title: Intrathecal immunoglobulin A and G antibodies to synapsin in a patient with limbic encephalitis.
abstract: OBJECTIVE
  To report on the identification of intrathecally synthesized immunoglobulin A (IgA) and immunoglobulin G (IgG) antibodies to synapsin, a synaptic vesicle-associated protein, in a patient with limbic encephalitis.
  
  
  METHODS
  Methods included clinical characterization, indirect immunofluorescence, immunoprecipitation, mass spectrometry, immunoblots of wild-type and synapsin I/II/III knockout mice, and cell-based assays with synapsin Ia, Ib, IIa, and IIb plasmids.
  
  
  RESULTS
  A 69-year-old man presented with confusion, disorientation, seizures, and left hippocampal hyperintensities on MRI. CSF examinations revealed an intrathecal IgA and IgG synthesis. Except for IgG antibodies to voltage-gated potassium channels in CSF, screening for known neuronal autoantibodies in serum and CSF was negative. However, indirect immunofluorescence using the patient's CSF showed binding of IgA to mouse hippocampus, amygdala, and cerebellum. Immunoprecipitation with CSF IgA followed by mass spectrometry identified synapsin as autoantigenic target. Knockout tissues and cell-based assays confirmed that IgA and IgG in the patient's CSF and serum reacted with synapsin Ia, Ib, and IIa. Calculation of antibody indices proved intrathecal synthesis of anti-synapsin IgA and IgG. The patient responded clinically to immunotherapy but developed left hippocampal atrophy. CSF IgA or IgG of the patient did not bind to live, unfixed, and nonpermeabilized mouse hippocampal neurons, compatible with synapsin being an intracellular antigen.
  
