Abstract Details

Title Conformational Antibodies to Proteolipid Protein-1 and Its Peripheral Isoform DM20 in Patients with CNS Autoimmune Demyelinating Diseases

Topic Autoimmune Neurology

Presentation(s) S38 - NMOSD, MOGAD, Demyelinating, and Other (2:00 PM-2:12 PM)

Poster/Presentation
Number 006

Objective

We aimed to investigate conformational PLP1-IgG in the whole autoimmune demyelinating diseases (ADD) spectrum.

Background Antibodies to proteolipid-protein-1 (PLP1-IgG), a major central myelin protein also expressed in the PNS as the isoform DM20, have been previously identified mostly in patients with MS, with unclear clinical implications. However, most studies relied on non-conformational immunoassays, and included few patients with non-MS CNS ADD.

Design/Methods

We devised a new live cell-based-assay (CBA) for PLP1-IgG and used it to test two cohorts (retrospective exploratory, n=284; prospective validation, n=824) of patients with ADD, and controls (n=177). Patients were classified as MS, NMOSD, MOGAD and other-ADD. PLP1-IgG-positive samples were tested for IgG subclasses, DM20-IgG, and on rat brain tissue-based-assay (TBA). Complement-dependent-cytotoxicity (CDC) was assessed on a live-CBA, and antigen-specificity and conformational binding through immunoadsorption/co-localization/fixation experiments.

Results

PLP1-IgG were found in 0/177 controls and 42/1104 ADD patients mainly diagnosed as other-ADD (19/42) with frequent myelitis/encephalomyelitis (14/19) and co-existing PNS involvement (13/19). Four/19 other-ADD patients fulfilled the seronegative-NMOSD criteria. PLP1-IgG were also found in MOGAD (11/42), more frequently with PNS involvement (p=0.01), and in MS (12/42), more frequently with atypical features (p<0.001). PLP1-IgG-positive MOGAD had higher EDSS scores (p<0.001) and PLP1-IgG-positive MS higher severity scores (MSSS, p<0.001) compared to those PLP1-IgG-negative. PLP1-IgG a) co-localized with their target on CBA-TBA, where their binding was abolished after immunoadsorption and fixation-induced conformational epitope alteration; b) mostly pertained to the IgG1/IgG3 subclass (68.3%) and were able to induce CDC; c) co-reacted with DM20 in all 12 patients with PNS involvement tested.

Conclusions

Conformational PLP1-IgG predominantly identify non-MS ADD patients. They should be tested mainly in those with CNS+PNS ADD, coherently with DM20-IgG co-reactivity. PLP1-IgG could also be investigated as disease modifiers and prognostic markers in MS and MOGAD. Preliminary evidence supports their pathogenic potential.

