Human cerebrospinal fluid monoclonal CASPR2 autoantibodies induce changes in electrophysiology, functional MRI, and behavior in rodent models.

Autor: van Hoof S; German Center for Neurodegenerative Diseases (DZNE) Berlin, 10117 Berlin, Germany; Department of Neurology and Experimental Neurology, Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität Berlin, 10117 Berlin, Germany; Helmholtz Innovation Lab BaoBab (Brain Antibody-omics and B-cell Lab), Berlin, Germany., Kreye J; German Center for Neurodegenerative Diseases (DZNE) Berlin, 10117 Berlin, Germany; Department of Neurology and Experimental Neurology, Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität Berlin, 10117 Berlin, Germany; Helmholtz Innovation Lab BaoBab (Brain Antibody-omics and B-cell Lab), Berlin, Germany; Department of Pediatric Neurology, Charité-Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany; Berlin Institute of Health at Charité - Universitätsmedizin Berlin, Charitéplatz 1, 10117 Berlin, Germany., Cordero-Gómez C; German Center for Neurodegenerative Diseases (DZNE) Berlin, 10117 Berlin, Germany; Department of Neurology and Experimental Neurology, Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität Berlin, 10117 Berlin, Germany., Hoffmann J; German Center for Neurodegenerative Diseases (DZNE) Berlin, 10117 Berlin, Germany; Department of Neurology and Experimental Neurology, Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität Berlin, 10117 Berlin, Germany., Momsen Reincke S; German Center for Neurodegenerative Diseases (DZNE) Berlin, 10117 Berlin, Germany; Department of Neurology and Experimental Neurology, Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität Berlin, 10117 Berlin, Germany; Berlin Institute of Health at Charité - Universitätsmedizin Berlin, Charitéplatz 1, 10117 Berlin, Germany., Sánchez-Sendin E; German Center for Neurodegenerative Diseases (DZNE) Berlin, 10117 Berlin, Germany; Department of Neurology and Experimental Neurology, Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität Berlin, 10117 Berlin, Germany; Helmholtz Innovation Lab BaoBab (Brain Antibody-omics and B-cell Lab), Berlin, Germany., Duong SL; German Center for Neurodegenerative Diseases (DZNE) Berlin, 10117 Berlin, Germany; Department of Neurology and Experimental Neurology, Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität Berlin, 10117 Berlin, Germany., Upadhya M; Institute of Health and Neurodevelopment, College of Health and Life Sciences, Aston University, Birmingham, UK., Dhangar D; Institute of Health and Neurodevelopment, College of Health and Life Sciences, Aston University, Birmingham, UK., Michór P; Institute of Health and Neurodevelopment, College of Health and Life Sciences, Aston University, Birmingham, UK., Woodhall GL; Institute of Health and Neurodevelopment, College of Health and Life Sciences, Aston University, Birmingham, UK., Küpper M; Oscar Langendorff Institute of Physiology, University of Rostock, Germany, Center of Transdisciplinary Neurosciences Rostock (CTNR), Germany., Oder A; Screening Unit, Leibniz Forschungsinstitut für Molekulare Pharmakologie, 13125 Berlin, Germany., Kuchling J; Department of Neurology and Experimental Neurology, Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität Berlin, 10117 Berlin, Germany; Neurocure Cluster of Excellence, NeuroCure Clinical Research Center, Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Germany., Koch SP; Department of Neurology and Experimental Neurology, Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität Berlin, 10117 Berlin, Germany; Center for Stroke Research Charité Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Germany; NeuroCure Cluster of Excellence and Charité Core Facility 7T Experimental MRIs, Charité - Universitätsmedizin Berlin, Germany; Charité 3R, Replace, Reduce, Refine, Charité - Universitätsmedizin Berlin, Germany., Mueller S; Department of Neurology and Experimental Neurology, Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität Berlin, 10117 Berlin, Germany; Center for Stroke Research Charité Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Germany; NeuroCure Cluster of Excellence and Charité