Anti-VGLUT2 autoantibodies in neurological diseases
- PMID: 40494504
- DOI: 10.1016/j.bbi.2025.06.014
Anti-VGLUT2 autoantibodies in neurological diseases
Abstract
Autoantibodies are important biomarkers for the diagnosis of autoimmune diseases that help to determine treatment strategies and to understand disease pathology. Despite the increasing numbers of neuronal autoantibody discoveries, there are still patients presenting with neurological autoimmune diseases and so far uncharacterized autoantibodies. Between 12/2016 and 06/2024, we collected sera of 314 patients with a distinct uncharacterized IgG pattern in neuronal tissue indirect immunofluorescence assay (IIFA). By immunoprecipitation and mass spectrometry we identified vesicular glutamate transporter 2 (VGLUT2) as the autoantibody target and confirmed it in sera of 285/314 patients by recombinant IIFA with VGLUT2-expressing HEK293 cells, competitive inhibition assays and colocalization studies with a commercial antibody. The main diagnoses available of 87/285 patients (mean age 58, range 1-92) were encephalitis 25/87, dementia/cognitive impairment 17/87 and polyneuropathy 16/87. Detailed clinical data of 18 patients were collected retrospectively. The major symptoms of those index patients (mean age 56, range 2-78) involved cognitive changes (10/18) including memory impairment, aphasia and disorientation as well as sensorimotor disturbances (9/18) and gait abnormalities (9/18), accompanied by visual impairments (8/18). (Poly)neuropathy was observed in 10/18 cases. The majority of the anti-VGLUT2 index patients had coexisting diabetes mellitus type 2 or other chronic multisystem disorders. In 8/12 index patients, immunotherapy had beneficial effects, although only slight improvements could be obtained in most of the cases. All 17 analyzed index patient sera recognized a cytoplasmic epitope between amino acid 520-564 of VGLUT2, determined by immunoblot with recombinant antigen fragments. Anti-VGLUT2 autoantibody-associated neurological diseases may represent a new type of autoimmune disorders that might benefit from immunomodulatory treatment and predominantly manifests with encephalitis, cognitive deficits and neuropathy.
Keywords: Autoantibody; Autoimmune dementia; Autoimmune encephalitis; Immunotherapy; Polyneuropathy; VGLUT2.
Copyright © 2025 Elsevier Inc. All rights reserved.
Conflict of interest statement
Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: MS, CR, YD, CP, LK and RMi are employees of EUROIMMUN, a company that manufactures diagnostic tests and instruments. RMi, YD, CR and KB have patent applications, concerning the detection of an autoantibody against VGLUT2 issued and pending. KW has received funding from the Deutsche Forschungsgemeinschaft (German Research Association) and STADAPHARM GmbH outside the present study. He has received honoraria for presentations/advisory boards/consultations from BIAL, Indorsia, Boston Scientific and STADAPHARM GmbH, outside the present study. He has received royalties from Thieme Press and Elsevier Press. He serves as an editorial board member of Wileys “Parkinson’s Disease”, “Behavioural Neurology” and PLOSone. NM has received honoraria for lecturing and travel expenses for attending meetings from Biogen Idec, GlaxoSmith Kline, Teva, Novartis Pharma, Bayer Healthcare, Genzyme, Alexion Pharmaceuticals, Fresenius Medical Care, Diamed, UCB Pharma, AngeliniPharma, BIAL and Sanofi-Aventis, has received royalties for consulting from UCB Pharma, Alexion Pharmaceuticals and Sanofi-Aventis and has received financial research support from Euroimmun, Fresenius Medical Care, Diamed, Alexion Pharmaceuticals and Novartis Pharma. MC, FAA, SW, FP, CS, PO, MB, MK, JPZ, TK, RMa, BT, CG, HP, SK, CF, GH, JB, MK, TW, KPW report no competing interests to the work described.