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

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

doi:10.1046/j.1523-1755.2001.0590031077.x

Cited by 321 publications

(168 citation statements)

References 23 publications

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“…Recently, analysis of O-glycans in IgA1 from patients with IgAN by fluorophore-assisted carbohydrate electrophoresis revealed an increase in the percentage of O-glycans with single GalNAc with no difference in the percentage of sialylated glycans. Two studies have also demonstrated that the eluted glomerular IgA are underglycosylated [32, 33]. These observations do not necessarily contradict our present finding in which the anionic pIgA1 subfraction from IgAN patients are found to be more sialylated.…”

Section: Discussionsupporting

confidence: 84%

Glycosylation Profile of Differently Charged IgA1 and Their Binding Characteristics to Cultured Mesangial Cells in IgA Nephropathy

Leung¹,

Chan²,

Tang³

et al. 2007

Nephron Exp Nephrol

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Background: IgA nephropathy (IgAN) is characterized by mesangial deposition of polymeric IgA1 (pIgA1), yet the pathogeneic mechanism remains unresolved. In the present study, we examined the glycosylation profile of differently charged IgA1 from IgAN patients. The binding characteristics of these IgA1 fractions to cultured human mesangial cells (HMC) and hepatoma cell lines (HepG2) were studied. Methods: Differently charged IgA1 were isolated by ion exchange chromatography. The glycosylation profile in the carbohydrate moieties of these differently charged IgA1 was analyzed by galactose (Gal)-, galactose-acetylgalactosamine (Gal-GalNAc)-, or sialic acid-specific enzyme-linked lectin binding assays (ELLA). The binding characteristic of these IgA1 to HMC was examined by flow cytometry and competitive binding assay. Results: Anionic pIgA from IgAN patients showed less reactivity in (Gal)- and (Gal-GalNAc)-specific ELLA (p < 0.01). There was higher reactivity for anionic pIgA1 in α(2,6)-linked sialic acid-specific ELLA (p < 0.01). Anionic pIgA1 from IgAN patients exhibited increased binding to cultured HMC and the binding was significantly reduced after neuraminidase treatment (p < 0.05). In contrast, anionic pIgA1 from IgAN patients bound less to cultured HepG2 cells and the binding was enhanced following neuraminidase treatment (p < 0.05). Conclusions: We demonstrated an unusual glycosylation and sialylation pattern of anionic pIgA1 in IgAN which may have an important effect on its pathogenesis.

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Section: Discussionsupporting

confidence: 84%

Glycosylation Profile of Differently Charged IgA1 and Their Binding Characteristics to Cultured Mesangial Cells in IgA Nephropathy

Leung¹,

Chan²,

Tang³

et al. 2007

Nephron Exp Nephrol

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“…Top-ranked genes have been reported with roles in disease, regulation, signaling, and apoptotic pathways, however formal Partek pathway analysis identified only three pathways with P < 0.05; top-ranked was mucin type O-glycan biosynthesis (P = 0.02) and it is of note that mucin-type O-glycosylation is important for kidney development with abnormalities associated with renal dysfunction, abnormal glomeruli, proximal tubules, and renal podocytes. [39][40][41] Enrichment based on gene ontology also highlighted O-glycosylation with the most significant results being for biological processes protein O-linked glycosylation via serine (P = 0.002, GO ID = 18 242) and protein O-linked glycosylation via threonine (P = 0.002, GO ID = 18 243). Analysis of the interaction profile did not reveal anything of note.…”

Section: Discussionmentioning

confidence: 99%

DNA hypermethylation and DNA hypomethylation is present at different loci in chronic kidney disease

et al. 2013

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“…As a result of their increased accessibility to glycosyltransferases, IgA glycans are more likely to be sialylated, which allows IgA clearance to be regulated by ASGP-Rs. In the setting of IgA-mediated nephropathy, alterations in IgA1 glycans have been well documented [30]. Decreased sialylation and galactosylation results in altered IgA1 aggregation and impaired ASGP-R-mediated clearance.…”

Section: A Vast Amount Of Information Is Stored In a Cell’s Glycocalyxmentioning

confidence: 99%

Glycans in the immune system and The Altered Glycan Theory of Autoimmunity: A critical review

Maverakis

Kim

Shimoda

et al. 2015

Journal of Autoimmunity

402

283

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Herein we will review the role of glycans in determining the functionality and specificity of various components of the immune system. Specific topics covered include: the specific glycosylation sites of IgE, IgM, IgD, IgE, IgA, and IgG; how glycans can encode “self” identity by functioning as either danger associated molecular patterns (DAMPs) or self-associated molecular patterns (SAMPs); the role of glycans as markers of protein integrity and age; how the glycocalyx can dictate the migration pattern of immune cells; and how the combination of Fc N-glycans and Ig isotype dictate the effector function of immunoglobulins. We speculate that the latter may be responsible for the well-documented association between alterations of the serum glycome and autoimmunity. Due to technological limitations, the extent of these autoimmune-associated glycan alterations and their role in disease pathophysiology has not been fully elucidated to date. Thus, we also review the current technologies available for glycan analysis, placing an emphasis on Multiple Reaction Monitoring (MRM), a rapid high-throughput technology that has great potential for glycan biomarker research. Finally, we put forth The Altered Glycan Theory of Autoimmunity, which states that each autoimmune disease will have a unique glycan signature characterized by the site-specific relative abundances of individual glycan structures on immune cells and serum proteins, especially the site-specific glycosylation patterns of specific antibody classes and subclasses.

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

Abstract: The O-glycan side chains in the hinge of the glomerular IgA1 were highly underglycosylated in IgAN. These results indicate that the decreased sialylation and galactosylation of the IgA1 hinge glycopeptides play a crucial role in its glomerular deposition in IgAN.

Cited by 321 publications

References 23 publications

Glycosylation Profile of Differently Charged IgA1 and Their Binding Characteristics to Cultured Mesangial Cells in IgA Nephropathy

Glycosylation Profile of Differently Charged IgA1 and Their Binding Characteristics to Cultured Mesangial Cells in IgA Nephropathy

DNA hypermethylation and DNA hypomethylation is present at different loci in chronic kidney disease

Glycans in the immune system and The Altered Glycan Theory of Autoimmunity: A critical review

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