title: Antibodies to inositol 1,4,5-triphosphate receptor 1 in patients with cerebellar disease.
abstract: OBJECTIVE
  To describe newly identified autoantibodies associated with cerebellar disorders.
  
  
  METHODS
  We first screened the sera of 15 patients with cerebellar ataxia, without any known associated autoantibodies, with immunocytochemistry on mouse brain. After characterization and validation of a newly identified antibody, 85 additional patients with suspected autoimmune cerebellar disease were screened using a cell-based assay.
  
  
  RESULTS
  Immunoglobulin G from one of the first 15 patients demonstrated a distinct staining pattern on Purkinje neurons. This autoantibody, as characterized further by immunoprecipitation and mass spectrometry, was binding inositol 1,4,5-triphosphate receptor 1 (IP3R1), an intracellular channel that mediates the release of Ca2+from intracellular stores. Anti-IP3R1 specificity was then validated with a cell-based assay. On this basis, screening of 85 other patients with cerebellar disease revealed 2 additional IP3R1-positive patients. All 3 patients presented with cerebellar ataxia; the first was eventually diagnosed with primary progressive multiple sclerosis, the second had a homozygous CAG insertion at the geneTBP, and the third was thought to have a neurodegenerative disease.
  
  
  CONCLUSIONS
  We independently identified an autoantibody against IP3R1, a protein highly expressed in Purkinje neurons, confirming an earlier report. Because a mouse knockout model for IP3R1 exhibits ataxia and epilepsy, this autoantibody may have a functional role. The heterogeneity of the antibody-positive patients suggests that this antibody may either have a direct involvement in disease pathogenesis or it is a surrogate marker secondary to cerebellar injury. Anti-IP3R1 antibodies should be further explored in various ataxic and epileptic syndromes as they may denote a marker of response to immunotherapies.
authors.affiliation: Neuroimmunology Unit, Department of Pathophysiology, Faculty of Medicine (P.F., H.A., I.C., A.T., M.C.D.), and Department of Biology (S.G.D.), National and Kapodistrian University of Athens; Department of Molecular Oncology (M.S., G.P.), B.S.R.C. "Alexander Fleming," Athens; and Center of Basic Research (P.P.), Biomedical Research Foundation of the Academy of Athens, Greece.
authors.forename: Penelope
authors.initials: P
authors.lastname: Fouka
authors.affiliation: Neuroimmunology Unit, Department of Pathophysiology, Faculty of Medicine (P.F., H.A., I.C., A.T., M.C.D.), and Department of Biology (S.G.D.), National and Kapodistrian University of Athens; Department of Molecular Oncology (M.S., G.P.), B.S.R.C. "Alexander Fleming," Athens; and Center of Basic Research (P.P.), Biomedical Research Foundation of the Academy of Athens, Greece.
authors.forename: Harry
authors.initials: H
authors.lastname: Alexopoulos
authors.affiliation: Neuroimmunology Unit, Department of Pathophysiology, Faculty of Medicine (P.F., H.A., I.C., A.T., M.C.D.), and Department of Biology (S.G.D.), National and Kapodistrian University of Athens; Department of Molecular Oncology (M.S., G.P.), B.S.R.C. "Alexander Fleming," Athens; and Center of Basic Research (P.P.), Biomedical Research Foundation of the Academy of Athens, Greece.
authors.forename: Ioanna
authors.initials: I
authors.lastname: Chatzi
authors.affiliation: Neuroimmunology Unit, Department of Pathophysiology, Faculty of Medicine (P.F., H.A., I.C., A.T., M.C.D.), and Department of Biology (S.G.D.), National and Kapodistrian University of Athens; Department of Molecular Oncology (M.S., G.P.), B.S.R.C. "Alexander Fleming," Athens; and Center of Basic Research (P.P.), Biomedical Research Foundation of the Academy of Athens, Greece.
authors.forename: Skarlatos G
authors.initials: SG
authors.lastname: Dedos
authors.affiliation: Neuroimmunology Unit, Department of Pathophysiology, Faculty of Medicine (P.F., H.A., I.C., A.T., M.C.D.), and Department of Biology (S.G.D.), National and Kapodistrian University of Athens; Department of Molecular Oncology (M.S., G.P.), B.S.R.C. "Alexander Fleming," Athens; and Center of Basic Research (P.P.), Biomedical Research Foundation of the Academy of Athens, Greece.
authors.forename: Martina
authors.initials: M
authors.lastname: Samiotaki
authors.affiliation: Neuroimmunology Unit, Department of Pathophysiology, Faculty of Medicine (P.F., H.A., I.C., A.T., M.C.D.), and Department of Biology (S.G.D.), National and Kapodistrian University of Athens; Department of Molecular Oncology (M.S., G.P.), B.S.R.C. "Alexander Fleming," Athens; and Center of Basic Research (P.P.), Biomedical Research Foundation of the Academy of Athens, Greece.
authors.forename: George
authors.initials: G
authors.lastname: Panayotou
authors.affiliation: Neuroimmunology Unit, Department of Pathophysiology, Faculty of Medicine (P.F., H.A., I.C., A.T., M.C.D.), and Department of Biology (S.G.D.), National and Kapodistrian University of Athens; Department of Molecular Oncology (M.S., G.P.), B.S.R.C. "Alexander Fleming," Athens; and Center of Basic Research (P.P.), Biomedical Research Foundation of the Academy of Athens, Greece.
authors.forename: Panagiotis
authors.initials: P
authors.lastname: Politis
authors.affiliation: Neuroimmunology Unit, Department of Pathophysiology, Faculty of Medicine (P.F., H.A., I.C., A.T., M.C.D.), and Department of Biology (S.G.D.), National and Kapodistrian University of Athens; Department of Molecular Oncology (M.S., G.P.), B.S.R.C. "Alexander Fleming," Athens; and Center of Basic Research (P.P.), Biomedical Research Foundation of the Academy of Athens, Greece.
authors.forename: Athanasios
authors.initials: A
authors.lastname: Tzioufas
authors.affiliation: Neuroimmunology Unit, Department of Pathophysiology, Faculty of Medicine (P.F., H.A., I.C., A.T., M.C.D.), and Department of Biology (S.G.D.), National and Kapodistrian University of Athens; Department of Molecular Oncology (M.S., G.P.), B.S.R.C. "Alexander Fleming," Athens; and Center of Basic Research (P.P.), Biomedical Research Foundation of the Academy of Athens, Greece.
authors.forename: Marinos C
authors.initials: MC
authors.lastname: Dalakas