  
  CONCLUSIONS
  This report identifies isoforms of the synaptic vesicle-associated protein synapsin as targets of intrathecally produced IgA and IgG antibodies in a patient with limbic encephalitis. Future studies should clarify the prevalence and pathogenic relevance of anti-synapsin antibodies in limbic encephalitis.
authors.affiliation: Department of Neurology (J.P., K.R.) and Institute for Integrative Neuroanatomy (M.H., J.-F.Z., G.A.-H.), Charité-Universitätsmedizin Berlin; St. Josefs-Krankenhaus Potsdam (C.O., H.H.), Germany; the Department of Neuroscience and Brain Technologies (A.S., F.C., F.B.), Istituto Italiano di Tecnologia, Genova, Italy; the Department of Physiology and Cell Biology (D.G.), Faculty of Health Sciences and Zlotowski Center for Neuroscience, Ben-Gurion University of the Negev, Beer-Sheva, Israel; and the Institute of Toxicology (A.P.), Hannover Medical School, Germany.
authors.forename: Johannes
authors.initials: J
authors.lastname: Piepgras
authors.affiliation: Department of Neurology (J.P., K.R.) and Institute for Integrative Neuroanatomy (M.H., J.-F.Z., G.A.-H.), Charité-Universitätsmedizin Berlin; St. Josefs-Krankenhaus Potsdam (C.O., H.H.), Germany; the Department of Neuroscience and Brain Technologies (A.S., F.C., F.B.), Istituto Italiano di Tecnologia, Genova, Italy; the Department of Physiology and Cell Biology (D.G.), Faculty of Health Sciences and Zlotowski Center for Neuroscience, Ben-Gurion University of the Negev, Beer-Sheva, Israel; and the Institute of Toxicology (A.P.), Hannover Medical School, Germany.
authors.forename: Markus
authors.initials: M
authors.lastname: Höltje
authors.affiliation: Department of Neurology (J.P., K.R.) and Institute for Integrative Neuroanatomy (M.H., J.-F.Z., G.A.-H.), Charité-Universitätsmedizin Berlin; St. Josefs-Krankenhaus Potsdam (C.O., H.H.), Germany; the Department of Neuroscience and Brain Technologies (A.S., F.C., F.B.), Istituto Italiano di Tecnologia, Genova, Italy; the Department of Physiology and Cell Biology (D.G.), Faculty of Health Sciences and Zlotowski Center for Neuroscience, Ben-Gurion University of the Negev, Beer-Sheva, Israel; and the Institute of Toxicology (A.P.), Hannover Medical School, Germany.
authors.forename: Carolin
authors.initials: C
authors.lastname: Otto
authors.affiliation: Department of Neurology (J.P., K.R.) and Institute for Integrative Neuroanatomy (M.H., J.-F.Z., G.A.-H.), Charité-Universitätsmedizin Berlin; St. Josefs-Krankenhaus Potsdam (C.O., H.H.), Germany; the Department of Neuroscience and Brain Technologies (A.S., F.C., F.B.), Istituto Italiano di Tecnologia, Genova, Italy; the Department of Physiology and Cell Biology (D.G.), Faculty of Health Sciences and Zlotowski Center for Neuroscience, Ben-Gurion University of the Negev, Beer-Sheva, Israel; and the Institute of Toxicology (A.P.), Hannover Medical School, Germany.
authors.forename: Hendrik
authors.initials: H
authors.lastname: Harms
authors.affiliation: Department of Neurology (J.P., K.R.) and Institute for Integrative Neuroanatomy (M.H., J.-F.Z., G.A.-H.), Charité-Universitätsmedizin Berlin; St. Josefs-Krankenhaus Potsdam (C.O., H.H.), Germany; the Department of Neuroscience and Brain Technologies (A.S., F.C., F.B.), Istituto Italiano di Tecnologia, Genova, Italy; the Department of Physiology and Cell Biology (D.G.), Faculty of Health Sciences and Zlotowski Center for Neuroscience, Ben-Gurion University of the Negev, Beer-Sheva, Israel; and the Institute of Toxicology (A.P.), Hannover Medical School, Germany.
authors.forename: Annyesha
authors.initials: A
authors.lastname: Satapathy
authors.affiliation: Department of Neurology (J.P., K.R.) and Institute for Integrative Neuroanatomy (M.H., J.-F.Z., G.A.-H.), Charité-Universitätsmedizin Berlin; St. Josefs-Krankenhaus Potsdam (C.O., H.H.), Germany; the Department of Neuroscience and Brain Technologies (A.S., F.C., F.B.), Istituto Italiano di Tecnologia, Genova, Italy; the Department of Physiology and Cell Biology (D.G.), Faculty of Health Sciences and Zlotowski Center for Neuroscience, Ben-Gurion University of the Negev, Beer-Sheva, Israel; and the Institute of Toxicology (A.P.), Hannover Medical School, Germany.
authors.forename: Fabrizia
authors.initials: F
authors.lastname: Cesca
authors.affiliation: Department of Neurology (J.P., K.R.) and Institute for Integrative Neuroanatomy (M.H., J.-F.Z., G.A.-H.), Charité-Universitätsmedizin Berlin; St. Josefs-Krankenhaus Potsdam (C.O., H.H.), Germany; the Department of Neuroscience and Brain Technologies (A.S., F.C., F.B.), Istituto Italiano di Tecnologia, Genova, Italy; the Department of Physiology and Cell Biology (D.G.), Faculty of Health Sciences and Zlotowski Center for Neuroscience, Ben-Gurion University of the Negev, Beer-Sheva, Israel; and the Institute of Toxicology (A.P.), Hannover Medical School, Germany.
authors.forename: Fabio
authors.initials: F
authors.lastname: Benfenati
authors.affiliation: Department of Neurology (J.P., K.R.) and Institute for Integrative Neuroanatomy (M.H., J.-F.Z., G.A.-H.), Charité-Universitätsmedizin Berlin; St. Josefs-Krankenhaus Potsdam (C.O., H.H.), Germany; the Department of Neuroscience and Brain Technologies (A.S., F.C., F.B.), Istituto Italiano di Tecnologia, Genova, Italy; the Department of Physiology and Cell Biology (D.G.), Faculty of Health Sciences and Zlotowski Center for Neuroscience, Ben-Gurion University of the Negev, Beer-Sheva, Israel; and the Institute of Toxicology (A.P.), Hannover Medical School, Germany.
authors.forename: Daniel
authors.initials: D
authors.lastname: Gitler
authors.affiliation: Department of Neurology (J.P., K.R.) and Institute for Integrative Neuroanatomy (M.H., J.-F.Z., G.A.-H.), Charité-Universitätsmedizin Berlin; St. Josefs-Krankenhaus Potsdam (C.O., H.H.), Germany; the Department of Neuroscience and Brain Technologies (A.S., F.C., F.B.), Istituto Italiano di Tecnologia, Genova, Italy; the Department of Physiology and Cell Biology (D.G.), Faculty of Health Sciences and Zlotowski Center for Neuroscience, Ben-Gurion University of the Negev, Beer-Sheva, Israel; and the Institute of Toxicology (A.P.), Hannover Medical School, Germany.
authors.forename: Andreas
authors.initials: A
authors.lastname: Pich
authors.affiliation: Department of Neurology (J.P., K.R.) and Institute for Integrative Neuroanatomy (M.H., J.-F.Z., G.A.-H.), Charité-Universitätsmedizin Berlin; St. Josefs-Krankenhaus Potsdam (C.O., H.H.), Germany; the Department of Neuroscience and Brain Technologies (A.S., F.C., F.B.), Istituto Italiano di Tecnologia, Genova, Italy; the Department of Physiology and Cell Biology (D.G.), Faculty of Health Sciences and Zlotowski Center for Neuroscience, Ben-Gurion University of the Negev, Beer-Sheva, Israel; and the Institute of Toxicology (A.P.), Hannover Medical School, Germany.
authors.forename: Johannes-Friedrich
authors.initials: JF
authors.lastname: Zander
authors.affiliation: Department of Neurology (J.P., K.R.) and Institute for Integrative Neuroanatomy (M.H., J.-F.Z., G.A.-H.), Charité-Universitätsmedizin Berlin; St. Josefs-Krankenhaus Potsdam (C.O., H.H.), Germany; the Department of Neuroscience and Brain Technologies (A.S., F.C., F.B.), Istituto Italiano di Tecnologia, Genova, Italy; the Department of Physiology and Cell Biology (D.G.), Faculty of Health Sciences and Zlotowski Center for Neuroscience, Ben-Gurion University of the Negev, Beer-Sheva, Israel; and the Institute of Toxicology (A.P.), Hannover Medical School, Germany.
authors.forename: Gudrun
authors.initials: G
authors.lastname: Ahnert-Hilger
authors.affiliation: Department of Neurology (J.P., K.R.) and Institute for Integrative Neuroanatomy (M.H., J.-F.Z., G.A.-H.), Charité-Universitätsmedizin Berlin; St. Josefs-Krankenhaus Potsdam (C.O., H.H.), Germany; the Department of Neuroscience and Brain Technologies (A.S., F.C., F.B.), Istituto Italiano di Tecnologia, Genova, Italy; the Department of Physiology and Cell Biology (D.G.), Faculty of Health Sciences and Zlotowski Center for Neuroscience, Ben-Gurion University of the Negev, Beer-Sheva, Israel; and the Institute of Toxicology (A.P.), Hannover Medical School, Germany.
authors.forename: Klemens
authors.initials: K
authors.lastname: Ruprecht