Identification of DAGLA as an autoantibody target in cerebellar ataxia.

Autor:	Miske R; Institute for Experimental Immunology, affiliated with EUROIMMUN Medizinische Labordiagnostika AG, Seekamp 31, 23560 Luebeck, Germany., Scharf M; Institute for Experimental Immunology, affiliated with EUROIMMUN Medizinische Labordiagnostika AG, Seekamp 31, 23560 Luebeck, Germany., Borowski K; Clinical Immunological Laboratory Prof. h.c. (RCH) Dr. med. Winfried Stöcker, Lübeck, Germany., Specht I; Agaplesion Diakonieklinikum Rotenburg, Rotenburg, Germany., Corty M; Clinical Immunological Laboratory Prof. h.c. (RCH) Dr. med. Winfried Stöcker, Lübeck, Germany., Loritz MJ; Städtisches Klinikum Karlsruhe, Karlsruhe, Germany., Rombach F; Städtisches Klinikum Karlsruhe, Karlsruhe, Germany., Laureys G; Department of Neurology, Ghent University Hospital, Gent, Belgium., Rochow N; Institute for Experimental Immunology, affiliated with EUROIMMUN Medizinische Labordiagnostika AG, Seekamp 31, 23560 Luebeck, Germany., Radzimski C; Institute for Experimental Immunology, affiliated with EUROIMMUN Medizinische Labordiagnostika AG, Seekamp 31, 23560 Luebeck, Germany., Schnitter L; Institute for Experimental Immunology, affiliated with EUROIMMUN Medizinische Labordiagnostika AG, Seekamp 31, 23560 Luebeck, Germany., Ratuszny D; Department of Neurology, Hannover Medical School, Hannover, Germany., Skripuletz T; Department of Neurology, Hannover Medical School, Hannover, Germany., Wattjes MP; Department of Neuroradiology, Hannover Medical School, Hannover, Germany., Hahn S; Institute for Experimental Immunology, affiliated with EUROIMMUN Medizinische Labordiagnostika AG, Seekamp 31, 23560 Luebeck, Germany., Denno Y; Institute for Experimental Immunology, affiliated with EUROIMMUN Medizinische Labordiagnostika AG, Seekamp 31, 23560 Luebeck, Germany., Guerti K; Department of Clinical Chemistry, Antwerp University Hospital, Edegem, Belgium., Oyaert M; Department of Laboratory Medicine, Ghent University Hospitals, Gent, Belgium., Benkhadra F; Department of Clinical Biology, Centre Hospitalier de Luxembourg, Luxembourg City, Luxembourg., Bien CI; Laboratory Krone, Bad Salzuflen, Bad Salzuflen, Germany., Nitsch S; Division of Neuropathology and Neurochemistry, Department of Neurology, Medical University of Vienna, Vienna, Austria., Wandinger KP; Institute of Clinical Chemistry, University Hospital Schleswig-Holstein, Kiel/Lübeck, Germany., van Pesch V; Department of Neurology, Cliniques universitaires Saint-Luc, Université catholique de Louvain (UCLouvain), Brussels, Belgium., Probst C; Institute for Experimental Immunology, affiliated with EUROIMMUN Medizinische Labordiagnostika AG, Seekamp 31, 23560 Luebeck, Germany., Teegen B; Clinical Immunological Laboratory Prof. h.c. (RCH) Dr. med. Winfried Stöcker, Lübeck, Germany., Komorowski L; Institute for Experimental Immunology, affiliated with EUROIMMUN Medizinische Labordiagnostika AG, Seekamp 31, 23560 Luebeck, Germany., Sühs KW; Department of Neurology, Hannover Medical School, Hannover, Germany Suehs.Kurt-Wolfram@mh-hannover.de.
Jazyk:	angličtina
Zdroj:	Journal of neurology, neurosurgery, and psychiatry [J Neurol Neurosurg Psychiatry] 2024 Oct 16; Vol. 95 (11), pp. 1064-1076. Date of Electronic Publication: 2024 Oct 16.
DOI:	10.1136/jnnp-2024-333458
Abstrakt:	Background: We aimed to investigate the clinical, imaging and fluid biomarker characteristics in patients with antidiacylglycerol lipase alpha (DAGLA)-autoantibody-associated cerebellitis. Methods: Serum and cerebrospinal fliud (CSF) samples from four index patients were subjected to comprehensive autoantibody screening by indirect immunofluorescence assay (IIFA). Immunoprecipitation, mass spectrometry and recombinant protein assays were used to identify the autoantigen. Sera from 101 patients with various neurological symptoms and a similar tissue staining pattern as the index patient samples, and 102 healthy donors were analysed in recombinant cell-based IIFA (RC-IIFA) with the identified protein. Epitope characterisation of all positive samples was performed via ELISA, immunoblot, immunoprecipitation and RC-IIFA using different DAGLA fragments. Results: All index patients were relatively young (age: 18-34) and suffered from pronounced gait ataxia, dysarthria and visual impairments. Paraclinical hallmarks in early-stage disease were inflammatory CSF changes and cerebellar cortex hyperintensity in MRI. Severe cerebellar atrophy developed in three of four patients within 6 months. All patient samples showed the same unclassified IgG reactivity with the cerebellar molecular layer. DAGLA was identified as the target antigen and confirmed by competitive inhibition experiments and DAGLA-specific RC-IIFA. In RC-IIFA, serum reactivity against DAGLA was also found in 17/101 disease controls, including patients with different clinical phenotypes than the one of the index patients, and in 1/102 healthy donors. Epitope characterisation revealed that 17/18 anti-DAGLA-positive control sera reacted with a C-terminal intracellular DAGLA 583-1042 fragment, while the CSF samples of the index patients targeted a conformational epitope between amino acid 1 and 157. Conclusions: We propose that anti-DAGLA autoantibodies detected in CSF, with a characteristic tissue IIFA pattern, represent novel biomarkers for rapidly progressive cerebellitis. Competing Interests: Competing interests: RM, MS, NR, CR, LS, SH, YD, CP and LK are employees of EUROIMMUN, a company that manufactures diagnostic tests and instruments. RM, MS, SH, YD, CP, FB and LK have patent applications, concerning the detection of an autoantibody against DAGLA issued and pending. KB, IS, MC, MJ-L, FR, GL, DR, TS, MPW, KG, MO, CIB, SN, K-PW, VvP, BT and K-WS report no competing interests to the work described. (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)
Databáze:	MEDLINE
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