Glycosylation changes of IgG associated with rheumatooid arthritis can activate complement via the mannose-binding protein

Malhotra, Rajneesh; Wormald, Mark R.; Rudd, Pauline M.; Fischer, Per; Dwek, Raymond A.; Sim, Robert B.

doi:10.1038/nm0395-237

Cited by 712 publications

(507 citation statements)

References 25 publications

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“…Our observation that high serum levels of MBL conferred increased risk of ischemic heart disease, including myocardial infarction, and death from ischemic heart disease only in patients with high levels of IgG-G0 is in accordance with the hypothesis that complexes of MBL and IgG-G0 are harmful in RA (25). Thus, it may be hypothesized that complexes of MBL and IgG-G0 deposited in the vessel wall could participate in an inflammation-driven pro-atherogenic process.…”

Section: Discussionsupporting

confidence: 89%

“…Thus, one explanation for our observations could be that MBL amplifies the inflammatory reaction in vessels through complement, by its interaction with damaged endothelial cells. Another likely explanation derives from the observation that oligosaccharides in IgG from patients with RA contain increased levels of IgG-G0 glycoforms (22;23): MBL binds to aggregated IgG-G0 (21), and the MBLaggregated IgG-G0 complexes may activate complement and initiate an inflammatory reaction (25). The latter two possible explanations are not mutually exclusive.…”

Section: Discussionmentioning

confidence: 99%

“…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). Based on the findings described above, we wished to determine whether MBL and IgG-G0 confer any additional risk of ischemic heart disease in RA.…”

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confidence: 99%

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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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Section: Discussionsupporting

confidence: 89%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

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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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“…Nimmerjahn et al (36) have analyzed the activity of IgG-G0 antibodies in mice with a genetic deletion of MBL (MBL-null mice), with the results demonstrating that IgG-G0 antibodies are unimpaired in MBL-null mice. In contrast, those authors have shown that the activity of these antibody glycovariants is fully dependent on the presence of activating Fc receptors, and that asialylated antibodies result in enhanced Fc receptor binding and, thus, enhanced pathogenicity in vivo (35,36). In contrast, high levels of terminal sialic acid residues of the IgG molecules resulted in a reduced affinity of IgG for all mouse Fc␥ receptors and impaired the activity of human IgG in a similar manner (37,38).…”

Section: Discussionmentioning

confidence: 95%

Sialylation levels of anti-proteinase 3 antibodies are associated with the activity of granulomatosis with polyangiitis (Wegener's)

Espy

Morelle²,

Kavian

et al. 2011

Arthritis & Rheumatism

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Objective. To investigate whether the glycosylation and sialylation levels of anti-proteinase 3 (anti-PR3) antibodies could affect their pathogenicity, and whether these levels could be correlated with the activity of granulomatosis with polyangiitis (Wegener's) (GPA).Methods. Forty-two serum samples positive for anti-PR3 antibodies from 42 patients with active or weakly active/inactive GPA were included. Anti-PR3 antibodies were assayed by enzyme-linked immunosorbent assay, and their levels of glycosylation and sialylation were assessed by enzyme-linked lectin assay. The glycosylation and sialylation levels of IgG purified from the serum of healthy donors and patients with active, remitted, or weakly active disease were assessed by permethylation and mass spectrometry analysis of glycans, following neuraminidase digestion. The neutrophil oxidative burst induced by purified IgG was assayed by spectrofluorimetry.Results. The mean sialylation ratio of anti-PR3 antibodies was significantly lower in patients with active disease than in patients with weakly active or inactive disease, and this was inversely correlated with the Birmingham Vasculitis Activity Score (BVAS) (P < 0.0001). Similar results were obtained using the BVAS/ GPA. The area under the receiver operating characteristic curve for the sialylation ratio of anti-PR3 antibodies, as a test to determine the activity of GPA, was 0.82 (P ‫؍‬ 0.0006). The characterization of N-glycans showed a decrease in 2,6-linked sialylated N-glycans and an increase in dHex 1 Hex 3 HexNAc 4 (mass/charge 1,836) agalactosylated structures in purified IgG from patients with active disease compared with controls. The anti-PR3 antibody-induced oxidative burst of neutrophils was inversely correlated with the sialylation levels of anti-PR3 IgG.

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“…22,23 Thus, it can be hypothesized that MBL deficiency might interfere with the activation of complement system by agalactosyl IgG and might be protective in the development of RA. However, recent studies indicated that there was either no association of MBL deficiency and RA 14,15 or even an increased risk for RA has been demonstrated in MBL deficiency.…”

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confidence: 99%

Mannose binding lectin (MBL) gene mutation is not a risk factor for systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA) in Japanese

et al. 2000

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Mannose binding lectin (MBL) deficiency may be associated with increased susceptibility to infection and autoimmune disorders, such as systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA). In the present study, we performed for the first systematic search for mutations in all the four exons of the MBL gene using polymerase chain reaction (PCR)/single-strand conformation polymorphism (SSCP) analysis. Of 49 healthy Japanese individuals studied, only the previously reported mutation at the codon 54 (substitution from Gly to Asp; G54D) was identified. The allele frequencies of G54D in 105 healthy Japanese individuals, 95 SLE patients and 59 RA patients, were 0.233, 0.226 and 0.178, respectively, which were not significantly different. In addition, two polymorhisms at positions of −550 and −221 in the promoter region were not associated with SLE and RA. It is unlikely that MBL deficiency plays a major role in the pathogenesis of SLE and RA in Japanese. Genes and Immunity (2000) 1, 464-466.Keywords: mannose binding lectin; mannose binding protein; Complement; autoimmune diseases; systemic lupus erythematosus; rheumatoid arthritis Mannose binding lectin (MBL), also known as mannose or mannan binding protein, is a member of the collectin family of proteins, characterized by the presence of collagen-like domains and carbohydrate recognition lectin domains. 1 MBL binds to high mannose and Nacetyl-glucosamine oligosaccharides present on the cell surface of yeasts, bacteria and viruses and serves as the initiator of the third pathway of complement system (lectin pathway). 2 MBL is considered to be involved in the innante immunity of host defence that works prior to the establishment of adaptive immune system. Previous studies suggest that homozygous deficiency of MBL is associated with recurrent infections in children 3,4 as well as increased susceptibility and shorter survival of human immunodeficiency virus (HIV) patients. 5,6 Although there are controversies, association of MBL deficiency with chronic hepatitis virus type B (HBV) infection 7 and its progression, 8 and with poor response to interferon in chronic hepatitis virus type C (HCV) 9 has also been reported. In addition MBL deficiency has also been implicated in the pathogenesis of autoimmune diseases. Studies in the UK and Spanish

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Glycosylation changes of IgG associated with rheumatooid arthritis can activate complement via the mannose-binding protein

Cited by 712 publications

References 25 publications

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

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

Sialylation levels of anti-proteinase 3 antibodies are associated with the activity of granulomatosis with polyangiitis (Wegener's)

Mannose binding lectin (MBL) gene mutation is not a risk factor for systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA) in Japanese

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