Autoimmunity Against Novel Antigens in Neuropsychiatric Dysfunction

Summary

Principal Investigator: Josep O Dalmau
Abstract: DESCRIPTION (provided by applicant): We propose to characterize the autoimmune responses to neuronal cell surface and synaptic proteins that result in catatonia, autistic behaviors and other neuropsychiatric disturbances. In 2007, we reported a group of young women who acutely developed psychotic behavior or schizophrenia-like symptoms, subsequently followed by memory defects, catatonia, abnormal movements, and autonomic dysfunction. Using a set of techniques that we optimized, we found that all patients had antibodies against the NR1 subunit of the N- methyl-D-aspartate receptor (NMDAR), a glutamate receptor involved in synaptic transmission and plasticity. In about 60% of these patients, the trigger of the immune response was an ovarian teratoma that contained ectopic nervous tissue expressing NMDAR. Since that report, the number of patients with this disorder has rapidly increased, and similar clinical and laboratory strategies applied to patients with other neuropsychiatric disorders have resulted in the discovery of 6 novel immune responses to cell surface/synaptic autoantigens, including among others the GluR1/2 subunits of the AMPA receptor (AMPAR), the GABA(B1) receptor (GABA(B1)R), Leucine rich glioma inactivated 1 (LGI1) and Contactin associated protein 2 (Caspr2). This work is significant because: 1) the disorders affect young adults, including men and children with or without tumors;2) they are responsive to immunotherapy;3) some antibodies define new syndromes;4) the characterization of the antigens has resulted in unambiguous diagnostic tests;and 5) patient antibodies have titer dependent and reversible effects on the function of the target receptors / proteins. Overall, these findings have led to the hypothesis that many subacute psychiatric disorders of unknown etiology, including catatonia or autistic behaviors, either alone or in association with other neurologic manifestations, are likely mediated by antibodies that affect neurotransmitter receptors at cell surface or synaptic sites. We will test this hypothesis in 3 goals. (1) We will select patients with one of 3 disorders for which we have preliminary evidence of serum or CSF antibodies to cell surface/synaptic proteins: rapidly progressive neuropsychiatric disorders with catatonic features, the spectrum of acquired rapidly progressive autistic behavior in children and adults, and limbic encephalopathy in children and adolescents. (2) We will identify the autoantigens in these 3 disorders, using highly sensitive methods we have developed and optimized to detect neuronal cell surface / synaptic antigens;and (3) We will use in vitro and in vivo studies to determine how patients'antibodies against novel cell surface/synaptic antigens affect neuron and synaptic structure and function, and how these recover after antibodies are removed. We will establish the autoimmune processes that lead to catatonia, autistic features, and limbic encephalopathy and the underlying cellular and synaptic mechanisms. Identification of autoimmune mechanisms will result in improved therapeutic interventions for these disorders in children and adults that will have a significant health impact and reduce the burden of neurological and neuropsychiatric disease.
Funding Period: 2011-08-01 - 2015-04-30
more information: NIH RePORT

