
12th International Conference on Myasthenia Gravis and Related Disorders
Monday, May 21, 2012 - Wednesday, May 23, 2012
The New York Academy of Sciences
Presented By
Presented by the New York Academy of Sciences and the Myasthenia Gravis Foundation of America, Inc.
Myasthenia gravis (MG) is a rare, acquired autoimmune syndrome in which pathogenic auto-antibodies attack key proteins at the neuromuscular junction—most often, the muscle nicotinic acetylcholine receptor—disrupting synaptic transmission. Often, the result is severe muscle weakness, fatigability, and disability in patients, which may be life threatening. In the last 30 – 40 years, significant advances in diagnosis and treatment of MG have reduced the burden of high mortality and severe disability, and more recently research has produced novel potential therapeutic targets, clearer definitions of MG clinical subtypes, and new clinical trials to improve treatment options. Yet, diagnosis remains problematic because of nonspecific and fluctuating symptoms, and available therapeutics primarily treat symptoms or involve global suppression of the immune system.
The Myasthenia Gravis Foundation of America and the New York Academy of Sciences present this 12th international conference to galvanize efforts among researchers studying autoimmune and neuromuscular junction disease and to encourage continued progress in the diagnosis and treatment of MG that will help to improve patient outcomes and quality of life. This 3-day international conference will feature topics that span basic, translational, and clinical neuroscience and immunology related to MG and other autoimmune and neuromuscular junction disorders.
Organizers
Emma Ciafaloni, MD
University of Rochester
Matthew N. Meriggioli, MD, FAAN
University of Illinois College of Medicine
Robert L. Ruff, MD, PhD
Louis Stokes Cleveland Department of Veterans Affairs Medical Center and Case Western Reserve University
Gil I. Wolfe, MD
University at Buffalo School of Medicine and Biomedical Sciences
Young Investigator Travel Fellowships
On behalf of the Myasthenia Gravis Foundation of America, we are pleased to announce the following travel fellowship winners. Winners were chosen based on their application materials and outstanding abstract submissions. Each winner will receive waived conference registration and $1000 towards their travel and accommodation expenses to attend the conference.
Revital Aricha, PhD, The Weizmann Institute of Science
Eyal Ben-Ami, MSc, Technion-Israel Institute of Technology
Alejandro M. Gomez, MSc Maastricht University
Maartje G. Huijbers, MSc, Leiden University Medical Centre
Paraskevi Zisimopoulou, PhD, Hellenic Pasteur Institute
Registration Pricing
By 4/13/2012 | After 4/13/2012 | Onsite: 5/20/2012 | |
Member | $550 | $600 | $650 |
Student / Postdoc / Fellow Member | $350 | $375 | $400 |
Nonmember Academic | $700 | $750 | $800 |
Nonmember Corporate | $850 | $900 | $950 |
Nonmember Not for Profit | $700 | $750 | $800 |
Student / Postdoc / Fellow Nonmember | $350 | $375 | $400 |
Myasthenia Gravis and other neuromuscular junction disease patients are eligible to register at NYAS member rates. For more information, please contact Ms. Melanie Koundourou at mkoundourou@nyas.org or 212.298.8681.
Presented by
Silver Sponsor
Grant Support
This project is supported by Grant Number R13NS077665 from the National Institute of Neurological Disorders and Stroke (NINDS), the National Center for Advancing Translational Sciences (NCATS), and the Office of Rare Diseases (ORD). The content is solely the responsibility of the authors and does not necessarily represent the official views of the NINDS, NCATS, ORD, or the National Institutes of Health.
For a full list of sponsors, please view the Sponsors tab.
Agenda
* Presentation times are subject to change.
Day One — Monday, May 21, 2012 | |
7:45 AM | Registration & Continental Breakfast |
8:30 AM | Opening Remarks |
Session I: Structure and Function of the Neuromuscular Junction: Recent AdvancesSession Chair: Henry J. Kaminski, MD, George Washington University | |
8:50 AM | Structure of the Neuromuscular Junction: Function and Cooperative Mechanisms in the Synapse |
9:10 AM | Presynaptic Organization of the Neuromuscular Junction |
9:30 AM | Dok7, MuSK and the Development of Neuromuscular Junction |
9:50 AM | Myasthenogenicity of the Main Immunogenic Region |
10:10 AM | Networking Break |
Session II: Advances in Immunology and their Relationship to Myasthenia GravisSession Chair: Angela Vincent, FRCP, FRS, University of Oxford | |
10:40 AM | Etiology of Autoimmune Diseases |
11:00 AM | Defects of Immunoregulatory Mechanisms in MG |
11:20 AM | A Journey from the Thymus to the Endplate |
11:40 AM | Functional Defect in Regulatory T Cells in Autoimmune Myasthenia Gravis |
