Direct Evidence for Decreased Sialylation and Galactosylation of Human Serum IgA1 Fc O-Glycosylated Hinge Peptides in IgA Nephropathy by Mass Spectrometry

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

doi:10.1006/bbrc.2000.2613

Cited by 80 publications

(70 citation statements)

References 27 publications

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“…Unlike IgA2 or IgG, IgA1 has a structurally exceptional hinge portion that comprises a prolinerich sequence and possesses multiple O-glycans. In the past few years, with the progress of MS analysis, capillary electrophoresis and so on, it has been well elucidated that the number of carbohydrate residues in the IgA1 hinge region is reduced in IgAN patients compared with normal controls (47)(48)(49). Furthermore, it has been reported that incompletely glycosylated IgA1 tends to aggregate in vitro (36,50).…”

Section: Discussionmentioning

confidence: 99%

Initiation of O-Glycan Synthesis in IgA1 Hinge Region Is Determined by a Single Enzyme, UDP-N-Acetyl-α-d-galactosamine:PolypeptideN-Acetylgalactosaminyltransferase 2

Iwasaki

Zhang

Tachibana

et al. 2003

Journal of Biological Chemistry

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The hinge region of human immunoglobulin A1 (*IgA1) possesses multiple O-glycans, of which synthesis is initiated by the addition of GalNAc to serine or threonine through the activity of UDP-N-acetyl-␣-D-galactosamine:polypeptide N-acetylgalactosaminyltransferases (pp-GalNAc-Ts). We found that six pp-GalNAc-Ts, ppGalNAc-T1, -T2, -T3, -T4, -T6, and -T9, were expressed in B cells, IgA-bearing B cells, and NCI-H929 IgA myeloma cells. pp-GalNAc-T activities of these six enzymes for a synthetic IgA hinge peptide, which has nine possible O-glycosylation sites, were examined using a reversed phase-high performance liquid chromatography, a matrix-assisted laser desorption ionization time of flight mass spectrometry, and peptide sequencing analysis. pp-GalNAc-T2 showed the strongest activity transferring GalNAc to a maximum of eight positions. Other pp-GalNAc-Ts exhibited different substrate specificities from pp-GalNAc-T2; however, their activities were extremely weak. It was reported that the IgA1 hinge region possesses a maximum of five O-glycans, and their amino acid positions have been determined. We found that pp-GalNAc-T2 selectively transferred GalNAc residues to the same five positions. These results strongly suggested that pp-GalNAc-T2 is an essential enzyme for initiation of O-linked glycosylation of the IgA1 hinge region.

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Section: Discussionmentioning

confidence: 99%

Initiation of O-Glycan Synthesis in IgA1 Hinge Region Is Determined by a Single Enzyme, UDP-N-Acetyl-α-d-galactosamine:PolypeptideN-Acetylgalactosaminyltransferase 2

Iwasaki

Zhang

Tachibana

et al. 2003

Journal of Biological Chemistry

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“…It has been reported that O-glycans of patients with IgAN contain more Tn antigen (GalNAc-Ser/Thr) compared with control subjects (18,33). Terminal GalNAc can be detected by specific lectins, including HAA.…”

Section: Interaction Of Piga With Haa Lectinmentioning

confidence: 99%

Differential Glycosylation of Polymeric and Monomeric IgA

Oortwijn

Roos²,

Royle³

et al. 2006

Journal of the American Society of Nephrology

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IgA nephropathy (IgAN) is characterized by mesangial deposition of polymeric IgA1 (pIgA1) and complement. Complement activation via mannose-binding lectin and the lectin pathway is associated with disease progression. Furthermore, recent studies have indicated a possible role for secretory IgA. IgAN is associated with abnormalities in circulating IgA, including aberrant O-linked glycosylation. This study characterized and compared functional properties and N-linked glycosylation of highly purified monomeric IgA (mIgA) and pIgA from patients with IgAN and control subjects. Total serum IgA was affinity-purified from patients (n ‫؍‬ 11) and control subjects (n ‫؍‬ 11) followed by size separation. pIgA but not mIgA contained secretory IgA, and its concentration was significantly higher in patients with IgAN than in control subjects. Both in patients with IgAN and in control subjects, IgA binding to the GalNAc-specific lectin Helix Aspersa and to mannose-binding lectin was much stronger for pIgA than for mIgA.

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“…The higher proportion of polymeric IgA1 in IgAN patient serum could have important implications given that mesangial deposits in IgAN are primarily composed of polymeric IgA1 [70]. A large number of alterations in IgA1 O-glycosylation and Nglycosylation were reported, including oversialylation [71] or undersialylation and undergalactosylation [72] of the Oglycans, and oversialylation [73] or truncation [74] of the N-glycans. Furthermore, an overall decrease in the number of O-glycosylation sites in the IgA1 hinge region was reported in IgA1 [72].…”

Section: Iga1 and Fcαri Aberrations Implicated In Iga Nephropathymentioning

confidence: 99%

IgA and IgA-specific receptors in human disease: structural and functional insights into pathogenesis and therapeutic potential

Gomes

Herr

2006

Springer Semin Immun

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IgA antibodies play an important role in humoral immunity. IgA is the predominant antibody in mucosal secretions and the second most prevalent in the serum. It occupies a unique position among human antibodies in that it can both trigger and suppress inflammatory responses, depending on the situation. Recent structural and functional studies have revealed details of the structure of IgA and its interaction with key cell-surface receptors. We look at the role IgA and IgA receptors (particularly FcalphaRI) play in the pathogenesis of diseases such as IgA nephropathy and other autoimmune conditions. Finally, we address the potential of IgA as a therapeutic tool to either trigger specific inflammatory responses to destroy target cells or suppress inflammatory responses in the case of autoimmune diseases, and the promise of mucosal vaccines for eliciting specific IgA responses to pathogens in mucosal environments.

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Direct Evidence for Decreased Sialylation and Galactosylation of Human Serum IgA1 Fc O-Glycosylated Hinge Peptides in IgA Nephropathy by Mass Spectrometry

Cited by 80 publications

References 27 publications

Initiation of O-Glycan Synthesis in IgA1 Hinge Region Is Determined by a Single Enzyme, UDP-N-Acetyl-α-d-galactosamine:PolypeptideN-Acetylgalactosaminyltransferase 2

Initiation of O-Glycan Synthesis in IgA1 Hinge Region Is Determined by a Single Enzyme, UDP-N-Acetyl-α-d-galactosamine:PolypeptideN-Acetylgalactosaminyltransferase 2

Differential Glycosylation of Polymeric and Monomeric IgA

IgA and IgA-specific receptors in human disease: structural and functional insights into pathogenesis and therapeutic potential

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