GALACTOSYLATION OF IgG ASSOCIATED OLIGOSACCHARIDES: REDUCTION IN PATIENTS WITH ADULT AND JUVENILE ONSET RHEUMATOID ARTHRITIS AND RELATION TO DISEASE ACTIVITY

Parekh, R. B.; Isenberg, David; Ansell, B. M.; Im, Roitt; Dwek, R A; Rademacher, T. W.

doi:10.1016/s0140-6736(88)91781-3

Cited by 210 publications

(138 citation statements)

References 8 publications

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“…Recently, de-fucosylation on the N297-linked glycan in the Fc part of the Ab has been shown to increase ADCC activity, indicating the importance of glyco-engineering of Ab for improved clinical efficacy [23]. On the other hand, Fab N-linked glycosylation in the hypervariable regions, while occurring much less frequently, has been reported to influence the binding affinity of antigens [24][25][26] and may also be involved in IgG self-association, aggregation, and cryo-precipitation [27].…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2007

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The glycosylation status of IgG has been implicated in the pathology of rheumatoid arthritis. Earlier, we reported the identification of a novel secreted endo-b-Nacetylglucosaminidase (EndoS), secreted by Streptococcus pyogenes that specifically hydrolyzes the b-1,4-di-N-acetylchitobiose core of the asparagine-linked glycan of human IgG. Here, we analyzed the arthritogenicity of EndoS-treated collagen type II (CII)-specific mouse mAb in vivo. Endoglycosidase treatment of the antibodies inhibited the induction of arthritis in (BALB/c Â B10.Q) F1 mice and induced a milder arthritis in B10.RIII mice as compared with the severe arthritis induced by non-treated antibodies. Furthermore, EndoS treatment did not affect the binding of IgG to CII and their ability to activate complement, but it resulted in reduced IgG binding to FccR and disturbed the formation of stable immune complexes. Hence, the asparagine-linked glycan on IgG plays a crucial role in the development of arthritis. IntroductionThe impact of glycosylation, one of the most important post-translational modifications, on the structure and biological properties of glycoproteins has been well documented [1,2]. IgG molecules are mainly glycosylated at Asn-297 of the CH2 domain within the Fc region [3,4], with variable galactosylation but limited sialylation. The remaining glycosylation occurs in the hypervariable regions of the Fab region, with the position and frequency of occurrence being dependent on the presence of the consensus sequence Asn-Xaa-Thr/ Ser for N-glycosylation, and is characterized by a high incidence of sialylated structures. Murine IgG contain 2.3 asparagine-linked (N-linked) biantennary oligosaccharide chains per molecule [5], and human IgG contain 2.8 [6]. The minimal oligosaccharide structure is a hexasaccharide (GlcNAc2Man3GlcNAc) with variable sugar residues attached, which results in the generation of the multiple glycoforms. About 30 variants of biantennary chains occur, resulting in Clinical immunology

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Section: Introductionmentioning

confidence: 99%

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

et al. 2007

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“…Glycosylation changes in the IgG Fc region are characteristic of RA (22,23). IgG from patients with RA has marked differences in the oligosaccharide moieties in the C2 region, whereby the content of oligosaccharide chains terminating in galactose is reduced, leading to exposure of N-acetylglucosamine.…”

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confidence: 99%

“…This glycosylation variant is called agalactosyl IgG, or IgG-G0. Increased serum levels of IgG-G0 have been associated with poor prognosis in patients with RA (23,24). IgG-G0 has been shown in vitro to interact with MBL through the exposed N-acetylglucosamine, thereby activating complement (25).…”

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confidence: 99%

Genetically determined high serum levels of mannose-binding lectin and agalactosyl IgG are associated with ischemic heart disease in rheumatoid arthritis

Troelsen¹,

Garred²,

Madsen³

et al. 2006

Arthritis Rheum

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Objective. Patients with rheumatoid arthritis (RA) have excess morbidity and mortality due to ischemic heart disease. It has been suggested that high serum levels of mannose-binding lectin (MBL) and agalactosyl IgG (IgG-G0) are associated with increased inflammation in RA. MBL also enhances inflammationmediated tissue injury during postischemic reperfusion. This study was undertaken to examine whether these factors are associated with increased risk of ischemic heart disease in RA.Methods. MBL alleles were genotyped in 229 Danish patients with RA. In addition, serum levels of MBL and IgG-G0 were measured. Incidences of ischemic heart disease, myocardial infarction, and death due to ischemic heart disease after the diagnosis of RA were assessed in a prospective study.Results. During a median followup of 9.5 years, ischemic heart disease was diagnosed in 8 of 27 patients with genetically determined high serum levels of MBL, as compared with 24 of the remaining 192 patients (data not available on 10 patients). After correction for other known risk factors, the hazard ratio (HR) was 3.6 (95% confidence interval [95% CI] 1.4-9.2). The corrected HR for myocardial infarction was 9.0 (95% CI 2.2-36.4).High serum levels of MBL also conferred an increased risk of death due to ischemic heart disease (age-and sex-adjusted HR 10.5, 95% CI 2.7-41.3). However, further analyses showed that these associations were present only in patients with high serum levels of IgG-G0.Conclusion. Genetically determined high serum levels of MBL and high serum levels of IgG-G0 are associated with increased risk of ischemic heart disease, myocardial infarction, and premature death in patients with RA.

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“…The Eco RI and Hind I11 restriction enzyme data presented for the GTA protein kinase gene locus provide evidence against the glycosylation defects in RA being due to a gross structural change in this gene. Although we cannot exclude the possibility of alterations in the gene encoding the transferase component itself, the recent demonstration that the degree of galactosylation fluctuates with disease activity (35) would be evidence against such a defect, because normal galactosylation is reestablished during remission. Therefore, differences in galactosylation may be due to subtle alterations in gene regulation.…”

Section: Discussionmentioning

confidence: 88%

Polymorphism and expression of the galactosyltransferase‐associated protein kinase gene in normal individuals and galactosylation‐defective rheumatoid arthritis patients

Delves

Lund

Axford

et al. 1990

Arthritis & Rheumatism

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We used restriction endonuclease digestion of leukocyte DNA to assess' the structural integrity of an N-acetylglucosamine pl+4 galactosyltransferase (GalTase)-associated (GTA) protein. kinase gene in rheumatoid arthritis (RA) patients. This analysis provides evidence that the gross structure of the GTA protein kinase gene locus remains intact in patients with defective galactosylation and that this gene locus is polymorphic both in normal individuals and in patients with RA, although no polymorphisms unique to RA patients were observed. Initial data on the expression of this gene indicate that comparable levels of GTA protein kinase messenger RNA are present in the lymphocytes of normal individuals and RA patiepts, irrespective of whether lymphocytes were obtained from patients with decreased or normal levels of galactosylation.

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GALACTOSYLATION OF IgG ASSOCIATED OLIGOSACCHARIDES: REDUCTION IN PATIENTS WITH ADULT AND JUVENILE ONSET RHEUMATOID ARTHRITIS AND RELATION TO DISEASE ACTIVITY

Cited by 210 publications

References 8 publications

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

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

Genetically determined high serum levels of mannose-binding lectin and agalactosyl IgG are associated with ischemic heart disease in rheumatoid arthritis

Polymorphism and expression of the galactosyltransferase‐associated protein kinase gene in normal individuals and galactosylation‐defective rheumatoid arthritis patients

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