Glutamic Acid Decarboxylase (GAD) Autoimmunity in Batten Disease

Glutamic Acid Decarboxylase (GAD) Autoimmunity in Batten Disease
National Institute of Neurological Disorders and Stroke
Hyatt Regency Hotel
Bethesda, Maryland, USA
November 13-14, 2003

1. Overview
2. Recommendations
3. Agenda
4. Participant List

1. Overview
   
   The National Institute of Neurological Disorders and Stroke (NINDS), the Office of Rare Diseases (ORD), and the National Institute of Diabetes and Digestive and Kidney Disease (NIDDK) co-sponsored this workshop. This workshop was organized by Dr. Danilo A. Tagle (NINDS), Dr. David Pearce (University of Rochester), Dr. Mark Atkinson (University of Florida), and Dr. Rose-Mary Boustany (Duke University). The workshop addressed key questions and issues regarding key discoveries in Batten Disease research, in particular the recent observation of GAD65 autoimmunity in juvenile ceroid lipofuscinosis (JNCL) patients and in animal models. The workshop served effectively to facilitate the exchange and integration of ideas, information and technologies from experts in Batten disease, type I diabetes, Stiff Person syndrome (SPS), Rasmussen's encephalitis and autoimmunity in the CNS (see Meeting Agenda). The goals of this workshop were to determine the scientific criteria that are necessary to measure the contribution of GAD65 autoantibodies to the pathological consequence of JNCL, to critically evaluate research to date on the autoimmune response in JNCL, to assess the role and contribution that mouse models to JNCL may have on understanding other diseases such as type I diabetes and SPS, to evaluate the efficacy of instituting treatments directed toward a pathological autoantibody in JNCL, to determine if end-points are in place for assessment of a putative-JNCL therapy. The speakers were tasked to consider these points in their presentations and to engage the participants in a meaningful and productive discussion after each session topic.
   
   The purpose of this workshop was to discuss the implications and to follow-up on strategies from research findings by NINDS grantee Dr. David. Pearce of the University of Rochester School of Medicine and Dentistry in New York where he demonstrated that mice lacking the gene that is mutated in juvenile Batten disease have an immune reaction against an important enzyme in the brain. Similar immune reactions were found in children with Batten disease. The enzyme, called glutamic acid decarboxylase 65 (GAD65), normally converts excitatory neurotransmitter glutamate into the inhibitory neurotransmitter GABA. These autoantibodies could be indicative of an autoimmune attack against GAD, which could result in excess excitatory neurotransmitter, leading to the seizures and other symptoms observed in Batten patients. The study is the first to find evidence that the immune system may play a role in Batten disease and provides new insights into the pathogenesis of Batten disease. This study was published in Human Molecular Genetics (Chattopadhyay, S., Ito, M., Cooper, J.D., et al. An autoantibody inhibitory to glutamic acid decarboxylase in the neurodegenerative disorder Batten disease, 2002; 11:1421-1431. An NINDS press release about this finding is available on the web at http://www.ninds.nih.gov/news_and_events/pressrelease_batten_052202.htm. A follow up study was later published in Chattopadhyay, S, Kriscenski-Perry, E., Wenger, D.A., Pearce, D.A. An autoantibody to GAD65 in sera of patients with juvenile neuronal ceroid lipofuscinoses. Neurology. 2002; 59:1816-1817. The redefinition of Batten disease as an autoimmune disorder could have radical implications for the treatment of Batten.
   
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2. Recommendations
   
   The workshop brought together neuroscientists, immunologists and clinicians who work on Batten disease and on a variety of autoimmune diseases, such as multiple sclerosis, Stiff Person Syndrome, Rasmussen's encephalitis, and type I diabetes. The attendees' response to the workshop was overwhelmingly positive. In addition to generating spirited discussion among researchers of different fields, who might not otherwise interact, several new collaborations were forged and valuable resources were offered for sharing.
   
   The group concluded that Pearce's result is intriguing, but will require certain key follow-up experiments in order to conclude that Batten is an autoimmune disease. Autoantibodies can be present in an individual without causing disease-the fundamental question is whether the GAD autoantibodies are activating T-cells to trigger a full-fledged immune response. There are two gold-standard experiments to address this question. The first is to remove the autoantibodies from a patient via plasma exchange and determine if the patient's condition improves (a test of whether the autoantibodies are necessary to develop the disease). The second is to inject the autoantibodies into a healthy mouse and determine whether it then develops the disease (a test of whether the autoantibodies are sufficient to confer the disease). Although there was some discussion of whether such experiments were warranted at this time, most workshop participants seemed satisfied with Dr. Pearce's plans to conduct preliminary experiments using transgenic mouse models. He will cross mouse mutants that carry Batten disease mutations with mice that have an impaired immune system. If the physical effects of Batten are in fact due primarily to an immune response, then these mice should not develop the full Batten phenotype.
   
