Lack of Galactosylation Enhances the Pathogenic Activity of IgG1 but Not IgG2a Anti-Erythrocyte Autoantibodies

Abstract

IgG bears asparagine-linked oligosaccharide side chains in the Fc region. Variations in their extent of galactosylation and sialylation could modulate IgG Fc-dependent effector functions, and hence Ab activity. However, it has not yet been clarified whether the pathogenic potential of IgG autoantibodies is consistently enhanced by the absence of galactose residues per se or the lack of terminal sialylation, which is dependent on galactosylation. Moreover, it remains to be defined whether the increased pathogenicity of agalactosylated IgG is related to activation of the complement pathway by mannose-binding lectin, as suggested by in vitro studies. Using a murine model of autoimmune hemolytic anemia, we defined the contribution of galactosylation or sialylation to the pathogenic activity of IgG1 and IgG2a anti-erythrocyte class-switch variants of 34-3C monoclonal autoantibody. We generated their degalactosylated or highly sialylated glycovariants and compared their pathogenic effects with those of highly galactosylated or desialylated counterparts. Our results demonstrated that lack of galactosylation, but not sialylation, enhanced the pathogenic activity of 34-3C IgG1, but not IgG2a autoantibodies. Moreover, analysis of in vivo complement activation and of the pathogenic activity in mice deficient in C3 or IgG FcRs excluded the implication of mannose-binding lectin-mediated complement activation in the enhanced pathogenic effect of agalactosylated IgG1 anti-erythrocyte autoantibodies.

Low anti‐RhD IgG‐Fc‐fucosylation in pregnancy: a new variable predicting severity in haemolytic disease of the fetus and newborn

“…Most importantly, addition of galactose to the Asn297 glycan in IgG has been shown to result in decreased binding to FcγR ( Li et al , 2006 ), which is further reduced by the addition of sialic acid in mice ( Kaneko et al , 2006 ). This is supported by a recent report showing that lack of galactosylation enhances the pathogenic activity of IgG1 anti-RBC autoantibodies ( Ito et al , 2014 ). Together this makes it very unlikely that the increased galactosylation we observed, with or without possible increased sialylation, will positively affect ADCC.…”

Inflammatory Bowel Disease Associates with Proinflammatory Potential of the Immunoglobulin G Glycome

“… 40 , 41 Thus, individual genetically predetermined differences in capacity to galactosylate IgG may be a predisposing factor for the development of IBD and other inflammatory diseases. 42 …”

Patients with IgG1-anti-red blood cell autoantibodies show aberrant Fc-glycosylation

“…The composition of the N-linked sugar moiety (glycan) attached to the Fc region at position 297 of the IgG-Fc tail influences the binding affinity to IgG Fc receptors (FcγR) on effector cells 6 – 8 . In addition to binding of C1q, activation of the complement cascade can also be modulated by Fc-linked glycans 5 , and some experimental although inconclusive evidence to support this, has been published 9 – 12 . The N297 glycan consists of an invariant core structure containing two N-acetylglucosamines (GlcNAc) and three mannoses.…”