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. 2015 Jun;21(6):1237-47.
doi: 10.1097/MIB.0000000000000372.

Inflammatory bowel disease associates with proinflammatory potential of the immunoglobulin G glycome

Irena Trbojević Akmačić  1 , Nicholas T Ventham, Evropi Theodoratou, Frano Vučković, Nicholas A Kennedy, Jasminka Krištić, Elaine R Nimmo, Rahul Kalla, Hazel Drummond, Jerko Štambuk, Malcolm G Dunlop, Mislav Novokmet, Yurii Aulchenko, Olga Gornik, Harry Campbell, Maja Pučić Baković, Jack Satsangi, Gordan Lauc; IBD-BIOM Consortium
Affiliations

Inflammatory bowel disease associates with proinflammatory potential of the immunoglobulin G glycome

Irena Trbojević Akmačić et al. Inflamm Bowel Dis. 2015 Jun.

Abstract

Background: Glycobiology is an underexplored research area in inflammatory bowel disease (IBD), and glycans are relevant to many etiological mechanisms described in IBD. Alterations in N-glycans attached to the immunoglobulin G (IgG) Fc fragment can affect molecular structure and immunological function. Recent genome-wide association studies reveal pleiotropy between IBD and IgG glycosylation. This study aims to explore IgG glycan changes in ulcerative colitis (UC) and Crohn's disease (CD).

Methods: IgG glycome composition in patients with UC (n = 507), CD (n = 287), and controls (n = 320) was analyzed by ultra performance liquid chromatography.

Results: Statistically significant differences in IgG glycome composition between patients with UC or CD, compared with controls, were observed. Both UC and CD were associated with significantly decreased IgG galactosylation (digalactosylation, UC: odds ratio [OR] = 0.71; 95% confidence interval [CI], 0.5-0.9; P = 0.01; CD: OR = 0.41; CI, 0.3-0.6; P = 1.4 × 10) and significant decrease in the proportion of sialylated structures in CD (OR = 0.46, CI, 0.3-0.6, P = 8.4 × 10). Logistic regression models incorporating measured IgG glycan traits were able to distinguish UC and CD from controls (UC: P = 2.13 × 10 and CD: P = 2.20 × 10), with receiver-operator characteristic curves demonstrating better performance of the CD model (area under curve [AUC] = 0.77) over the UC model (AUC = 0.72) (P = 0.026). The ratio of the presence to absence of bisecting GlcNAc in monogalactosylated structures was increased in patients with UC undergoing colectomy compared with no colectomy (FDR-adjusted, P = 0.05).

Conclusions: The observed differences indicate significantly increased inflammatory potential of IgG in IBD. Changes in IgG glycosylation may contribute to IBD pathogenesis and could alter monoclonal antibody therapeutic efficacy. IgG glycan profiles have translational potential as IBD biomarkers.

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Conflict of interest statement

G. Lauc is the founder and owner of Genos Ltd, a private research organization that specializes in high-throughput glycomic analysis and has several patents in this field. D. Fernandes is the CEO of Ludger Ltd, a commercial company that specializes in the development and validation of glycoprofiling technology for biologic therapeutics and biological tissues. Some of the Ludger products include glycan purification kits and glycan release kits. There are no patents and products in development. I. K. Pemberton is the Research Director of IP Research Consulting SAS, a privately owned research-intensive SME under the commercial name of Photeomix Protein Discovery that specializes in the discovery and validation of biomarkers based on posttranslational protein modification activities. There are no patents, products in development, or marketed products to declare. Y. Aulchenko is the Director of PolyOmica—a privately owned research-intensive SME that specializes in Omics data analysis. The work of Y. Aulchenko was supported by grant from the Russian Science Foundation (Grant number 14-14-00313). E. Theodoratou is a recipient of the University of Edinburgh Chancellors Fellowship. The remaining authors have no conflicts of interest to disclose.

Figures

FIGURE 1
FIGURE 1
UPLC analysis of IgG glycosylation. Each IgG contains 1 conserved N-glycosylation site on Asn297 of its heavy chain. Different glycans can be attached to this site, and the process seems to be highly regulated. UPLC analysis can reveal composition of the glycome attached to a population of IgG molecules by separating total IgG N-glycome into 24 chromatographic glycan peaks (GP1–GP24), mostly corresponding to individual glycan structures.
FIGURE 2
FIGURE 2
The distribution of IgG glycans in patients with UC and CD and healthy controls (HC). A, Directly measured glycan structures; B, Derived traits that measure sialylation and bisecting GlcNAc; C, Derived traits that measure galactosylation. Full set of glycans is available in Fig., Supplemental Digital Content 3, http://links.lww.com/IBD/A793.
FIGURE 3
FIGURE 3
ROC curves illustrating the performance of logistic regression model in predicting disease status for patients with UC and healthy controls (A) and patients with CD and healthy controls (B). Principal component analysis plots for patients with UC and healthy controls (C) and patients with CD and healthy controls (D).
See this image and copyright information in PMC

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