Soon-Tae Lee1, Byoung Joo Lee2, Ji-Yeon Bae1, Young Sook Kim1, Do-Hyun Han3,4, Hyun-Sook Shin3, Soyun Kim1, Dong-Kyu Park1, Sang Won Seo5, Kon Chu1, Sang Kun Lee1, Won-Kyung Ho2,6. 1. Department of Neurology, Seoul National University Hospital, Seoul National University College of Medicine, Seoul, South Korea. 2. Department of Physiology and Neuroscience Research Center, Seoul National University College of Medicine, Seoul, South Korea. 3. Proteomics Core Facility, Seoul National University Hospital, Seoul, South Korea. 4. Proteomics & Biomarker Laboratory, Departments of Biomedical Engineering and Biomedical Sciences, Seoul National University College of Medicine, Seoul, South Korea. 5. Department of Neurology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, South Korea. 6. Department of Brain and Cognitive Sciences, Seoul National University College of Natural Sciences, Seoul, South Korea.
Abstract
OBJECTIVE: Discovery of a novel antibody would enable diagnosis and early treatment of autoimmune encephalitis. The aim was to discover a novel antibody targeting a synaptic receptor and characterize the pathogenic mechanism. METHOD: We screened for unknown antibodies in serum and cerebrospinal fluid samples from autoimmune encephalitis patients. Samples with reactivity to rat brain sections and no reactivity to conventional antibody tests underwent further processing for antibody discovery, using immunoprecipitation to primary neuronal cells, mass-spectrometry analysis, an antigen-binding assay on an antigen-overexpressing cell line, and an electrophysiological assay with cultured hippocampal neurons. RESULTS: Two patients had a novel antibody against CaV α2δ (voltage-gated calcium channel alpha-2/delta subunit). The patient samples stained neuropils of the hippocampus, basal ganglia, and cortex in rat brain sections and bound to a CaV α2δ-overexpressing cell line. Knockdown of CaV α2δ expression in cultured neurons turned off the immunoreactivity of the antibody from the patients to the neurons. The patients were associated with preceding meningitis or neuroendocrine carcinoma and responded to immunotherapy. In cultured neurons, the antibody reduced neurotransmitter release from presynaptic nerve terminals by interfering with tight coupling of calcium channels and exocytosis. INTERPRETATION: Here, we discovered a novel autoimmune encephalitis associated with anti-CaV α2δ antibody. Further analysis of the antibody in autoimmune encephalitis might promote early diagnosis and treatment. ANN NEUROL 2021;89:740-752.
OBJECTIVE: Discovery of a novel antibody would enable diagnosis and early treatment of autoimmune encephalitis. The aim was to discover a novel antibody targeting a synaptic receptor and characterize the pathogenic mechanism. METHOD: We screened for unknown antibodies in serum and cerebrospinal fluid samples from autoimmune encephalitispatients. Samples with reactivity to rat brain sections and no reactivity to conventional antibody tests underwent further processing for antibody discovery, using immunoprecipitation to primary neuronal cells, mass-spectrometry analysis, an antigen-binding assay on an antigen-overexpressing cell line, and an electrophysiological assay with cultured hippocampal neurons. RESULTS: Two patients had a novel antibody against CaV α2δ (voltage-gated calcium channel alpha-2/delta subunit). The patient samples stained neuropils of the hippocampus, basal ganglia, and cortex in rat brain sections and bound to a CaV α2δ-overexpressing cell line. Knockdown of CaV α2δ expression in cultured neurons turned off the immunoreactivity of the antibody from the patients to the neurons. The patients were associated with preceding meningitis or neuroendocrine carcinoma and responded to immunotherapy. In cultured neurons, the antibody reduced neurotransmitter release from presynaptic nerve terminals by interfering with tight coupling of calcium channels and exocytosis. INTERPRETATION: Here, we discovered a novel autoimmune encephalitis associated with anti-CaV α2δ antibody. Further analysis of the antibody in autoimmune encephalitis might promote early diagnosis and treatment. ANN NEUROL 2021;89:740-752.
Authors: Shehrazade Dahimene; Leonie von Elsner; Tess Holling; Lauren S Mattas; Jess Pickard; Davor Lessel; Kjara S Pilch; Ivan Kadurin; Wendy S Pratt; Igor B Zhulin; Hongzheng Dai; Maja Hempel; Maura R Z Ruzhnikov; Kerstin Kutsche; Annette C Dolphin Journal: Brain Date: 2022-08-27 Impact factor: 15.255