   The following are the outstanding issues that the group indicated should be addressed in assessing the potential autoimmune nature of Batten Disease:
   
   
   • What are the specific roles, if any, for humoral and cellular immune responses in the pathogenesis of Batten disease?
   • Other than GAD65, what additional neuronal molecules serve as antigenic targets of autoantibodies?
   • Are studies of immune based therapies (e.g., plasma exchange, immunosuppression) warranted for Batten patients at this time?
   • Are there associations between Batten disease and other putative autoimmune disorders (i.e., is there a clustering with other autoimmune diseases or one autoimmune disorder in particular)?
   • What is the exact function of the CLN3 molecule in the pathogenesis of Batten Disease?
   • Given their demonstrative ability to inhibit enzymatic activity in vitro, do GAD autoantibodies in Batten disease interfere with GABAergic regulation in vivo?
   • If autoimmune in basis, why does the development of Batten disease occur in such a protracted form?
   • Why does anti-GAD immunity represent such a common feature to a variety of clinical disorders?
   
   A review of the field and relevant discussions from the workshop is published in the Journal Neurology
   
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3. Agenda
   
   8:00 - 8:30 a.m.
   Continental Breakfast/Registration
   
   8:30 - 8:45 a.m.
   Welcome Remarks by NINDS Deputy Director, Dr. Audrey Penn (mp3 - 487 KB)
   Statement of Workshop Goals, Danilo A. Tagle
   
   8:45 - 10:25 a.m.
   Session 1 - Immunology of the Nervous System and Immune Mechanisms Underlying Autoimmune Neurological Diseases
   Chair: David Pearce, University of Rochester
   
   Wolfgang Streit, University of Florida - Microglia: The Brain's Immune System (mp3 - 4,051 KB)
   Hugo Moser, John Hopkins University - Brain Inflammatory Responses in X-linked Adrenoleukodystrophy (mp3 - 3,737 KB)
   Angela Vincent, University of Oxford, UK - Antibody-mediated Neurological Diseases (mp3 - 3,146 KB)
   Darrel Lewis, Duke University - Autoimmunity in Rasmussen's Encephalitis (mp3 - 2,708 KB)
   (Discussion 20 minutes, 5 minutes after each talk)
   
   10:25 - 10:45 a.m.
   Break
   
   10:45 - 12:15 p.m.
   Session 2 - Glutamic Acid Decarboxylase: Role in Autoimmune Disease and Autoimmunity
   Chair: Rose-Mary Boustany, Duke University
   
   Hans-Michael Dosch, Sick Kids, Toronto - Neuronal Elements of Type I Diabetic Autoimmunity (mp3 unavailable)
   David Hafler, Harvard Medical School, - T-cell reactivity to GAD in Patients with IDDM (mp3 - 3,335 KB)
   Ed Leiter, Jackson Labs, - Human GAD65 over expressed in NOD/Lt beta cells by transgenesis: Effects on pathogenesis (mp3 - 2,952 KB)
   (Discussion 30 minutes, 10 minutes after each talk)
   
   12:15 - 1:15 p.m.
   Lunch
   
   1:15 - 2:45 p.m.
   Session 3 - JNCL: Is There a GAD Autoimmune Component to This Disease?
   
   What is JNCL? Chair: Mark Atkinson, University of Florida
   
   Rose-Mary Boustany, Duke University, - JNCL: The disease and the CLN3 protein (mp3 unavailable)
   Steven Walkley, Einstein, - Pathology associated to JNCL (mp3 - 4,433 KB)
   Beverly Davidson, University of Iowa, - Animal Models of JNCL and CLN3 Cell Biology (mp3 - 2,250 KB)
   
   2:45 - 3:05 p.m.
   Break
   
   3:05 - 5:00 p.m.
   Session 4 - JNCL: Is There a GAD Autoimmune Component to This Disease? Studies on GAD Autoimmunity in JNCL
   Chair: Rose-Mary Boustany, Duke University
   
   David Pearce, University of Rochester, - Biochemical Evidence of an Autoimmune Component in JNCL and Studies on GAD65 Autoantibodies in Batten Disease (mp3 - 911 KB) (mp3 - 5,211 KB)
   Jonathan Cooper, Kings College London - Immune responses in the CNS of murine and human JNCL (mp3 - 5,632 KB)
   
   (Discussion 60 minutes) "What Studies Need To Be Addressed in Evaluating the Potential Pathogenicity of GAD Autoantibodies in Batten Disease?
   
