How Sugar Coatings on Antibodies Drive Neuroimmune Disease and New Treatments

Glycosylation — the enzymatic attachment of sugar chains (glycans) to proteins — is a critical post-translational modification present in roughly half of all proteins. In immunoglobulins (antibodies), glycosylation profoundly shapes immune function. This 2025 review from Central South University focuses on IgG, the most abundant serum antibody, and its N-glycosylation at asparagine 297 (Asn297) in the Fc region — the site most directly governing antibody effector functions such as complement activation, antibody-dependent cellular cytotoxicity (ADCC), and phagocytosis.

The review systematically covers five major neuroimmune diseases: multiple sclerosis (MS), neuromyelitis optica spectrum disorder (NMOSD), Guillain-Barré syndrome (GBS), chronic inflammatory demyelinating polyradiculoneuropathy (CIDP), and myasthenia gravis (MG). Across all five conditions, a convergent glycosylation fingerprint emerges — reduced galactosylation, reduced sialylation, and reduced core fucosylation on IgG. These changes are not trivial: low galactosylation impairs anti-inflammatory signaling via FcγRIIb and Dectin-1; reduced sialylation eliminates IgG's capacity to engage inhibitory SIGN-R1/DC-SIGN pathways that normally suppress inflammation; and decreased core fucosylation paradoxically enhances ADCC by increasing FcγRIIIa affinity, amplifying NK cell and macrophage-mediated tissue damage.

Importantly, the review argues that IgG glycosylation may explain why antibody titer alone does not reliably correlate with disease severity in conditions like MG and NMOSD. The same antibody at the same titer can be more or less pathogenic depending on its glycan decoration. Disease-specific glycan profiles also track with relapse versus remission states in MS and NMOSD, suggesting utility as dynamic biomarkers.

On the therapeutic side, the review highlights two promising strategies. First, engineering therapeutic monoclonal antibodies with tailored glycan profiles — such as afucosylated antibodies to boost ADCC for tumor or infection targets, or hypersialylated IgG to mimic the anti-inflammatory effects of intravenous immunoglobulin (IVIg). Second, using glycosidases (enzymes that trim specific sugars) to modulate endogenous IgG glycosylation in vivo, a strategy already entering early clinical exploration for autoimmune disease.

The review also addresses IgG Fab glycosylation, present in 15–25% of circulating IgGs and acquired during somatic hypermutation. Fab glycans can modulate antigen-binding affinity and are particularly relevant in antigen-specific pathogenic antibodies in diseases like MG. Overall, the authors frame IgG glycosylation as a disease hallmark that bridges molecular mechanism and translational opportunity, warranting dedicated study in neuroimmunology.