CSF ‐Compartmentalized Antibody Glycoprofiles in NMDAR Encephalitis Associate with Etiology and Functional Recovery

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.