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Multiple Sclerosis Immunology
Takashi Yamamura • Bruno GranEditors
Multiple SclerosisImmunology
A Foundation for Current and FutureTreatments
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EditorsTakashi Yamamura Bruno GranImmunology, MS Center Division of Clinical NeurosciencesNCNP University of Nottingham School of MedicineTokyo NottinghamJapan UK
ISBN 978-1-4614-7952-9 ISBN 978-1-4614-7953-6 (eBook)DOI 10.1007/978-1-4614-7953-6Springer New York Heidelberg Dordrecht London
Library of Congress Control Number: 2013947058
© Springer Science+Business Media New York 2013This work is subject to copyright. All rights are reserved by the Publisher, whether the whole or partof the material is concerned, specifically the rights of translation, reprinting, reuse of illustrations,recitation, broadcasting, reproduction on microfilms or in any other physical way, and transmission orinformation storage and retrieval, electronic adaptation, computer software, or by similar or dissimilarmethodology now known or hereafter developed. Exempted from this legal reservation are brief excerptsin connection with reviews or scholarly analysis or material supplied specifically for the purpose ofbeing entered and executed on a computer system, for exclusive use by the purchaser of the work.Duplication of this publication or parts thereof is permitted only under the provisions of the CopyrightLaw of the Publisher’s location, in its current version, and permission for use must always be obtainedfrom Springer. Permissions for use may be obtained through RightsLink at the Copyright ClearanceCenter. Violations are liable to prosecution under the respective Copyright Law.The use of general descriptive names, registered names, trademarks, service marks, etc. in this publicationdoes not imply, even in the absence of a specific statement, that such names are exempt from the relevantprotective laws and regulations and therefore free for general use.While the advice and information in this book are believed to be true and accurate at the date ofpublication, neither the authors nor the editors nor the publisher can accept any legal responsibility forany errors or omissions that may be made. The publisher makes no warranty, express or implied, withrespect to the material contained herein.
Printed on acid-free paper
Springer is part of Springer Science+Business Media (www.springer.com)
Preface
I was diagnosed with secondary progressive multiple sclerosis (MS) in 1994 at theQueen’s Medical Centre in Nottingham. At that time, I was told that there wasno treatment available apart from steroids. After being diagnosed, I joined the MSsociety of Great Britain and Northern Ireland. I became a member of its ResearchNetwork, when it was formed with the aim to actively involve people affected byMS in all aspects of the Society’s research programme and the communication ofresearch results.
Through the Research Network, I have been involved in reviewing grant ap-plications and as a ‘research buddy’ to researchers in the field. It is through suchscheme that I along with two other network members (also affected by MS) wereassigned to Dr Gran’s research project investigating the role of Toll-like receptors inthe modulation of human regulatory T cells. As a consequence of my involvementin this project, I was asked by Dr Gran to talk on “What people with multiple scle-rosis would like from Immunology” at the 2-day conference held in Nottingham inOctober 2010 entitled ‘Multiple Sclerosis Immunology: A foundation for currentand future treatments’, on which this book is based.
The conference brought together researchers and clinical neurologists from allover the world and gave all those who attended a chance to see where the field ofMS research stands and where it is heading. It is an exciting time in MS research asmany new treatments, mostly immunotherapies, have either been approved or are inthe pipeline. Progress is also being made into understanding how the immune systemfunctions in MS and with greater understanding come new potential treatment targets.A continued dialogue between basic and clinical scientists ensures that translationfrom bench to treatment is more likely to be effective.
People with MS would obviously ultimately like a cure to be found for this debili-tating condition, but most would settle for keeping the disease where it is, stopping itsprogression. A diagnosis of MS brings with it fear and uncertainty; you never knowwhat symptom will hit you next, how long it will last or if indeed it will resolve.Present disease-modifying treatments reduce the number of relapses and may slowprogression. I was very interested that trials on alemtuzumab showed an improve-ment in disability. Unfortunately, the side effects of the treatment are more severethan those of current treatments. With new treatments come new dilemmas for both
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patients and neurologists in weighing up the pros and cons. Apart from the work onalemtuzumab presented by Dr Coles, I found the presentations by Prof Yamamura,the keynote speaker, and Prof Constantinescu, Head of Academic Neurology in Not-tingham, particularly interesting. The first was a fascinating talk on the potential roleof gut flora and the increased incidence of MS in Japan. The second was about thefrequent association of MS with other autoimmune conditions.
