Changes in IgG glycoform levels are associated with remission of arthritis during pregnancy

Rook, G.A.W.; Steele, J.; Brealey, R.; Whyte, A.; Isenberg, David; Sumar, N.; Nelson, J. Lee; Bodman, K B; Young, Adam; Im, Roitt; Williams, Paul; Scragg, Ian G.; Edge, Christopher J.; Arkwright, Peter D.; Ashford, David A.; Wormald, Mark R.; Rudd, Pauline M.; Redman, C.W.G.; Dwek, R A; Rademacher, T. W.

doi:10.1016/0896-8411(91)90173-a

Cited by 201 publications

(151 citation statements)

References 29 publications

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“…The incidence of structures lacking galactose is dramatically increased in arthritis. Interestingly, elevated levels of agalactosyl glycoforms were found in female RA patients, while decreased levels were correlated with disease remission during gestation followed by postpartum recurrence [50]. The glycoform distribution of serum IgG was shown to change with age [51,52].…”

Section: Discussionmentioning

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: Discussionmentioning

confidence: 99%

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

et al. 2007

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“…Whereas 25-35% of the IgG molecules of healthy individuals are of the IgG-G0 type, Ͼ50% of the serum IgG of these patients carries this sugar moiety (15,16). The appearance of the IgG-G0 glycovariant correlates with disease activity, and serum transfer studies showed that it can induce disease (17,18). These results are recapitulated in autoimmune-prone mouse strains, such as the MRL/lpr strain, which has increased levels of IgG-G0 antibodies (19,20).…”

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confidence: 99%

Agalactosylated IgG antibodies depend on cellular Fc receptors forin vivoactivity

Nimmerjahn

Anthony²,

Ravetch³

2007

Proc. Natl. Acad. Sci. U.S.A.

232

179

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IgG antibodies are glycoproteins containing a branched sugar moiety attached to the asparagine 297 residue in the antibody constant region (Fc). This glycan is essential for maintaining a functional Fc structure, which is a prerequisite for antibodymediated effector functions, such as the interaction with cellular Fc receptors or the complement component C1q. Variations in the composition of the sugar moiety can dramatically influence antibody activity. Moreover, humans and mice with autoimmune disorders, such as rheumatoid arthritis, have altered IgG glycosylation patterns with increased levels of antibodies lacking terminal sialic acid and galactose residues (IgG-G0). There is great interest in understanding whether this altered glycosylation pattern influences antibody-mediated effector functions. In vitro studies have suggested that IgG-G0 antibodies gain the capacity to activate the complement pathway via mannose-binding lectin (MBL), which could contribute to antibody-mediated inflammation. We have analyzed the activity of IgG-G0 antibodies in mice with a genetic deletion of MBL (MBL-null mice) and demonstrate that IgG-G0 antibodies are unimpaired in MBL-null mice. In contrast, the activity of these antibody glycovariants is fully dependent on the presence of activating Fc receptors.galactose ͉ glycosylation ͉ sialic acid ͉ inflammation

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“…Rook and colleagues [1] detected a similar change in IgG galactose in DBA/1 mice but in this strain the changes were detected as early as the fourth day of pregnancy. Studies in CBA strain mice [2] and in human subjects [1,3] have also shown increased IgG galactose during pregnancy. In the present study the level of IgG galactosylation in the Balb/c mice was shown to be still raised 8 days post-partum in lactating mice.…”

Section: Discussionmentioning

confidence: 88%

“…Changes in IgG glycosylation have been reported in normal human and murine pregnancy [1][2][3]. The number of terminal galactose residues on N-linked oligosaccharides increases during normal pregnancy and following delivery, before eventually returning to normal levels.…”

Section: Introductionmentioning

confidence: 99%

The Stability of Lymphocytic β1,4‐Galactosyltransferase Expression During Pregnancy and Lactation

et al. 1997

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Jeddi PA, Keusch J, Lydyard PM, Delves PJ. The Stability of Lymphocytic b1,4-Galactosyltransferase Expression During Pregnancy and Lactation. Scand J Immunol 1997;45:145-150 The authors used murine pregnancy as a model to investigate the regulation of IgG glycosylation. Pregnancy is associated with decreased levels of circulating IgG. The oligosaccharides on this IgG from late (day 15), but not early (day 8), pregnant Balb/c mice exhibited increased levels of terminal galactose. The levels remained elevated 8 days post-partum in lactating mice. Nonetheless, splenic b1,4-GalTase mRNA and enzyme activity remained relatively constant throughout pregnancy and into lactation. This was in contrast to a pregnancyassociated increase in mammary gland b1,4-GalTase mRNA. Thus the increased IgG galactose levels seen in pregnancy are regulated by mechanisms which are independent of transcriptional control of b1,4-GalTase expression.Dr P. J. Delves,

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Changes in IgG glycoform levels are associated with remission of arthritis during pregnancy

Cited by 201 publications

References 29 publications

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

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

Agalactosylated IgG antibodies depend on cellular Fc receptors forin vivoactivity

The Stability of Lymphocytic β1,4‐Galactosyltransferase Expression During Pregnancy and Lactation

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