CSF-Compartmentalized Antibody Glycoprofiles in NMDAR Encephalitis Associate with Etiology and Functional Recovery
Laura Marmolejo1, Claudia Papi1,2, Chiara Milano1,3
1Neuroimmunology Program, Fundació de Recerca Clínic Barcelona-Institut d'Investigacions Biomédiques August Pi i Sunyer (FRCB-IDIBAPS), University of Barcelona, Spain and Caixa Research Institute (CRI), Barcelona, Spain.
Objective:
To characterize Fc-glycosylation profiles in patients with anti-N-methyl-D-aspartate receptor encephalitis (NMDARe) and assess their association with antibody compartmentalization (cerebrospinal fluid [CSF] vs serum), disease triggers (viral, tumor-related or idiopathic), and 1-year outcomes.
Methods:
We analyzed immunoglobulin (Ig) G1 and IgG2/3 Fc-glycosylation by liquid chromatography-mass spectrometry in paired serum/CSF samples from 50 age- and sex-matched patients with NMDARe identified in IDIBAPS/Hospital Clinic of Barcelona database and the Spanish study on herpes encephalitis. Patients were classified by disease trigger as post-herpetic, tumor-related, or idiopathic. One-year outcomes were defined as good (modified Rankin Scale [mRS] ≤2) or poor (≥3). Fc glycoprofiles were quantified for fucosylation, sialylation, galactosylation, and bisecting N-acetylglucosamination.
Results:
Across IgG subclasses (IgG1-3), CSF antibodies showed significantly reduced sialylation and galactosylation compared to serum (p < 0.0001), indicating a pro-inflammatory compartmentalized response within the central nervous system. These inflammatory Fc-glycoforms were predominant in post-herpetic cases of NMDARe (p < 0.01) compared to tumor-related and idiopathic forms, suggesting that viral-induced NMDAR may alter antibody Fc-glycosylation via B-cell glycosylation pathway modulation. Furthermore, reduced sialylation, galactosylation and fucosylation in CSF and serum were associated with poor 1-year outcomes (p < 0.05), suggesting that compartmentalized inflammation and enhanced innate immune activation, including natural killer (NK) cell-mediated cytotoxicity driven by afucosylated antibodies, might contribute to neurological dysfunction.
Interpretation:
In NMDARe, CSF Fc-glycosylation profiles are both compartment- and trigger-specific. Because glycan signatures shape innate immune interactions (e.g., with NK cells), these findings highlight distinct pathogenic mechanisms and support Fc-glycosylation profiling as a potential prognostic biomarker. ANN NEUROL 2026;99:1468-1479.
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