Margarita Habib, Anna-Lena Wiessler, Patrik Fischer, Michele Niesner, Mareike Selcho, Ligia Abrante, Christian Werner, Annemarie Sodmann, Maximilian Koch, Abdolhossein Zare, Harald Prüss, Justina Dargvainiene, Jan Lewerenz, Robert Handreka, Peter Körtvelyessy, Dirk Reinhold, Franziska S Thaler, Kalliopi Pitarokoili, Robert J Kittel, Michael Briese, Michael Sendtner, Heike Rittner, Frank Leypoldt, Claudia Sommer, Robert Blum, Kathrin Doppler, Carmen Villmann
{"title":"Neuropathic Pain and Distinct CASPR2 Autoantibody IgG Subclasses Drive Neuronal Hyperexcitability.","authors":"Margarita Habib, Anna-Lena Wiessler, Patrik Fischer, Michele Niesner, Mareike Selcho, Ligia Abrante, Christian Werner, Annemarie Sodmann, Maximilian Koch, Abdolhossein Zare, Harald Prüss, Justina Dargvainiene, Jan Lewerenz, Robert Handreka, Peter Körtvelyessy, Dirk Reinhold, Franziska S Thaler, Kalliopi Pitarokoili, Robert J Kittel, Michael Briese, Michael Sendtner, Heike Rittner, Frank Leypoldt, Claudia Sommer, Robert Blum, Kathrin Doppler, Carmen Villmann","doi":"10.1212/NXI.0000000000200423","DOIUrl":null,"url":null,"abstract":"<p><strong>Background and objectives: </strong>Patients with autoantibodies (aAbs) against the contactin-associated protein-like 2 (CASPR2) suffer from a variety of clinical syndromes including neuropathic pain. CASPR2 is an adhesion protein of the neurexin family and part of the voltage-gated potassium channel complex (VGKC complex) in dorsal root ganglia (DRG) neurons. The pathologic mechanisms following the binding of CASPR2 aAbs and their association with pain are only partially understood. CASPR2 aAbs are mainly of the IgG4 subclass; however, previous studies have neglected subclass-dependent effects.</p><p><strong>Methods: </strong>We investigated 49 subclassified patient serum samples positive for CASPR2 aAbs combining superresolution lattice structural illumination microscopy (SIM<sup>2</sup>) and functional readouts by calcium imaging and electrophysiologic recordings on cultured DRG neurons. CASPR2-positive patient sera subclassified in IgG4 together with at least 1 other IgG subclass (IgGX) and patients with only IgG4 were further subdivided into the pain and no pain groups.</p><p><strong>Results: </strong>A decrease of CASPR2 expression along the axons after exposure to CASPR2 aAbs was observed for all patient groups except the group without pain and IgG4. Moreover, binding of CASPR2 aAbs from patients with pain increased the distance between CASPR2 and associated potassium channels along DRG axons determined by SIM<sup>2</sup> microscopy. CASPR2 aAbs of patients with pain significantly increased overall neuronal excitability of cultured DRG neurons as measured by calcium imaging. Patch-clamp recordings revealed significantly decreased current amplitudes of voltage-gated potassium (Kv) channels after incubation with all 4 CASPR2 aAb subclassifications with the most prominent effect of serum samples harboring IgG4 aAbs only. Replacement of patient aAbs by healthy control serum rescued Kv channel function to normal levels suggesting that the affected potassium channel function is due to structural blockage and disrupted interactions within the VGKC complex. The last might also be rescued on novel protein synthesis and membrane trafficking of CASPR2.</p><p><strong>Discussion: </strong>IgG4 aAbs seem to be the major modifier of potassium channel function. The DRG hyperexcitability is primarily due to impaired Kv channel conductance as a consequence of CASPR2 aAb binding. However, additional unidentified signal pathways contribute to this process in patients with neuropathic pain.</p>","PeriodicalId":19472,"journal":{"name":"Neurology® Neuroimmunology & Neuroinflammation","volume":"12 4","pages":"e200423"},"PeriodicalIF":7.8000,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12202018/pdf/","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Neurology® Neuroimmunology & Neuroinflammation","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1212/NXI.0000000000200423","RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"2025/6/25 0:00:00","PubModel":"Epub","JCR":"Q1","JCRName":"CLINICAL NEUROLOGY","Score":null,"Total":0}
引用次数: 0
Abstract
Background and objectives: Patients with autoantibodies (aAbs) against the contactin-associated protein-like 2 (CASPR2) suffer from a variety of clinical syndromes including neuropathic pain. CASPR2 is an adhesion protein of the neurexin family and part of the voltage-gated potassium channel complex (VGKC complex) in dorsal root ganglia (DRG) neurons. The pathologic mechanisms following the binding of CASPR2 aAbs and their association with pain are only partially understood. CASPR2 aAbs are mainly of the IgG4 subclass; however, previous studies have neglected subclass-dependent effects.
Methods: We investigated 49 subclassified patient serum samples positive for CASPR2 aAbs combining superresolution lattice structural illumination microscopy (SIM2) and functional readouts by calcium imaging and electrophysiologic recordings on cultured DRG neurons. CASPR2-positive patient sera subclassified in IgG4 together with at least 1 other IgG subclass (IgGX) and patients with only IgG4 were further subdivided into the pain and no pain groups.
Results: A decrease of CASPR2 expression along the axons after exposure to CASPR2 aAbs was observed for all patient groups except the group without pain and IgG4. Moreover, binding of CASPR2 aAbs from patients with pain increased the distance between CASPR2 and associated potassium channels along DRG axons determined by SIM2 microscopy. CASPR2 aAbs of patients with pain significantly increased overall neuronal excitability of cultured DRG neurons as measured by calcium imaging. Patch-clamp recordings revealed significantly decreased current amplitudes of voltage-gated potassium (Kv) channels after incubation with all 4 CASPR2 aAb subclassifications with the most prominent effect of serum samples harboring IgG4 aAbs only. Replacement of patient aAbs by healthy control serum rescued Kv channel function to normal levels suggesting that the affected potassium channel function is due to structural blockage and disrupted interactions within the VGKC complex. The last might also be rescued on novel protein synthesis and membrane trafficking of CASPR2.
Discussion: IgG4 aAbs seem to be the major modifier of potassium channel function. The DRG hyperexcitability is primarily due to impaired Kv channel conductance as a consequence of CASPR2 aAb binding. However, additional unidentified signal pathways contribute to this process in patients with neuropathic pain.
期刊介绍:
Neurology Neuroimmunology & Neuroinflammation is an official journal of the American Academy of Neurology. Neurology: Neuroimmunology & Neuroinflammation will be the premier peer-reviewed journal in neuroimmunology and neuroinflammation. This journal publishes rigorously peer-reviewed open-access reports of original research and in-depth reviews of topics in neuroimmunology & neuroinflammation, affecting the full range of neurologic diseases including (but not limited to) Alzheimer's disease, Parkinson's disease, ALS, tauopathy, and stroke; multiple sclerosis and NMO; inflammatory peripheral nerve and muscle disease, Guillain-Barré and myasthenia gravis; nervous system infection; paraneoplastic syndromes, noninfectious encephalitides and other antibody-mediated disorders; and psychiatric and neurodevelopmental disorders. Clinical trials, instructive case reports, and small case series will also be featured.