to offer the This program book provides an program to audiences at their in-depth look at the etiology, Jerry S. Wolinsky, MD convenience over the course or the study of the causes, of of the year. multiple sclerosis. Bartels Family and Opal C. Rankin Professor of Neurology University of Texas Health Science Center at Houston

6 | Who? Why? How? Searching for the Cause of MS | 7 presenter biographies

Dr. Jeffrey L. Bennett is currently Professor of Neurology and Ophthalmology at the University of Colorado Denver and is a faculty member of the Dr. Bennett is internationally Rocky Mountain MS Center recognized as a leader in the Jeffrey L. at Anschutz Medical Campus. fields of neuroimmunology, Dr. Bennett maintains active Bennett, MD Dr. Bennett attended Case West- neuro-ophthalmology, and specialty practices in neuro- ern Reserve University, where demyelinating disease. He directs ophthalmology and multiple Professor of Neurology he graduated summa cum laude clinical and basic research sclerosis, and is regularly voted and Ophthalmology with degrees in Biochemistry programs on optic neuritis, one of the Best Doctors in University of Colorado — and Philosophy. He received multiple sclerosis, and neuro- America. In 2006, he received Denver School of Medicine his medical and doctoral degrees myelitis optica. His research the Stephen Reingold Award at Stanford University. Dr. Bennett is supported by the National from the National Multiple completed his internship and Institutes of Health, National Sclerosis Society. Dr. Bennett residency in Neurology at the Multiple Sclerosis Society, Guthy- has written many clinical and University of Colorado, fellow- Jackson Charitable Foundation, scientific publications, been ship in neuroophthalmology at and private industry. In the awarded numerous scholarly the University of Pennsylvania, laboratory, Dr. Bennett’s research distinctions, serves on several and post-doctoral research in is focused on using advanced scientific review committees, and the Department of Molecular, techniques in molecular immuno- serves in an editorial capacity Cellular, and Developmental logy to identify the target of the for numerous scholarly publi- Biology at the University of immune response in neuro- cations in both neurology and Colorado, Boulder. inflammatory disorders. ophthalmology.

8 | Who? Why? How? Searching for the Cause of MS | 9 He was one of the Executive Directors of the Program in Dr. David A. Hafler is the Gilbert Immunology at Harvard Medical H. Glaser Professor and Chair- School and was on the faculty of man, Department of Neurol- the Harvard-MIT Health Science His laboratory focuses on the David A. ogy, Yale Schools of Medicine, and Technology program where understanding of human auto- Hafler, MD and the Neurologist-in-Chief of Dr. Hafler is a clinical scientist he was actively involved in the immune diseases with the theme the Yale-New Haven Hospital. with a research interest in Gilbert H. Glaser training of graduate students that investigation of naturally- He graduated magna cum laude understanding the mechanism Professor of Neurology and post-doctoral fellows. occurring human diseases gives in 1974 from Emory University of autoimmunity, with a part- insight into the basic processes with combined B.S. and M.Sc. Dr. Hafler has been elected to icular interest in inflammatory Chairman, Department of T cell regulation, in addition degrees in biochemistry, and membership in the American central nervous system diseases. of Neurology, Yale to providing fundamental under- received his MD degree from the Society of Clinical Investigation, He has more than 300 publi- School of Medicine standing and development of new University of Miami School The American Neurological cations in the field of auto- therapies for human diseases. of Medicine in 1978. He then Association, the Alpha Omega immunity and immunology. completed his internship in int- Society, and was a Harvey Weaver He received the first National Dr. Hafler is a founding mem- ernal medicine at Johns Hopkins Scholar of the National Multiple Multiple Sclerosis Five-Year ber of the International MS followed by a neurology residency Sclerosis Society. He is currently a Collaborative Center Award Genetics Consortium, a group at Cornell Medical Center-New member of the editorial boards of for work on the MS genetic recently formed to define the York Hospital in New York. the Journal of Clinical Investigation effort. Dr. Hafler led the NIH genetic causes of MS, which Dr. Hafler received training in and the Journal of Experimental Autoimmunity Prevention includes scientists from Univ- immunology at the Rockefeller Medicine, and is co-founder Center Grant at Harvard, and ersity of Cambridge and the University, then at Harvard where of the Federation of Clinical is a Jacob Javits Merit Award University of California, San he joined the faculty in 1984. Immunology Societies. Recipient from the NIH. Francisco.

10 | Who? Why? How? Searching for the Cause of MS | 11 Dr. O’Looney holds a bachelor’s degree in Molecular Biology Dr. Paul O’Connor is a neurolo- from Regis College, Weston, MA, gist and Director of the Multiple and a Master’s Degree and a Sclerosis Program at St. Michael’s As Vice President of Biomedical Ph.D. in Medical Biochemistry Hospital, University of Toronto. Research at the National MS from the George Washington He is a Professor of Medicine Society, Dr. O’Looney directs University Medical School (Neurology) at the University and oversees the administration in Washington, D.C. After of Toronto and holds the Waugh of the Society’s biomedical completing her postdoctoral Family Chair in Multiple Sclerosis research funding programs. training, Dr. O’Looney held a Research. He directs the Clinical Since joining the Society dual faculty appointment in and Research Program at one in 1988, she has provided the Departments of Medicine of the largest MS Clinics in leadership in directing and ex- and Biochemistry at the Medical Paul W. North America. panding the Society’s research School where she conducted O’Connor, initiatives and encouraging Dr. O’Connor’s research interests by the American Board of Psych- research studies in lipoprotein MD, MSC, FRCPC collaborations across scientific include the development of new iatry and Neurology in 1986. He metabolism in autoimmune disciplines in MS research. She Director, University therapies for MS. He played a received a Masters of Science diseases. She is a past recipient of Patricia A. has guided several of the Society’s of Toronto Program leading role in successful clinical degree in Clinical Epidemiology the New Investigator Research O’Looney, PhD special research portfolios focus- in Multiple Sclerosis trials of natalizumab for MS that in 1991. In addition to the Award from the National ing on MS genetics, on gender resulted in the approval of this development of new therapies for Vice President of Institutes of Health and is the National Scientific differences in MS, on repair treatment in relapsing-remitting MS, he has an ongoing interest Biomedical Research author of several publications & protection of the damage in and Clinical Advisor, disease. His more recent research in clinical trial design and ethics. in scientific/medical journals. MS, as well as components of MS Society of Canada interests have focused on the National MS Society Dr. O’Connor also serves as the the Promise 2010 Campaign. Memberships include the New development of oral therapies National Scientific and Clinical In addition to coordinating York Academy of Sciences and for MS, including teriflunomide, Advisor for the Multiple Sclerosis the activities of the National the American Society for Bio- fingolimod and vitamin D. Society of Canada, and plays a Scientific Advisory Committees, chemistry and Molecular Biology. Dr. O’Connor is a graduate of major role in research adminis- she acts as a liaison between She is also listed in several edi- the University of Toronto and tration and policy development the medical & scientific com- tions of Who’s Who, including received his medical degree on behalf of the MS Society of munity and those individuals that of American Women, of from the Royal College of Canada. He is also president- suffering with MS by providing Men and Women in Science, Physicians and Surgeons of elect of the Americas Committee information about MS research and Who’s Who in Medicine Canada in Neurology in 1985, for Treatment and Research in developments to the MS com- & Healthcare, and Who’s Who with certification in Neurology MS (ACTRIMS). munity. in the East.