12:00 PM | Neuronal Acetylcholine Receptor Autoimmunity |
12:20 PM | The Role of B Cell Activating Factor in Autoimmune Myasthenia Gravis |
12:40 PM | Panel Discussion |
1:00 PM | Networking Lunch |
Session III: Myasthenia Gravis: Clinical and Laboratory DevelopmentsSession Chair: Richard J.Barohn, MD, University of Kansas Medical Center | |
2:30 PM | Population Differences in the Clinical Presentation and Serology of MG |
2:50 PM | Cell-Based Assays in Myasthenia Gravis |
3:10 PM | Concentric Needle Jitter Studies |
3:30 PM | Management Challenges in Muscle-Specific Tyrosine Kinase MG |
3:50 PM | Genome-Wide Association Study of Myasthenia Gravis |
4:10 PM | Networking Break |
Session IV: Myasthenia Gravis: Outcome Measurements and Clinical Trial DevelopmentSession Chair: Ted M. Burns, MD, University of Virginia | |
4:40 PM | MG Activities of Daily Living (ADL) Profile |
5:00 PM | Quality of Life in Myasthenia; Why and How to Measure It |
5:20 PM | The MG Composite |
5:40 PM | Patient Registries: Useful Tools for Clinical Research in Myasthenia Gravis |
6:00 PM | Panel Discussion |
Poster Session Short Talks | |
6:20 PM | Identification of a New Gene Causing Congenital Myasthenic Syndrome |
6:30 PM | Proteasome Inhibition with Bortezomib Eliminates Plasma Cells in Cultured Thymic Cells from Myasthenia Gravis Patients |
6:40 PM | LRP4 (Low-Denslty Lipoprotein Receptor-Related Protein 4) Is a Novel Autoimmune Target in Patients with Seronegative Myasthenia Gravis |
6:50 – 8:50 PM | Welcome Reception and Poster Session I |
Day Two — Tuesday, May 22, 2012 | |
7:45 AM | Registration & Continental Breakfast |
8:30 AM | Keynote Address Biologics and Other Novel Approaches in Autoimmune Neuromuscular Disorders as Applicable in Myasthenia Gravis |
Session V: Animal Models of Neuromuscular Junction DiseaseSession Chair: Matthew N. Meriggioli, MD, FAAN, University of Illinois College of Medicine; Chair, Medical Scientific Advisory Board, Myasthenia Gravis Foundation of America | |
9:20 AM | The Role of Complement in Experimental Autoimmune MG |
9:40 AM | Acute Severe Model of Anti-Muscle Specific Kinase Myasthenia |
10:00 AM | Animal Models of AChR-Related MG |
10:20 AM | Regulatory T Cells in Experimental Autoimmune MG |
10:40 AM | Networking Break |
Session VI: Myasthenia Gravis — Treatment Update and What Lies AheadSession Chair: Emma Ciafaloni, MD, University of Rochester | |
11:10 AM | Update on Mycophenolate Mofetil Treatment of MG |
11:30 AM | Efficacy of Prednisone in the Treatment of Ocular Myasthenia - Epitome |
11:50 AM | Intravenous Immunoglobulin versus Plasma Exchange for MG Exacerbations |
12:10 PM | Panel Discussion |
12:30 PM | Networking Lunch |
Session VI: (CONT.) Myasthenia Gravis — Treatment Update and What Lies AheadSession Chair: Emma Ciafaloni, MD, University of Rochester | |
2:00 PM | Randomized, Double-Blind, Placebo-controlled, Crossover, Multicenter, Phase II Study of Eculizumab in Patients with Refractory Generalized Myasthenia Gravis (GMG) |
2:20 PM | Further Developments with Antisense Treatment for Myasthenia Gravis |
2:40 PM | Phase II Trial of Methotrexate in Myasthenia Gravis |
3:00 PM | Rituximab in Myasthenia Gravis |
3:20 PM | Networking Break |
3:50 PM | Antigen-Specific Apheresis of Autoantibodies in MG |
4:10 PM | Issues in Clinical Trial Design for Myasthenia Gravis |
4:30 PM | Panel Discussion |
Poster Session Short Talks | |
4:50 PM | Epitope Mapping of Anti-Musk Autoantibodies in Myasthenia Gravis |
5:00 PM | Experimental MG in Aire KO Mice—A Link Between Aire and Treg Cells |
5:10 PM | Novel Calcium Channel Agonists as Potential Therapeutics in LEMS and Other Neuromuscular Diseases |
5:20 – 7:20 PM | Poster Session II |
Day Three — Wednesday, May 23, 2012 | |
7:45 AM | Registration & Continental Breakfast |
Session VII: Congenital Myasthenic SyndromesSession Chair: Andrew G. Engel, MD, Mayo Clinic | |
8:30 AM | Synaptic Basal Lamina - Associated Congenital Myasthenic Syndromes |
8:50 AM | DOK7 Mutations Underlie Neuromuscular Junction Synaptopathy |
9:10 AM | Synaptic Dysfunction in Congenital Myasthenic Syndromes |
9:30 AM | Congenital Myasthenic Syndromes (CMS) in 2012 |
9:50 AM | Clinical and Electrodiagnostic Observations in Congenital Myasthenic Syndromes |
10:10 AM | Networking Break |
Session VIII: Lambert-Eaton Myasthenic SyndromeSession Chair: Donald B. Sanders, MD, Duke University Medical Center | |
10:40 AM | Treatment in Lambert-Eaton Myasthenic Syndrome |
11:00 AM | SOX1 in Lambert-Eaton Myasthenic Syndrome and Screening for Small Cell Lung Cancer |
11:20 AM | Panel Discussion |
Session IX: Thymus, Thymectomy, and the MGTX TrialSession Chairs: Gil I. Wolfe, MD, University at Buffalo School of Medicine and Biomedical Sciences | |
