IgG N-glycosylation in autoimmune diseases.

IgG is the most abundant antibody in the human circulation. It carries a single conserved glycosylation site, Asparagine 297, in its Fc domain. This N-glycan is critical for the ability of the antibody to activate immune cells via binding to, and cross-linking Fc receptors in order to elicit functional responses. First documented in the context of rheumatoid arthritis (RA), the IgG N-glycan may undergo changes that are correlated to host health. We present a narrative in-depth comparison of changes incurred by IgG N-glycans in autoimmune diseases; RA, systemic lupus erythematosus, multiple sclerosis, type I diabetes, primary biliary cholangitis and inflammatory bowel disease (Crohn's disease and ulcerative colitis). Based on a systematic literature search, we identify common traits and features that are specific for any one autoimmune disease. Our analysis shows that the single most common trend in most of the conditions analyzed here is increased IgG agalactosylation. Changes to the IgG N-glycan typically accompany and often precede disease onset and flare-ups, while they decrease in remission and pregnancy. The correlation of agalactosylated IgG with inflammatory disease is so striking that the agalactosylated IgG N-glycan has long been viewed as inflammatory and even pathogenic. Yet, despite the association with inflammation, any mechanism by which disease-associated IgG N-glycans may mediate their pro-inflammatory nature remains enigmatic.