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.

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. 

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. 

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.