I recently completed a master’s degree in parasitology and studied how helminthsproduce excretory/secretory molecules, which modulate the immune system in thehost and are being investigated as potential treatments in various autoimmune con-ditions. Recruitment has just started in Nottingham for a clinical trial, in which theimmunomodulatory effects of the hookworm Necator americanus will be tested forthe treatment of MS.
Overall, I feel that what immunology can do for people with MS is to give themhope for the future, that the condition can be managed and the slide into disabilitystaved off indefinitely. I find it very encouraging that so much work is being done inthe field of MS.
Manchester, UK Ms. Rebecca Rushworth
Contents
1 Th17 Cells in Autoimmune Inflammation and Demyelination inthe Central Nervous System . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1Vijay K. Kuchroo and Thomas Korn
2 Regulatory T Cells in MS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 27Barbara B. Gawlik and David A. Hafler
3 T-bet: A Critical Regulator of Encephalitogenic T Cells . . . . . . . . . . . . . 49Amy E. Lovett-Racke and Michael K. Racke
4 Antigen-Presenting Cells in the Central Nervous System . . . . . . . . . . . . 71Nathalie Koning, Juan M. Ilarregui, Juan J. García-Vallejoand Yvette van Kooyk
5 The Role of B Cells in Multiple Sclerosis . . . . . . . . . . . . . . . . . . . . . . . . . . 95Bernhard Hemmer, Markus C. Kowarik and Martin S. Weber
6 Diet, Gut Flora, and Multiple Sclerosis: Current Researchand Future Perspectives . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 115Takashi Yamamura and Sachiko Miyake
7 GM-CSF in Autoimmune Inflammation of the CentralNervous System . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 127Mohamed El-Behi, Bogoljub Ciric and Abdolmohamad Rostami
8 The Role of Toll-Like Receptors in Multiple Sclerosisand Experimental Autoimmune Encephalomyelitis . . . . . . . . . . . . . . . . . 149Mukanthu H. Nyirenda, James Crooks and Bruno Gran
9 Macrophages and Microglia in Experimental AutoimmuneEncephalomyelitis and Multiple Sclerosis . . . . . . . . . . . . . . . . . . . . . . . . . 177Manoj Kumar Mishra and V. Wee Yong
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viii Contents
10 Genetics of Multiple Sclerosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 197Julia Y. Mescheriakova, Karim L. Kreft and Rogier Q. Hintzen
11 Gene Expression Profiling and Pathway Analysis for Identificationof Molecular Targets in MS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 229Jun-ichi Satoh
12 Systems Biology for the Study of Multiple Sclerosis . . . . . . . . . . . . . . . . 257Pablo Villoslada and Lawrence Steinman
13 Checkpoints in the Development of Pathogenic and Regulatory TCells in Experimental Autoimmune Encephalomyelitis—A Basisfor Current and Future Interventions in MS . . . . . . . . . . . . . . . . . . . . . . 269Denise C. Fitzgerald and Stephen M. Anderton
14 Modeling MS in Nonhuman Primates . . . . . . . . . . . . . . . . . . . . . . . . . . . . 295Bert A. ’t Hart, S. Anwar Jagessar, Krista Haanstra, Yolanda S. Kapand Jon D. Laman
15 A Novel Concept of Treatment in MS: Targeting BothOligodendrocyte Death and Inflammatory Processes by InhibitingPoly(Adp-Ribose) Polymerase . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 315Zsolt Illes, Hans Lassmann and Ferenc Gallyas
16 Association of Multiple Sclerosis with OtherAutoimmune Diseases . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 341Ali Manouchehrinia, Laura J. Edwards and Cris S. Constantinescu
17 Current and Future Treatments of Multiple Sclerosis . . . . . . . . . . . . . . 357Aiden Haghikia and Ralf Gold
18 Targeting CD52 for the Treatment of Multiple Sclerosis . . . . . . . . . . . . 385Alasdair Coles and Joanne Jones
19 Haematopoietic Stem Cells for the Treatment of MS . . . . . . . . . . . . . . . 401Sofia Abrahamsson, Miriam Mattoscio and Paolo A. Muraro
20 Mesenchymal Stem Cells for the Treatmentof Multiple Sclerosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 433Laura Lovato, Nicole Kerlero de Rosbo and Antonio Uccelli
Index . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 457