12 | Who? Why? How? Searching for the Cause of MS | 13 His scientific contributions have Dr. Segal received a bachelor’s been recognized by numerous degree in biochemistry in 1984 awards, including a Commen- and medical degree in 1988, dation Medal for Excellence both from Brown University. from the Public Health Service, He served an internship a Harry Weaver Junior Faculty Dr. Benjamin M. Segal joined in Internal Medicine at the Dr. Segal’s research interest is Award from the National Multiple the University of Michigan University of Chicago and a in the immunopathology of Sclerosis Society, and the Stanley faculty in 2007, and directs the residency in Neurology at the multiple sclerosis. His discoveries Aronson Award for Excellence Multiple Sclerosis Center and Weill Medical College of Cornell have contributed to the current in the Clinical Neurosciences. the Holtom-Garrett Program University. He conducted res- understanding of how different Dr. Segal is a member of in Neuroimmunology. The earch in Neuroimmunology types of white blood cells and the American Association of Benjamin program’s mission is to provide as a Clinical Associate in the the chemical messengers they Immunologists, the American M. Segal, MD and support excellent diagnostic National Institute of Neuro- secrete perpetuate inflammation Academy of Neurology and and medical management logical Disorders and Stroke and mediate tissue injury in Holtom-Garrett the American Neurological services for patients with MS. at the National Institutes of the central nervous system Professor of Neurology Association. He is an ad hoc It also supports cutting-edge Health (NIH) from 1992–93, during multiple sclerosis and reviewer for NIH study sections Director, Multiple research in the pathophysiology and as a Research Associate in similar diseases. His research and numerous professional Sclerosis Center of MS and protective treatments, the Laboratory of Immunology led to three patents for immuno- journals, including Cellular and the education of young at the National Institute of therapeutic agents in MS. Immunology, Clinical Immunology University of Michigan physicians and scientists in Allergy and Infectious Diseases Dr. Segal’s studies have been and Immunopathology, Immuno- MS-related research. from 1993-99. Throughout his published in prestigious journals pharmacology, Journal of Immuno- NIH tenure, Dr. Segal served Dr. Segal’s goal is to see discoveries such as The Journal of Experi- logy, Journal of Experimental as a Lieutenant Commander made in the laboratory translated mental Medicine, Blood, and Medicine, Neurology, and in the Public Health Service. into practical treatments. His the Cutting Edge section of Proceedings of the National multidisciplinary team is seeking Dr. Segal was on faculty at the The Journal of Immunology.His Academy of Sciences. He also to develop therapeutic vaccines University of Rochester as an discoveries have been featured in serves as a volunteer on one and novel immune-modulating attending Neurologist, Associate Nature Reviews Immunology and of the National MS Society’s agents to improve the treatment Professor and Director of Neuro- highlighted in the “Discoveries scientific advisory committees of MS and advance nervous immunology Research prior to in Neuroscience” section of on the scientific study section tissue repair. coming to Michigan. Annals of Neurology. of the National MS Society.

14 | Who? Why? How? Searching for the Cause of MS | 15 Dr. Jerry S. Wolinsky, MD, holds the Bartels Family and Opal C. Rankin Professorship Dr. Helen Tremlett is an of Neurology and is a member associate professor on the Faculty of the faculty of the Graduate of Medicine (Neurology) at the School of Biomedical Sciences University of British Columbia, at The University of Texas Health Vancouver, Canada, and holds Science Center at Houston, an associate position within where he also serves as director of the School of Population and Jerry S. the Multiple Sclerosis Research Public Health. Group and the Magnetic Reso- Dr. Tremlett also heads the Wolinsky, MD nance Imaging Analysis Center. Dr. Tremlett’s research is funded Pharmacoepidemiology in MS He joined the faculties of The Bartels Family and Helen by a Don Paty Career Develop- (PIMS) research group and is Dr. Wolinsky received his Johns Hopkins University School Opal C. Rankin Tremlett, PhD ment award from the MS Society the author of more than 35 medical degree in 1969 from of Medicine, and the School of Professor of Neurology of Canada. She is a Michael peer-reviewed publications and The University of Illinois. Public Health in 1978 before Department of Neurology Smith for Health Research Scholar over 50 abstracts presented at University of Texas Residency training in clinical settling in Houston in 1983. University of and is principal investigator national and international con- Health Science Center at neurology, followed by a fellow- In Baltimore he applied more British Columbia on grants from the Canadian ferences. Her current research Houston ship in experimental neuropa- molecular tools to his basic invest- Institutes of Health Research, interests include: the natural thology and faculty appointment igations and became increasingly US National MS Society, UK’s history of MS; prognosis and at The University of California interested in the primary and MS Trust, and the BC Clinical predictors of disease progression San Francisco. While in San secondary immunopathogen- Genome Network. Originally in MS; effectiveness of the Francisco his research interests esis of neural disease. He trained as a pharmacist from the immunomodulatory drugs concentrated on the pathogenesis currently is active in the design, UK, Dr. Tremlett has specialized (IMDs) in MS; adverse effects of viral infections of the nervous implementation, conduct, and in epidemiology and multiple of the MS IMDs; MS epidem- system, and his clinical efforts analysis of clinical trials of MS sclerosis. She is research director iology; cancer and MS; pregnancy began to focus on experimental and conducts basic and applied of the British Columbia Multiple outcomes in MS; as well as therapeutics of infections of research in quantitative MRI Sclerosis database, one of the vitamin D, sunlight, infections the central nervous system and MR spectroscopic imaging largest of its kind in the world. and MS disease activity. and multiple sclerosis (MS). in demyelinating diseases.

16 | Who? Why? How? Searching for the Cause of MS | 17 What is the Cause of MS?

An important question that must be asked about any disease, including multiple sclerosis (MS), is “what causes it?”. This is technically known as the etiology of the disease. Only when we begin to understand the answers to this question does it become possible to develop better therapies to effectively treat and prevent Dr. Wolinsky currently oversees the centralized image the disease. analysis programs for the NINDS-sponsored CombiRx Trial and the Sanofi Aventis clinical development studies of teriflunomide in MS. He MS involves immune-system environmental agent that, upon is past chair of the Research attacks against the body’s own exposure, triggers an autoimmune Programs Advisory Committee brain and spinal cord. The response. Since a combination and current chair of the National disease is not directly inherited, of several factors appears to be Clinical Advisory Board of the but it is known to occur in people needed for MS to develop, the National MS Society, and current who have a genetic predisposition cause of MS is what is termed Dr. Wolinsky has served on President of Americas Committee to develop it. However, a great multifactorial, meaning that it review and advisory committees for Treatment and Research in deal of evidence suggests that requires more than one agent of the National Institutes of MS (ACTRIMS). He is on the most people who are genetically or event to occur at the right Health, MS International editorial board of Multiple susceptible to MS will only time and in the right sequence Federation, U.S. Food and Drug Sclerosis, and recognized in develop the disease if they are to trigger the disease. Administration, numerous Best Doctors in America and exposed to some other factor or pharmaceutical companies, the America’s Top Doctors. He has factors in their environment or One leading hypothesis is that Sylvia Lawry Centre for MS authored more than 250 pub- life experience. Some researchers MS occurs as the result of viral Research, and as interim Dean lications in neurovirology and theorize that MS develops because infection in genetically suscep- of the University of Texas Medical neuroimmunology, clinical a person is born with a genetic tible individuals, but many School at Houston. trials, and the imaging of MS. predisposition to react to some other possibilities have been

