Novel autoantibody against DAGLA discovered in cerebellitis

Diacylglycerol lipase alpha (DAGLA) has been identified as a novel autoantibody target in patients with rapid progressive cerebellar ataxia. The autoantibodies were characterised as part of a collaborative study between scientists at EUROIMMUN (Lübeck, Germany), the Hannover Medical School, (Hannover, Germany) and further institutes and clinics. The study was published in April 2024 the journal Neurology, Neurosurgery & Psychiatry.

Autoimmune cerebellar ataxias are strongly disabling disorders characterised by an impaired ability to coordinate muscle movement. Cerebellar autoantibodies serve as useful biomarkers to support rapid disease diagnosis, but in many cases the autoantibody target has not yet been identified. In this study, DAGLA was identified as the autoantibody target in four young patients aged 18 to 34, who suffered from pronounced gait ataxia, dysarthria and visual impairments. In three of the four patients, severe cerebellar atrophy developed within 6 months. None of the patients had a malignancy.

To identify the antigen, serum and cerebrospinal fluid (CSF) from the four index patients were subjected to comprehensive autoantibody screening by indirect immunofluorescence assays (IIFA). The four patients’ samples all showed a characteristic IgG reactivity with the molecular layer of cerebellum cryosections. The autoantibodies bound exclusively to the dendrites of the Purkinje cells, whereas the somata remained unstained. Immunoprecipitation and mass spectrometry were used to identify the target antigen. Results were confirmed by competitive inhibition experiments and recombinant-cell (RC) IIFA based on transfected HEK293 cells expressing DAGLA. Sera and CSF from the index patients reacted strongly positive in the anti-DAGLA RC-IIFA, whereas the control cells did not demonstrate any specific antibody binding.

Sera from 101 patients with various neurological symptoms and sera from 102 healthy blood donors were additionally analysed using the anti-DAGLA RC-IIFA. Serum reactivity against DAGLA was found in 17 disease controls and 1 healthy donor. Epitope characterisation revealed that 17 of these 18 sera reacted with a linear intracellular epitope between amino acids 583 and 1042, whereas the CSF of the index patients targeted a conformational epitope between amino acids 1 and 157. These data indicate the existence of at least two subtypes of anti-DAGLA autoantibodies targeting distinct epitopes, which should be taken into consideration in the antibody detection. The proposed testing strategy comprises RC-IIFA using full-length DAGLA protein, with confirmation of positive results using RC-IIFA based on a DAGLA 1-582 fragment.

The authors conclude that anti-DAGLA autoantibodies detected in CSF with a characteristic tissue IIFA pattern represent novel biomarkers for rapidly progressing cerebellitis. They surmise that earlier diagnosis of the associated neurological disorder followed by more aggressive and prolonged immunotherapy could inhibit dramatic disease progression.

Read the full publication in Journal of Neurology, Neurosurgery & Psychiatry:

Miske R, Scharf M, Borowski K, et al. Identification of DAGLA as an autoantibody target in cerebellar ataxia. Journal of Neurology, Neurosurgery & Psychiatry Published Online First: 25 April 2024. doi: 10.1136/jnnp-2024-333458

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