Contributors
Sofia Abrahamsson Division of Brain Sciences, Faculty of Medicine, Building560/Burlington Danes, Room E415, Imperial College London, 160 Du Cane Road,London W12 0NN UKe-mail: [email protected]
Stephen M. Anderton Centre for Inflammation Research, Centre for MultipleSclerosis Research and Centre for Immunity Infection and Evolution, University ofEdinburgh, Edinburgh, UKe-mail: [email protected]
Bogoljub Ciric Department of Neurology, Thomas Jefferson University, Philadel-phia, PA 19107, USAe-mail: [email protected]
Alasdair Coles Department of Clinical Neurosciences, University of Cambridge,Addenbrooke’s Hospital, Box 165, Cambridge, CB2 0QQ, UKe-mail: [email protected]
Cris S. Constantinescu Division of Clinical Neurosciences, University of Notting-ham; C Floor South Block, Queen’s Medical Centre, Nottingham NG7 2UH, UKe-mail: [email protected]
James Crooks Division of Clinical Neurosciences, University of Nottingham; CFloor South Block, Queen’s Medical Centre, Nottingham NG7 2UH, UKe-mail: [email protected]
Laura J. Edwards Division of Clinical Neurosciences, University of Nottingham;C Floor South Block, Queen’s Medical Centre, Nottingham NG7 2UH, UKe-mail: [email protected]
Mohamed El-Behi Institut du Cerveau et de la Moelle Epinière, INSERM U975,Paris, Francee-mail: [email protected]
Denise C. Fitzgerald Centre for Infection and Immunity, Queen’s UniversityBelfast, Belfast, UKe-mail: [email protected]
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x Contributors
Ferenc Gallyas Department of Biochemistry and Medical Chemistry, University ofPecs Medical School, Pecs, Hungary
Nuclear-Mitochondrial Interactions Research Group, Hungarian Academy ofSciences, Budapest, Hungarye-mail: [email protected]
Juan J. García-Vallejo Department of Molecular Cell Biology and Immunology,VU University Medical Center, 7057, 1007 MB Amsterdam, The Netherlandse-mail: [email protected]
Barbara B. Gawlik Departments of Neurology and Immunobiology, Yale Schoolof Medicine, New Haven, CT 06520, USAe-mail: [email protected]
Ralf Gold Department of Neurology, St. Josef-Hospital Bochum, Ruhr-Universität,Bochum, Germanye-mail: [email protected]
Bruno Gran Division of Clinical Neurosciences, University of Nottingham; CFloor South Block, Queen’s Medical Centre, Nottingham NG7 2UH, UKe-mail: [email protected]
Krista Haanstra Department of Immunobiology, Biomedical Primate ResearchCentre (BPRC), PO Box 3306, 2280 GH, Rijswijk, The Netherlandse-mail: [email protected]
David A. Hafler Departments of Neurology and Immunobiology, Yale School ofMedicine, New Haven, CT 06520, USAe-mail: [email protected]
Aiden Haghikia Department of Neurology, St. Josef-Hospital Bochum, Ruhr-Universität, Bochum, Germanye-mail: [email protected]
Nuffield Department of Clinical Neurosciences and MRC Human ImmunologyUnit,Weatherall Institute of Molecular Medicine, John Radcliffe Hospital, Univer-sity of Oxford, Oxford, UK
B. A. ’t Hart Department of Immunobiology, Biomedical Primate Research Centre(BPRC), PO Box 3306, 2280 GH, Rijswijk, The Netherlandse-mail: [email protected]
Department of Medical Physiology, University Medical Centre Groningen, Gronin-gen, The Netherlands
Department of Immunology, Erasmus Medical Center, Rotterdam, The Netherlands
MS center ErasMS, Rotterdam, The Netherlands
Contributors xi
Bernhard Hemmer Department of Neurology, Technische Universität München,Klinikum rechts der Isar, Department of Neurology, Ismaninger Strasse 22 Mu-nich, Germanye-mail: [email protected]
Rogier Q. Hintzen Department of Neurology, Erasmus MC, Room Ba 4.92, P.O.Box 2040, 3000 CA, Rotterdam, The Netherlandse-mail: [email protected]
Juan M. Ilarregui Department of Molecular Cell Biology and Immunology, VUniversity Medical Center, 7057, 1007 MB Amsterdam, The Netherlandse-mail: [email protected]
Zsolt Illes Division of Clinical and Experimental Neuroimmunology, Departmentof Neurology, University of Pecs Medical School, Pecs, Hungarye-mail: [email protected]
Clinical Neuroscience MR Research Group, Hungarian Academy of Sciences,University of Pecs, Pecs, Hungary
Department of Neurology and Institute of Clinical Research, University of SouthernDenmark, Odense, Denmark
