Circulating immune complexes in IgA nephropathy consist of IgA1 with galactose-deficient hinge region and antiglycan antibodies

Tomana, Milan; Novák, Jan; Julian, Bruce A.; Matoušovic, K; Konecný, K; Městecký, Jiří

doi:10.1172/jci5535

Cited by 428 publications

(478 citation statements)

References 55 publications

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“…13 The analyses were performed with a gas chromatograph (Model 5890, Hewlett-Packard, Sacramento, CA, USA equipped with a 25-m fused silica (0.22-mm inner diameter) OV-1701 WCOT column (Chrompack, Bridgewater, NJ, USA) and electron capture detector. About 20 μg of each purified IgA1 protein (DAKIKI and IgA1 [Mce] myeloma protein) was used for the analysis.…”

Section: Monosaccharide Compositional Analysismentioning

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

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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.

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Section: Monosaccharide Compositional Analysismentioning

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

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“…IgA1 is unusual in that it has a heavily O-glycosylated hinge region between the CH1 and CH2 domains of the a H chain (1,2). The presence of poorly galactosylated IgA1 O-glycoforms in the serum of patients with IgAN favors formation of circulating immune complexes (IC), which are prone to deposition in the glomerular mesangium (3)(4)(5)(6). Once deposited, these IgA IC trigger mesangial cell activation.…”

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confidence: 99%

Spleen Tyrosine Kinase Is Important in the Production of Proinflammatory Cytokines and Cell Proliferation in Human Mesangial Cells following Stimulation with IgA1 Isolated from IgA Nephropathy Patients

Kim

McDaid

McAdoo

et al. 2012

The Journal of Immunology

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IgA immune complexes are capable of inducing human mesangial cell (HMC) activation, resulting in release of proinflammatory and profibrogenic mediators. The subsequent inflammation, cellular proliferation, and synthesis of extracellular matrix lead to the progression of IgA nephropathy (IgAN). Spleen tyrosine kinase (SYK) is an intracellular protein tyrosine kinase involved in cell signaling downstream of immunoreceptors. In this study, we determined whether SYK is involved in the downstream signaling of IgA1 stimulation in HMC, leading to production of proinflammatory cytokines/chemokines and cell proliferation. Incubation of HMC with IgA1 purified from IgAN patients significantly increased the synthesis of MCP-1 in a dose-dependent manner. There was also significantly increased production of IL-6, IL-8, IFN-γ–inducible protein-10, RANTES, and platelet-derived growth factor-BB. Stimulation of HMC with heat-aggregated IgA1 purified from IgAN patients induced significantly increased HMC proliferation. Both pharmacological inhibition of SYK and knockdown of SYK by small interfering RNA significantly reduced the synthesis of these mediators and inhibited HMC proliferation. Moreover, positive immunostaining for total and phospho-SYK in glomeruli of kidney biopsies from IgAN patients strongly suggests the involvement of SYK in the pathogenesis of IgAN. To our knowledge, we demonstrate, for the first time, the involvement of SYK in the downstream signaling of IgA1 stimulation in HMC and in the pathogenesis of IgAN. Hence, SYK represents a potential therapeutic target for IgAN.

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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%

“…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). These epitopes are recognized by naturally occurring antiglycan IgG or IgA1 antibodies and, consequently, circulating immune complexes are formed (9,10,15) that can deposit in the glomerular mesangia.…”

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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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Circulating immune complexes in IgA nephropathy consist of IgA1 with galactose-deficient hinge region and antiglycan antibodies

Cited by 428 publications

References 55 publications

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

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

Spleen Tyrosine Kinase Is Important in the Production of Proinflammatory Cytokines and Cell Proliferation in Human Mesangial Cells following Stimulation with IgA1 Isolated from IgA Nephropathy Patients

Clustered O-Glycans of IgA1

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