18 | Who? Why? How? Searching for the Cause of MS | 19 The Role of Genetics in the Development of Multiple Sclerosis MS is considered to be an autoimmune disease, in which the body misidentifies some part Finding a way to prevent MS of itself as a foreign invader. In Although MS is not hereditary in a strict sense, having a first- will require understanding MS, the part of the body that the genes that make people is mistaken as an invader is the degree relative such as a parent or sibling with MS does increase susceptible to developing the studied, including environ- protective covering of nerve disease, and also identifying mental and industrial toxins, fibers — the myelin sheath. The a person’s risk of developing the disease several-fold above the the environmental triggers diet, trace metal exposures, and cells that make myelin are also to avoid or otherwise derail certain climatic elements such damaged, as are the underlying risk for the general population. There is a higher prevalence of so that MS is prevented from as sunlight. nerve fibers themselves. It is not developing. certain genes in populations with higher rates of MS. Common known at this time whether these As yet, none of these have are direct targets of the immune Because genetic susceptibility been causally linked to MS, genetic factors have also been found in some families in which attacks or simply bystanders. appears to be the key to under- and exactly what factor(s) may standing the cause of MS, we first be involved remains an open It is possible that the initial cause more than one person has MS. Sophisticated new techniques for discuss what is known about the question. of MS could be an overreaction genetics of MS, followed by a identifying genes may help answer questions about their role in to a real foreign invader, such as Many investigators believe that consideration of possible trig- a virus or bacteria. This over- no single infectious agent or gering factors in the environment, the development of MS. reaction could cause the immune environmental factor is “the” including infectious agents. We system to attack myelin in cause of MS. Rather, they are then review what is known about addition to the invading virus exploring how a susceptible the immunology of MS, where or bacteria. person’s immune system reacts genetic and environmental factors to a variety of viral or other It is important to note that, ultimately have their effect. Lastly, infections and environmental although a viral or other infection we look at chronic cerebrospinal exposures, and how immune may be involved in its develop- venous insufficiency (CCSVI), a function is linked to hormonal ment, there is no evidence that MS newcomer to the theories about and other factors. is either infectious or contagious. what causes MS.

20 | Who? Why? How? Searching for the Cause of MS | 21 Advances in molecular genetics and the identification of multiplex families facilitated scientists’ efforts to uncover MS susceptibility genes. The National Genetic inheritance appears to MS Society and others have be only one of several factors that supported projects searching determine who gets MS. Most for these genes. The research likely, an individual’s genetic teams have the challenging blueprint ultimately determines task of finding an unknown whether he or she will be sus- number of genes that confer New Techniques ceptible to a triggering factor susceptibility to MS. This or factors in the environment, Help Pinpoint Risk for MS is also affected in requires searching the 3.2 billion which in turn initiates the auto- Genetic Factors If genes were solely responsible part by a person’s ethnic back- components of the DNA that immune process that leads to the for determining who gets MS, ground and other factors that In the past several decades, form the code of the 30,000 development of MS. an identical twin of someone have not as yet been clearly scientists have developed tools to 40,000 genes in the human with MS would always develop identified. For example, there that give them the ability to genome. Genetic the disease; the fact that the risk is a higher prevalence of certain pinpoint the genetic factors When one of these markers was Susceptibility is only one in four demonstrates genes in populations that have a that make a person susceptible Looking for identified, scientists focused on Among Family that other factors — including higher rate of MS, even though to MS. These tools are the DNA Markers that area, seeking additional Members of gender, geography, ethnicity, and they do not all develop MS. This methods of molecular genetics In the 1990s, genetics research markers closer to that gene. People with MS infections — are likely involved is true in the Scandinavian — techniques used to isolate in MS focused on multiplex Eventually, the location of the as well. countries, which have a high and determine the chemical The average person in the families participating in genetic gene was identified. By 1996, incidence of MS compared to structure of genes. United States has about one However, these risk estimates studies. The researchers were many locations that might other areas of Europe, and higher- chance in 750 of developing are oversimplifications that can In the 1980s, scientists began looking for patterns of genetic contain genes contributing to than-average levels of MS are MS. First-degree relatives of easily be misinterpreted. For to apply these tools to human material that are consistently MS had been identified, but seen in those regions of North people with MS — such as example, they can vary greatly diseases caused by defects in single inherited by people with MS. no single gene could be shown America with significant numbers children, siblings or non-identical depending upon the structure genes. This led to major advances These recognizable patterns are to have a major influence on MS of individuals of Scandinavian twins — have a higher chance of a person’s family. In families in understanding diseases such as called DNA markers. To do susceptibility. It became clear descent. Specific genes have been of developing the disease. This in which MS occurs in many Duchenne muscular dystrophy this, scientists probed family that many genes are probably linked to MS in this population. increase is significant but still relatives — called multiplex and cystic fibrosis. The situation members’ DNA, searching for involved in making people relatively low. The identical families — the risks for any Sophisticated new techniques for a multifactorial disease such identifiable patterns or markers susceptible to MS, and this twin of someone with MS, given individual are significantly for identifying genes may help as MS is more complicated, in the DNA code inherited by research also made it clear that who shares all the same genes, increased. Common genetic answer questions about the role requiring the right combination the individuals with the disease a new approach would be has a 25–30% chance of devel- factors have been found in some of genes in the development of and timing of genetic and but absent in their relatives who needed to make better headway oping the disease. of these families. MS. triggering factors. do not have MS. in understanding MS genes.