11:40 AM | MGTX: Update on the Thymectomy Trial in Non-Thymomatous Myasthenia Gravis |
12:00 PM | Biomarker Development for Myasthenia Gravis |
12:20 PM | Networking Lunch |
Session IX: (CONT.) Thymus, Thymectomy, and the MGTX Trial | |
1:50 PM | Thymus Pathology Observed in the MGTX Trial |
2:10 PM | Minimally Invasive Thymectomy: An Update |
2:30 PM | Thymectomy for Myasthenia Gravis Patients- The Robotic Approach |
2:50 PM | The MGTX International Trial: Methods for Management and Lessons Learned |
3:10 PM | Panel Discussion |
3:30 PM | Networking Break |
Session X: Hot Topics Selected from Submitted AbstractsSession Chair: Robert L. Ruff, MD, PhD, Louis Stokes Cleveland Department of Veterans Affairs Medical Center and Case Western Reserve University | |
4:00 PM | The search for New Antigenic Targets in Myasthenia Gravis |
4:20 PM | IgG4 Subclass Autoantibodies from MuSK Myasthenia Gravis Patients Cause Defective Neuromuscular Synaptic Transmission in Mice |
4:40 PM | Molecular Recognition of Nicotinic Acetylcholine Receptors by Agonist and a-Neurotoxins: Structural and Mechanistic Insights |
5:00 PM | Failure of Neuromuscular Transmission in Myasthenia Gravis: Decline in Safety Factor and Susceptibility of Extraocular Muscles |
5:20 PM | Mesenchymal Stem Cells-Mediated Immunomodulation of Myasthenia Gravis Patients' Lymphocytes |
5:40 – 6:00 PM | Closing Remarks |
Speakers
Inmaculada B. Aban
University of Alabama School of Public Health
Revital Aricha, PhD
Weitzmann Institute of Science
Jean-François Bach
Necker Hospital
Fulvio Baggi
Neurological Institute "Carlo Besta"
Richard Barohn
University of Kansas Medical Center
David Beeson
University of Oxford
Katsiaryna Belaya, PhD
University of Oxford
Eyal Ben-Ami, MSc
Technion-Israel Institute of Technology
Michael Benatar
University of Miami
Sonia Berrih-Aknin
University Pierre et Marie Curie & Institut National de la Santé et de la Recherche Médicale
Vera Bril
University Health Network & University of Toronto
Ted M. Burns
University of Virginia
Premkumar Christadoss
University of Texas Medical Branch
Emma Ciafaloni
University of Rochester
Judith Cossins, DPhil
University of Oxford
Gary Cutter
University of Alabama School of Public Health
Marinos C. Dalakas
Marc De Baets
Maastricht University
Daniel B. Drachman
Johns Hopkins School of Medicine
Andrew G. Engel
Mayo Clinic
Amelia Evoli
Catholic University – Roma
Pier Cristoforo Giulianotti
University of Illinois at Chicago
Alejandro M. Gomez, MSc
Maastricht University
Charles (Mike) Harper
Mayo Clinic College of Medicine
James F. Howard, Jr.
University of North Carolina at Chapel Hill
Maartje G. Huijbers, MSc
Leiden University Medical Centre
Henry J. Kaminski
George Washington University
Linda L. Kusner
George Washington University
Jon Martin Lindstrom
Medical School of the University of Pennsylvania
Robert P. Lisak
Wayne State University
Paul Maddison
Nottingham University Hospitals – Queen's Medical Centre
Alexander Marx
University of Heidelberg
Ricardo A. Maselli
University of California – Davis
Janice Massey
Duke University Medical Center
Arthur Melms, MD
Tübingen University Medical Center
Matthew Meriggioli
University of Illinois College of Medicine; Chair, Medical Scientific Advisory Board, Myasthenia Gravis Foundation of America
Stephen D. Meriney, PhD
University of Pittsburgh
Dan M. Meyer
University of Texas Southwestern Medical Center
Greg Minisman
University of Alabama School of Public Health
Srikanth Muppidi
University of Texas Southwestern Medical Center
Hiroshi Nishimune
University of Kansas Medical School
Jacqueline Palace
Oxford University Hospital
Jaap J. Plomp, PhD
Leiden University Medical Centre
David P. Richman
University of California – Davis
Michael Rose
King's College Hospital
Robert Ruff
Louis Stokes Cleveland Department of Veterans Affairs Medical Center and Case Western Reserve University
Donald B. Sanders
Duke University Medical Center
Alessandro Serra, MD, PhD
Veterans Affairs Medical Center and Case Medical Center
Zaeem Siddiqi
University of Alberta
Steven M. Sine, PhD
Mayo Clinic
Miriam C. Souroujon
Open University of Israel and Weizmann Institute of Science
Erik Stålberg
University Hospital Uppsala
Jon D. Sussman
Greater Manchester Neuroscience Centre
Masaharu Takamori
Kanazawa University
Rup Tandan
University of Vermont (UVM) Fletcher Allen Health Care
Maarten J. Titulaer
University of Pennsylvania
Socrates Tzartos
Hellenic Pasteur Institute and University of Patras
Steven Vernino
University of Texas Southwestern Medical Center
Angela Vincent
University of Oxford
Gil I. Wolfe
University at Buffalo School of Medicine and Biomedical Sciences
Yuji Yamanashi
The University of Tokyo
Sponsors
For sponsorship opportunities, please contact Melinda Miller at mmiller@nyas.org or 212.298.8648.
