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Antibodies to the inositol 1,4,5-trisphosphate receptor type 1 (ITPR1) in cerebellar ataxia

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      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.

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      Inositol trisphosphate and calcium signalling.

       M J Berridge (1993)
      Inositol trisphosphate is a second messenger that controls many cellular processes by generating internal calcium signals. It operates through receptors whose molecular and physiological properties closely resemble the calcium-mobilizing ryanodine receptors of muscle. This family of intracellular calcium channels displays the regenerative process of calcium-induced calcium release responsible for the complex spatiotemporal patterns of calcium waves and oscillations. Such a dynamic signalling pathway controls many cellular processes, including fertilization, cell growth, transformation, secretion, smooth muscle contraction, sensory perception and neuronal signalling.
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        Recommended diagnostic criteria for paraneoplastic neurological syndromes.

        Paraneoplastic neurological syndromes (PNS) are defined by the presence of cancer and exclusion of other known causes of the neurological symptoms, but this criterion does not separate "true" PNS from neurological syndromes that are coincidental with a cancer. To provide more rigorous diagnostic criteria for PNS. An international panel of neurologists interested in PNS identified those defined as "classical" in previous studies. The panel reviewed the existing diagnostic criteria and recommended new criteria for those in whom no clinical consensus was reached in the past. The panel reviewed all reported onconeural antibodies and established the conditions to identify those that would be labelled as "well characterised". The antibody information was obtained from published work and from unpublished data from the different laboratories involved in the study. The panel suggest two levels of evidence to define a neurological syndrome as paraneoplastic: "definite" and "possible". Each level can be reached combining a set of criteria based on the presence or absence of cancer and the definitions of "classical" syndrome and "well characterised" onconeural antibody. The proposed criteria should help clinicians in the classification of their patients and the prospective and retrospective analysis of PNS cases.
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          Antibodies to the GABA(B) receptor in limbic encephalitis with seizures: case series and characterisation of the antigen.

          Some encephalitides or seizure disorders once thought idiopathic now seem to be immune mediated. We aimed to describe the clinical features of one such disorder and to identify the autoantigen involved. 15 patients who were suspected to have paraneoplastic or immune-mediated limbic encephalitis were clinically assessed. Confocal microscopy, immunoprecipitation, and mass spectrometry were used to characterise the autoantigen. An assay of HEK293 cells transfected with rodent GABA(B1) or GABA(B2) receptor subunits was used as a serological test. 91 patients with encephalitis suspected to be paraneoplastic or immune mediated and 13 individuals with syndromes associated with antibodies to glutamic acid decarboxylase 65 were used as controls. All patients presented with early or prominent seizures; other symptoms, MRI, and electroencephalography findings were consistent with predominant limbic dysfunction. All patients had antibodies (mainly IgG1) against a neuronal cell-surface antigen; in three patients antibodies were detected only in CSF. Immunoprecipitation and mass spectrometry showed that the antibodies recognise the B1 subunit of the GABA(B) receptor, an inhibitory receptor that has been associated with seizures and memory dysfunction when disrupted. Confocal microscopy showed colocalisation of the antibody with GABA(B) receptors. Seven of 15 patients had tumours, five of which were small-cell lung cancer, and seven patients had non-neuronal autoantibodies. Although nine of ten patients who received immunotherapy and cancer treatment (when a tumour was found) showed neurological improvement, none of the four patients who were not similarly treated improved (p=0.005). Low levels of GABA(B1) receptor antibodies were identified in two of 104 controls (p<0.0001). GABA(B) receptor autoimmune encephalitis is a potentially treatable disorder characterised by seizures and, in some patients, associated with small-cell lung cancer and with other autoantibodies. National Institutes of Health. Copyright 2010 Elsevier Ltd. All rights reserved.
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            Author and article information

            Affiliations
            [ ]Molecular Neuroimmunology, Department of Neurology, University of Heidelberg, Im Neuenheimer Feld 400, 69120 Heidelberg, Germany
            [ ]Institute of Experimental Immunology, affiliated to Euroimmun AG, Seekamp 31, 23560 Lübeck, Germany
            [ ]Department of Biochemistry and Molecular Biology, The University of Texas Medical School at Houston, 6431 Fannin Street, Houston, TX 77030 USA
            [ ]Leibniz Institute for Age Research/Fritz Lipmann Institute, Beutenbergstraße 11, D-07745 Jena, Germany
            [ ]Institut d’ Investigació Biomèdica August Pi i Sunyer (IDIBAPS), Villarroel 170, Barcelona, 08036 Spain
            [ ]Department of Neurology Mazarin, Hôpital Pitié-Salpêtrière, University René Descartes, 47-83, Boulevard de l’Hôpital, 75651 Paris, Cedex 13 France
            Contributors
            sven.jarius@med.uni-heidelberg.de
            m.scharf@euroimmun.de
            n.begemann@euroimmun.de
            w.stoecker@euroimmun.de
            c.probst@euroimmun.de
            irina.i.serysheva@uth.tmc.edu
            snagel@fli-leibniz.de
            fgraus@clinic.ub.es
            dimitri.psimaras@psl.aphp.fr
            brigitte.wildemann@med.uni-heidelberg.de
            l.komorowski@euroimmun.de
            Journal
            J Neuroinflammation
            J Neuroinflammation
            Journal of Neuroinflammation
            BioMed Central (London )
            1742-2094
            11 December 2014
            11 December 2014
            2014
            : 11
            : 1
            25498830
            4300617
            206
            10.1186/s12974-014-0206-3
            © Jarius et al.; licensee BioMed Central. 2014

            This is an Open Access article distributed under the terms of the Creative Commons Attribution License ( http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

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