Abstract Details

Title Identification of DAGLA as an Autoantibody Target in Cerebellar Ataxia

Topic Autoimmune Neurology

Presentation(s) S18 - Paraneoplastic Neurological Disorders, irAE, Stiff Person, IGLON5 (1:00 PM-1:12 PM)

Poster/Presentation
Number 001

Background NA

Objective We report the identification of diacylglycerol lipase α (DAGLA) as target autoantigen in severe cerebellitis.

Design/Methods Serum and cerebrospinal fluid samples from four index patients were subjected to comprehensive autoantibody screening by indirect immunofluorescence assay (IFA), showing an unclassified pattern on tissue substrates. Immunoprecipitation followed by mass spectrometry was used to identify the autoantibody target, which was verified by recombinant protein assays. Sera from patients with various neurological symptoms showing a similar tissue IFA pattern as the index patient samples, and healthy control sera were analyzed in recombinant cell-based IFA using HEK293 cells expressing the identified protein. Epitope characterization was performed using different immunoassays.

Results All four index patients suffered from rapidly progressive midline-accentuated cerebellar syndrome. Severe cerebellar atrophy developed in 3/4 patients within six months. In IFA on cerebellar tissue sections, all patient samples revealed a consistent IgG reactivity with the molecular layer. DAGLA was identified as the target antigen and confirmed by competitive inhibition experiments and RC-IFA with recombinant DAGLA. Among disease and healthy control sera, additional anti-DAGLA positive samples were detected by RC-IFA, including patients with different clinical phenotypes compared to the index patients, but only one with tissue IFA-positive CSF. In ELISA using six DAGLA fragments, none of the cerebellitis patient samples displayed a positive reaction, while 16/17 DC sera and the anti-DAGLA-positive HC serum reacted with the C-terminal, intracellular DAGLA aa 583–1042 fragment. In immunoprecipitations or RC-IFA with C-terminally truncated DAGLA variants lacking the C-terminal intracellular domain, only the sera or CSF of the cerebellitis patients reacted positively.

Conclusions Our data indicate the existence of at least two subtypes of anti-DAGLA autoantibodies targeting different epitopes and having distinguishable clinical associations. We propose that anti-DAGLA autoantibodies detected in CSF showing a characteristic tissue IFA pattern, represent novel biomarkers for a severe form of autoimmune cerebellitis.

Authors/Disclosures
Jackie Weiss, PhD PRESENTER	Dr. Weiss has received personal compensation for serving as an employee of EUROIMMUN US.
Ramona Miske	Ramona Miske has received personal compensation for serving as an employee of Euroimmun. Ramona Miske has received intellectual property interests from a discovery or technology relating to health care.
Madeleine Scharf, PhD	Dr. Scharf has received personal compensation for serving as an employee of Euroimmun AG.
Kathrin Borowski	Mrs. Borowski has nothing to disclose.
Ina Specht (Agaplesion Diakonieklinikum Rotenburg)	No disclosure on file
Merle Corty (Clinical Immunology Laboratory Prof. Dr. med W. Stocker)	No disclosure on file
Monika-Johanna Lortiz (Städt. Klinikum Karlsruhe)	No disclosure on file
Frederik Rombach (Städt. Klinikum Karlsruhe)	No disclosure on file
Guy Laureys, MD, PhD (UZ Gent)	The institution of Dr. Laureys has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Roche. The institution of Dr. Laureys has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Merck. The institution of Dr. Laureys has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Biogen. The institution of Dr. Laureys has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Novartis. The institution of Dr. Laureys has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Sanofi. Dr. Laureys has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Roche. Dr. Laureys has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Novartis. Dr. Laureys has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Biogen. Dr. Laureys has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Celgene. Dr. Laureys has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Sanofi. Dr. Laureys has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Merck.
Nadine Rochow	Mrs. Rochow has received personal compensation for serving as an employee of Euroimmun.
Christiane Radzimski, PhD	Dr. Radzimski has received personal compensation for serving as an employee of EUROIMMUN AG.
Linda Schnitter	No disclosure on file
Dominica Ratuszny (Hannover Medical School)	No disclosure on file
Thomas Skripuletz	Thomas Skripuletz has received personal compensation in the range of $50,000-$99,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Alexion, Alnylam Pharmaceuticals, Biogen, Centogene, CSL Behring, Grifols, Hexal AG, Janssen-Cilag, Merck Serono, Novartis, Roche, Sanofi, Swedish Orphan Biovitrum, Viatris. Thomas Skripuletz has received personal compensation in the range of $50,000-$99,999 for serving on a Speakers Bureau for from Alexion, Alnylam Pharmaceuticals, argenx, Bayer Vital, Biogen, Bristol Myers Squibb, Celgene, Centogene, CSL Behring, Euroimmun, Grifols, Hexal AG, Horizon, Janssen-Cilag, Merck Serono, Novartis, Pfizer, Roche, Sanofi, Siemens, Swedish Orphan Biovitrum, Teva, Viatris.
Mike Wattjes	No disclosure on file
Stefanie Hahn (Institute for Experimental Immunology, EUROIMMUN AG)	No disclosure on file
Yvonne Denno (Institute for Experimental Immunology, EUROIMMUN AG)	No disclosure on file
Khadija Guerti, MD	Dr. Guerti has nothing to disclose.
Matthijs U. Oyaert, Sr., PhD	Dr. Oyaert has nothing to disclose.
Farid Benkhadra (Centre Hospitalier de Luxembourg)	No disclosure on file
Corinna Bien (Labor Krone)	No disclosure on file
Sophie Nitsch	No disclosure on file
Klaus Peter Wandinger, MD	Prof. Wandinger has nothing to disclose.
Vincent Van Pesch, MD, PhD (Cliniques Universitaires Saint-Luc)	Vincent Van Pesch, MD, PhD has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Roche. Vincent Van Pesch, MD, PhD has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Merck. Vincent Van Pesch, MD, PhD has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Sanofi. Vincent Van Pesch, MD, PhD has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Novartis. Vincent Van Pesch, MD, PhD has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Celgene. Vincent Van Pesch, MD, PhD has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Biogen. The institution of Vincent Van Pesch, MD, PhD has received research support from Biogen.
Christian Probst (Institute for Experimental Immunology, EUROIMMUN AG)	No disclosure on file
Bianca Teegen (Clinical Immunology Laboratory Prof. Dr. med W. Stocker)	No disclosure on file
Lars Komorowski	Lars Komorowski has received personal compensation in the range of $100,000-$499,999 for serving as an officer or member of the Board of Directors for EUROIMMUN . Lars Komorowski has stock in Revvity. Lars Komorowski has received intellectual property interests from a discovery or technology relating to health care.
Kurt-Wolfram Suhs	Kurt-Wolfram Suhs has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Biogen. Kurt-Wolfram Suhs has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Merck. Kurt-Wolfram Suhs has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for Novartis. Kurt-Wolfram Suhs has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for Roche. The institution of Kurt-Wolfram Suhs has received research support from Bristol Myers Squibb.

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