22 | Who? Why? How? Searching for the Cause of MS | 23 The IMSGC’s high-powered analysis resulted in the identification of two novel genetic variations that showed a highly significant association with MS. These variations are in the genes In 2003, the National MS that control the function of Novel Genetic Society and the NIH brought messenger protein. Since that together most of the leading Variations time, dozens of genes have been researchers focusing on searching These researchers used a DNA linked to MS through the use of for MS genes. These included “chip,” a new technological similar genome-wide scanning the Finnish Study of MS Genes advance that uses a grid contain- techniques involving samples (looking at a unique, ethnically ing multiple genetic components. from thousands of people who homogenous population of The field of genetics exploded Implications for This enabled the collaborators have MS. Most of the genes families with MS in Finland); in 2003 with the completion People with MS to test 500,000 individual identified to date are related to the Canadian Collaborative of The Human Genome Project genetic locations (sites within immune function, and several Taken together, these studies Project on Genetic Susceptibility — the map of all genetic material In 2003, Drs. David A. Hafler genes) at one time for possible have also been identified as point to potential mechanisms in MS (utilizing a database of in humans — which essentially (Harvard Medical School and involvement in MS. This, in turn, playing potential roles in other underlying the disease and approximately 21,000 people created a reference library for Brigham and Women’s Hospital), enabled them to scan blocks of autoimmune diseases. Work is present possible new targets with MS and relatives at 19 genetic studies. The follow-up Stephen Hauser (University of the human genome for variations underway to: for designing better therapies clinics throughout Canada); to the Human Genome Project, California, San Francisco), and that were more commonly n to stop the immune attack in the Melbourne MS Genetics the International HapMap Eric Lander (Broad Institute Finalize the identification of inherited by people with MS MS. Group (a team investigating Project, added even more of MIT and Harvard) jointly all of the common genetic compared to those without the population of Tasmania, power to the field of genetics by received the Palmer Collab- variations that are linked to Investigators agree that right the disease. They screened the Australia); GAMES (Genetic mapping common genetic varia- orative MS Research Center MS susceptibility. (The IMSGC now, the identification of many genome in 931 “trio families,” Analysis of MS in Europeans, a tions in the human population. Award from the National MS is now conducting a genome- gene variations linked to MS each of which included a person collaboration of 19 groups from Comparing these variations Society for the MS Targeted wide scan in 10,000 people susceptibility is unlikely to with one of several different 16 European countries); and in people with and without Haplotype Project. The Project with MS which they hope will change current clinical practice, types of MS and his or her the U.S. MS Genetics Group disease can help to pinpoint was designed to pool expertise finally identify all common gene and that there are likely many unaffected parents. (a collaboration of researchers at disease genes. These projects, and resources in an attempt to variations linked to MS.) more genes that contribute to speed work toward discovering Vanderbilt University, Duke and the development of gene To double-check their findings, n Determine the functions of disease susceptibility. As these MS genes. This award propelled University, and the University “chip” technology that can anal- the researchers performed a these variations and how they additional genes are probed the formation of the International of California, San Francisco). yze hundreds of thousands of second analysis of other sets influence immune activity. further for their role in MS, This important meeting opened variations at once, are the latest Multiple Sclerosis Genetics of families, individual cases they may lead both to a greater up new lines of communication tools that MS gene searchers Consortium (IMSGC), a colla- of MS, and a control group. n Explore genes that may control understanding of the cause of and spurred consideration of are using to shed light on the borating group of many of the Ultimately, all samples were individual responses to therapy MS, and also to the recognition several new strategies for identi- multiple genes that can make major MS genetics investigator combined for a final analysis and others that may help protect of important new therapeutic fying MS genes. a person susceptible to MS. laboratories around the world. of more than 12,000 people. against development of the disease. targets.

24 | Who? Why? How? Searching for the Cause of MS | 25 Epidemiology: n MS occurs in most ethnic groups, including African-Americans, Who Develops MS? Asians, and Hispanics/Latinos, but is more common in Caucasians of northern European ancestry. Observations Epidemiology n Some possible risk factors leads to and investigates hypotheses about the cause from epidem- for MS have been identified, of a disease, and has contributed a great deal to our understanding iologic studies including cigarette smoking These include: and previous exposure to the Recent research of what causes MS. A major focus of epidemiologic studies is Epstein Barr virus. n There are an estimated 400,000 projects related to to determine who develops MS. This type of study has helped people living with MS in the n Some possible protective factors epidemiology and United States, and at least 2.1 have been identified for MS, possible infectious to identify factors that may be related to the risk of developing million people worldwide that including vitamin D and greater triggers of ms have the disease. exposure to sunlight (through sponsored by the MS, including geography, genetics, environment, and infectious which the body manufactures national ms Society n Most people are diagnosed vitamin D). & the ms Society agents, but we still have few definitive answers. Although almost between the ages of 20 and 50, although MS can occur in young The National MS Society and of canada anyone may develop MS, some people appear to be at greater the MS Society of Canada children and older adults. These include: sponsor many epidemiology risk than others. n MS is at least two to three times research studies that focus on Anthony J. McMichael, MBBS, more common in women than triggering or risk factors that PhD (The Australian National in men. This type of gender bias influence whether a person University) is conducting a case is seen in many autoimmune develops the disease. These control study of past sun expo- diseases. include disease patterns, such sure and first demyelinating as variations in geography, demo- events to investigate whether n As discussed in the previous section, genetic factors make graphics, socioeconomic status, vitamin D, through sunlight certain individuals more susc- genetics, environmental risk exposure, reduces the risk of eptible than others, although factors, and exposure to infectious developing MS. Recent research there is no evidence that MS is agents. These studies provide vital indicates that ultraviolet radiation directly inherited. information about relationships (UVR) or vitamin D synthesized among these factors, so that we via UVR exposure can dampen n MS occurs more frequently in can better understand who gets the immune attack. This might relatives of people with MS, MS and why, as well as identify provide a biological mechanism indicating that genetic factors and explain areas with high or for reduced MS where UVR are involved in developing MS. low rates. exposure is higher.

26 | Who? Why? How? Searching for the Cause of MS | 27 Environmental Factors & The team is comparing lifetime sun exposure in two groups — people at risk for developing MS Helen Tremlett, PhD (University Multiple Sclerosis (because they experienced an of British Columbia) is asking: initial neurologic episode) and Do relapses affect disease progression people without MS — using in MS? by evaluating the long- advanced imaging technology to term relationship between MS occurs more frequently in areas that are farther from the examine skin, measuring vitamin MS attacks and disability. The D status (produced by UVR), and majority of people with MS equator. Epidemiologists are looking at many factors in an effort to administering a questionnaire experience disabling relapses about sun exposure. This study that can last weeks to months Lauren Krupp, MD (State understand why, including variations in geography, demographics may bring us new insight into before a full or partial recovery University of New York at Stony non-genetic factors that may occurs. However, the progression Brook) has been identifying (age, gender, and ethnic background), genetics, infectious causes, make people susceptible to the to permanent disability is not cases and characteristics of development of MS, and may necessarily associated with a pediatric MS (in children under and migration patterns. Migration patterns show that people suggest new avenues for treatment relapse. 18) in a region of New York, to or prevention. lay the groundwork for future born in an area of the world with a high risk of MS who move to an The team is focusing on patients studies of this condition. Researchers at the University of enrolled in a database of 6,000 area with a lower risk often acquire the risk of their new area. This Utah are following up on evidence people with MS in British Since this study began, thanks that colds caused by picorno- Columbia. They are examining to its Promise: 2010 campaign, suggests that exposure to some environmental agent may predispose viruses are associated with MS relapse rates in over 2,500 people the National MS Society attacks. They are seeking to who have not taken disease- established the first-of-its-kind a person to develop MS. determine whether specific modifying drugs and have been network of six Pediatric MS viruses that cause colds may followed for up to 23 years. They Centers of Excellence, including be linked to MS attacks, and to are investigating the effect of MS a Center led by Dr. Krupp. The compare MS attack rates in relapses occurring at different Centers provide comprehensive individuals whose colds are due stages of the disease on disability evaluation and care to children to picorno-viruses as compared progression, using measures such with MS and related central to other types of virus. This as the Expanded Disability Status nervous system demyelinating study may provide important Scale (EDSS). This study may disorders. Now the way is clear clues to the specific viral triggers provide much needed information for deeper research into the of some MS attacks, as well on the progression of MS, and triggers of MS in young children, as new leads for preventing or on how to tailor treatments for which may clarify the cause of treating those attacks. individuals with the disease. MS in adults as well.