Top Publications

  1. pmc Investigations of caspr2, an autoantigen of encephalitis and neuromyotonia
    Eric Lancaster
    Department of Neurology, University of Pennsylvania School of Medicine, Philadelphia, 19104, USA
    Ann Neurol 69:303-11. 2011
  2. pmc Persistent intrathecal antibody synthesis 15 years after recovering from anti-N-methyl-D-aspartate receptor encephalitis
    Hans Christian Hansen
    Department of Neurology and Psychiatry, Friedrich Ebert Hospital, Neumunster, Germany
    JAMA Neurol 70:117-9. 2013
  3. ncbi A novel treatment-responsive encephalitis with frequent opsoclonus and teratoma
    Thais Armangue
    Neurology Service, Hospital Clinic, August Pi i Sunyer Biomedical Research Institute University of Barcelona, Barcelona, Spain Pediatric Neurology Service, Vall d Hebron Maternal Infant Hospital, Autonomous University of Barcelona, Barcelona, Spain
    Ann Neurol 75:435-41. 2014
  4. pmc Anti-N-methyl-D-aspartate-glutamic-receptor encephalitis presenting as paroxysmal exercise-induced foot weakness
    Angelo Labate
    Institute of Neurology University Magna Graecia, Catanzaro, Italy
    Mov Disord 28:820-2. 2013
  5. pmc Clinical Neuropathology practice guide 4-2013: post-herpes simplex encephalitis: N-methyl-Daspartate receptor antibodies are part of the problem
    Romana Hoftberger
    Institute of Neurology, Medical University of Vienna, Austria
    Clin Neuropathol 32:251-4. 2013
  6. pmc Autoimmunity, seizures, and status epilepticus
    Rebecca Davis
    Department of Neurology, University of Pennsylvania, Philadelphia, PA, U S A
    Epilepsia 54:46-9. 2013
  7. ncbi Determination of neuronal antibodies in suspected and definite Creutzfeldt-Jakob disease
    Oriol Grau-Rivera
    Service of Neurology, Hospital Clinic, Barcelona, Spain
    JAMA Neurol 71:74-8. 2014
  8. ncbi Encephalitis with refractory seizures, status epilepticus, and antibodies to the GABAA receptor: a case series, characterisation of the antigen, and analysis of the effects of antibodies
    Mar Petit-Pedrol
    August Pi i Sunyer Biomedical Research Institute IDIBAPS, Barcelona, Spain Hospital Clínic, University of Barcelona, Barcelona, Spain
    Lancet Neurol 13:276-86. 2014
  9. pmc Autoimmune encephalitis update
    Josep Dalmau
    Institució Catalana de Recerca i Estudis Avançats ICREA at Institut d Investigació Biomèdica August Pi i Sunyer IDIBAPS, Department of Neurology, Hospital Clinic, University of Barcelona, Barcelona, Spain J D Hospital Clínic IDIBAPS, Department of Neurology, Barcelona, Spain M R R
    Neuro Oncol 16:771-8. 2014
  10. pmc Autoimmune encephalitis as differential diagnosis of infectious encephalitis
    Thais Armangue
    aAugust Pi i Sunyer Biomedical Research Institute IDIBAPS, Service of Neurology, Hospital Clinic, University of Barcelona bCatalan Institution for Research and Advanced Studies ICREA, Barcelona, Spain cDepartment of Neurology, University of Pennsylvania, Philadelphia, USA
    Curr Opin Neurol 27:361-8. 2014

Research Grants

  1. Emory Alzheimer's Disease Center
    Allan I Levey; Fiscal Year: 2013
  2. Plasticity at the Excitatory Synapse
    Richard L Huganir; Fiscal Year: 2013
  3. Paraneoplastic Disorders of the CNS: Autoantigen Profiling
    Josep O Dalmau; Fiscal Year: 2013
  4. Alzheimer's Disease Research Center
    Douglas R Galasko; Fiscal Year: 2013
  5. Molecular Mechanisms linking Aging, Abeta Proteotoxicity and Neurodegeneration
    Jeffery W Kelly; Fiscal Year: 2013
  6. Center for Narcolepsy and Related Disorders (P50)
    Emmanuel J Mignot; Fiscal Year: 2013
  7. MOLECULAR ETIOLOGY OF EARLY ONSET TORSION DYSTONIA
    XANDRA OWENS BREAKEFIELD; Fiscal Year: 2013
  8. Intellectual and Development Disabilities Research Center
    Marc Yudkoff; Fiscal Year: 2013
  9. Vermont Center on Behavior and Health
    Stephen T Higgins; Fiscal Year: 2013
  10. Antineuronal antibodies in autoimmune neurological disease
    JOHN EDWARD GREENLEE; Fiscal Year: 2013