Core Facility 7T Experimental MRIs, Charité - Universitätsmedizin Berlin, Germany; Charité 3R, Replace, Reduce, Refine, Charité - Universitätsmedizin Berlin, Germany., Boehm-Sturm P; Department of Neurology and Experimental Neurology, Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität Berlin, 10117 Berlin, Germany; Center for Stroke Research Charité Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Germany; NeuroCure Cluster of Excellence and Charité Core Facility 7T Experimental MRIs, Charité - Universitätsmedizin Berlin, Germany; Charité 3R, Replace, Reduce, Refine, Charité - Universitätsmedizin Berlin, Germany., von Kries JP; Screening Unit, Leibniz Forschungsinstitut für Molekulare Pharmakologie, 13125 Berlin, Germany., Finke C; Department of Neurology and Experimental Neurology, Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität Berlin, 10117 Berlin, Germany; Neurocure Cluster of Excellence, NeuroCure Clinical Research Center, Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Germany., Kirschstein T; Oscar Langendorff Institute of Physiology, University of Rostock, Germany, Center of Transdisciplinary Neurosciences Rostock (CTNR), Germany., Wright SK; Institute of Health and Neurodevelopment, College of Health and Life Sciences, Aston University, Birmingham, UK; Department of Paediatric Neurology, The Birmingham Women's and Children's Hospital National Health Service Foundation Trust, Birmingham, UK., Prüss H; German Center for Neurodegenerative Diseases (DZNE) Berlin, 10117 Berlin, Germany; Department of Neurology and Experimental Neurology, Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität Berlin, 10117 Berlin, Germany; Helmholtz Innovation Lab BaoBab (Brain Antibody-omics and B-cell Lab), Berlin, Germany. Electronic address: harald.pruess@charite.de.
Jazyk: angličtina
Zdroj: Brain, behavior, and immunity [Brain Behav Immun] 2024 Nov; Vol. 122, pp. 266-278. Date of Electronic Publication: 2024 Aug 13.
DOI: 10.1016/j.bbi.2024.08.027
Abstrakt: Anti-contactin associated protein receptor 2 (CASPR2) encephalitis is a severe autoimmune encephalitis with a variable clinical phenotype including behavioral abnormalities, cognitive decline, epileptic seizures, peripheral nerve hyperexcitability and neuropathic pain. The detailed mechanisms of how CASPR2 autoantibodies lead to synaptic dysfunction and clinical symptoms are largely unknown. Aiming for analyses from the molecular to the clinical level, we isolated antibody-secreting cells from the cerebrospinal fluid of two patients with CASPR2 encephalitis. From these we cloned four anti-CASPR2 human monoclonal autoantibodies (mAbs) with strong binding to brain and peripheral nerves. All were highly hypermutated and mainly of the IgG4 subclass. Mutagenesis studies determined selective binding to the discoidin domain of CASPR2. Surface plasmon resonance revealed affinities with dissociation constants K D in the pico- to nanomolar range. CASPR2 mAbs interrupted the interaction of CASPR2 with its binding partner contactin 2 in vitro and were internalized after binding to CASPR2-expressing cells. Electrophysiological recordings of rat hippocampal slices after stereotactic injection of CASPR2 mAbs showed characteristic afterpotentials following electrical stimulation. In vivo experiments with intracerebroventricular administration of human CASPR2 mAbs into mice and rats showed EEG-recorded brain hyperexcitability but no spontaneous recurrent seizures. Behavioral assessment of infused mice showed a subtle clinical phenotype, mainly affecting sociability. Mouse brain MRI exhibited markedly reduced resting-state functional connectivity without short-term structural changes. Together, the experimental data support the direct pathogenicity of CASPR2 autoantibodies. The minimally invasive EEG and MRI techniques applied here may serve as novel objective, quantifiable tools for improved animal models, in particular for subtle neuropsychiatric phenotypes or repeated measurements.
Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
(Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)
Databáze: MEDLINE
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