Tamao Endo
Department of Glycobiology, Tokyo Metropolitan
Rheumatoid arthritis (RA) affects about 1% of the population worldwide. Abnormalities of both humoral and cellular immunity have been implicated to be involved in initiating and maintaining the chronicity of inflammation in this disease. Although the pathogenesis of this complicated disease remains undefined, it has been considered to be an autoimmune disease with the presence of anti IgG antibodies (rheumatoid factor) and immune complex formation. After the interesting finding of change in the glycosylation state of serum IgG of patients with RA, there is growing the interest and an enormous volume of data suggest that RA may be a dysregulated glycosylation disease. This glycopathologic topic is expected to provide new insights into RA pathogenesis.
Human IgG is a glycoprotein with a conserved N-glycosylation site in the CH2 domain at Asn 297. N-Glycan structures of human serum IgG are basically of the biantennary complex type as shown in Fig. 1. However, extremely high microheterogeneity has been found: the presence or absence of two galactoses, of the bisecting N-acetylglucosamine and of the fucose residues. In 1985 a striking finding was reported, i.e. the N-glycans in the IgG from patients with RA were prominently deficient in galactose and contained increased levels of two terminal N-acetylglucosamine glycoforms 1. These findings have been confirmed and extended 2. The extent of the changes correlates with the severity of disease and is a good biochemical marker for this disease 3. Agalactosyl glycoforms of IgG may be considered to be more directly involved in RA pathogenesis 4. On the other hand, galactose depletion causes deterioration of IgG functions, complement activation and Fc-receptor binding 5.
Fig. 1 Structures of N-glycans from human serum IgG.
The galactose deficiency of serum IgG of patients with RA is considered to result from the altered beta-1,4-galactosyltransferase (GalT) activity in IgG-producing B cells. In fact, the beta-1,4-GalT activities in B cells from RA patients were reduced by 30-70% compared to those of control individuals. Recently, several human beta-1,4-GalT genes have been cloned (see GlycoWord/Glycoprotein-B03 and ref. 6). It is important to determine which beta-1,4-GalT is responsible for galactosylation of IgG in B cells. Such studies will open a new way in RA pathogenesis.