Detail Information

Publications26

  1. pmc Investigations of caspr2, an autoantigen of encephalitis and neuromyotonia
    Eric Lancaster
    Department of Neurology, University of Pennsylvania School of Medicine, Philadelphia, 19104, USA
    Ann Neurol 69:303-11. 2011
    ....
  2. pmc Persistent intrathecal antibody synthesis 15 years after recovering from anti-N-methyl-D-aspartate receptor encephalitis
    Hans Christian Hansen
    Department of Neurology and Psychiatry, Friedrich Ebert Hospital, Neumunster, Germany
    JAMA Neurol 70:117-9. 2013
    ..Anti- N-methyl-D-aspartate receptor (NMDAR) encephalitis is a severe autoimmune disorder characterized by high intrathecal antibody synthesis. Little is known about the long-term follow-up of the cerebrospinal fluid antibody status...
  3. ncbi A novel treatment-responsive encephalitis with frequent opsoclonus and teratoma
    Thais Armangue
    Neurology Service, Hospital Clinic, August Pi i Sunyer Biomedical Research Institute University of Barcelona, Barcelona, Spain Pediatric Neurology Service, Vall d Hebron Maternal Infant Hospital, Autonomous University of Barcelona, Barcelona, Spain
    Ann Neurol 75:435-41. 2014
    ..The triad of young age (teenager to young adult), systemic teratoma, and high response to treatment characterize this novel brainstem-cerebellar syndrome...
  4. pmc Anti-N-methyl-D-aspartate-glutamic-receptor encephalitis presenting as paroxysmal exercise-induced foot weakness
    Angelo Labate
    Institute of Neurology University Magna Graecia, Catanzaro, Italy
    Mov Disord 28:820-2. 2013
    ..Patients with anti-N-methyl-D-aspartate-glutamic-receptors (NMDAR) encephalitis often develop complex abnormal movements that may manifest early in the course of illness...
  5. pmc Clinical Neuropathology practice guide 4-2013: post-herpes simplex encephalitis: N-methyl-Daspartate receptor antibodies are part of the problem
    Romana Hoftberger
    Institute of Neurology, Medical University of Vienna, Austria
    Clin Neuropathol 32:251-4. 2013
    ..It is important to be aware of this differential diagnosis because patients respond to immunotherapy. ..
  6. pmc Autoimmunity, seizures, and status epilepticus
    Rebecca Davis
    Department of Neurology, University of Pennsylvania, Philadelphia, PA, U S A
    Epilepsia 54:46-9. 2013
    ..This review focuses on the novel group of autoimmune encephalitis and also discusses some classical paraneoplastic syndromes that constitute another group of autoimmune disorders that may result in seizures. ..
  7. ncbi Determination of neuronal antibodies in suspected and definite Creutzfeldt-Jakob disease
    Oriol Grau-Rivera
    Service of Neurology, Hospital Clinic, Barcelona, Spain
    JAMA Neurol 71:74-8. 2014
    ..Establishing the correct diagnosis has practical implications in the management of care for these patients...
  8. ncbi Encephalitis with refractory seizures, status epilepticus, and antibodies to the GABAA receptor: a case series, characterisation of the antigen, and analysis of the effects of antibodies
    Mar Petit-Pedrol
    August Pi i Sunyer Biomedical Research Institute IDIBAPS, Barcelona, Spain Hospital Clínic, University of Barcelona, Barcelona, Spain
    Lancet Neurol 13:276-86. 2014
    ..We aimed to describe the clinical features of a new epileptic disorder, and to establish the target antigen and the effects of patients' antibodies on neuronal cultures...
  9. pmc Autoimmune encephalitis update
    Josep Dalmau
    Institució Catalana de Recerca i Estudis Avançats ICREA at Institut d Investigació Biomèdica August Pi i Sunyer IDIBAPS, Department of Neurology, Hospital Clinic, University of Barcelona, Barcelona, Spain J D Hospital Clínic IDIBAPS, Department of Neurology, Barcelona, Spain M R R
    Neuro Oncol 16:771-8. 2014
    ..As early treatment speeds recovery, reduces disability, and decreases relapses that can occur in about 20% of cases, it is important that the immune pathogenesis of these disorders is recognized. ..
  10. pmc Autoimmune encephalitis as differential diagnosis of infectious encephalitis
    Thais Armangue
    aAugust Pi i Sunyer Biomedical Research Institute IDIBAPS, Service of Neurology, Hospital Clinic, University of Barcelona bCatalan Institution for Research and Advanced Studies ICREA, Barcelona, Spain cDepartment of Neurology, University of Pennsylvania, Philadelphia, USA
    Curr Opin Neurol 27:361-8. 2014
    ..This review describes the main types of autoimmune encephalitis with special emphasis on those associated with antibodies against neuronal cell surface or synaptic proteins, and the differential diagnosis with infectious encephalitis...
  11. pmc N-methyl-D-aspartate receptor antibodies in herpes simplex encephalitis
    Harald Prüss
    Department of Neurology, Charite University Medicine Berlin, Chariteplatz 1, Berlin, Germany
    Ann Neurol 72:902-11. 2012
    ..To determine the presence and kinetics of antibodies against synaptic proteins in patients with herpes simplex virus encephalitis (HSE)...
