Preprint Altered spike IgG Fc N-linked glycans are associated with hyperinflammatory state in adult COVID and [MIS-C], 2024, Sherman et al.

[SNT Gatchaman]

Altered spike IgG Fc N-linked glycans are associated with hyperinflammatory state in adult COVID and Multisystem Inflammatory Syndrome in Children
Jacob D. Sherman; Vinit Karmali; Bhoj Kumar; Trevor W. Simon; Sarah Bechnak; Anusha Panjwani; Caroline R. Ciric; Dongli Wang; Chris Huerta; Brandi Johnson; Evan J. Anderson; Nadine Rouphael; Matthew H. Collins; Christina A. Rostad; Parastoo Azadi; Erin M. Scherer

BACKGROUND
Severe COVID and multisystem inflammatory syndrome (MIS-C) are characterized by excessive inflammatory cytokines/chemokines. In adults, disease severity is associated with SARS-CoV-2-specific IgG Fc afucosylation, which induces pro-inflammatory cytokine secretion from innate immune cells. This study aimed to define spike IgG Fc glycosylation following SARS-CoV-2 infection in adults and children and following SARS-CoV-2 vaccination in adults and the relationships between glycan modifications and cytokine/chemokine levels.

METHODS
We analyzed longitudinal (n=146) and cross-sectional (n=49) serum/plasma samples from adult and pediatric COVID patients, MIS-C patients, adult vaccinees, and adult and pediatric healthy controls. We developed methods for characterizing bulk and spike IgG Fc glycosylation by capillary electrophoresis (CE) and measured levels of ten inflammatory cytokines/chemokines by multiplexed ELISA.

RESULTS
Spike IgG were more afucosylated than bulk IgG during acute adult COVID and MIS-C. We observed an opposite trend following vaccination, but it was not significant. Spike IgG were more galactosylated and sialylated and less bisected than bulk IgG during adult COVID, with similar trends observed during pediatric COVID/MIS-C and following SARS-CoV-2 vaccination. Spike IgG glycosylation changed with time following adult COVID or vaccination. Afucosylated spike IgG exhibited inverse and positive correlations with inflammatory markers in MIS-C and following vaccination, respectively; galactosylated and sialylated spike IgG inversely correlated with pro-inflammatory cytokines in adult COVID and MIS-C; and bisected spike IgG positively correlated with inflammatory cytokines/chemokines in multiple groups.

CONCLUSIONS
We identified previously undescribed relationships between spike IgG glycan modifications and inflammatory cytokines/chemokines that expand our understanding of IgG glycosylation changes that may impact COVID and MIS-C immunopathology.


Link | PDF (Preprint: MedRxiv) [Open Access]

 

[SNT Gatchaman]

An area of increasing investigation is whether irregular IgG Fc glycosylation is triggering dysregulated inflammation in COVID and MIS-C. The IgG Fc region contains a conserved asparagine(N)-linked glycosylation site at N297 on each heavy chain. This glycan is composed of a core seven saccharides containing three mannose and four N-acetylglucosamine (GlcNAc) residues that can be differentially modified with other sugar residues (Fig. 1).

This diversity of structures has implications for an Fc’s interaction with Fc gamma receptors (FcγRs), which can have downstream signaling effects on an active immune response. For example, it has been demonstrated that afucosylated IgG-Fc have an increased affinity for FcγRIIIa, an activating FcγR found on the surface of monocytes, macrophages, and NK cells, as well as FcγRIIIb, an activating FcγR found on neutrophils.

 

[mariovitali]

This association is confirmed by machine learning methods. Note the mention on asparagine and N-Linked glycosylation.


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