Functional consequences of IgG glycosylation

The oligosaccharides of the Fc do not appear to be involved in binding of antigen, protein A, or recognition by rheumatoid factor. This has been shown by several authors who have compared aglycosyl IgG produced by culturing cells in the presence of tunicamycin, with native IgG. Proteolytic susceptibility and those interactions between IgG and Clq or cellular-bound receptors are, however, critically affected by Fc oligosaccharides. For example, binding to monocyte and macrophage Fc receptors, induction of cellular toxicity, rapid clearance of immune complexes from serum, and feedback immunosuppression are all severely reduced in agly-

Conserved qiycosyfahon siles

Non conserved glycosylate sites

Neu5Ac \

GlcNAc

Neu5ac Glcnac

Figure 1 (A) A schematic representation of an IgG molecule indicating the positions of conserved N-glycosylation sites (at Asn297 in the Ch2 domains), and nonconserved A/-glycosylation sites (in the hypervariable regions (dotted) of the Fab). The relative size of an immunoglobulin domain and a fully extended A/-linked biantennary complex oligosaccharide are similar. Complex-type oligosaccharides present on IgG can be subdivided into an outer-arm region (a, a', b, b', c, c'), and the core, which is composed of a trimannosyl unit (d, d', e) and a ft/,/V'-diacetylchitobiosyl unit (f,g). The 'bisect' GlcNAc (residue i) is linked 3(1 —4) and the fucose (residue h) is linked «(1-6). The arrow between residues e and f indicates the site of interaction between the two oligosaccharides in B and C. (B) Refined structure at 2.80 A of rabbit Fc fragment. The two carbohydrate chains, each attached at Asn297, differ in conformation, may also differ in sequence and bridge the CH2 domains. The «(1—3) arm of the chain (left side) is always devoid of galactose and interacts through its j8(1-2)-linked GlcNAc residue (c) with the Man/3(1-4)GlcNAc segment of the opposing (right side) oligosaccharide chain (see A). The «(1-3) arm of the right chain extends outwards between the domains with no apparent steric constraints on its length. A Neu5Ac unit (a') is shown on one «(1-6) arm only (left). (C) Fragment containing oligosaccharides devoid of galactose and sialic acid on each of the a(1-6) arms. Since these residues in normal IgG are in contact with the surface of the protein (see B), their absence vacates oligosaccharide-binding sites in IgG from arthritic patients, and could make IgG 'sticky by creating a lectin-like activity.

Asn297 Asn297

Ol A

Figure 1 (A) A schematic representation of an IgG molecule indicating the positions of conserved N-glycosylation sites (at Asn297 in the Ch2 domains), and nonconserved A/-glycosylation sites (in the hypervariable regions (dotted) of the Fab). The relative size of an immunoglobulin domain and a fully extended A/-linked biantennary complex oligosaccharide are similar. Complex-type oligosaccharides present on IgG can be subdivided into an outer-arm region (a, a', b, b', c, c'), and the core, which is composed of a trimannosyl unit (d, d', e) and a ft/,/V'-diacetylchitobiosyl unit (f,g). The 'bisect' GlcNAc (residue i) is linked 3(1 —4) and the fucose (residue h) is linked «(1-6). The arrow between residues e and f indicates the site of interaction between the two oligosaccharides in B and C. (B) Refined structure at 2.80 A of rabbit Fc fragment. The two carbohydrate chains, each attached at Asn297, differ in conformation, may also differ in sequence and bridge the CH2 domains. The «(1—3) arm of the chain (left side) is always devoid of galactose and interacts through its j8(1-2)-linked GlcNAc residue (c) with the Man/3(1-4)GlcNAc segment of the opposing (right side) oligosaccharide chain (see A). The «(1-3) arm of the right chain extends outwards between the domains with no apparent steric constraints on its length. A Neu5Ac unit (a') is shown on one «(1-6) arm only (left). (C) Fragment containing oligosaccharides devoid of galactose and sialic acid on each of the a(1-6) arms. Since these residues in normal IgG are in contact with the surface of the protein (see B), their absence vacates oligosaccharide-binding sites in IgG from arthritic patients, and could make IgG 'sticky by creating a lectin-like activity.

cosyl IgG. Further, serial lectin chromatography on total serum IgG has shown that there normally exists within serum IgG a range of affinities for monocyte Fc receptors, and this range is independent of subclass or antigenic specificity but correlates with Fc

N-glycosylation. That is, both the presence and nat ure of Fc glycosylation affcct its interaction with the monocyte Fc receptor, and the naturally occurring glycoforms of IgG differ in this respect.

While interaction with cell surface receptors is clearly sensitive to Fe N-glycosylation, Fab N-glyco-sylation appears to exert more influence on solubility and aggregation phenomena. Naturally occurring univalent (and therefore nonprecipitating) antibodies are formed by N-glycosylation of only one of the Fab arms (asymmetric glycosylation). Apparently, the presence of an N-linked oligosaccharide at certain positions of certain Fab moieties leads to a marked reduction in affinity for antigen at that Fab. Enzymatic removal of such an oligosaccharide restores the natural antigen affinity and renders the molecule bivalent. Interestingly, the oligosaccharide rendering some IgG molecules univalent almost invariably carries nonreducing terminal mannose residue(s), suggesting that such antibodies, though univalent, may activate the alternative complement pathway through interaction with serum mannan binding-lectin. The aggregation of IgG into IgG complexes is in some cases also Fab oligosaccharide-related. The cryoglobulin and cold agglutinin properties of some IgM and IgG monoclonal antibodies are dependent on the presence of certain Fab oligosaccharides.

A study of IgG N-glycosylation has provided new insights into the etiopathology of certain human diseases, particularly rheumatoid arthritis (RA), tuberculosis (TB), and Crohns disease. When the N-linked oligosaccharides of total serum IgG from normal individuals and patients suffering from active RA are compared, it is found that IgG from RA patients has a dramatically decreased incidence of structures terminating in outer-arm galactose, and therefore a corresponding increase in structures terminating with outer-arm N-acetylglucosamine (P < 0.001 by analysis of covariance). In effect, IgG totally lacking galactose [IgG(0)] is markedly raised. This change is also found in juvenile-onset RA (irrespective of the precise mode of onset), TB, Crohns disease, and systemic lupus erythematosus with Sjögrens. It is not found in myositis, scleroderma, psoriatic arthropathy, ankylosing spondylitis, osteoarthritis, reactive arthritis, sarcoidosis, multiple sclerosis, Klebsiella infection, or a variety of viral infections such as rubella and mumps. The change in galactosylation is therefore not a correlate of chronic inflammation, autoimmune rheumatic diseases, arthropathies, or infectious diseases, but is highly specific to adult and juvenile-onset RA, TB and Crohn's disease, and furthermore, the extent of the reduction in galactosylation closely parallels disease activity. Recent in vivo studies by Rademacher and colleagues have demonstrated that IgG(0) is pathogenic in the collagen-induced arthritis model in DBA/1 strain mice.

See also: Adhesion molecules; Carbohydrate antigens; Lewisx/sialyl-Lewisx (CD15/CD15s); Cytokines; Immunoglobulin gene superfamily; Immunoglobulin structure; Lectins; Selectins (CD62-E/L/P).

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