28 | Who? Why? How? Searching for the Cause of MS | 29 Geography & Migration Patterns

The incidence of a disease whose cause is entirely genetic will be unaffected by migration. On the other hand, an alteration in the The human body produces risk of disease after migration is vitamin D naturally when the compelling evidence that one or In fact, if parents born in skin is exposed to sunlight, more environmental factors North Africa/Asia Minor and people who live closer must be involved in its devel- migrated to Israel more than to the equator are exposed to opment. The extensive data five years before giving birth greater amounts of sunlight Israel is a unique setting for on migration and its impact in Israel, the incidence of MS year-round. As a result, they migration studies: the popu- Additionally, preliminary on the risk of developing MS among those children was tend to have higher levels of lation includes immigrants research indicates that vitamin clearly support the existence higher than in children of parents naturally-produced vitamin D, from regions with more MS D can alter immune attacks in MS clusters — higher-than- of an interaction between who migrated less than five years which is thought to have a bene- (Europe, North America) and mice with MS-like disease. expected numbers of cases of environment and genetics. before the child was born. Dr. ficial impact on immune function less MS (North Africa, Asia MS that have occurred over a Alter’s team hypothesizes that and may help protect against A team of researchers at Oxford Studying people with MS has Minor). Looking at people specific time period and/or in lifestyle factors in Israel — autoimmune diseases such as University led by Dr. George already led to some surprising who immigrated to Israel from a certain area — may provide such as diet — are affecting MS. The possible relationship Ebers has found what may be epidemiologic discoveries. World- North Africa/Asia Minor, Milton clues to environmental factors MS risk. between MS and sunlight the link between vitamin D wide, as a general rule, MS occurs Alter, MD, PhD, and his that might cause or trigger the exposure is currently being and genetics; he demonstrated with much greater frequency in colleagues at the Lankenau disease. Vitamin D looked at in a Society-funded that vitamin D affects the ability areas that are farther away from Institute for Medical Research, & Sunlight epidemiologic study in Australia. of a genetic variant previously The study of environmental the equator. MS also occurs Wynnewood, PA have found linked to the development of factors that affect MS is closely more frequently in people of that cases of MS increased Migration patterns and other Another study indicated that MS to function normally. linked to epidemiology. A wide Northern European ancestry. with the length of time spent epidemiologic data show that women whose intake of vitamin variety of possible environmental However, migrating from one in Israel, no matter what age people who live nearer to the D is greater than or equal to So, can vitamin D supplements factors have been looked at over geographic area to another can migration occurred. (A few equator have a lower chance about 400 IU/day from supple- alter MS disease activity? Dr. past decades. Although none has actually increase or decrease a earlier migration studies had of developing MS than those ments and food, or from Paul O’Connor, (St. Michael’s been determined as the cause person’s risk of developing MS. suggested that MS susceptibility who live farther from it. Some supplements alone, had a 40% Hospital, Toronto) and colleagues of MS, some appear promising This strange clue has served as peaked before age 15; more scientists think the reason may lower risk of developing MS compared 25 people with MS as contributing to the multi- the basis for some informative recent, larger studies suggest that have something to do with than women who did not take over 52 weeks, with 24 untreated factorial nature of MS. studies. there is no exact age cutoff.) vitamin D. vitamin D supplements. controls.

30 | Who? Why? How? Searching for the Cause of MS | 31 Toxic Substances Radon exposure is being invest- People living near hazardous igated in a case-controlled study waste sites in the US have of 100 people with MS and 100 Reporting early findings at expressed concern to public non-MS neurology patients the October 2007 ECTRIMS health officials about a perceived in the Kansas City area. All meeting, the researchers found It is not clear how smoking high prevalence of MS in their participants are being asked to that calcium levels did not may contribute to MS risks, communities and its possible complete questionnaires that reach abnormally high levels but there are plenty of reasons link to exposure to chemical include questions on occupation, in this small study. The relapse not to smoke. It is known to agents from the waste sites. Pre- exposure to chemicals, family rate was reduced more in the produce shortness of breath, liminary studies have collected The Agency for Toxic Substances history of MS, smoking, and Previous studies of oral contra- treatment group, but this finding susceptibility to lung infections, prevalence data for some of these and Disease Registry (ATSDR) other factors. Part of this group ceptives and MS have shown did not reach statistical signifi- and heartbeat irregularities areas, but much additional work at the Centers for Disease Control will be asked to allow their homes mixed results. Harvard researchers cance. The group says it is now in many people. These might is needed to fully investigate even and Prevention (CDC) has to be measured for radon gas. have published a study suggesting planning a phase II study of transform a mild or moderate a fraction of these proposed sites. attempted to help local health The results of this study have that women who use oral contra- vitamin D supplementation in neurologic limitation into a departments investigate several not yet been published. ceptives during the three years A potentially important clue 150 to 200 people with MS. severe disability. potential MS “clusters” in various prior to diagnosis had a 40% to MS is to understand who parts of the U.S. They found it Hormones reduction in the risk of developing In a study published in spring gets the disease. Is MS on the Smoking impossible to determine if there MS compared to nonusers. 2010, Harvard researchers, with rise? Are more women getting MS is approximately two to actually were local “spikes” of Evidence from several studies collaborators in Australia and MS than ever before? These three times more common This study provides further MS since accurate estimates of suggests a statistically significant Sweden, found that two indi- and other questions cannot in women than in men, and support for the concept of the incidence and prevalence of association between smoking vidual factors that had been be answered without having attacks are less likely during hormonal influences in MS, MS in the surrounding area were and the risk of developing MS. previously identified as increasing a solid base number of how pregnancy — findings that have but does not provide direct not known with any accuracy. A recent study funded by the the likelihood of developing MS many people have the disease. led to a number of studies on evidence that oral contraceptives National MS Society reported — exposure to Epstein-Barr virus In the U.S., no one knows how The National MS Society the possible influence of sex can prevent the onset of this that smoking is associated with and tobacco smoking — may many people are diagnosed is advocating for a national hormones on the disease. This disease. Currently, a form of a moderate increase in the risk interact and multiply to sub- with MS every year (incidence) surveillance system that could research has also led to hypo- estrogen is being tested in a of developing MS, and also stantially increase the risk of or how many have MS right be an important step in driving theses about a possible association multi-center clinical trial in found an association between developing MS in those with now (prevalence), although the research to understand inter- between oral contraceptives, women with relapsing MS to smoking and the risk of MS both risk factors. Further research National MS Society estimates actions between genetic and which may include the sex determine whether this hormone progression in people already is needed to understand how that about 400,000 people have environmental factors that hormones estrogen or proges- can enhance the benefits of diagnosed with the disease. these factors may interact. the disease. cause MS. terone, and a reduced risk of MS. interferon beta therapy.