Presented by
Silver Sponsor
Academy Friend
Promotional Partners
American Association of Immunologists
American Association of Neuromuscular & Electrodiagnostic Medicine (AANEM)
American Neurological Association
A.I.M. Associazione Italiana Miastenia e Malattie Immunodegenerative — Amici del Besta Onlus
The New York Academy of Medicine
Grant Support
This project is supported by Grant Number R13NS077665 from the National Institute of Neurological Disorders and Stroke (NINDS), the National Center for Advancing Translational Sciences (NCATS), and the Office of Rare Diseases (ORD). The content is solely the responsibility of the authors and does not necessarily represent the official views of the NINDS, NCATS, ORD, or the National Institutes of Health.
Supported by a grant from BioMarin Pharmaceutical Inc.
Supported by an unrestricted educational grant from Alexion Pharmaceuticals
Abstracts
Day 1: Monday, May 21, 2012
Session I: Structure and Function of the Neuromuscular Junction: Recent Advances
Structure of the Neuromuscular Junction: Function and Cooperative Mechanisms in Synapse
Masaharu Takamori, MD, Kanazawa-Nishi Hospital and Kanazawa University
Acetylcholine (ACh)-mediated signal transmission in the neuromuscular junction depends on coordinated interaction between the presynaptic active zone where synaptic vesicles fuse and the postsynaptic differentiation where ACh receptors (AChRs) are clustered. As cooperative mechanisms in the presynapse, the activation of G protein-coupled receptor (M1 muscarinic AChR) and tyrosine kinase B receptor helps on the Ca2+ influx mediated by voltage-gated Ca2+ channel (P/Q-type) and non-voltage-gated Ca2+ channel (Transient receptor potential canonical, TRPCs 3, 6 and 7). These signals are mediated through phospholipase C activation and lead to the Ca2+-triggered exocytosis and also the fast-mode of endocytosis which requires larger influx of external Ca2+. The synaptic vesicle recycling is thus promoted and potentially compensates synaptic fatigue. In the postsynapse, the Dok7-stimulated MuSK contributes to AChR clustering via its interacting sites for the signals including agrin/Lrp4 (via MuSK Ig1/2 domains), Wnts/Dishevelled (via MuSK Frizzled-like cysteine-rich domain), Tid1s (helps rapsyn stabilization via Hsps 70 and 90β), neuregulin/ErbB, and collagen Q (C-terminus). In the muscle contraction, the TRPC3 collaborates with ryanodine receptor-1 for sarcoplasmic Ca2+ release, refilling Ca2+ after the store depletion in cooperation with Orai1 (Ca2+ influx channel) and STIM1 (Ca2+ sensor). The IP3-dependent dissociation of the TRPC-Homer1-IP3R complex allows STIM1 access to TRPC. The various sites in these structures are immunologically targeted in Lambert-Eaton myasthenic syndrome and myasthenia gravis.
Presynaptic Organization of Neuromuscular Junction
Hiroshi Nishimune, PhD, University of Kansas Medical School
Presynaptic active zones play essential roles for the function and pathology of neuromuscular junctions (NMJs) because they are synaptic vesicle release sites. We recently reported that the number of active zones increases as the size of mouse NMJs increases 3-fold during postnatal development, however, the density of active zones remains constant from postnatal day 0 to 54. Interestingly, the active zone density decreases at the NMJs of aged mice. These results suggest that NMJs maintain the density of synaptic vesicle release sites while they mature, but this density becomes impaired during aging. What is the molecular mechanism for organizing active zones? Recent findings in the central and peripheral nervous systems demonstrate that synaptic channel proteins are involved in the formation and maintenance of synapses by interacting directly with synapse organizers. We identified recently that presynaptic voltage-dependent calcium channels (VDCC) of NMJs interact extracellularly with the muscle-derived synapse organizer laminin β2 and intracellularly with active zone proteins, Bassoon, CAST/Erc2, and ELKS. These results suggest that VDCCs function as a scaffolding protein to organize the active zones. Consistent with this model, double knock out mice for P/Q- and N-type VDCCs has a significantly reduced number of active zones at NMJs and features an attenuation of the active-zone proteins. These molecular mechanisms of active zone organization and the loss of active zones in VDCC knock out mice are consistent with the pathological conditions observed in Lambert-Eaton myasthenic syndrome cause by autoantibodies against VDCCs and Pierson syndrome caused by laminin β2 mutation.
Dok7, MuSK and the Development of Neuromuscular Junction
Yuji Yamanashi, PhD, The University of Tokyo
Skeletal muscle contraction is controlled by motor neurons, which contact the muscle at the neuromuscular junction (NMJ). Defective neuromuscular transmission at NMJs gives rise to the fatigable muscle weakness known as myasthenia. The formation of the NMJ is orchestrated by the muscle-specific receptor tyrosine kinase MuSK and by neural agrin, which can activate MuSK via the coreceptor Lrp4. Previously, we demonstrated that the muscle protein Dok-7 is essential for neuromuscular synaptogenesis, and also demonstrated in collaboration with David Beeson and his colleagues that mutations in DOK7 underlie a limb-girdle type of congenital myasthenic syndrome, DOK7 myasthenia, which is associated with abnormally small and simplified NMJs. In addition, we showed that Dok-7 directly interacts with the cytoplasmic portion of MuSK and activates the receptor tyrosine kinase, and that neural agrin requires Dok-7 in order to activate MuSK in myotubes. In vivo overexpression of exogenous Dok-7 indeed increased MuSK activation and promoted NMJ formation in mice, which did not exhibit defects in motor function. Interestingly, the overexpression of Dok-7 promoted NMJ formation in the appropriate location, namely, the central region of the skeletal muscle. These observations indicate that Dok-7 positively regulates the development of NMJs by controlling MuSK activity and its responsiveness to neural agrin, identifying the Dok-7-MuSK signaling pathway as a new therapeutic target not only for DOK7 myasthenia but also other NMJ synaptopathies.
