Mass spectrometry proves under-O-glycosylation of glomerular IgA1 in IgA nephropathy

Hiki, Yoshiyuki; Odani, Hiroko; Takahashi, M.; Yasuda, Yoshinari; Nishimoto, Akeyo; Iwase, Hitoo; Shinzato, Toru; Kobayashi, Yutaka; Maeda, Kenji

doi:10.1046/j.1523-1755.2001.00591.x

Cited by 87 publications

(130 citation statements)

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“…Patients with IgAN have increased serum levels of IgA1 with truncated galactose-deficient hinge region O-glycans (Gd-IgA1) [4][5][6][7][8][9][10][11][12][13][14] and IgA1 eluted from the glomeruli in renal tissue of patients with IgAN has the same glycosylation aberrancy. 9,15 In the absence of galactose, terminal GalNAc residues are exposed.…”

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confidence: 99%

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Autoantibodies Targeting Galactose-Deficient IgA1 Associate with Progression of IgA Nephropathy

Berthoux

Suzuki

Thibaudin

et al. 2012

Journal of the American Society of Nephrology

225

155

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Mesangial and circulating IgA1 with aberrantly glycosylated hinge region O-glycans characterize IgA nephropathy (IgAN). Unlike healthy individuals, some IgA1 is galactose deficient in patients with IgAN, leaving terminal N-acetylgalactosamine residues in the hinge region exposed. Circulating autoantibodies that recognize such galactose-deficient IgA1 as an autoantigen, or the levels of the autoantigen itself, may allow prediction of disease progression. Here, we analyzed serum samples obtained at diagnosis for autoantigen and autoantibodies from 97 patients with IgAN selected from our prospective cohort according to their absolute renal risk for progression to dialysis or death (0, very low; 1, low; 2, high; 3, very high). We also analyzed samples from controls comprising 30 healthy volunteers and 30 patients with non-IgAN disease. The mean follow-up was 13.8 years. We found that mean serum levels of total autoantigen, normalized IgG autoantibody, and total IgA autoantibody were significantly higher in patients than in the combined controls (all P#0.01). Furthermore, increasing levels correlated with worse clinical outcomes. In Cox regression and Kaplan-Meier analyses, IgG autoantibody levels $1.33 predicted dialysis or death (both P#0.01). In conclusion, these data suggest that serum levels of IgG and IgA autoantibodies strongly associate with the progression of IgAN nephropathy.

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confidence: 99%

“…9,15 In the absence of galactose, terminal GalNAc residues are exposed. Consequently, such IgA1 molecules are presented as autoantigens, 16 and IgG or IgA1 glycan-specific autoantibodies recognize Gd-IgA1 to form immune complexes 17 either in the circulation or in situ in the glomerular mesangium, and renal injury ensues.…”

mentioning

confidence: 99%

Autoantibodies Targeting Galactose-Deficient IgA1 Associate with Progression of IgA Nephropathy

Berthoux

Suzuki

Thibaudin

et al. 2012

Journal of the American Society of Nephrology

225

155

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“…Aberrantly glycosylated IgA1, deficient in Gal in some of the O-glycans in the HR, in serum is rare in healthy individuals but is present at elevated levels in IgAN patients (13,15). This distinctive IgA1 is in circulating immune complexes (8,10,15) and in the glomerular deposits of IgAN patients (16,29). The absence of Gal apparently leads to the exposure of neoepitopes, including terminal and sialylated N-acetylgalactosamine (GalNAc) residues (9,10).…”

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confidence: 99%

Clustered O-Glycans of IgA1

Takahashi

Wall

Suzuki

et al. 2010

Molecular & Cellular Proteomics

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Glycosylation is one of the most common post-translational modifications of proteins. It is estimated that over half of mammalian proteins are glycosylated. Patients with several autoimmune disorders, chronic inflammatory diseases, and some infectious diseases exhibit abnormal glycosylation of serum immunoglobulins and other glycoproteins (1-5). The biological functions of these modifications in health and disease have become a significant area of interest in biomedical research (6). A subset of these glycoproteins has clustered sites of O-glycosylation with serine-and threonine-rich stretches within the amino acid sequence. Mucins, such as membrane-associated MUC1, are perhaps the best known family of proteins that are heavily O-glycosylated. Their altered expression and aberrant glycosylation have made them potential targets as biomarkers for early detection of cancer (7). Immunoglobulin A1 (IgA1) 1 contains both O-and N-glycans (Fig. 1). Aberrant O-glycosylation of IgA1 is involved in the pathogenesis of IgA nephropathy (IgAN) and the closely related Henoch-Schö nlein purpura nephritis (1, 8). Interestingly, the aberrantly glycosylated molecules, IgA1 in IgAN and MUC1 in cancer, are recognized by the immune system as neoepitopes as evidenced by formation of specific antibodies (9 -11). Mucin-like bacterial surface proteins exhibit similar properties: the molecules have clustered bacterial O-glycans that mediate cellular adhesion, and blocking antibodies target these glycan-containing epitopes (12).An O-glycosylated protein from a single source contains a population of variably O-glycosylated isoforms that show a distinct distribution of microheterogeneity of the O-glycan chains in terms of number, sites of attachment, and composition. Characterizing these clustered sites and understanding how the distributions change under different biological conditions or disease states are an analytical challenge. Enzymatic or chemical release of O-glycans is not selective. The heterogeneity, composition, and quantitative aspects of different O-glycan chains can be assessed and quantified by gas chromatographic and/or mass spectrometric techniques.

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“…Experimental data suggest that aberrantly glycosylated IgA1 molecules have an increased tendency to self-aggregate (5), form antigen-antibody complexes with IgG antibodies that are directed against IgA1 hinge epitopes (6), and aggregate with extracellular matrix components (5), all producing complexes that are prone to mesangial trapping. IgA1 eluted from IgAN glomeruli is aberrantly O-glycosylated and is more abnormal in this regard than serum IgA1, strongly implicating altered glycosylation in the process of IgA deposition (7,8).…”

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confidence: 99%

O-Glycosylation of Serum IgA1 Antibodies against Mucosal and Systemic Antigens in IgA Nephropathy

Smith

Molyneux

Feehally

et al. 2006

Journal of the American Society of Nephrology

111

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Mass spectrometry proves under-O-glycosylation of glomerular IgA1 in IgA nephropathy

Cited by 87 publications

References 0 publications

Autoantibodies Targeting Galactose-Deficient IgA1 Associate with Progression of IgA Nephropathy

Autoantibodies Targeting Galactose-Deficient IgA1 Associate with Progression of IgA Nephropathy

Clustered O-Glycans of IgA1

O-Glycosylation of Serum IgA1 Antibodies against Mucosal and Systemic Antigens in IgA Nephropathy

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