2025 American Academy of Neurology Abstract Website

Laura Marmolejo Alcaide¹, Claudia Papi², Chiara Milano³, Esther Aguilar¹, Estibaliz Maudes¹, Ivana Duvnjak Orešković⁴, Jerko Štambuk⁴, Maja Pučić-Baković⁴, Gemma Olivé⁵, Thais Armangue⁵, Josep Dalmau¹, Marianna Spatola¹
¹Neuroimmunology Program, Fundació de Recerca Clínic Barcelona-Institut d'Investigacions Biomédiques August Pi i Sunyer (FRCB-IDIBAPS), University of Barcelona, Spain - Caixa Research Institute (CRI), Barcelona, Spain, ²Neuroimmunology Program, Fundació de Recerca Clínic Barcelona-Institut d'Investigacions Biomédiques August Pi i Sunyer (FRCB-IDIBAPS), University of Barcelona, Spain - Caixa Research Institute (CRI), Barcelona, Spain & Department of Neuroscience, Catholic University of the Sacred Heart, Rome, Italy, ³Neuroimmunology Program, Fundació de Recerca Clínic Barcelona-Institut d'Investigacions Biomédiques August Pi i Sunyer (FRCB-IDIBAPS), University of Barcelona, Spain - Caixa Research Institute (CRI), Barcelona, Spain & Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy, ⁴Genos Glycoscience Research Laboratory, HR-10 000 Zagreb, ⁵Neuroimmunology Program, Fundació de Recerca Clínic Barcelona-Institut d'Investigacions Biomédiques August Pi i Sunyer (FRCB-IDIBAS), University of Barcelona, Spain - Caixa Research Institute (CRI), Barcelona, Spain & Pediatric Neuroimmunology Unit, Neurology Service, Sant Joan de Déu (SJD) Children's Hospital, University of Barcelona, Barcelona, Spain

Objective:

To identify Fc-glycosylation profiles in patients with anti-N-methyl-D-aspartate receptor encephalitis (NMDARe) that track with compartmentalization of antibody responses in CSF (vs serum) and with disease triggers.

Background:

NMDARe is characterized by pathogenic antibodies in serum and CSF. These antibodies are mainly IgG1 (some patients also harbor IgG2 and IgG3) and directly cause neuronal dysfunction. NMDARe triggers include tumor (mostly ovarian teratoma) and herpes simplex virus encephalitis, although in many cases the underlying cause is unknown (idiopathic). Studies on B-cell-receptor sequencing have suggested that the antibody response in the brain is compartmentalized, compared to the periphery. However, whether antibody responses are qualitatively different (for example in their glycosylation profiles) between serum and CSF and according to disease trigger is unknown.

Design/Methods:

Using liquid-chromatography-mass-spectrometry we determined the Fc-glycosylation profiles of IgG1 and IgG2/3 in paired serum and CSF samples from (age- and sex-matched) patients with NMDARe (n=50). Patients were classified based on disease trigger into post-herpetic, tumor-related or idiopathic. Glycoprofiles were determined by quantification of fucosylation, sialylation, galactosylation and bisecting N-glucosamination.

Results:

Compared to serum, CSF IgG1 and IgG2/3 from NMDARe patients exhibited a more inflammatory Fc-glycan profile characterized by reduced levels of sialylation and galactosylation (p<0.001). Compared to patients with tumor-related or idiopathic triggers, those with post-herpetic cause showed lower sialylation, reduced galactose levels, and increased bisecting N-glucosamination in both IgG1 and IgG2/3 profiles (p<0.001). These differences across trigger-related groups were not observed in serum. Fucosylation levels were similar across compartments and triggers.

Conclusions:

In patients with NMDARe, CSF shows distinct Fc-glycosilation profiles, supporting a compartmentalized antibody response within the brain. Post-herpetic NMDARe is associated with more inflammatory glycoprofiles than other triggers. As glycan signatures determine different interactions with the innate immunity (e.g. complement, NK cells), these findings suggest distinct pathogenic mechanisms that might be harnessed to develop compartment-specific and trigger-specific therapeutic strategies in NMDARe.