Myasthenogenicity of the Main Immunogenic Region
Jon Martin Lindstrom, PhD, Medical School of the University of Pennsylvania
In myasthenia gravis (MG) and experimental autoimmune MG (EAMG), many pathologically significant autoantibodies are directed at the main immunogenic region (MIR), a conformation-dependent region at the extracellular tip of α1 subunits of muscle nicotinic acetylcholine receptors (AChRs). Human muscle AChR α1 MIR sequences were integrated into Aplesia ACh-binding protein (AChBP). The chimera was potent at inducing both acute and chronic EAMG, though less potent than Torpedo electric organ AChR. Wild-type AChBP also induced EAMG but was even less potent, and weakness developed slowly without an acute phase. AChBP is more closely related in sequence to neuronal α7 AChR, however, autoimmune responses were induced to muscle AChR, but not to neuronal AChR subtypes. The greater accessibility of muscle AChRs to antibodies, compared to neuronal AChRs, may allow muscle AChRs to induce self-sustaining autoimmune responses. The human α1 subunit MIR is a potent immunogen for producing pathologically significant autoantibodies. Additional epitopes in this region or other parts of the AChR extracellular domain contribute significantly to myasthenogenicity. We show that an AChR-related protein can induce EAMG. Thus, in principle, an AChR-related protein could induce MG. AChBP is a water-soluble protein resembling the extracellular domain of AChRs, yet rats immunized with chimeras developed autoantibodies to both extracellular and cytoplasmic domains of muscle AChRs. We propose that an initial autoimmune response directed at the MIR on the extracellular surface leads to an autoimmune response sustained by muscle AChRs. Autoimmune stimulation sustained by endogenous muscle AChR may be a target for specific immunosuppression.
Session II: Advances in Immunology and their Relationship to Myasthenia Gravis
Etiology of Autoimmune Diseases
Jean-François Bach, MD, DSc, Necker Hospital
There is not a single cause for autoimmune diseases but a combination of genetic and acquired predisposing factors. Genetic determinism is complex involving many genes. A growing number of genes or more often genetic regions have been identified but their pertinence to the disease etiology is made uncertain by the low or very low relative risk associated with a given gene polymorphisms. The only exception is that of HLA genes whose involvement in disease pathogenesis is, however, not as clearly understood as generally assumed. Environmental factors are very diverse. Some are clearly identified: specific virus or bacteria in a small number of autoimmune diseases. Several candidate infectious agents, notably viruses, have been incriminated as in the case of multiple sclerosis (EBV) or of Type 1 diabetes (T1D) (Coxsackie virus) without any definite evidence perhaps due to the long time elapsed between viral infection and disease onset (hit and run hypothesis). Other factors have been considered such as defective vitamin D exposure, chemical modification of auto-antigenes or polyclonal B or T cell stimulation as in the case of some drug induce auto-immunity. The problem is complicated by the fact that the environment often has a protective rather than a triggering role. A correlation has been observed, over the last decades, between the decline of certain infectious diseases and the increase in autoimmune diseases. The causal relationship between these two observations has been directly demonstrated in animal models and indirectly in man. The mechanisms underlying the protective effect of infections are becoming better known with, in particular, the involvement of homeostatic competition regulatory T cells and Toll-like receptors with a possible influence of microbiota.
Defects of Immunoregulatory Mechanisms in MG
Sonia Berrih-Aknin, PhD, University Pierre et Marie Curie & Institut National de la Santé et de la Recherche Médicale
Regulatory CD4+CD25+ T cells prevent the activation of auto-reactive T cells and play a key role in the induction of peripheral tolerance. Using purified CD4+CD25+ (Treg) and CD4+CD25- (Tconv) cells from Myasthenia Gravis (MG) thymus, we previously showed a severe defect in the autologous suppression assay compared to control cells. Cross-experiments (using MG Treg cells and healthy T conv, and conversely) showed that not only MG Treg cells were defective in suppressing healthy Tconv cell proliferation, but also that MG Tconv cells were resistant to suppression by healthy Treg cells. The resistance of MG Tconv cells to suppression was not due to their over-proliferation. However, after activation, MG Tconv cells expressed a lower expression of FoxP3 compared to CTRL cells, and secreted higher levels of IL-6 and IL-17, two cytokines implicated in Treg regulation and auto-immunity. These results were corroborated by the transcriptomic analysis of Treg and Tconv subsets, which pointed out a dysregulation of TH17 related genes (IL17A, IL17F, IL17RA, IL21, IL22, IL23R) in MG cells compared to controls.
Altogether, our results demonstrate that the defects of immunoregulation observed in MG patients are due to both Treg and Tconv cells, and that IL-17 and related cytokines could play an important role in this defect. This work was supported by FP7 FIGHT-MG project.
