title: Antibodies to the inositol 1,4,5-trisphosphate receptor type 1 (ITPR1) in cerebellar ataxia.
abstract: We report on a serum autoantibody associated with cerebellar ataxia. Immunohistochemical studies of sera from four patients referred for autoantibody testing revealed binding of high-titer (up to 1:5,000) IgG antibodies, mainly IgG1, to the molecular layer, Purkinje cell layer, and white matter on mouse, rat, porcine, and monkey cerebellum sections. The antibody bound to PC somata, dendrites, and axons, resulting in a binding pattern similar to that reported for anti-Ca/anti-ARHGAP26, but did not react with recombinant ARHGAP26. Extensive control studies were performed to rule out a broad panel of previously described paraneoplastic and non-paraneoplastic anti-neural autoantibodies. The characteristic binding pattern as well as double staining experiments suggested inositol 1,4,5-trisphosphate receptor type 1 (ITPR1) as the target antigen. Verification of the antigen included specific neutralization of the tissue reaction following preadsorption with ITPR1 (but not ARHGAP26) and a dot-blot assay with purified ITPR1 protein. By contrast, anti-ARHGAP26-positive sera did not bind to ITPR1. In a parallel approach, a combination of histoimmunoprecipitation and mass spectrometry also identified ITPR1 as the target antigen. Finally, a recombinant cell-based immunofluorescence assay using HEK293 cells expressing ITPR1 and ARHGAP26, respectively, confirmed the identification of ITPR1. Mutations of ITPR1 have previously been implicated in spinocerebellar ataxia with and without cognitive decline. Our findings suggest a role of autoimmunity against ITPR1 in the pathogenesis of autoimmune cerebellitis and extend the panel of diagnostic markers for this disease.
authors.affiliation: Molecular Neuroimmunology, Department of Neurology, University of Heidelberg, Im Neuenheimer Feld 400, 69120, Heidelberg, Germany. sven.jarius@med.uni-heidelberg.de.
authors.forename: Sven
authors.initials: S
authors.lastname: Jarius
authors.affiliation: Institute of Experimental Immunology, affiliated to Euroimmun AG, Seekamp 31, 23560, Lübeck, Germany. m.scharf@euroimmun.de.
authors.forename: Madeleine
authors.initials: M
authors.lastname: Scharf
authors.affiliation: Institute of Experimental Immunology, affiliated to Euroimmun AG, Seekamp 31, 23560, Lübeck, Germany. n.begemann@euroimmun.de.
authors.forename: Nora
authors.initials: N
authors.lastname: Begemann
authors.affiliation: Institute of Experimental Immunology, affiliated to Euroimmun AG, Seekamp 31, 23560, Lübeck, Germany. w.stoecker@euroimmun.de.
authors.forename: Winfried
authors.initials: W
authors.lastname: Stöcker
authors.affiliation: Institute of Experimental Immunology, affiliated to Euroimmun AG, Seekamp 31, 23560, Lübeck, Germany. c.probst@euroimmun.de.
authors.forename: Christian
authors.initials: C
authors.lastname: Probst
authors.affiliation: Department of Biochemistry and Molecular Biology, The University of Texas Medical School at Houston, 6431 Fannin Street, Houston, TX, 77030, USA. irina.i.serysheva@uth.tmc.edu.
authors.forename: Irina I
authors.initials: II
authors.lastname: Serysheva
authors.affiliation: Leibniz Institute for Age Research/Fritz Lipmann Institute, Beutenbergstraße 11, D-07745, Jena, Germany. snagel@fli-leibniz.de.
authors.forename: Sigrun
authors.initials: S
authors.lastname: Nagel
authors.affiliation: Institut d' Investigació Biomèdica August Pi i Sunyer (IDIBAPS), Villarroel 170, Barcelona, 08036, Spain. fgraus@clinic.ub.es.
authors.forename: Francesc
authors.initials: F
authors.lastname: Graus
authors.affiliation: Department of Neurology Mazarin, Hôpital Pitié-Salpêtrière, University René Descartes, 47-83, Boulevard de l'Hôpital, 75651, Paris, Cedex 13, France. dimitri.psimaras@psl.aphp.fr.
authors.forename: Dimitri
authors.initials: D
authors.lastname: Psimaras
authors.affiliation: Molecular Neuroimmunology, Department of Neurology, University of Heidelberg, Im Neuenheimer Feld 400, 69120, Heidelberg, Germany. brigitte.wildemann@med.uni-heidelberg.de.
authors.forename: Brigitte
authors.initials: B
authors.lastname: Wildemann
authors.affiliation: Institute of Experimental Immunology, affiliated to Euroimmun AG, Seekamp 31, 23560, Lübeck, Germany. l.komorowski@euroimmun.de.
authors.forename: Lars
authors.initials: L
authors.lastname: Komorowski
mesh_terms: D000328:Adult; D000818:Animals; D001323:Autoantibodies / Q000032:analysis / Q000276:immunology / Q000378:metabolism*; D002524:Cerebellar Ataxia / Q000175:diagnosis* / Q000276:immunology / Q000378:metabolism*; D005260:Female; D057809:HEK293 Cells; D006801:Humans; D053496:Inositol 1,4,5-Trisphosphate Receptors / Q000032:analysis / Q000276:immunology / Q000378:metabolism*; D008253:Macaca mulatta; D051379:Mice; D051381:Rats; D013552:Swine
chemical_list: D001323:Autoantibodies; C506926:ITPR1 protein, human; D053496:Inositol 1,4,5-Trisphosphate Receptors