Composition of the immunoglobulin G glycome associates with the severity of COVID-19

Abstract

A large variation in the severity of disease symptoms is one of the key open questions in COVID-19 pandemics. The fact that only a small subset of people infected with SARS-CoV-2 develop severe disease suggests that there have to be some predisposing factors, but biomarkers that reliably predict disease severity have not been found so far. Since overactivation of the immune system is implicated in a severe form of COVID-19 and the IgG glycosylation is known to be involved in the regulation of different immune processes, we evaluated the association of inter-individual variation in IgG N-glycome composition with the severity of COVID-19. The analysis of 166 severe and 167 mild cases from hospitals in Spain, Italy and Portugal revealed statistically significant differences in the composition of the IgG N-glycome. The most notable difference was the decrease in bisecting N-acetylglucosamine (GlcNAc) in severe patients from all three cohorts. IgG galactosylation was also lower in severe cases in all cohorts, but the difference in galactosylation was not statistically significant after correction for multiple testing. To our knowledge, this is the first study exploring IgG N-glycome variability in COVID-19 severity.

Profile of Immunoglobulin G N-Glycome in COVID-19 Patients: A Case-Control Study

“…Lower levels of sialylated IgG glycans and galactosylated glycans were observed in the severe patients compared to the mild ones. These results support earlier findings in the European COVID-19 patients ( 18 ), suggesting that the lectin-initiated alternative complement pathway modulated by the decreased sialylation and galactosylation might induce a severe inflammatory process in severe COVID-19 ( 11 ). It was noted that the mild cases (mean age 42.3 years) are significantly younger than the severe cases (mean age 57.0 years).…”

“…Moreover, a study showed that IgG against SARS-CoV-2 S protein is characterized by afucosylation, whereas IgG against N protein has a higher level of fucosylation ( 20 ). These findings support the notion that changes in IgG glycome composition are closely related to the loss of the immunosuppressive function and contribute to the immune-mediated pathologies of SARS-CoV-2 infection ( 18 ). We aimed to profile the IgG N -glycome in COVID-19 patients by an age- and sex-matched case-control study.…”

“…Afucosylation upregulates the capability of IgG to trigger antibody-dependent cell cytotoxicity (ADCC) and leads to the enhancement of inflammatory cytokines produced by monocytes. An increase in IgG afucosylation has been observed among severe COVID-19 patients in earlier studies involving Caucasian populations ( 18 , 20 ). As shown in Figure 1 , 14 fucosylated glycans (GP4, GP6, GP8, GP9, GP10, GP14, GP16, GP18, GP19, F n total , FG2 n total /G2 n , F n , FG1 n /G1 n , and FG2 n /G2 n ) were significantly lower in the COVID-19 group when compared to the controls.…”

“…However, there is limited knowledge on IgG glycosylation that is associated with SARS-CoV-2 infection. Recently, the levels of bisecting N -acetylglucosamine (GlcNAc) and galactosylation of IgG were reported to be negatively correlated to the severity of the European COVID-19 patients ( 18 ). Meanwhile, IgG afucosylation was observed to be positively correlated with the severity of COVID-19 ( 19 ).…”

An observational cohort study to assess N-acetylglucosamine for COVID-19 treatment in the inpatient setting

“…Molecular research confirms NAG's involvement with acute and chronic inflammation processes and supports multiple potential mechanisms of action in COVID-19 patients. For example, a study by Petrović et al investigating variation in immunoglobulin G glycome composition based on the severity of COVID-19 found a significant decrease of bisecting NAG in patients with severe COVID-19 [ 35 ]; these results potentially indicate NAG depletion following increased immunometabolism to fight infection or inflammation. Another study by Krick et al demonstrated that increased levels of O-linked β-NAG protein modification correlated with increased immune cell secretion in a pathway mediating chronic inflammatory airway diseases [ 20 ].…”