A Journey from the Thymus to the Endplate
Marc De Baets, MD, PhD, Maastricht University
Abstract pending
Functional Defect in Regulatory T Cells in Autoimmune Myasthenia Gravis
Matthew N.Meriggioli, MD, FAAN, University of Illinois College of Medicine
Published studies examining the role of regulatory T cells (Tregs) in the pathogenesis of myasthenia gravis (MG) have reported conflicting results. In these investigations, isolation of Tregs was achieved based on expression of CD25 alone, likely resulting in the isolation of impure and/or heterogenous human "Treg" populations. In this study, we used surface CD4, CD25high, and CD127low expression to isolate a relatively pure population of Tregs, and then investigated whether there was a deficiency and/or a functional defect in these cells in the peripheral blood of MG patients.
We collected blood samples from 24 MG patients and 22 age-matched healthy control subjects. Peripheral blood mononuclear cells (PBMCs) were isolated, and the expression of surface CD4, CD25, and CD127, and intracellular FOXP3 was analyzed by flow cytometry, and the function of Tregs (CD4+CD25highCD127low/- cells) was assessed by co-culture experiments with CD25-negative autologous responder T cells (Tresp). Expression of intracellular FOXP3 was assessed by flow cytometry and RT-PCR, and cytokine profiles from T cell co-culture supernatants were analyzed.
No alteration in the relative numbers of Tregs within the peripheral CD4+ T cell pool was seen in MG patients. In vitro proliferation assays demonstrated that Treg-mediated suppression of responder T cells (Tresp) was impaired, both for polyclonal activation (anti-CD3 Abs) and activation with specific antigen (acetylcholine receptor peptides). This defect was associated with a reduced cellular expression of FOXP3 at both the protein and mRNA level. Both polyclonal and AChR-activated Tresp cells from MG patients could be effectively suppressed using Tregs isolated from healthy controls, while polyclonal-activated Tresp cells from controls were not suppressed using Tregs isolated from MG patients. Cytokine profiles revealed altered levels of IL-6, IL-17, IFN-?, and IL-10 in MG patients.
Our findings indicate a clinically relevant Treg-intrinsic defect in immune regulation in MG that may reveal a novel therapeutic target. Study supported by: This work was supported by the NIH (National Institute of Neurologic Disorders and Stroke, K08NS058800, and the Muscular Dystrophy Association (MDA); and National Institute of Allergy and Infectious Diseases, RO1 AI 058190, BSP.
Neuronal Acetylcholine Receptor Autoimmunity
Steven Vernino, MD, PhD, University of Texas Southwestern Medical Center
Autoimmunity against acetylcholine receptors (AChR) at the neuromuscular junction is the usual cause of myasthenia gravis. Neuronal nicotinic AChRs that are highly homologous to the neuromuscular AChR are found throughout the nervous system. The ganglionic neuronal AChR mediates fast synaptic transmission in sympathetic, parasympathetic and enteric autonomic ganglia. Impaired ganglionic synaptic transmission is one important cause of autonomic failure.
Ganglionic AChR antibodies are found in many patients with autoimmune autonomic ganglionopathy (AAG). Patients with high levels of ganglionic AChR antibodies typically present with rapid onset of severe autonomic failure, with orthostatic hypotension, gastrointestinal dysmotility, anhidrosis, bladder dysfunction and sicca symptoms. A characteristic impairment of the pupillary light reflex is often seen. Lower levels of ganglionic AChR antibodies may be found in patients with other disorders including those with malignancy. However, AAG is only rarely associated with malignancy such as thymoma, lung cancer or lymphoma.
Like myasthenia gravis, AAG is an antibody-mediated neurological disorder. Antibodies from patients with AAG inhibit synaptic transmission in autonomic ganglia. Animal models of AAG provide additional evidence that AAG is an antibody-mediated disorder caused by impairment of synaptic transmission in autonomic ganglia. AAG patients improve clinically when treated with therapies to reduce antibody levels (such as plasma exchange, IVIG, corticosteroids, or immunsuppression). Although symptoms improve, most patients continue to have objective evidence of severe autonomic failure.
Autoimmunity against other neuronal nicotinic or muscarinic AChR subtypes may also be important, and studies are ongoing in this area.
The Role of B Cell Activating Factor in Autoimmune Myasthenia Gravis
Robert P. Lisak, MD, Wayne State University
Autoimmune myasthenia gravis (MG) is a disease mediated by antibodies directed against molecules of the post-synaptic portion of the neuromuscular junction (NMJ), most often skeletal muscle nicotinic acetylcholine receptor (AChR). In addition, many patients with MG also have increased incidence of other organ specific and non-organ specific autoantibodies as well as other autoimmune diseases. This supports the hypothesis that MG patients have increased activity of B cells and their progeny, plasmablasts and plasma cells. B cell activating factor (BAFF) is a member of the tumor necrosis factor superfamily and is an important factor in B cell development, activation, and survival. Increased serum levels of BAFF have been reported by several groups in MG as well as in some other autoimmune diseases. BAFF is found in germinal follicles at sites of inflammation along with the chemokine CXCL13, a major chemotactic factor for B cells. Thus it is not surprising that BAFF has been found in germinal follicles within the hyperplastic thymus of patients with MG along with increased expression of CXCL13. Production of anti-AChR as well as antibodies to other antigens by cells from the thymus of patients with MG has also been reported. Several BAFF antagonists exist and treatment of patients with these might offer an additional approach to treatment of patients with MG.
