Agalactosyl glycoforms of IgG autoantibodies are pathogenic.

Rademacher, Thomas W.; Williams, Phil; Dwek, Raymond A.

doi:10.1073/pnas.91.13.6123

Cited by 231 publications

(167 citation statements)

References 27 publications

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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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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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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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“…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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Agalactosylated IgG antibodies depend on cellular Fc receptors forin vivoactivity

Nimmerjahn

Anthony²,

Ravetch³

2007

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

232

178

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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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“…Glycoproteins play fundamental roles in humans (1,2) where they are active in cell recognition and adhesion, development, and homeostasis (3)(4)(5)(6)(7). Defects in protein glycosylation lead to a variety of disease states known collectively as congenital disorders of glycosylation (CDG).…”

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The X-ray Crystal Structures of Human α-Phosphomannomutase 1 Reveal the Structural Basis of Congenital Disorder of Glycosylation Type 1a

Silvaggi

Zhang

et al. 2006

Journal of Biological Chemistry

118

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Agalactosyl glycoforms of IgG autoantibodies are pathogenic.

Cited by 231 publications

References 27 publications

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

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

Agalactosylated IgG antibodies depend on cellular Fc receptors forin vivoactivity

The X-ray Crystal Structures of Human α-Phosphomannomutase 1 Reveal the Structural Basis of Congenital Disorder of Glycosylation Type 1a

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