A unique serum glycosylation signature of IgGs predicts the development of Crohn's disease and is associated with pathogenic anti-mannose glycan (ASCA) antibodies.

Inflammatory Bowel Disease (IBD) is characterized by a chronic inflammation in the gut. There is growing evidence in Crohn´s Disease (CD) of the existence of a preclinical period characterized by immunological changes preceding symptom onset that starts years before diagnosis. Gaining insight into this preclinical phase will allow disease prediction and prevention. Analysis of preclinical serum samples, up to 6 years before IBD diagnosis (from the PREDICTs cohort), revealed the identification of a unique glycosylation signature on circulating antibodies (IgGs) characterized by lower galactosylation levels of IgG fragment crystallizable (Fc) domain that remained stable until disease diagnosis. This specific IgG2 Fc glycan trait correlated with increased anti-microbial antibodies, specifically with anti-Saccharomyces cerevisiae antibody (ASCA) levels, pinpointing a glycome-ASCA hub, detected in serum, that predates by years the development of CD. Mechanistically, we demonstrated that this agalactosylated glycoform of ASCA IgG, detected in the preclinical phase, elicits a pro-inflammatory immune pathway through the activation and reprogramming of innate immune cells (such as dendritic cells and natural killer cells), via Fc?R-dependent mechanism, triggering NF-kB and CARD9 signaling and leading to inflammasome activation. This pro-inflammatory role of ASCA was demonstrated to be dependent on mannose glycan recognition and on the galactosylation levels in IgG Fc domain. The pathogenic properties of (anti-mannose) ASCA IgG were validated in vivo. Adoptive transfer of anti-mannan antibodies (ASCA) to recipient WT mice resulted in increased susceptibility to intestinal inflammation that was recovered in recipient Fc?R KO mice. This is the first demonstration of the identification of an altered glycosylation signature in circulating IgGs preceding CD onset, pinpointing a specific glycome-ASCA pathway as a central player in the initiation of inflammation many years before CD diagnosis. This pathogenic glyco-hub may constitute a promising new serum biomarker for CD prediction and a potential target for disease prevention.