S. Anwar Jagessar Department of Immunobiology, Biomedical Primate ResearchCentre (BPRC), PO Box 3306, 2280 GH, Rijswijk, The Netherlandse-mail: [email protected]
Joanne Jones Department of Clinical Neurosciences, University of Cambridge,Addenbrooke’s Hospital, Box 165, Cambridge, CB2 0QQ, UKe-mail: [email protected]
Yolanda S. Kap Department of Immunobiology, Biomedical Primate ResearchCentre (BPRC), PO Box 3306, 2280 GH, Rijswijk, The Netherlandse-mail: [email protected]
Department of Immunology, Erasmus Medical Center, Rotterdam, The Netherlands
MS center ErasMS, Rotterdam, The Netherlands
Nicole Kerlero de Rosbo Department of Neurology, Rehabilitation, Ophthalmol-ogy, Genetics, Maternal and Child Health, University of Genoa, Italye-mail: [email protected]
Nathalie Koning Department of Molecular Cell Biology and Immunology, VUUniversity Medical Center, 7057, 1007 MB Amsterdam, The Netherlandse-mail: [email protected]
Yvette van Kooyk Department of Molecular Cell Biology and Immunology, VUUniversity Medical Center, 7057, 1007 MB Amsterdam, The Netherlandse-mail: [email protected]
Thomas Korn Klinikum rechts der Isar, Department of Neurology, TechnischeUniversität München, Ismaninger Str. 22, 81675 Munich, Germanye-mail: [email protected]
xii Contributors
Markus C. Kowarik Department of Neurology, Technische Universität München,Klinikum rechts der Isar, Department of Neurology, Ismaninger Strasse 22 Munich,Germanye-mail: [email protected]
Karim L. Kreft Department of Neurology, Erasmus University Medical Centre,Dr. Molewaterplein 50, 3015 GE, Rotterdam, The Netherlandse-mail: [email protected]
Vijay K. Kuchroo Brigham & Women’s Hospital, Center for Neurologic Diseases,Harvard Medical School, Boston, MA, USAe-mail: [email protected]
Jon D. Laman Department of Immunology, Erasmus Medical Center, Rotterdam,The Netherlandse-mail: [email protected]
Hans Lassmann Center for Brain Research, Medical University of Vienna, Vienna,Austriae-mail: [email protected]
Laura Lovato Department of Neurology, Rehabilitation, Ophthalmology, Genetics,Maternal and Child Health University of Genoa, Italye-mail: [email protected]
Amy E. Lovett-Racke Department of Microbial Infection and Immunity, The OhioState University, Columbus, OH 43210, USAe-mail: [email protected]
Ali Manouchehrinia Division of Clinical Neurosciences, University of Nottingham,C Floor, South Block, Queen’s Medical Centre, Nottingham NG7 2UH, UKe-mail: [email protected]
Miriam Mattoscio Division of Brain Sciences, Faculty of Medicine, Building560/Burlington Danes, Room E415, Imperial College London, 160 Du Cane Road,London W12 0NN UKe-mail: [email protected]
Julia Y. Mescheriakova Department of Neurology, Erasmus University MedicalCentre, Dr. Molewaterplein 50, 3015 GE, Rotterdam, The Netherlandse-mail: [email protected]
Manoj K. Mishra Hotchkiss Brain Institute, University of Calgary, 3330 HospitalDrive, Calgary, AB T2N 4N1, Canadae-mail: [email protected]
Sachiko Miyake Department of Immunology, National Institute of Neuroscience,National Center of Neurology and Psychiatry, Tokyo, Japane-mail: [email protected]
Contributors xiii
Paolo A. Muraro Division of Brain Sciences, Faculty of Medicine, Building560/Burlington Danes, Room E415, Imperial College London, 160 Du Cane Road,London W12 0NN UKe-mail: [email protected]
Mukanthu H. Nyirenda Division of Clinical Neurosciences, University of Not-tingham, C Floor, South Block, Queen’s Medical Centre, Nottingham NG7 2UH,UK
Neuroimmunology Unit, Montreal Neurological Institute, McGill University,Montreal, Quebec H3A 2B4, Canada.e-mail: [email protected]
Michael K. Racke Department of Neurology, The Ohio State University, Columbus,OH 43210, USAe-mail: [email protected]
Abdolmohamad Rostami Department of Neurology, Thomas Jefferson University,Philadelphia, PA 19107, USAe-mail: [email protected]
Jun-ichi Satoh Department of Bioinformatics and Molecular Neuropathology,Meiji Pharmaceutical University, 2–522-1 Noshio, Kiyose, Tokyo 204–8588, Japane-mail: [email protected]
Lawrence Steinman Department of Neurology and Neurological Sciences,Stanford University, Stanford, CA 94305, USAe-mail: [email protected]
