On the interaction between agalactosyl IgG and Fcγ receptors

Abstract

One of the serum abnormalities observed in autoimmune diseases such as rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE) is the occurrence of IgG that lacks the terminal galactose on asparagine-linked biantennary complex type oligosaccharides [Gal(0)-IgG] located in the CH2 domain. Additionally, IgG without glycosylation is known to be defective in several effector functions due to a reduced ability to bind to its specific receptors (Fc gamma R). It has thus been speculated that, by analogy with unglycosylated IgG, Gal(0)-IgG may also be functionally impaired or exert altered effector mechanisms. If this were true, Gal(0)-IgG could contribute to the phenotype of above-mentioned autoimmune diseases, like impaired immune complex clearance and defective down-regulation of activated B cells. Here, we show by three different methods that the interaction of Gal(0)-IgG and normally glycosylated IgG with the low-affinity Fc gamma RII (CD32) is indistinguishable with respect both to binding and receptor-mediated signalling. These data argue against a prominent role for Fc gamma R-dependent Gal(0)-IgG interactions in the etiology or pathogenesis of autoimmune diseases.

Agalactosylated IgG antibodies depend on cellular Fc receptors forin vivoactivity

“…2, both degalactosylated 6A6 IgG subclasses bound Ϸ2-fold better to MBL, whereas binding to C1q was decreased, consistent with earlier observations (15,25). Previous studies dealing with the effect of the lack of galactose on FcR binding were inconclusive, with some studies finding reduced binding (25)(26)(27), whereas others found only slight or no major changes (28)(29)(30)(31). Importantly, many of these studies used different methods, FcRs, and antibody isotypes, which might explain some of these contradictory results.…”

Fucosylation and Galactosylation of IgG Heavy Chains Differ between Acute and Remission Phases of Juvenile Chronic Arthritis

“…1) (4). However, some results argue against this hypothesis (8) and further studies are needed to resolve the issue. Through the creation of novel, potentially immunogenic structures (5), and/or the alteration of IgG receptor binding (6), de-galactosylation may be one of the causes, and not the consequence of the disease (7).…”

The antibody paradigm: present and future development as a scaffold for biopharmaceutical drugs

“…Studies of the influence of terminal galactose residues on IgG-Fc effector functions have also resulted in conflicting reports; probably because the impact of core fucosylation was not appreciated in earlier studies (Mimura et al, 2000;Mimura et al, 2001;Lund et al, 1990;Krapp et al, 2003;Walker et al, 1989;Yamaguchi et al, 2006;Kumpel et al, 1995;Groenink et al, 1996;Kumpel et al, 2007). Only a "slight" differences in binding/adherence to FcγRI, FcγRII or FcγRIII bearing cells was reported for highly galactosylated anti-D antibody, compared to pauci-galactosylated anti-D, however, a consistent reduction in lysis of erythrocytes mediated through FcγRIIIA on NK cells was reported (Kumpel et al, 1995;Groenink et al, 1996;Kumpel et al, 2007).…”

“…Only a "slight" differences in binding/adherence to FcγRI, FcγRII or FcγRIII bearing cells was reported for highly galactosylated anti-D antibody, compared to pauci-galactosylated anti-D, however, a consistent reduction in lysis of erythrocytes mediated through FcγRIIIA on NK cells was reported (Kumpel et al, 1995;Groenink et al, 1996;Kumpel et al, 2007). No difference in binding or receptor mediated signalling though FcγRII was reported for G0 and G2 glycoforms of the anti-CD52 humanised IgG1 Campath-1H antibody (Boyd et al, 1995).…”