Vesicular glutamate transporter 2 (VGLUT2) has been identified as a novel target antigen of autoantibodies in patients with neurological disorders, frequently accompanied by comorbidities with cardiovascular and inflammatory involvement. The discovery was made in a collaborative study between Euroimmun and different laboratories and clinics in Germany, which was published recently in the journal Brain, Behavior, and Immunity.
Autoantibodies are important biomarkers for autoimmune neurological diseases and are typically associated with distinct clinical phenotypes. Analysis of neural autoantibodies can support disease classification, determination of treatment strategies and research into disease pathology. In recent years, many new target antigens have been identified, encompassing both intracellular and cell-surface proteins. Nevertheless, in a subset of patients, the target antigen remains unknown.
In this study, sera from 314 patients exhibiting a distinct, but uncharacterised IgG pattern in indirect immunofluorescence assay (IFA) on neuronal tissue were investigated. VGLUT2 was identified as the autoantibody target by immunoprecipitation and mass spectrometry. The target was confirmed in 285 of the 314 sera using transfected HEK293 cells expressing VGLUT2, competitive inhibition assays and colocalisation studies with a commercial antibody. Epitope characterisation in 17 sera revealed that the autoantibodies recognised a cytoplasmic C-terminal epitope between amino acids 520-564 of VGLUT2.
Initial diagnoses were available for 87 of the patients and most frequently included encephalitis, dementia, cognitive impairment and polyneuropathy. Detailed clinical data for 18 index patients were collected retrospectively. The most common symptoms in these patients were cognitive changes, including memory impairment, aphasia and disorientation, followed by sensorimotor disturbances, gait abnormalities and visual impairments. Polyneuropathy was also a common observation. The majority of the index patients had co-existing chronic multisystem disorders, including diabetes mellitus type 2 and vasculitis. Immunotherapy was used to treat 12 patients and showed beneficial effects in 8 of these, although in most cases only slight improvements could be achieved.
The authors conclude that anti-VGLUT2 autoantibody-associated neurological disease may represent a new type of autoimmune disorder that might benefit from immunomodulatory treatment. VGLUT2 seropositive patients show deficits in both the central and peripheral nervous system, in line with the expression of VGLUT2 in glutamatergic excitatory neurons throughout the entire brain and spinal cord. The high frequency of non-neurological illnesses could emphasize the relevance of anti-VGLUT2 autoantibodies as markers for systemic autoimmune processes with nerve involvement.
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