GlycomePREDICTS: IgG Glycome as a Predictor of Inflammatory Bowel Disease Development

Inflammatory bowel diseases (IBD, one of the Fiscal Year 2018 Peer Reviewed Medical Research Program Topic Areas), such as Crohn's disease (CD) and ulcerative colitis (UC), are chronic immune-mediated disorders of the gastrointestinal tract that typically affect patients between 15 to 30 years, in the most productive and active period of life, having a significant impact on a patient's quality of life. The incidence of IBD is increasing worldwide with the highest prevalence reported in North America and Europe. The precise etiopathogenesis of IBD is still unknown and the disease remains incurable. Evidences suggest that IBD is a progressive disorder, characterized by a period in which immunological changes start to occur, preceding clinical. The identification of this early-stage of IBD development, in a preclinical phase, remains to be elucidated being urgently needed as this will shift the paradigm of IBD management towards primary and secondary preventive strategies that ultimately will impact in better prognosis and better disease course.

These urgent needs in the clinic led us to set the current proposal of which the main goal is to assess, for the first time, whether the serum IgG glycome will inform the primary biological processes that drive bowel inflammation, assisting in the early diagnosis and secondary prevention of IBD.

Preliminary results from the team on the PREDICTS cohort (DoD Serum Repository, constituted by IBD cases and matched controls from US Military Service members), using high-throughput proteomics analysis, have identified a significant enrichment in pathways related with glycosylation in pre-IBD patients as compared to controls. Furthermore, previous evidences from the Principal Investigator's (PI's) lab also demonstrated that glycans are implicated in the mechanisms underlying the immunopathogenesis of IBD. These preliminary evidences on the impact of glycosylation alterations in IBD development support our hypothesis in testing glycosylation as a mechanism that to date has been poorly explored in the preclinical phase of IBD.

Immunoglobulin G (IgG) antibodies are the predominant antibody class in circulation and comprise multiple glycoforms owing to the addition of diverse type of glycans in the IgG Fc (crystallizable fragment) region. The composition of IgG Fc in terms of fucose, galactose, and sialic acid varies among individuals, which reflects a significant heterogeneity in IgG Fc glycome among the population.

The goal of this international and multicenter project is to identify a minimally invasive predictive biomarker of IBD development. The identification of change in IgG glycome signature associated with the onset of pre-IBD disease may advance the development of a predictive algorithm, which promises to aid in early diagnosis as well as in supporting the identification of novel therapeutic and preventive strategies.

We believe that the identification of a minimally invasive serological biomarker with significant predictive capacity to stratify high-risk patients to develop IBD will foster the development of effective preventive strategies in personalized medicine that, from the military point of view, is of utmost importance for maintenance of both health in Force readiness and health in the economics of the Department of Defense.