ANTIBODY FC GLYCAN SIGNATURES TRACK WITH COMPARTMENTS, ETIOLOGY AND ONE-YEAR OUTCOMES IN ANTI-NMDA RECEPTOR ENCEPHALITIS

Anti–N-methyl-D-aspartate receptor encephalitis (anti-NMDAR encephalitis) is an autoimmune neurological disorder mediated by pathogenic NMDAR antibodies (mainly IgG1 but also IgG2-3). Although these antibodies are often detected in both serum and cerebrospinal fluid (CSF), some patients show CSF-restricted antibodies, together with CSF-specific IgG oligoclonal bands, suggesting local antibody production and immune compartmentalization within the central nervous system (CNS). However, it remains unclear whether NMDAR antibodies differ qualitatively between serum and CSF or according to disease aetiology (which include ovarian teratoma, herpes simplex virus encephalitis (HSE), or idiopathic causes), or functional recovery.
Here, we aimed to determine whether IgG Fc-glycosylation differs between serum and CSF and whether distinct glycoprofiles associate with disease aetiologies and outcomes. Paired serum and CSF samples from anti-NMDAR encephalitis patients (n=50) were analyzed by LC–MS to quantify IgG1 and IgG2/3 Fc-glycosylation, including fucose, sialic acid, galactose and bisecting N-acetylglucosamine, then compared across compartments, disease triggers and one-year outcomes (measured by modified Rankin scale [mRS] 0-1=good, 2-5=bad).
Across all IgG subclasses, CSF antibodies showed a more inflammatory Fc-glycosylation profiles, characterized by decreased sialic acid and galactose compared to serum. These antibody features were enriched in post-HSE, compared to tumor-associated and idiopathic cases, and in patients with bad outcomes.
In conclusion, antibody Fc-glycosylation in anti-NMDAR encephalitis is compartmentalized, with more inflammatory glycoforms in CSF compared to serum. These pro-inflammatory glycosignatures are most prominent in post-HSE and in patients with poor one-year recovery, suggesting that compartmentalized CNS inflammation contributes to neurological dysfunction and highlighting Fc-glycans as potential prognostic biomarkers.