Abnormal IgG galactosylation in MRL‐lpr/lpr mice: Pathogenic role in the development of arthritis

Abstract

MRL-lpr/lpr (MRL/lpr) mice spontaneously develop arthritis by an increase in the incidence of agalactosylated oligosaccharides in serum IgG, similar to rheumatoid arthritis patients. However, whether this association has a pathogenic significance is still unknown. In this study, we analyzed the oligosaccharide structure of serum IgG in various MRL mice with or without arthritis, to clarify the relationship between the oligosaccharide abnormality and the development of arthritis. The level of agalactosylation in serum IgG was comparable in both arthritis-free MRL/lpr and MRL-+/+ (MRL/+) mice at 6 weeks of age. In contrast, the incidence of IgG lacking galactose markedly increased in MRL/lpr mice at 6 months of age (the age at which arthritis occurred), compared with that from age-matched MRL/+ mice without arthritis. However, the proportion of agalactosylated IgG increased similarly in anti-CD4 monoclonal antibody-treated MRL/lpr mice at 6 months of age, despite the absence of the development of arthritis, because of depletion of CD4+ T cells. These results suggest that the abnormality in IgG galactosylation of MRL/lpr mice developed in an age-dependent manner, but it did so independently of CD4+ T cell-dependent B-cell activation and is not a consequence of the development of arthritis.

Endoglycosidase treatment abrogates IgG arthritogenicity: Importance of IgG glycosylation in arthritis

“…The glycoform distribution of serum IgG was shown to change with age [51,52]. It has been suggested that low galactosylation of IgG may have a critical role in the pathology of autoimmune disorders such as RA and SLE [53][54][55], but can also occur through aging [56]. Functional differences have been recognized between these glycoforms.…”

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

“…In contrast, studies with degalactosylated human IgG1 mAbs obtained through treatment with galactosidase failed to show enhanced Fc-dependent effector functions, as compared with their wild-type (WT) counterparts (18,19). Moreover, studies on autoimmuneprone MRL-Fas lpr mice displaying the aberrant IgG galactosylation (5,20) revealed that increases of agalactosylated IgG occurred independently of disease activity (21). Thus, it has been unclear whether the pathogenic potential of IgG autoantibodies is consistently enhanced by the absence of galactosylation.…”

New Insights into Rheumatoid Arthritis Associated Glycosylation Changes

“…Reduced B cell GTase activity and the corresponding decreased IgG galactosylation (IgG-G0) in RA, and various animal models (3,5,(7)(8)10), appear to be directly linked to the pathogenic features associated with RA (9,11). For example, agalactosylation of IgG can trigger the inappropriate activation of complement (21), is an important component of rheumatoid factor-IgG complexes in RA (22,23) and has been shown to be pathogenic in animal models of this disease (8,11).…”

“…For example, agalactosylation of IgG can trigger the inappropriate activation of complement (21), is an important component of rheumatoid factor-IgG complexes in RA (22,23) and has been shown to be pathogenic in animal models of this disease (8,11). In addition, IgG-G0 has been found to be a significant diagnostic and prognostic feature of RA, which together with rheumatoid factor status predicts a more severe disease (24)(25)(26).…”

“…The link between RA, reduced b1,4-Galactosyltransferase (GTase) enzyme activity (1-7), and immunoglobulin G (IgG) hypo-galactosylation is a well documented phenomenon that may be linked to the pathology of rheumatoid arthritis (RA; 3, [8][9][10][11].…”