title: Inositol 1,4,5-trisphosphate receptor type 1 autoantibodies in paraneoplastic and non-paraneoplastic peripheral neuropathy.
abstract: Recently, we described a novel autoantibody, anti-Sj/ITPR1-IgG, that targets the inositol 1,4,5-trisphosphate receptor type 1 (ITPR1) in patients with cerebellar ataxia. However, ITPR1 is expressed not only by Purkinje cells but also in the anterior horn of the spinal cord, in the substantia gelatinosa and in the motor, sensory (including the dorsal root ganglia) and autonomic peripheral nervous system, suggesting that the clinical spectrum associated with autoimmunity to ITPR1 may be broader than initially thought. Here we report on serum autoantibodies to ITPR1 (up to 1:15,000) in three patients with (radiculo)polyneuropathy, which in two cases was associated with cancer (ITPR1-expressing adenocarcinoma of the lung, multiple myeloma), suggesting a paraneoplastic aetiology.
  
  
  
  Serological and other immunological studies, and retrospective analysis of patient records.
  
  
  
  The clinical findings comprised motor, sensory (including severe pain) and autonomic symptoms. While one patient presented with subacute symptoms mimicking Guillain-Barré syndrome (GBS), the symptoms progressed slowly in two other patients. Electrophysiology revealed delayed F waves; a decrease in motor and sensory action potentials and conduction velocities; delayed motor latencies; signs of denervation, indicating sensorimotor radiculopolyneuropathy of the mixed type; and no conduction blocks. ITPR1-IgG belonged to the complement-activating IgG1 subclass in the severely affected patient but exclusively to the IgG2 subclass in the two more mildly affected patients. Cerebrospinal fluid ITPR1-IgG was found to be of predominantly extrathecal origin. A3H-thymidine-based proliferation assay confirmed the presence of ITPR1-reactive lymphocytes among peripheral blood mononuclear cells (PBMCs). Immunophenotypic profiling of PBMCs protein demonstrated predominant proliferation of B cells, CD4 T cells and CD8 memory T cells following stimulation with purified ITPR1 protein. Patient ITPR1-IgG bound both to peripheral nervous tissue and to lung tumour tissue. A nerve biopsy showed lymphocyte infiltration (including cytotoxic CD8 cells), oedema, marked axonal loss and myelin-positive macrophages, indicating florid inflammation. ITPR1-IgG serum titres declined following tumour removal, paralleled by clinical stabilization.
  
  
  
  Our findings expand the spectrum of clinical syndromes associated with ITPR1-IgG and suggest that autoimmunity to ITPR1 may underlie peripheral nervous system diseases (including GBS) in some patients and may be of paraneoplastic origin in a subset of cases.
authors: Molecular Neuroimmunology Group, Department of Neurology, University Hospital Heidelberg, Otto Meyerhof Center, Im Neuenheimer Feld 350, 69120, Heidelberg, Germany. sven.jarius@med.uni-heidelberg.de.
authors: Sven
authors: S
authors: Jarius
authors: Department of Neurology, Medical Faculty, Heinrich Heine University, Moorenstraße 5, 40225, Düsseldorf, Germany.
authors: Marius
authors: M
authors: Ringelstein
authors: Molecular Neuroimmunology Group, Department of Neurology, University Hospital Heidelberg, Otto Meyerhof Center, Im Neuenheimer Feld 350, 69120, Heidelberg, Germany.
authors: Jürgen
authors: J
authors: Haas
authors: Department of Biochemistry and Molecular Biology, The University of Texas Medical School at Houston, 6431 Fannin Street, Houston, TX, 77030, USA.
authors: Irina I
authors: II
authors: Serysheva
authors: Institute of Experimental Immunology, affiliated to Euroimmun AG, Seekamp 31, 23560, Lübeck, Germany.
authors: Lars
authors: L
authors: Komorowski
authors: Institute of Experimental Immunology, affiliated to Euroimmun AG, Seekamp 31, 23560, Lübeck, Germany.
authors: Kai
authors: K
authors: Fechner
authors: Department of Neurology, University of Schleswig Holstein, Ratzeburger Allee 160, 23538, Lübeck, Germany.
authors: Klaus-Peter
authors: KP
authors: Wandinger
authors: Department of Neurology, Medical Faculty, Heinrich Heine University, Moorenstraße 5, 40225, Düsseldorf, Germany.
authors: Philipp
authors: P
authors: Albrecht
authors: Department of Neurology, Medical Faculty, Heinrich Heine University, Moorenstraße 5, 40225, Düsseldorf, Germany.
authors: Harald
authors: H
authors: Hefter
authors: Department of Neurology, University of Schleswig Holstein, Ratzeburger Allee 160, 23538, Lübeck, Germany.
authors: Andreas
authors: A
authors: Moser
authors: Department of Neuropathology, Medical Faculty, Heinrich Heine University, Moorenstraße 5, 40225, Düsseldorf, Germany.
authors: Eva
authors: E
authors: Neuen-Jacob
authors: Department of Neurology, Medical Faculty, Heinrich Heine University, Moorenstraße 5, 40225, Düsseldorf, Germany.
authors: Hans-Peter
authors: HP
authors: Hartung
authors: Molecular Neuroimmunology Group, Department of Neurology, University Hospital Heidelberg, Otto Meyerhof Center, Im Neuenheimer Feld 350, 69120, Heidelberg, Germany.
authors: Brigitte
authors: B
authors: Wildemann
authors: Department of Neurology, Medical Faculty, Heinrich Heine University, Moorenstraße 5, 40225, Düsseldorf, Germany. orhan.aktas@uni-duesseldorf.de.
authors: Orhan
authors: O
authors: Aktas
mesh_terms: D000230:Adenocarcinoma / Q000378:metabolism / Q000473:pathology; D000328:Adult; D000368:Aged; D000818:Animals; D001323:Autoantibodies / Q000134:cerebrospinal fluid* / Q000145:classification; D049109:Cell Proliferation / Q000502:physiology; D016207:Cytokines / Q000378:metabolism; D005260:Female; D006801:Humans; D053496:Inositol 1,4,5-Trisphosphate Receptors / Q000276:immunology*; D007963:Leukocytes, Mononuclear / Q000378:metabolism / Q000473:pathology; D008175:Lung Neoplasms / Q000378:metabolism / Q000473:pathology; D008253:Macaca mulatta; D008297:Male; D008875:Middle Aged; D010523:Peripheral Nervous System Diseases / Q000134:cerebrospinal fluid* / Q000276:immunology*; D051381:Rats; D012189:Retrospective Studies; D013116:Spinal Cord / Q000378:metabolism / Q000473:pathology
chemical_list: D001323:Autoantibodies; D016207:Cytokines; C506926:ITPR1 protein, human; D053496:Inositol 1,4,5-Trisphosphate Receptors
keywords: Acute sensorimotor polyradiculopathy; Adenocarcinoma of the lung; Anti-neuronal autoantibodies; Autoimmune cerebellar ataxia; Autonomic neuropathy; Cranial nerve palsy; Facial nerve paralysis; Guillain-Barré syndrome (GBS)﻿; Inositol 1,4,5-trisphosphate type 1 receptor antibodies; Lung c﻿ancer; Multiple myeloma; Neuritis; Neuropathology; Pain; Paraneoplastic neurological syndrome; Polyneuropathy