Authors/Disclosures
Matteo Gastaldi, MD, PhD (IRCCS Mondino Foundation) PRESENTER	Dr. Gastaldi has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for UCB, AMGEN, ROCHE, ALEXION. The institution of Dr. Gastaldi has received research support from Italian Ministry of Health.
Stefano Masciocchi, MD	Dr. Masciocchi has nothing to disclose.
Pietro Businaro	Pietro Businaro has nothing to disclose.
Giacomo Greco	Giacomo Greco has nothing to disclose.
Silvia Scaranzin (IRCCS C. Mondino)	Silvia Scaranzin has nothing to disclose.
Antonio Malvaso, MD (IRCCS Mondino Foundation)	Dr. Malvaso has nothing to disclose.
Chiara Morandi, Biologist	Dr. Morandi has nothing to disclose.
elisabetta zardini	Dr. zardini has nothing to disclose.
Mario Risi, MD	Dr. Risi has nothing to disclose.
Elisa Vegezzi, MD, PhD	Dr. Vegezzi has nothing to disclose.
Luca Diamanti, MD, PhD	Dr. Diamanti has nothing to disclose.
Paola Bini, MD	Dr. Bini has nothing to disclose.
Sabrina Siliquini, MD	Dr. Siliquini has nothing to disclose.
Maria Pia Giannoccaro, MD, PhD	Dr. Giannoccaro has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Argenx. Dr. Giannoccaro has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Argenx. Dr. Giannoccaro has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Amgen. The institution of Dr. Giannoccaro has received research support from MIUR.
Luana Morelli (Department of Biomedical and Neuromotor Sciences, University of Bologna (DIBINEM), Bologna, Italy)	No disclosure on file
Rocco Liguori, MD	Dr. Liguori has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Argenx. Dr. Liguori has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for HEALTHWARE GROUP s.r.l. . Dr. Liguori has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for ALEXION PHARMA ITALY s.r.l. . Dr. Liguori has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for SANOFI GENZYME CORPORATION . Dr. Liguori has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for ECM NETWORK s.r.l. . Dr. Liguori has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for ALEXION PHARMA ITALY s.r.l.. Dr. Liguori has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for PTS s.r.l. . Dr. Liguori has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for ALEXION PHARMA ITALY s.r.l.. Dr. Liguori has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for AIM EDUCATION s.r.l. . Dr. Liguori has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for MAYA IDEE SUD s.r.l. . Dr. Liguori has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for ISTITUTO SUPERIORE DI SANITA' . Dr. Liguori has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for QbGROUP s.r.l. . Dr. Liguori has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for SYMPOSIUM s.r.l. . Dr. Liguori has received publishing royalties from a publication relating to health care.
Francesco Patti, MD	Dr. Patti has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Alexion. The institution of Dr. Patti has received personal compensation in the range of $10,000-$49,999 for serving as a Consultant for Almirall. Dr. Patti has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Bristol Meyers. Dr. Patti has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Johnson and Johnson. The institution of Dr. Patti has received personal compensation in the range of $10,000-$49,999 for serving as a Consultant for Merck. The institution of Dr. Patti has received personal compensation in the range of $10,000-$49,999 for serving as a Consultant for Novartis. The institution of Dr. Patti has received personal compensation in the range of $10,000-$49,999 for serving as a Consultant for Roche. The institution of Dr. Patti has received personal compensation in the range of $10,000-$49,999 for serving as a Consultant for Sanofi. Dr. Patti has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Alexion, Almirall, Bayer, Biogen, Bristol Meyers and Squibb Merck, Roche, Sanofi, TEVA. Dr. Patti has received personal compensation in the range of $500-$4,999 for serving as an officer or member of the Board of Directors for University of Catania and AISM/FISM, Fondazione Italiana Sclerosi Multipla. Dr. Patti has received personal compensation in the range of $0-$499 for serving as an Editor, Associate Editor, or Editorial Advisory Board Member for Frontiers in Neurology.
Valeria De Giuli, MD	Dr. De Giuli has nothing to disclose.
Emilio Portaccio	Emilio Portaccio has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Biogen. Emilio Portaccio has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Merck Serono. Emilio Portaccio has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Sanofi. Emilio Portaccio has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Roche. Emilio Portaccio has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for Sanofi. Emilio Portaccio has received personal compensation in the range of $0-$499 for serving on a Speakers Bureau for Biogen. Emilio Portaccio has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for Merck Serono. Emilio Portaccio has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for Roche. Emilio Portaccio has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for Novartis. Emilio Portaccio has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for Janssen. Emilio Portaccio has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for BMS Cellgene.
Chiara Zanetta (Neurology and Neurorehabilitation Units, Multiple Sclerosis Center, IRCCS San Raffaele Hospital, Milan, Italy)	No disclosure on file
Stefania Bergamoni (Childhood and Adolescence Neurology and Psychiatry Unit, ASST GOM Niguarda, Milan, Italy.)	No disclosure on file
Anna Maria Simone, Sr., MD, PhD	Dr. Simone has nothing to disclose.
Roberta Lanzillo	Roberta Lanzillo has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Merck, Biogen. Roberta Lanzillo has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for Biogen, Roche, Novartis.
Antonio Gallo	Antonio Gallo has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Sanofi. Antonio Gallo has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Roche. Antonio Gallo has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Merck. Antonio Gallo has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Novartis.
Alvino Bisecco	Alvino Bisecco has nothing to disclose.
Massimiliano Di Filippo, MD	No disclosure on file
Flavia Pauri, MD	No disclosure on file
Antonella Toriello, Jr., MD	Dr. Toriello has nothing to disclose.
Paolo Barone, MD (University of Napoli Dept of Neuroscience)	No disclosure on file
Francesco Tazza, MD	Dr. Tazza has nothing to disclose.
Sebastiano Bucello, MD (Azienda Ospedaliera Provinciale Siracusa)	Dr. Bucello has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Sanofi. Dr. Bucello has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Biogen.
Martina Fabris, MD	Prof. Fabris has nothing to disclose.
Loredana Raciti, MD, PhD	Dr. Raciti has nothing to disclose.
Maria Claudia Vigliani, Sr., MD, PhD	Dr. Vigliani has nothing to disclose.
Tommaso Bocci, MD	Prof. Bocci has nothing to disclose.
Irene Volonghi, MD	Dr. Volonghi has nothing to disclose.
Matteo Paoletti, MD	Dr. PAOLETTI has nothing to disclose.
Elena Colombo	No disclosure on file
Massimo Filippi, MD, FAAN (Ospedale San Raffaele, Neuroimaging Research Unit)	Dr. Filippi has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for Alexion, Almirall, Biogen, Merck, Novartis, Roche, Sanofi. Dr. Filippi has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Alexion, Biogen, Bristol-Myers Squibb, Merck, Novartis, Roche, Sanofi, Sanofi-Aventis, Sanofi-Genzyme, Takeda. Dr. Filippi has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for Bayer, Biogen, Celgene, Chiesi Italia SpA, Eli Lilly, Genzyme, Janssen, Merck-Serono, Neopharmed Gentili, Novartis, Novo Nordisk, Roche, Sanofi, Takeda, and TEVA. Dr. Filippi has received personal compensation in the range of $10,000-$49,999 for serving as an Editor, Associate Editor, or Editorial Advisory Board Member for Springer Nature. The institution of Dr. Filippi has received research support from Biogen Idec, Merck-Serono, Novartis, Roche, the Italian Ministry of Health, the Italian Ministry of University and Research, and Fondazione Italiana Sclerosi Multipla.
Anna Pichiecchio, MD	Prof. Pichiecchio has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Guerbet. Prof. Pichiecchio has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Amicu ther. Prof. Pichiecchio has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for Bayer.
Enrico Marchioni	Enrico Marchioni has nothing to disclose.
Diego Franciotta, MD (C.M.C. Momdino)	Dr. Franciotta has nothing to disclose.

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