   Friday, November 14, 2003
   
   8:00 - 8:30 a.m.
   Continental Breakfast/Registration
   
   8:30 - 10:30 a.m.
   Session 5 - Human Autoimmune Disease: Predictive and Therapeutic Strategies Involving GAD
   Chair: Mark Atkinson, University of Florida
   
   Mark Atkinson, University of Florida, - GAD Antibodies and T cells as Predictive Markers in Type I Diabetes (mp3 - 3,415 KB)
   
   Matthew During, University of Auckland, - Studies on GAD gene transfer and vaccination (mp3 - 2,962 KB)
   
   Christiane Hampe, University of Washington, - GAD Therapeutics in Humans with Type I Diabetes, LADA, and SPS (mp3 - 2,047 KB)
   
   Marinos Dalakas, NINDS, - High-Dose Intravenous Immune Globulin for SPS (mp3 - 4,481 KB)
   
   (Discussion 40 minutes, 10 minutes after each talk)
   
   10:30 - 10:45 a.m.
   Break
   
   10:45 - 12:00 p.m.
   Final Session - Recommendations (mp3 - 7147 KB)
   Discussion leaders: David Pearce, Rose-Mary Boustany, and Mark Atkinson
   • Future research priorities
   • Potential collaborations
   • Funding strategies
   
   12:00 - 1:00 p.m.
   Lunch
   
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4. Participant List

   Beena Akolkar, Ph.D.
   National Institute of Diabetes, Digestive and Kidney Diseases
   National Institutes of Health

   Mark Atkinson, Ph.D.
   University of Florida

   Ronald Bellisario, Ph.D.
   New York State Department of Health

   Rose-Mary Boustany, M.D.
   Duke University Medical Center

   Julian Castaneda, B.S., B.A.
   University of Rochester School of Medicine and Dentistry

   Jonathan Cooper, Ph.D.
   Kings College London Institute of Psychiatry

   Marinos Dalakas, M.D.
   National Institute of Neurological Disorders and Stroke
   National Institutes of Health

   Beverly Davidson, Ph.D.
   University of Iowa

   Hans-Michael Dosch, M.D., Ph.D.
   The Hospital for Sick Children

   Matthew During, M.D., D.Sc.
   University of Auckland

   Anders Essen-Moller, MSc.
   Diamyd Medical AB

   Rebecca Farkas, Ph.D.
   National Institute of Neurological Disorders and Stroke
   National Institutes of Health

   David Hafler, M.D.
   Harvard Medical School

   Christine Hampe, Ph.D.
   University of Washington, Seattle

   Lance Johnston
   Batten Disease Support and Research Association

   Story Landis, Ph.D.
   National Institute of Neurological Disorders and Stroke
   National Institutes of Health

   Edward Leiter, Ph.D.
   The Jackson Laboratory

   Darrell Lewis, M.D.
   Duke University Medical Center

   Qiang Li, M.D., Ph.D.
   Duke University Medical Center

   Ming Lim, BMBS, M.D.
   Institute of Psychiatry, London

   Kathleen Monahan
   Battens Disease Support and Research Association

   Ann Moser
   Johns Hopkins University & Kennedy Krieger Institute

   Hugo Moser, M.D.
   Kennedy Krieger Institute

   David A. Pearce, Ph.D.
   University of Rochester School of Medicine and Dentistry

   Audrey Penn, M.D.
   National Institute of Neurological Disorders and Stroke
   National Institutes of Health

   Pat Pfaller
   Observer

   Raghavan Raja, Ph.D.
   National Institute of Neurological Disorders and Stroke
   National Institutes of Health

   Denia Ramirez-Montealegre, M.D.
   University of Rochester School of Medicine and Dentistry

   John Robertson, Ph.D.
   Diamyd Medical AB

   James Stables
   National Institute of Neurological Disorders and Stroke
   National Institutes of Health

   Wolfgang Streit, Ph.D.
   University of Florida College of Medicine

   Danilo Tagle, Ph.D.
   National Institute of Neurological Disorders and Stroke
   National Institutes of Health

   Angela Vincent, M.B., B.S., M.S.c.
   University of Oxford

   Steven Walkley, DVM, Ph.D.
   Albert Einstein College of Medicine

   Clive Wasserfall, M.S.
   University of Florida

   Melinda Watson
   Luke and Rachel Batten Disease Research Foundation

   Sam Watson
   Luke and Rachel Batten Disease Research Foundation

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