Beckman Center for Molecular Medicine, 279 Campus Drive, Room B002, StanfordUniversity, Stanford, CA 94305, USA
Antonio Uccelli Department of Neurology, Rehabilitation, Ophthalmology, Genet-ics, Maternal and Child Health, University of Genoa, Italye-mail: [email protected]
Center of Excellence for Biomedical Research, University of Genoa, Italy
Advanced Biotechnology Center, Genoa, Italy
Department of Neurology, Rehabilitation, Ophthalmology, Genetics, Maternal andChild Health (DINOGMI), University of Genoa, Largo Paolo Daneo 3, 16132Genoa, Italy
Pablo Villoslada Department of Neurology, Center of Neuroimmunology, Insti-tute of Biomedical Research August Pi Sunyer (IDIBAPS)—Hospital Clinic ofBarcelona, Villarroel 170, 08036 Barcelona, Spaine-mail: [email protected]
Martin S. Weber Department of Neurology, Technische Universität München,Klinikum rechts der Isar, Department of Neurology, Ismaninger Strasse 22 Munich,Germanye-mail: [email protected]
xiv Contributors
Takashi Yamamura Department of Immunology, National Institute of Neuro-science, National Center of Neurology and Psychiatry, Tokyo, Japane-mail: [email protected]
V. Wee Yong Hotchkiss Brain Institute, University of Calgary, 3330 Hospital Drive,Calgary, AB T2N 4N1, Canadae-mail: [email protected]
List of Abbreviations
APC Antigen-presenting cellCLP Common lymphoid progenitorCNS Central nervous systemCSF Cerebrospinal fluidDAVID Database for Annotation, Visualization and Integrated DiscoveryDEGs Differentially expressed genesDM Diabetes mellitusDZ DizygoticEAE Experimental autoimmune encephalomyelitisETP Early thymic progenitorGEO Gene Expression OmnibusGWA study Genome-wide association studyHLA Human leucocyte antigenHPRD Human Reference Protein DatabaseHSC Hematopoietic stem cellIBD Identical by descentIM Infectious mononucleosisIPA Ingenuity pathways analysisIMSGC International Multiple Sclerosis Genetic ConsortiumKEGG Kyoto Encyclopedia of Genes and GenomesLD Linkage disequilibriummiRNA Micro-ribonucleic acidMS Multiple sclerosisMudPIT Multidimensional Protein Identification TechnologyMZ MonozygoticNGS Next-generation sequencingOR Odds ratioPANTHER Protein Analysis Through Evolutionary RelationshipsPBMC Peripheral blood mononuclear cellsRA Rheumatoid arthritisRISC RNA-induced silencing complexRR Risk ratioSNP Single-nucleotide polymorphism95 % CI 95 % confidence interval
xv
List of Definitions
SNP Single-nucleotide polymorphism; a single nucleotidevariation in a genetic sequence that occurs at appreciablefrequency in the population
Tagging SNP An SNP that can predict other SNPs in the region withsmall probability of error, because SNPs are physicallyclose to one another and tend to be inherited together
Linkage disequilibrium The non-random association between two or more allelessuch that certain combinations of alleles are more likely tooccur together on a chromosome than other combinationsof alleles
Synonymous A substitution of one base for another in an exon of a genecoding for a protein, such that the produced amino acidsequence is not modified
Non-synonymous A non-synonymous substitution results in a change inamino acid
Allele An allele is one of two or more versions of a gene. Anindividual inherits two alleles for each gene, one fromeach parent. If the two alleles are the same, the individualis homozygous for that gene. If the alleles are different,the individual is heterozygous
Locus The position that a given gene occupies on a chromosomeConcordance rate A quantitative statistical expression for the concordance
(the occurrence of a given trait in both members of a twinpair) of a given genetic trait, in pairs of twins in geneticstudies
Multiplex family Multicase family with affected individuals present in >1generation
IBD Identical by descent; a measure of how many alleles ofany gene in each of the two individuals came from thesame ancestral chromosome
Familial aggregation Occurrence of a trait in more members of a family thancan be readily accounted for by chance
Missense Mutation resulting in a codon that codes for a differentprotein
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