2025 American Academy of Neurology Abstract Website

Stefano Masciocchi¹, Pietro Businaro¹, Giacomo Greco², Silvia Scaranzin¹, Antonio Malvaso¹, Chiara Morandi¹, Elisabetta Zardini¹, Mario Risi³, Elisa Vegezzi⁴, Luca Diamanti⁴, Paola Bini⁴, Sabrina Siquilini⁵, Maria Pia Giannoccaro⁶, Luana Morelli⁶, Rocco Liguori⁶, Francesco Patti⁷, Valeria De Giuli⁸, Emilio Portaccio⁹, Chiara Zanetta¹⁰, Stefania Bergamoni¹¹, Anna Maria Simone¹², Roberta Lanzillo¹³, Antonio Gallo³, Alvino Bisecco³, Massimiliano Di Filippo¹⁴, Flavia Pauri¹⁵, Antonella Toriello¹⁶, Paolo Barone¹⁶, Francesco Tazza¹⁷, Sebastiano Bucello¹⁸, Martina Fabris¹⁹, Loredana Raciti²⁰, Maria Claudia Vigliani²¹, Tommaso Bocci²², Irene Volonghi²³, Matteo Paoletti²⁴, Elena Colombo², Massimo Filippi²⁵, Anna Pichiecchio²⁴, Enrico Marchioni⁴, Diego Franciotta¹, Matteo Gastaldi¹
¹Neuroimmunology Research Section, IRCCS Mondino Foundation, Pavia, Italy, ²Multiple Sclerosis Unit, IRCCS Mondino Foundation, Pavia, Italy, ³Department of Advanced Medical and Surgical Sciences, University of Campania "Luigi Vanvitelli", Naples, Italy, ⁴Neuroncology and Neuroinflammation Unit, IRCCS Mondino Foundation, Pavia, Italy, ⁵Child Neurology and Psychiatry Unit, Children's Hospital "G. Salesi", Ospedali Riuniti Ancona, Ancona, Italy, ⁶Department of Biomedical and Neuromotor Sciences, University of Bologna (DIBINEM), Bologna, Italy, ⁷Department of Neuroscience, University of Catania Department of Surgical and Medical Sciences and Advanced Technologies 'G.F. Ingrassia', Catania, Italy, ⁸Neurology Unit, ASST Cremona, Cremona, Italy, ⁹Department of NEUROFARBA, University of Florence, Florence, Italy, ¹⁰Neurology and Neurorehabilitation Units, Multiple Sclerosis Center, IRCCS San Raffaele Hospital, Milan, Italy, ¹¹Childhood and Adolescence Neurology and Psychiatry Unit, ASST GOM Niguarda, Milan, Italy., ¹²Neurology Unit, Ramazzini Hospital, 41012 Carpi, Italy, ¹³University of Naples, Naples, Italy; Multiple Sclerosis Unit, Policlinico Federico II University Hospital, Naples, Italy, ¹⁴Section of Neurology, Department of Medicine, University of Perugia, Perugia, Italy, ¹⁵Department of medico-surgical Sciences and Biotechnologies Neurosciences, Sapienza University of Rome, Rome, Italy, ¹⁶Department of Medicine, Surgery and Dentistry "Scuola Medica Salernitana", Neuroscience Section, University of Salerno, Salerno, Italy, ¹⁷Divisione di Neurologia, Ospedale San Paolo, ASL 2 Savonese, Savona, Italy, ¹⁸Multiple Sclerosis Center, "E. Muscatello" Hospital - ASP8, Augusta (SR), Italy, ¹⁹Institute of Clinical Pathology, DMED, University of Udine and University Hospital of Udine, Udine, Italy, ²⁰Unità Spinale Unipolare, AOE Cannizzaro, 98102 Catania, Italy, ²¹Dipartimento di Neuroscienze, Ospedale San Giovanni Battista, Via Cherasco 15, 10126 Torino, Italy, ²²Aldo Ravelli' Center for Neurotechnology and Experimental Brain Therapeutics, Department of Health Sciences, University of Milan, 20142 Milan, Italy, ²³Department of Clinical and Experimental Sciences, Neurology Unit, University of Brescia, Brescia, Italy., ²⁴Neuroradiology Department, IRCCS Mondino Foundation, Pavia, Italy, ²⁵Neurology Unit, IRCCS San Raffaele Scientific Institute, Milan, Italy. Vita-Salute San Raffaele University, Milan, Italy

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.