The INDIVIDUALIST

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Glycomics

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Description

One of the most exciting things to hit rheumatoid arthritis (RA) in the last few years has been the discovery that the patients' IgG is abnormally glycosylated. The occurrence of N-linked oligosaccharides lacking galactose is significantly higher than normal in serum IgG of patients with rheumatoid arthritis (RA) in whom rheumatoid factor (RF), an autoantibody against autologous IgG, has been detected.

The two CH2 domains in the Fc region are held apart by two asparagine-linked sugars. The 1,3 arms from each sugar provide a bridge between the domains while the 1,6 sugars are directed towards the protein surface where the terminal sialic acid-galactose lies in a special 'lectin-like' pocket . Some chains end in N-acetyl-glucosamine and lack the terminal sialic acid-galactose sugars. In normal individuals, some 14% of the IgG chains. What is extraordinary is that the percentage of sugars completely lacking galactose in the IgG of rheumatoid arthritis patients is always higher than in the controls and can go as high as 60%. This glycosylation defect could lead to con- formational change in the Fc structure with two possible consequences:1 the Fc may have increased autoantigenicity, and2 self-associated IgG complexes would be held together more strongly if the terminal sialic acid-galactose on the Fab sugar on one IgG fits into the lectin site on the CH2 left vacant by the lack of galactose on the Fc sugar. (1)

Discussion

One reason that has been elucidated is the fact that intracellular galactosyltransferase (GTase) activity is reduced in RA and this ultimately leads to reduced galactosylation of IgG. It is thought that RA is associated with a set of GTase Iso-enzymes, that may be less active due to an increase in their sialylation.

Biantennary complex type N-glycans of IgG hardly ever completed into fully sialylated molecules. Most molecules remain with one or more terminal beta-linked Gal residues (so-called G1 and G2 molecules).

In rheumatoid arthritis, major fraction of glycans on serum IgG molecules have decreased galactosylation, some carrying no galactose at all (so-called Go molecules).

Severity of disease correlates with % Go, and spontaneous improvement during pregnancy correlates with increases in G1 and G2.

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References


1. Roitt I. Essential Immunology, 6th Edition. Blackwell Scientific Publishers, Oxford UK 1989.

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