Session III: Myasthenia Gravis: Clinical and Laboratory Developments
Population Differences in the Clinical Presentation and Serology of MG
Janice M. Massey, MD, Duke University Medical Center
Clinical classification of MG, epidemiologic data and serologic status define various subsets of MG. Previous studies showed 16% of patients persist with restricted ocular disease but 25% of untreated patients with generalized weakness died. Thymoma is found in 15% of patients. MG has an incidence of 14-20/100,000 and appears to be increasing in part due to better diagnosis in an aging population. While women predominate in younger and men in older populations, each increase with age, as does the incidence of MG. AChR antibodies are present in 50-80% of patients with a higher sensitivity in more severe patients. of seronegative patients, 20-40% have antibodies to MuSK. Patients with MuSK MG (MMG) are often female and may have distinct clinical and electrophysiologic patterns. While some MMG patients are indistinguishable from AChR+ MG, others show facial and bulbar weakness with marked muscle atrophy while another group has prominent neck extensor, shoulder or trunk weakness and frequent crisis. Furthermore, there are differences in response to certain treatments. Cholinesterase inhibitors may produce worsening, while a sustained improvement may occur with rituximab. The recognition of these clinical patterns among patients with MG is evolving. Further delineation by serotyping or genotyping may allow for targeting phenotypes for specific or novel therapies and provide further insights in questions of basic pathophysiology of MG.
Cell-Based Assays in Myasthenia Gravis
Angela Vincent, FRS, University of Oxford
The increasing number of antibody-mediated diseases, and the diversity of target antigens now known, make it imperative to establish diagnostic antibody assays that are sensitive, informative and distinguish between different forms of a disease or syndrome. In myasthenia gravis, antibodies to the AChR are still measured mainly by radioimmunoprecipitation as first reported by Lindstrom et al in 1976. This assay, although sensitive and specific, does not usually distinguish between antibodies to the fetal and adult forms of the AChR which can be relevant to fetal or neonatal disorders. Moreover, a proportion of those that are negative for AChR antibodies have antibodies to MuSK and a few to LRP4, so these also need to be measured separately in many cases. And there are other potential antigens at the neuromuscular junction that need to be explored.
We have performed cell-based assays for each of these antibodies. These involve expressing the antigen on the surface of live human embryonic kidney (HEK) cells by DNA transfection, and measurement of antibody binding by indirect immunofluorescence. By clustering the AChRs using co-transfection with rapsyn, we have improved the sensitivity for AChR antibodies in both generalized (Leite et al 2008) and ocular MG and shown that these antibodies are pathogenic (Jacob, et al 2012). We have also used the same approach to look for antibodies to other neuromuscular junction proteins in cohorts of patients previously negative for AChR or MuSK antibodies.
The cell-based approach offers not only increased sensitivity but also the knowledge that the antibodies are binding to the extracellular domain of the antigen and are therefore potentially pathogenic; antibodies that bind to intracellular epitopes will not be detected on the unpermeabilised live cells. In addition, they have the potential to be used for multiple antigen (multiplex) testing; mosaics of fixed HEK cells expressing different antigens can be placed together for testing each serum (as already being done for some of the CNS antigens by Euroimmun AG, Luebeck, Germany). In this manner it should be possible in the future to provide simultaneous sensitive assays for antibodies to fetal and adult AChRs, MuSK, LRP4 and other antigens in a single test.
Concentric Needle Jitter Studies
Erik Stålberg, MD, PhD, Pro.em, University Hospital Uppsala
The presence of abnormal neuromuscular jitter is the most sensitive electrophysiologic evidence of disturbed neuromuscular transmission. Jitter has usually been measured using SFEMG needle electrodes (SFE). Recently, many countries do not allow reusable electrodes, thus an alternative to the SFE must be found. The best surrogate at the moment is the smallest available concentric electrode (CNE), a so-called facial electrode. It has a recording surface area three times that of the SFE, and thus usually records from more than one muscle fiber. There is a significant risk of obtaining a summation signal from more than one muscle fiber in a motor unit. It is however possible to obtain reasonable signals mainly representing single fiber action potentials, called "apparent single muscle fiber action potentials "(ASFAP), which can be used for jitter analysis.
This method is more difficult than SFEMG in muscles with large or dense motor units, e.g. large limb muscles, and in reinnervation. In facial muscles it is easier to obtain acceptable signals.
Reference CNE jitter values have been obtained in extensor digitorumn, orbicularis and frontalis muscles. The CNE reference limits are somewhat lower than with the SFEMG electrode. The diagnostic sensitivity of CNE in MG is similar to that of SFEMG, thus very high.
The CNE can be used for jitter studies. Until more reference values have been obtained using standardized equipment, signal and measurement criteria, borderline findings should be interpreted with caution.
Management Challenges in Muscle-Specific Tyrosyne Kinase MG
Amelia Evoli, MD, Catholic University, Roma
Myasthenia gravis with antibodies to muscle-specific tyrosine kinase (MuSK-MG) is generally considered a severe disease on account of weakness distribution with prevalent involvement of bulbar muscles and a rapidly progressive course with early respiratory crises. Its treatment can be unrewarding owing to poor response to acetyl-cholinesterase inhibitors in most patients, disease relapses in spite of high-dose immunosuppression and development of permanent bulbar weakness. In a population of 75 MuSK-MG patients treated in our Institution for at least 2 years (follow-up ranging 2-35 years), the maximum MGFA clinical class was IIIb or greater in 89%, with 32% rate of respiratory crises. High-dose prednisone plus plasma-exchange, as in other forms of MG, is the recommended approach in treating rapidly progressive bulbar weakness. Maximum disease severity did not predict the disease course. Twenty patients (26.6%) suffered from two or more disease relapses while under combined immunosuppressive therapy, and 15 (20%) developed fixed facial and oro-pharyngeal weakness (most patients who developed permanent weakness also had relapsing disease). In the management of these patients, oral steroids proved effective through the whole disease course, and repeated plasma-exchange produced clear albeit short-term improvement, while conventional immunosuppressants resulted comparatively less effective. Rituximab is a very promising treatment for refractory MuSK-MG, as all treated patients, reported so far, achieved significant improvement with substantial decrease of medication. It is yet to be clarified whether the early use of rituximab could prevent the permanent oro-pharyngeal weakness which constitutes a relevant disability in these patients.