32 | Who? Why? How? Searching for the Cause of MS | 33 Perhaps the best-known clusters Evidence For are a series of alleged epidemics that occurred in the Faroe Islands, a Danish possession in an Infectious Clusters the Atlantic between Norway Tetanus Vaccine & Epidemics and Iceland. Although the inhabitants are Nordic and Cause of MS A recently published study by A cluster of MS can be defined as considered a high-risk group Harvard researchers reported higher-than-expected numbers for the disease, there were no that people who had received of cases of MS that have occurred known reports of MS prior tetanus vaccine were one-third over a specific time period and/or to 1943 among native-born Since initial exposure to numerous viruses, bacteria, and other less likely to develop MS than in a certain area, and may provide residents. In the early 1960s, those who had not been vac- clues to environmental or genetic Dr. John Kurtzke became microbes occurs during childhood, and since viruses are well cinated. The investigators used risk factors that might cause intrigued with a report by a sophisticated analytic techniques or trigger the disease. However, Danish investigator, K. Hyll- recognized as causes of demyelination and inflammation, it is to pool the results of nine pre- although certain “clusters” of ested, about 25 cases of MS in vious studies to compare 963 MS have been suggested, to the Faroes that had occurred possible that a virus or other infectious agent is the triggering individuals with MS to 3,126 date they have not produced starting in 1943. “controls” who were friends or factor in MS. More than a dozen viruses and bacteria have been clear evidence for a causative relatives, who had other neuro- It appeared that the disease or triggering factor in MS. logic disorders, or who were had been brought into the or are being investigated to determine if they are involved in the from the general population. Clusters are difficult to inves- Faroes since it hadn’t been The controls were more likely tigate because it is difficult to reported there before. development of MS, but none have been definitively proven to to have had a history of tetanus determine what constitutes The most significant event that trigger MS. Most MS experts believe that some infectious agent, vaccine than those in the MS an “excess” of cases of MS. had taken place on the Faroes group. Surprising as it sometimes was the British occupation during most probably a virus, is involved in initiating the disease process. seems, an apparently extraordi- The authors suggest that some- World War II. Many of the nary number of MS cases in a thing about tetanus vaccination occupation soldiers were from Researchers have long searched for a specific, identifiable virus neighborhood or county may may be protective against MS, the Scottish Highlands, where the turn out to be the “expected” related to MS, with the hope that this will result in a relatively and that further research is MS prevalence is quite high: number. warranted to determine the 90 cases per 100,000. If MS is simple explanation for the disease, and that combating such a possible role of the timing of In addition, MS clusters are triggered by a virus, the disease the immunization and the difficult to investigate due might have been brought to the virus with a specific vaccination will result in a safe and effective number of doses. As this was to the uncertainty of the MS Faroes by the soldiers. However, a retrospective study, based on diagnosis, the lag time between despite years of intensive inves- prevention strategy (as was the case in the control of poliomyelitis retrievable reports in the literature, clinical onset and diagnosis, tigation, no factor has yet been no firm conclusions as to cause and the possibility of simple identified that can definitively beginning in the 1950s) or a specific virus-focused treatment. and effect can be drawn. coincidence. account for the alleged epidemic.

34 | Who? Why? How? Searching for the Cause of MS | 35 The possible involvement of a virus or viruses in the The Epstein- development of MS is suggested Although many different viruses Barr Virus (EBV) by several observations: have been studied as possible causes of MS, there has not yet Since virtually everyone in the EBV is a very common virus n Virus infections can cause human been definitive proof linking population has been exposed to that causes infectious mono- diseases that have characteristics any one virus to the autoimmune these viruses, but not everyone nucleosis and other disorders. similar to those of MS. reaction that is believed to be has MS, the question arises as to Several studies have suggested

n Certain viral diseases in laboratory responsible for the demyelin- how common infectious agents that it may be involved in the animals result in myelin damage ation seen in MS. At one time might be involved with MS when development of MS, and it is similar to that seen in MS. or another, canine distemper relatively few people have the a good example of the promise n In 2006, investigators reported In recent years, most of the virus, measles virus, herpes virus disease. Are these false leads and and problems associated with that individuals who showed signs n focus has been on viruses Some viral infections, particularly (HHV-6), rubella (German not really causes of MS? Are the study of viruses and MS: of significant exposure to EBV that are very common in the those that affect the upper measles) virus, HTLV-1 virus, such agents simply associated were twice as likely to develop general population — not n A study published in 2003 respiratory tract, may trigger and others have been reported to with MS or are they “co-factors” MS up to 20 years later. More necessarily isolated only in suggested that increased levels acute exacerbations in people be associated with MS. Measles, that are required, but not in recent studies have added evidence individuals with MS — such of immune antibodies to EBV who already have MS. mumps, rubella, and varicella are themselves sufficient, to cause to the link between EBV and as EBV, the cause of infectious might be associated with an common childhood infections, the disease? If so, what else might MS, but they still do not prove n As discussed above, data from mononucleosis. The possible increased risk of developing and all have been considered as be required for the disease to that EBV actually causes MS. epidemiologic studies suggest involvement of one or more of MS, although no specific causal potential causal agents. appear? that exposure to an infectious these viruses in the development relationship was established. The n In 2007, investigators reported agent may be involved in causing At least 30 case control studies of MS is based on epidemiologic This is wheregenetic susceptibility researchers found that, although finding traces of EBV in brains MS. have investigated the association studies, the presence of higher may have its impact: while a virtually all of the study partici- examined after death from people between measles and MS, with levels of antibodies against a common infectious agent may pants — with and without MS with different forms of MS. They n Some viruses are known to have be a trigger for MS, perhaps the — had been exposed to this found traces of EBV infection in a long latency period between mixed results. With the exception given virus in individuals with disease will only occur in people virus, levels of antibodies to immune cells that were present in time of infection and appearance of HHV-6, later studies have MS, or — more recently — who carry a genetic suscepti- EBV were consistently higher 21 out of 22 brains from people of clinical symptoms, as is thought not substantiated these reports, evidence from very sophisticated bility to it. Is it possible that in those individuals who sub- with MS, but not in the brains of to be the case in MS. and there is no proof that any polymerase chain reaction (PCR) of them causes MS. To date, an analysis that can detect the “foot- both — a triggering agent and sequently developed MS than people who had other neuro- n Increased antibodies to many association with the Epstein- print” of a viral protein in body the “right” genetic background in those who did not. Further- logic diseases that, like MS, different viruses have been Barr virus (EBV) appears to fluids and tissues even if the virus — are required, and that neither more, the risk of developing MS involve inflammation. Thus far, found in the blood and cerebro- be the most promising line of has been long eliminated by alone is sufficient for MS to increased with increasing levels these findings have not been spinal fluid of people with MS. investigation. the immune system. develop? of antibodies. confirmed by other laboratories.

36 | Who? Why? How? Searching for the Cause of MS | 37 The Role of Immunology in Non-specific Immune Reactions in MS Multiple Sclerosis Many investigators believe that no specific virus, bacterium, or other infectious agent will It is now generally accepted that MS involves an autoimmune be found to be a cause of MS. Rather, they are concentrating process — an abnormal response of the body’s immune system on research that explores how a susceptible person’s immune that is directed against the myelin (the fatty sheath that surrounds system reacts to a variety of viral or other infections, or and insulates the nerve fibers) in the central nervous system CNS( how immune function is tied to hormonal and other factors — the brain, spinal cord and optic nerves). Ongoing efforts to that might explain the initiation However, as is also the case with of the MS process. learn more about the autoimmune process in MS — what sets it other viruses studied as a possible “cause” of MS, it is still not Studies in the last 15 years or so, in motion, how it works, and how to slow, stop, or repair it — are possible to determine whether largely in laboratory animals, EBV causes MS, or whether its have helped to explain how an bringing us closer to understanding the cause of MS. Alterations presence is a consequence of MS, immune system that has lost If the molecular structure of the because the follow-up studies its ability to distinguish “self” infectious agent mimics part in the way the immune system responds is essentially the “final needed to confirm a relationship from “non-self” tissue can be of the molecular structure of to MS have been unsuccessful. tricked by certain infectious myelin, an effective and natural common denominator” of genetic and environmental factors that Most such claims have been a agents into mounting an attack immune response mounted predispose an individual to develop the disease. result of inadequate experimental against a person’s own myelin. against a common infectious sampling or laboratory cont- The “trick” might be a very close agent might result in a damaging amination. Nonetheless, there similarity of molecular structure “cross-reaction” with myelin. remains the possibility that between some viruses, bacteria, This scenario of “mistaken specific infections may be and myelin itself — called identity” may explain much of related to MS, and virologists molecular mimicry to reflect the the origin of MS and help to who focus on this disease remain similarity of molecular structure determine how the disease can at the forefront of ongoing between some parts of myelin be prevented from occurring searches. and some infectious agents. in susceptible people.

