Galactose-deficient IgA1 in sera of IgA nephropathy patients is present in complexes with IgG

Tomana, Milan; Matoušovic, K; Julian, Bruce A.; Rádl, J.; Konecný, K; Městecký, Jiří

doi:10.1038/ki.1997.361

Cited by 280 publications

(277 citation statements)

References 54 publications

Supporting

Mentioning

268

Contrasting

Order By: Relevance

“…This hypothesis is based on the observation that sialylated GalNAc cannot be galactosylated or otherwise modified by additional glycan residues. 39 29 we had hypothesized that another mechanism may be premature sialylation of the GalNAc residue. 9 We based this hypothesis on the observation that addition of SA to GalNAc prevents attachment of Gal to GalNAc 39 and thus precludes further growth of the glycan.…”

Section: Discussionmentioning

confidence: 99%

Identification and Characterization of CMP-NeuAc:GalNAc-IgA1 α2,6-Sialyltransferase in IgA1-producing Cells

Raška¹,

Moldoveanu²,

Suzuki³

et al. 2007

Journal of Molecular Biology

Self Cite

View full text Add to dashboard Cite

SummaryGlycosylation defects occur in several human diseases. In IgA nephropathy, IgA1 contains O-glycans that are galactose-deficient and consist mostly of core 1 α2,6 sialylated N-acetylgalactosamine, a configuration suspected to prevent β1,3 galactosylation. We confirmed the same aberrancy in IgA1 secreted by the human DAKIKI B cell line. Biochemical assays indicated CMP-NeuAc:GalNAcIgA1 α2,6-sialyltransferase activity in this cell line. However, a candidate enzyme, ST6-GalNAcI, was not transcribed in DAKIKI cells, B cells isolated from blood, or Epstein-Barr virus (EBV)-immortalized IgA1-producing cells from the blood of IgAN patients and healthy controls. Instead, ST6-GalNAcII transcription was detected at a high level. Expression of the ST6-GalNAcII gene and activity of the CMP-NeuAc:GalNAc-IgA1 α2,6-sialyltransferase were higher in IgA1-producing cell lines from IgAN patients than in such cells from healthy controls. These data are the first evidence that human cells that lack ST6-GalNAcI can sialylate core 1 GalNAc-Ser/Thr.

show abstract

Section: Discussionmentioning

confidence: 99%

Identification and Characterization of CMP-NeuAc:GalNAc-IgA1 α2,6-Sialyltransferase in IgA1-producing Cells

Raška¹,

Moldoveanu²,

Suzuki³

et al. 2007

Journal of Molecular Biology

Self Cite

View full text Add to dashboard Cite

show abstract

“…Carbohydratespecific lectin analysis of O-glycoproteins can provide information on glycan composition and comparative differences between samples, such as those from healthy controls and patients with various disease states. We have successfully demonstrated this in the analysis of IgA1 O-glycans from patients with IgAN versus healthy controls and disease controls (13)(14)(15). This included proximal assessment of sites with galactose (Gal)-deficient O-glycans after digests with IgAspecific proteases (8).…”

mentioning

confidence: 99%

“…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).…”

mentioning

confidence: 99%

Clustered O-Glycans of IgA1

Takahashi

Wall

Suzuki

et al. 2010

Molecular & Cellular Proteomics

Self Cite

View full text Add to dashboard Cite

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.

show abstract

“…The IgA1 found in the circulation and deposited in glomerular lesions was shown to be galactosedeficient, forming immune complexes with IgG or IgA1 [2,3]. Genome-wide association studies identified loci in the MHC, CFH/CFHR, HORMAD2 as well as other genes associated with IgA nephropathy [4].…”

Section: Introductionmentioning

confidence: 99%