Daniel B. Drachman, MD, Johns Hopkins School of Medicine
Abstract pending
Session IV: Myasthenia Gravis: Outcome Measurements and Clinical Trial Development
MG Activities of Daily Living (ADL) Profile
Srikanth Muppidi, MD, University of Texas Southwestern Medical Center
The MG-specific Activities of Daily Living scale (MG-ADL) was developed to assess the status of symptoms and activities in MG. MG-ADL is an eight-item patient-reported questionnaire that can be completed in a few minutes without need for equipment or training. Previously in 254 MG patients, MG-ADL score was compared to quantitative MG score (QMG). MG-ADL correlates well with Quantitative MG score (r= 0.583, P < 0.001). Recently, we analyzed the performance of MG-ADL during a multicenter, prospective scale validation study. Eighty-seven patients completed the MG-ADL, MG Composite and MG-QOL15 on the first visit and 76 returned for the second visit. The mean initial MG-ADL score was 4.89 (±3.54) and improved to 3.59 (±3.3) at the second visit. At the first visit, there was a strong positive correlation between the MG-ADL and MGC (r=0.85, P < 0.0001) and the MG-QOL15 (r=0.76, P<0.0001). Correlation of the change in MG-ADL score and physician impression of change between the two visits was also strong (r= 0.70, P < 0.0001). Test-retest analysis demonstrated a high reliability coefficient. Sensitivity/specificity analysis revealed that a 2-point improvement in the MG-ADL best predicted clinical improvement. The MG-ADL correlates strongly with QMG, other newer validated MG outcome measures and a 2-point improvement in MG-ADL indicates clinical improvement. The MG-ADL is useful as a secondary outcome measure in MG treatment trials and was responsive to change MG status in recent MG treatment trials. Because of the simplicity and ease of use, MG-ADL can also be used in routine clinical management.
Michael Rose, MD, FRCP, King's College Hospital
Abstract pending
The MG Composite
Ted M. Burns, MD, University of Virginia
The "MG Composite" (MGC) scale consists of test items that measure symptoms and signs of MG, with weighted response options. The individual test items of the MGC were selected from existing MG-specific scales based on their performance during two randomized, controlled clinical trials of mycophenolate. Test items were selected so as to be meaningful to both the physician and the patient, frequently abnormal in patients with active disease, responsive to clinical change and appropriately weighted. The MGC was validated in a 175-subject study (11 sites). Total MGC scores showed excellent concurrent validity with other scales. Analyses of sensitivities and specificities of the MGC for identifying clinical improvement revealed that a 3-point improvement in MGC score was optimal for signifying clinical improvement. A 3-point improvement in the MGC appeared to be meaningful to the patient, as indicated by improved MG-QOL15 scores. The test-retest reliability coefficient was 98%, indicating excellent test-retest reliability. Rasch analysis of the MGC was also performed to investigate additional properties, including its unidimensionality and the appropriateness of the weights assigned to the response categories for the MGC items. The fit statistics indicated that the items belong together and can be summated for a total score. There was an overall absence of item order distortion between response categories. The Rasch model expected category response values were compatible with item weights previously assigned. Our Rasch analysis suggested that: 1) the score can be summated to estimate an overall disease severity score; 2) the response options of the ten items are not significantly distorted; and, 3) the assigned weights of the response options are appropriate.
Patient Registries: Useful Tools for Clinical Research in Myasthenia Gravis
Fulvio Baggi, PhD, Neurological Institute "Carlo Besta"
Clinical trials in MG are challenging, not least because of the numerous disease subcategories that must be considered: AChR-MG, MuSK-MG, Double Negative-MG, Ocular-MG, Generalized-MG, Childhood-MG, Early-and Late-Onset MG, and Thymoma-MG. MG Registries can facilitate clinical trials in several ways, including as a source of clinical, biological and immunological data on large numbers of patients, and as a source of referrals.
A European-MG database (European MG Network, Grant EU-2005105, DG SANCO) has been developed, and the Myasthenia Gravis Foundation of America is developing a patient-driven registry, to be used in support of research, advocacy and public awareness.
Physician-derived registries have the advantage of incorporating diagnostic and treatment data that may allow comparison of outcomes from different therapeutic approaches, which can be supplemented with patient self-reported data. By analyzing data on disease progression and responses to different disease management strategies, registries may help to improve disease outcomes.
We present an ongoing collaborative project involving two large physician-derived registries, the Duke MG Patient Registry (US) and the INNCB MG Registry (Italy), and our efforts to develop and implement a common platform with a core of Common Data Elements (CDE) that are concordant with an ongoing NINDS project to establish MG-specific CDEs. Registries have inherent ethical issues about privacy and data use that must be clearly discussed and presented to patients via informed consent. MG Patient Associations should play a pivotal role in disseminating information about registries and encouraging patient participation.
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