  12. pmc Encephalitis and antibodies to dipeptidyl-peptidase-like protein-6, a subunit of Kv4.2 potassium channels
    Anna Boronat
    Institute of Biomedical Research August Pi i Sunyer and Service of Neurology, Hospital Clinic, University of Barcelona, Spain
    Ann Neurol 73:120-8. 2013
    ..To report a novel cell surface autoantigen of encephalitis that is a critical regulatory subunit of the Kv4.2 potassium channels...
  13. pmc Anti-N-methyl-D-aspartate receptor encephalitis: a newly recognized inflammatory brain disease in children
    Nadia Luca
    University of Toronto and Hospital for Sick Children, Toronto, Ontario, Canada
    Arthritis Rheum 63:2516-22. 2011
    ..The present study was undertaken to describe characteristic clinical features and outcomes in children diagnosed as having anti-NMDAR encephalitis...
  14. ncbi Analysis of antibodies to surface epitopes of contactin-2 in multiple sclerosis
    Anna Boronat
    Center for Neuroimmunology, Service of Neurology, Hospital Clinic and Institut d Investigació Biomèdica August Pi i Sunyer, Universitat de Barcelona, Barcelona, Spain
    J Neuroimmunol 244:103-6. 2012
    ..In conclusion, contactin-2-ab are identified in a minority of MS patients but their presence is not associated with a particular clinical-radiological profile...
  15. pmc The frequency of autoimmune N-methyl-D-aspartate receptor encephalitis surpasses that of individual viral etiologies in young individuals enrolled in the California Encephalitis Project
    Mary S Gable
    Communicable Disease and Emergency Response Branch, Division of Communicable Disease Control, California Department of Public Health, Richmond, CA 94804, USA
    Clin Infect Dis 54:899-904. 2012
    ..We report here the relative frequency and differences among encephalitides caused by anti-NMDAR and viral etiologies within the CEP experience...
  16. pmc Reversible paraneoplastic encephalitis in three patients with ovarian neoplasms
    Janos L Tanyi
    Division of Gynecologic Oncology, University of Pennsylvania Health System, Philadelphia, PA, USA
    Acta Obstet Gynecol Scand 91:630-4. 2012
    ..Our experience suggests that prompt syndrome recognition followed by tumor removal and immunotherapy usually results in neurological recovery...
  17. pmc Neuronal autoantigens--pathogenesis, associated disorders and antibody testing
    Eric Lancaster
    Department of Neurology, 3 W Gates, 3400 Spruce Street, University of Pennsylvania, Philadelphia, PA 19104, USA
    Nat Rev Neurol 8:380-90. 2012
    ..We also provide an algorithm to identify and assess antibodies that bind to cell-surface and synaptic antigens...
  18. pmc Anti-NMDA receptor encephalitis antibody binding is dependent on amino acid identity of a small region within the GluN1 amino terminal domain
    Amy J Gleichman
    Department of Neurology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA
    J Neurosci 32:11082-94. 2012
    ..These findings provide tools for detailed comparison of antibodies across patients and suggest an interaction between antibody binding and channel function...
  19. pmc Extreme delta brush: a unique EEG pattern in adults with anti-NMDA receptor encephalitis
    Sarah E Schmitt
    PENN Epilepsy Center, Department of Neurology, Hospital of the University of Pennsylvania, Philadelphia, USA
    Neurology 79:1094-100. 2012
    ..To determine continuous EEG (cEEG) patterns that may be unique to anti-NMDA receptor (NMDAR) encephalitis in a series of adult patients with this disorder...
  20. pmc Autoimmune encephalitis in children
    Thais Armangue
    Institut d Investigacio Biomedica August Pi i Sunyer IDIBAPS, Service of Neurology, Hospital Clinic, University of Barcelona, Barcelona, Spain
    J Child Neurol 27:1460-9. 2012
    ..Recognition of novel immune-mediated encephalitis is important because some of these disorders are highly responsive to immunotherapy...
  21. pmc Glycine receptor autoimmune spectrum with stiff-man syndrome phenotype
    Andrew McKeon
    Department of Neurology, Mayo Clinic, Rochester, Minnesota, USA
    JAMA Neurol 70:44-50. 2013
    ....
  22. pmc Pediatric anti-N-methyl-D-aspartate receptor encephalitis-clinical analysis and novel findings in a series of 20 patients
    Thais Armangue
    Institut d Investigacio Biomedica August Pi i Sunyer IDIBAPS, Service of Neurology, Hospital Clinic, University of Barcelona, Barcelona, Spain
    J Pediatr 162:850-856.e2. 2013
    ..To report the clinical features of 20 pediatric patients with anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis...
  23. ncbi Acute mechanisms underlying antibody effects in anti-N-methyl-D-aspartate receptor encephalitis
    Emilia H Moscato
    Department of Neuroscience, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA
    Ann Neurol 76:108-19. 2014
    ..However, acute effects of the antibodies, fate of the internalized receptors, type of neurons affected, and whether neurons develop compensatory homeostatic mechanisms were unknown and are the focus of this study...