38 | Who? Why? How? Searching for the Cause of MS | 39 The prefix “auto” means “self.” An autoimmune disease occurs when the immune system reacts against normally occurring antigens — proteins that trigger It is not known what causes an immune response in the T-cells in people with MS to body — as if they were foreign. become activated but — as discussed earlier — both genetic Individual T-cells are able to Other diseases thought to have and environmental factors appear recognize only certain antigens. an autoimmune basis include to be important. Recently, Their ability to discriminate myasthenia gravis, rheumatoid it has been shown that B cells between antigens is conferred arthritis, systemic lupus erythe- Immune function is helped by by protein molecules on the cell play a more active role in MS As noted earlier, there is now n matosis, and insulin-dependent two kinds of white blood cells. Increased numbers of activated than was previously known, surface called receptors. The information linking vitamin (Type 1) diabetes. Ongoing The “B cells” (called such because T-cells passing into the brain and research continues to receptor and the antigen fit D’s apparent protective effect efforts to learn more about they develop in bone marrow) from peripheral blood, which explore their role. together like a lock and key, against MS to specific genes the auto-immune process in produce antibodies. The “T-cells” then attract other immune cells but only when their shapes that code for receptors that MS — what sets it in motion, (which develop in the thymus into the brain; match perfectly. The number bind to cytokines and affect the how it works, and how to slow gland) are responsible for a variety Research and specificity of T-cell receptors ability of regulatory T-cells to n The presence of T-cells in MS or stop it — are bringing us of other immune responses. Directed at appear to be determined by the turn off the immune attack. plaques; and, closer to understanding the These include: 1) attacking the Role of cell’s genes. cause of MS. foreign substances such as the Immune n Increased frequency of activated bacteria, viruses, or foreign System in MS There are three broad categories The Roles T-cells against the myelin seen in In MS, it is believed that the tissues; 2) augmenting the B- of T-cells: of T-cells in MS patients compared to healthy abnormal response of the body’s Scientists have begun to identify cell response; and 3) producing Multiple Sclerosis controls. immune system is directed the sites or “receptors” on the n Helper T-cells augment the substances called cytokines that against myelin in the CNS. T-cells that bind to the myelin. immune response by recognizing Over the last 15 years, much While much more information direct responses and activities The exact antigen that the The precise identification of the presence of a foreign antigen knowledge has been gained is needed before the exact nature in other immune cells. immune cells are sensitized these receptor sites may help and then stimulating antibody about the specific roles of T- of the autoimmune response to attack remains unknown. In people with MS, T-cells lead to the development of more production and producing cyto- cells. Among the activities that in MS is explained, it appears Researchers have identified become sensitized to myelin and specific immunosuppressant kines that “turn on” or activate have been observed are: that T-cells and their cytokines which cells of the immune cross the blood-brain barrier into therapies that destroy these other T-cells. are the keys to this process. n Decreased regulatory T-cell system are responsible for an the CNS. Once there, these sensitized T-cells while leaving Ongoing research in these areas n Regulatory T-cells function in an function in the peripheral blood MS attack, some of the factors cells not only injure myelin, other cells intact. Much of opposite manner; they dampen of MS patients during an acute may provide new, specific im- that cause them to attack, and but also secrete chemicals that the ongoing research in MS is or turn off the immune response. exacerbation (also known as an munotherapies that will stop some of the sites, or receptors, damage nerve fibers (axons) directed toward finding answers attack, relapse, or flare); the progression of MS without on the attacking cells that appear and recruit more damaging to questions about the role of n Cytotoxic or “killer” T-cells directly harming any immune cells to be attracted to the myelin to immune cells to the site of the immune system in the attack and destroy cells bearing n Increased numbers of helper that are not involved in the begin the destructive process. inflammation. development of MS. antigenic material. T-cells in the spinal fluid; process of myelin destruction.

40 | Who? Why? How? Searching for the Cause of MS | 41 Chronic Cerebro- spinal Venous Insufficiency (CCSVI): A Possible Factor in the To date, surgical procedures to correct CCSVI in people with MS Development of MS? Based on the results of his initial have been “open label” rather preliminary findings published than done in the context of in June 2009 from a study of controlled trials. Several private, approximately 65 patients, Dr. mostly for-profit groups are Recent preliminary studies have suggested that a phenomenon Zamboni and colleagues state advertising procedures to improve that this pilot study warrants blood flow by inserting a tiny called chronic cerebrospinal venous insufficiency (CCSVI), a a subsequent larger and better balloon or stent into blocked controlled study to definitively veins. It is prudent that such reported abnormality in blood drainage from the brain and evaluate the possible impact surgical procedures be under- of CCSVI on the MS disease taken in conjunction with formal The National MS Society and spinal cord, may contribute to nervous system damage in MS. process. clinical trials in order to assure the MS Society of Canada that rigorous safety protocols It is not yet known how many are pursuing this new and This hypothesis has been put forth by Dr. Paolo Zamboni from and long-term monitoring people with MS have CCSVI, potentially promising research standards are followed. the University of Ferrara in Italy. Now, the MS Societies in the but preliminary evidence from a direction by funding seven new prevalence study at the University studies to investigate CCSVI Dr. Zamboni and others U.S. and Canada have launched seven new studies to investigate at Buffalo suggests that a pro- and its possible role in MS. New emphasize the need for more portion of people without MS projects stemming from the research on his hypothesis, noting CCSVI and its possible role in the disease process. also show signs of this condition. Society’s request for applications that it is still not proven whether Further studies are now taking began July 1, 2010. Go to CCSVI is a cause of MS or is place at other centers, including nationalMSsociety.org/ccsvi for related to MS in some other the University at Buffalo, where the latest information about manner. He recommends that researchers are collaborating with these projects and for other people with MS remain on their Dr. Zamboni’s team. information about CCSVI. immunomodulatory therapies.

