Abstract
This study indicates that glycosylation of immunoglobulin G, the most abundant antibody in human blood, may convey useful information with regard to inflammation and metabolic health. IgG occurs in the form of different subclasses, of which the effector functions show significant variation. Our method provides subclass-specific IgG glycosylation profiling, while previous large-scale studies neglected to measure IgG2-specific glycosylation. We analysed the plasma Fc glycosylation profiles of IgG1, IgG2 and IgG4 in a cohort of 1826 individuals by liquid chromatography-mass spectrometry. For all subclasses, a low level of galactosylation and sialylation and a high degree of core fucosylation associated with poor metabolic health, i.e. increased inflammation as assessed by C-reactive protein, low serum high-density lipoprotein cholesterol and high triglycerides, which are all known to indicate increased risk of cardiovascular disease. IgG2 consistently showed weaker associations of its galactosylation and sialylation with the metabolic markers, compared to IgG1 and IgG4, while the direction of the associations were overall similar for the different IgG subclasses. These findings demonstrate the potential of IgG glycosylation as a biomarker for inflammation and metabolic health, and further research is required to determine the additive value of IgG glycosylation on top of biomarkers which are currently used.
Highlights
Glycosylation is known to reflect the physiological state of an organism and changes thereof[1]
By performing nanoLC-ESI-quadrupole time-of-flight (QTOF)-MS analysis on tryptic immunoglobulin G (IgG) glycopeptides, fragment crystallisable (Fc) glycosylation profiles of IgG1, IgG2 and IgG4 were determined for nearly 2000 participants of the Leiden Longevity study
While the type of sialic acid linkage could not be determined by our methods, it is known from literature that the vast majority of sialic acids from plasma-derived Fc-IgG are 2,6-linked[54,55,56]
Summary
Glycosylation is known to reflect the physiological state of an organism and changes thereof[1]. Since IgG glycosylation is known to be altered during a state of inflammation, it is not surprising that associations between certain glycoforms and the inflammatory marker C-reactive protein (CRP) have been reported[18,19,20,21]. Other large cohort studies (>100 healthy participants) on IgG glycosylation report either a released glycan profile[23,24], which does not contain any subclass-specific information, or a joint profile for IgG2 and IgG325,26. This is due to the shared peptide sequence of the tryptic glycopeptides of these two subclasses, which prevents separate analysis www.nature.com/scientificreports/. The current analysis is performed with nanoLC-ESI-QTOF-MS, which offers enhanced sensitivity and a more extensive glycoprofiling of the samples: 20 N-glycopeptides were identified for IgG1 and IgG2 and 10 for IgG4, providing novel information on the sialylation and fucosylation of these samples
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