A Novel Autoantibody against Plexin D1 in Patients with Neuropathic Pain
Takayuki Fujii MD
Department of Neurology, Neurological Institute, Graduate School of Medical Sciences, Kyushu University, Fukuoka
Search for more papers by this authorRyo Yamasaki MD, PhD
Department of Neurology, Neurological Institute, Graduate School of Medical Sciences, Kyushu University, Fukuoka
Search for more papers by this authorKyoko Iinuma MS
Department of Neurology, Neurological Institute, Graduate School of Medical Sciences, Kyushu University, Fukuoka
Search for more papers by this authorDaisuke Tsuchimoto PhD
Department of Immunobiology and Neuroscience, Medical Institute of Bioregulation, Kyushu University, Fukuoka
Search for more papers by this authorYoshinori Hayashi PhD
Department of Aging Science and Pharmacology, Graduate School of Dental Science, Kyushu University, Fukuoka
Search for more papers by this authorBan-yu Saitoh MD
Department of Neurology, Neurological Institute, Graduate School of Medical Sciences, Kyushu University, Fukuoka
Search for more papers by this authorTakuya Matsushita MD, PhD
Department of Neurology, Neurological Institute, Graduate School of Medical Sciences, Kyushu University, Fukuoka
Search for more papers by this authorMizuho A. Kido DDS, PhD
Department of Anatomy and Physiology, Faculty of Medicine, Saga University, Saga
Search for more papers by this authorShinichi Aishima MD, PhD
Department of Pathology and Microbiology, Faculty of Medicine, Saga University, Saga
Search for more papers by this authorHiroshi Nakanishi PhD
Department of Pharmacology, Faculty of Pharmaceutical Sciences, Yasuda Women's University, Hiroshima, Japan
Search for more papers by this authorYusaku Nakabeppu DVM, PhD
Department of Immunobiology and Neuroscience, Medical Institute of Bioregulation, Kyushu University, Fukuoka
Search for more papers by this authorCorresponding Author
Jun-ichi Kira MD, PhD
Department of Neurology, Neurological Institute, Graduate School of Medical Sciences, Kyushu University, Fukuoka
Address correspondence to Dr Kira, Department of Neurology, Neurological Institute, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan. E-mail: [email protected]Search for more papers by this authorTakayuki Fujii MD
Department of Neurology, Neurological Institute, Graduate School of Medical Sciences, Kyushu University, Fukuoka
Search for more papers by this authorRyo Yamasaki MD, PhD
Department of Neurology, Neurological Institute, Graduate School of Medical Sciences, Kyushu University, Fukuoka
Search for more papers by this authorKyoko Iinuma MS
Department of Neurology, Neurological Institute, Graduate School of Medical Sciences, Kyushu University, Fukuoka
Search for more papers by this authorDaisuke Tsuchimoto PhD
Department of Immunobiology and Neuroscience, Medical Institute of Bioregulation, Kyushu University, Fukuoka
Search for more papers by this authorYoshinori Hayashi PhD
Department of Aging Science and Pharmacology, Graduate School of Dental Science, Kyushu University, Fukuoka
Search for more papers by this authorBan-yu Saitoh MD
Department of Neurology, Neurological Institute, Graduate School of Medical Sciences, Kyushu University, Fukuoka
Search for more papers by this authorTakuya Matsushita MD, PhD
Department of Neurology, Neurological Institute, Graduate School of Medical Sciences, Kyushu University, Fukuoka
Search for more papers by this authorMizuho A. Kido DDS, PhD
Department of Anatomy and Physiology, Faculty of Medicine, Saga University, Saga
Search for more papers by this authorShinichi Aishima MD, PhD
Department of Pathology and Microbiology, Faculty of Medicine, Saga University, Saga
Search for more papers by this authorHiroshi Nakanishi PhD
Department of Pharmacology, Faculty of Pharmaceutical Sciences, Yasuda Women's University, Hiroshima, Japan
Search for more papers by this authorYusaku Nakabeppu DVM, PhD
Department of Immunobiology and Neuroscience, Medical Institute of Bioregulation, Kyushu University, Fukuoka
Search for more papers by this authorCorresponding Author
Jun-ichi Kira MD, PhD
Department of Neurology, Neurological Institute, Graduate School of Medical Sciences, Kyushu University, Fukuoka
Address correspondence to Dr Kira, Department of Neurology, Neurological Institute, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan. E-mail: [email protected]Search for more papers by this authorAbstract
Objective
To identify novel autoantibodies for neuropathic pain (NeP).
Methods
We screened autoantibodies that selectively bind to mouse unmyelinated C-fiber type dorsal root ganglion (DRG) neurons using tissue-based indirect immunofluorescence assays (IFA) with sera from 110 NeP patients with various inflammatory and allergic neurologic diseases or other neuropathies, and 50 controls without NeP including 20 healthy subjects and 30 patients with neurodegenerative diseases or systemic inflammatory diseases. IgG purified from IFA-positive patients' sera was subjected to Western blotting (WB) and immunoprecipitation (IP) using mouse DRG lysates. Immunoprecipitates were analyzed by liquid chromatography tandem mass spectrometry (LC-MS/MS) to identify target autoantigens.
Results
Antiunmyelinated C-fiber type DRG neuron antibodies were more frequent in patients with NeP than non-NeP subjects (10% vs 0%; p < 0.05). These autoantibodies were all from the IgG2 subclass and colocalized mostly with isolectin B4- and P2X3-positive pain-conducting small neurons but not with S100β-positive myelinated neurons. WB revealed a common immunoreactive band (approximately 220kDa). IP and LC-MS/MS studies identified plexin D1 as a target autoantigen. Immunoadsorption tests with recombinant human plexin D1 in IFA revealed that all 11 anti–small DRG neuron antibody-positive patients had anti–plexin D1 antibodies. Application of anti–plexin D1 antibody-positive patient sera to cultured DRG neurons increased membrane permeability, leading to cellular swelling. NeP patients with anti–plexin D1 antibodies commonly developed burning pain and current perception threshold abnormalities for C-fibers. Main comorbidities were atopy and collagen-vascular disease. Immunotherapies ameliorated NeP in 7 treated cases.
Interpretation
Anti–plexin D1 antibodies are a novel biomarker for immunotherapy-responsive NeP. Ann Neurol 2018;84:208–224
Potential Conflicts of Interest
Nothing to report.
Supporting Information
| Filename | Description |
|---|---|
| ana25279-sup-0001-SupInfo.docxWord 2007 document , 28 KB |
Supplementary Table 1. Antibodies used for immunohistochemistry Supplementary Table 2. Results of anti-plexin D1 antibody detection Supplementary Table 3. Clinical and laboratory findings of patients with anti-plexin D1 antibodies Supplementary Table 4. Summary of clinical findings for 11 patients with anti-plexin D1 antibodies |
Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.
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