Antibodies against MLC1 found in patients with NMOSD-like disease mediate astrocytopathy in rodent models
The identification of autoantibodies against aquaporin-4 (AQP4) and myelin oligodendrocyte glycoprotein (MOG) has been essential in distinguishing neuromyelitis optica spectrum disorder (NMOSD) and MOG antibody-associated disease (MOGAD) from classical multiple sclerosis (MS), with important implications for treatment. However, for several patients within this disease spectrum, the target of the autoimmune response remains unknown. Here, we describe the modulator of VRAC current 1 (MLC1), a membrane protein with extracellular epitopes enriched at astrocytic end feet, as an autoantigen. Serum MLC1 antibodies were verified with a cell-based assay, identifying four MLC1 immunoglobulin G (IgG)-positive patients among 297 patients with inflammatory autoimmune diseases of the central nervous system who were screened. All four MLC1 IgG-positive patients exhibited overlapping yet atypical clinical features of MS and NMOSD and tested negative for AQP4 and MOG antibodies. Moreover, treatment with a monoclonal MLC1 antibody induced astrocytopathy in mouse cerebellar slice cultures and in a rat encephalitis model. Thus, MLC1 antibodies identify a subset of patients with an NMOSD-like phenotype, underscoring their potential as a disease marker with pathogenic relevance.
Authors
- Katharina Elisabeth Marianne Bräuer (ORCID: https://orcid.org/0009-0003-0184-1098)
- Martin Kerschensteiner (ORCID: https://orcid.org/0000-0003-4898-9383)
- Franziska S. Thaler (ORCID: https://orcid.org/0000-0001-6548-0410)
- Tomas Olsson (ORCID: https://orcid.org/0000-0002-2938-1877)
- Jeffrey L. Bennett (ORCID: https://orcid.org/0000-0002-3346-1394)
- Arek Kendirli (ORCID: https://orcid.org/0000-0001-6888-9131)
- Tania Kümpfel (ORCID: https://orcid.org/0000-0001-7509-5268)
- Naoto Kawakami (ORCID: https://orcid.org/0000-0001-7693-3489)
- Edgar Meinl (ORCID: https://orcid.org/0000-0002-2570-6785)
- Selia Baier
- Mohsen Khademi (ORCID: https://orcid.org/0000-0003-0801-1444)
- Hoi Kiu Wong
- Stephan Winklmeier (ORCID: https://orcid.org/0000-0001-8675-0387)
- Lisa Ann Gerdes (ORCID: https://orcid.org/0000-0002-7053-3924)
- Markus Reindl (ORCID: https://orcid.org/0000-0003-2817-1402)
- Regina Feederle (ORCID: https://orcid.org/0000-0002-3981-367X)
- Monika Bradl (ORCID: https://orcid.org/0000-0003-2239-1586)
- Kathrin Schanda (ORCID: https://orcid.org/0000-0001-7851-6523)
- Heike Rübsamen
- Fredrik Piehl (ORCID: https://orcid.org/0000-0001-8329-5219)
- Eva Oswald (ORCID: https://orcid.org/0009-0004-0888-0978)
- Simone Mader (ORCID: https://orcid.org/0000-0002-2844-9091)
- Qian Yu (ORCID: https://orcid.org/0000-0002-5334-3918)
- Dorina Shqau (ORCID: https://orcid.org/0009-0001-5047-4410)
- Katherine S. Given
- Samantha Ho (ORCID: https://orcid.org/0009-0003-7279-9595)
Institutions
- Karolinska University Hospital (SE)
- Innsbruck Medical University (AT)
- Friedrich-Alexander-Universität Erlangen-Nürnberg (DE)
- Universität Innsbruck (AT)
- German Center for Neurodegenerative Diseases (DE)
- Helmholtz Zentrum München (DE)
- LMU Klinikum (DE)
- Universitätsklinikum Erlangen (DE)
- Munich Cluster for Systems Neurology (DE)
- University of Colorado Anschutz Medical Campus (US)
- Medical University of Vienna (AT)
- Ludwig-Maximilians-Universität München (DE)
Publication Details
- Journal
- Science Translational Medicine
- Published
- 2026-08-26
- DOI
- https://doi.org/10.1126/scitranslmed.ady0403
- Primary Topic
- Multiple Sclerosis Research Studies
- Type
- article
- Field-Weighted Citation Impact
- 0.00
Funders
- Deutsche Forschungsgemeinschaft
- National Institute of Neurological Disorders and Stroke