42 | Who? Why? How? Searching for the Cause of MS | 43 Summary GLOSSARY

Axon

Multiple sclerosis appears to result from a complex interaction The extension or prolongation of Antibody a nerve cell (neuron) that conducts of genetic susceptibility, environmental factors, and an infectious impulses to other nerve cells agent that may be a virus. Advances in the past several decades Protein produced by certain or muscles. Axons are generally Chronic cells of the immune system smaller than 1 micron (1 micron = Cerebrospinal have resulted in the identification of many of these factors, and have in response to bacteria, viruses, 1/1,000,000 of a meter) in dia- Venous and other types of foreign meter, but can be as much as a Insufficiency half meter in length. Many axons begun to suggest the ways in which they interact. This knowledge antigens. (CCSVI) See Antigen. in the central nervous system will hopefully lead to new and better ways to manage MS. are covered with myelin. A reported abnormality in blood Antigen drainage from the brain and B-cell spinal cord that may contribute Any substance that triggers the to nervous system damage in MS. immune system to produce an A type of lymphocyte (white blood cell) manufactured in antibody; generally refers to Central infectious or toxic substances. the bone marrow that makes nervous system See Antibody. antibodies. The part of the nervous system Autoimmune Blood-brain that includes the brain, optic disease barrier nerves, and spinal cord.

A process in which the body’s A semipermeable cell layer Cytokines immune system causes illness around blood vessels in the by mistakenly attacking healthy brain and spinal cord that pre- Messenger chemicals produced cells, organs, or tissues in the vents large molecules, immune by various cells, particularly body that are essential for good cells, and potentially damaging those of the immune system, to health. Multiple sclerosis is substances and disease-causing influence the activity of other cells. believed to be an autoimmune organisms (e.g., viruses) from disease, along with systemic lupus passing out of the blood stream DNA erythematosus, rheumatoid into the central nervous system arthritis, scleroderma, and many (brain, spinal cord and optic Short for deoxyribonucleic others. The precise origin and nerves). A break in the blood- acid, DNA constitutes the pathophysiologic processes of brain barrier may underlie the chemical basis for genes, the these diseases are unknown. disease process in MS. basic units of heredity.

44 | Who? Why? How? Searching for the Cause of MS | 45 Lymphocyte

Epidemic A type of white blood cell that is part of the immune system. The occurrence of a group of Immune- Lymphocytes can be subdivided illnesses of a similar nature, Helper mediated disease into two main groups: B-lympho- clearly in excess of normal T-lymphocytes cytes, which originate in the bone expectancy, deriving from a A disease in which components Immuno- marrow and produce antibodies; common or propagated source. White blood cells that are of the immune system — T-cells, suppression T-lymphocytes, which are a major contributor to the antibodies, and others — are produced in the bone marrow Epidemiology immune system’s inflammatory responsible for the disease either In MS, a form of treatment and mature in the thymus. response against myelin. directly (as occurs in autoimmu- that slows or inhibits the body’s Helper T-lymphocytes heighten The branch of medical science nity) or indirectly (for example, natural immune responses, the production of antibodies that deals with the study of Human genome Because MS is more prevalent when damage to the body occurs including those directed against by B-lymphocytes; suppressor incidence, distribution, and in regions with high standards of secondary to an immune assault the body’s own tissues. Examples T-lymphocytes suppress B- control of a disease in a popu- The total set of genes (approx- hygiene, researchers are testing on a foreign antigen such as a of immuno-suppressive treat- lymphocyte activity and seem lation. imately 90,000 to 100,000) the idea that lack of exposure bacteria or virus). ments in MS include mitoxan- to be in short supply during an arranged on two sets of 23 to common innocuous agents trone, cyclosporine, methotrexate, MS exacerbation. Etiology chromosomes in most cells of may lead the immune system to Immuno- and azathioprine. the human body. over-react and cause MS. Early competent cells Macrophage The study of all factors that may clinical trials are now underway Incidence be involved in the development Hygiene testing whether introducing White blood cells (B- and T- A white blood cell with scav- of a disease, including the patient’s Hypothesis harmless parasitic worms, which lymphocytes and others) that The number of new cases of a enger characteristics that has the susceptibility, the nature of the interact with the immune system defend against invading agents disease in a specified population ability to ingest and destroy disease-causing agent, and Scientists have noted that when they reach the intestine, in the body. over a defined period of time. The foreign substances such as the way in which the person’s autoimmune diseases and might alter immune attacks incidence of MS in the United bacteria and cell debris. body is invaded by the agent. allergies are less common in in MS. Immunoglobulin States is approximately 10,000 underdeveloped regions. Some newly diagnosed people per year. Myelin Gene researchers have noted that Immune system See Antibody. early exposure to common Inflammation A soft, white coating of nerve A basic unit of heredity con- infectious agents, such as what A complex network of glands, Immunology fibers in the central nervous taining coded instructions for occurs to people in less devel- tissues, circulating cells, and A tissue’s immunologic response system, composed of lipids (fats) manufacturing a protein. Genes oped regions, may stimulate processes that protect the body The science that concerns the to injury, characterized by mobi- and protein. Myelin serves as are sub-units of chromosomes, the immune regulation in a by identifying abnormal or body’s mechanisms for protecting lization of white blood cells insulation and as an aid to which are strands of DNA positive way and aid healthy foreign substances and neutral- itself from abnormal or foreign and antibodies, swelling, and efficient nerve fiber conduction. contained within most cells. immune responses. izing them. substances. fluid accumulation. When myelin is damaged in

46 | Who? Why? How? Searching for the Cause of MS | 47 Nervous system Twins — Includes all of the neural struc- dizygotic tures in the body: the central nervous system consists of the Also known as fraternal twins, MS, nerve fiber conduction is brain, spinal cord, and optic two babies that come from faulty or absent. Impaired bodily nerves; the peripheral nervous separate, simultaneously fertil- functions or altered sensations system consists of the nerve ized eggs. If one dizygotic twin associated with those demye- roots, nerve plexi, and nerves develops MS, the other has linated nerve fibers are identified throughout the body. the same genetic risk for MS as symptoms of MS in various (approximately 2–5/100 as any parts of the body. Prevalence other sibling or first-degree relative. Myelin The number of all new and old basic protein cases of a disease in a defined Twins — population at a particular point monozygotic One of several proteins associated in time. The prevalence of with the myelin of the central MS in the United States at any Also known as identical twins, nervous system, which may be given time is about 1/750 — two babies that come from found in higher than normal approximately 400,000 people. single fertilized egg and share concentrations in the cerebro- identical genetic makeup. If one spinal fluid of individuals with Suppressor monozygotic twin develops MS, MS and other diseases that T-lymphocytes the other has a 25–30/100 damage myelin. risk of developing the disease, White blood cells that act as indicating that factors other Nerve part of the immune system than genetic makeup contribute and may be in short supply to the etiology of MS. A bundle of nerve fibers (axons). during an MS exacerbation. The fibers are either afferent White matter (leading toward the brain and T-cell serving in the perception of The part of the brain that sensory stimuli of the skin, joints, A lymphocyte (white blood contains myelinated nerve fibers muscles, and inner organs) or cell) that develops in the bone and appears white, in contrast efferent(leading away from the marrow, matures in the thymus, to the cortex of the brain, which brain and mediating contractions and works as part of the immune contains nerve cell bodies and of muscles or organs). system in the body. appears gray.

48 | Who? Why? How? On the cover: Kim (left), diagnosed in 1986 AJ (middle), diagnosed in 2000 Beverly (right), diagnosed in 2001 Who? Why? How? Searching for the Cause of Multiple Sclerosis

North american education program 2010 Who? Why? Why? Who?

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