Research Grants30

  1. Emory Alzheimer's Disease Center
    Allan I Levey; Fiscal Year: 2013
    ..abstract_text> ..
  2. Plasticity at the Excitatory Synapse
    Richard L Huganir; Fiscal Year: 2013
    ..Understanding these basic mechanisms of synaptic transmission and plasticity will provide insight into normal and abnormal brain function. ..
  3. Paraneoplastic Disorders of the CNS: Autoantigen Profiling
    Josep O Dalmau; Fiscal Year: 2013
    ....
  4. Alzheimer's Disease Research Center
    Douglas R Galasko; Fiscal Year: 2013
    ..It will provide an environment and core resources to enhance research, foster professional and community training, and coordinate interdisciplinary research. ..
  5. Molecular Mechanisms linking Aging, Abeta Proteotoxicity and Neurodegeneration
    Jeffery W Kelly; Fiscal Year: 2013
    ..abstract_text> ..
  6. Center for Narcolepsy and Related Disorders (P50)
    Emmanuel J Mignot; Fiscal Year: 2013
    ..We also want to understand why the immune system destroys hypocretin neurons in narcolepsy and to prevent/cure it. ..
  7. MOLECULAR ETIOLOGY OF EARLY ONSET TORSION DYSTONIA
    XANDRA OWENS BREAKEFIELD; Fiscal Year: 2013
    ..Nutan Sharma. These integrated studies capitalize on the extensive and complementary expertise of this group focused on the molecular etiology and pathophysiology of early onset dystonia. ..
  8. Intellectual and Development Disabilities Research Center
    Marc Yudkoff; Fiscal Year: 2013
    ..5 million from NICHD). The Center includes an excess of 70 Penn faculty at 15 departments at the Schools of Medicine, Veterinary Medicine, Nursing, the Wistar Institute, and the College of Arts and Sciences. ..
  9. Vermont Center on Behavior and Health
    Stephen T Higgins; Fiscal Year: 2013
    ..S. public health. ..
  10. Antineuronal antibodies in autoimmune neurological disease
    JOHN EDWARD GREENLEE; Fiscal Year: 2013
    ..Information gained from the research should also be of value in understanding the role of antibody-neuron interactions in host defense against infection and in immunotherapy of degenerative neurological diseases. ..
  11. Neuroplasticity Associated with Acute Toluene Inhalation
    JACOB THOMAS BECKLEY; Fiscal Year: 2013
    ..Results from these experiments will help determine the neurological substrates of toluene's abuse potential. ..
  12. Aptamer Imaging: A Theranostic Approach to Treat Substance Abuse
    Philip K Liu; Fiscal Year: 2013
    ..Because transcription factor binding domains are conserved from rodents to humans, our innovative technique, once validated, has potential for theranostic application, from rodents to primates. ..
  13. Stress, Depression, Serotonin, and Plasticity of Excitatory Transmission
    Scott M Thompson; Fiscal Year: 2013
    ..The normal function of this system is not well understood. Our experiments are designed to better understand the role played by this system in information processing in the healthy brain and how it may malfunction in mental illness. ..
  14. CRCNS: Modeling Activation of CaMKII in Spines
    Terrence J Sejnowski; Fiscal Year: 2013
    ..abstract_text> ..