Development of Immunoglobulin A Nephropathy- Like Disease in β-1,4-Galactosyltransferase-I-Deficient Mice

Nishie, Toshikazu; Miyaishi, Osamu; Azuma, Haruhito; Kameyama, Akihiko; Naruse, Chie; Hashimoto, Noriyoshi; Yokoyama, Hitoshi; Narimatsu, Hisashi; Wada, Takashi; Asano, Masahide

doi:10.2353/ajpath.2007.060559

Cited by 66 publications

(50 citation statements)

References 54 publications

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“…The polymeric IgA in BAFF-Tg mice resisted detergent dissociation, suggesting disulfide bond-mediated assembly into higher, perhaps IgM-like, oligomers. Underglycosylation could simply be uncoupled from the pathogenicity, but this seems unlikely given that a β−1-4-galactosyltransferase-1-deficient mouse develops a similar IgA-associated renal disease with expansion of the extracellular matrix in the glomeruli (55). In another mouse model, bcl2-Tg (NZW × C57BL/6)F 1 , IgA is aberrantly glycosylated and becomes polymeric and pathogenic in spite of the lack of the hinge region glycosylation (36).…”

Section: Figurementioning

confidence: 99%

Mice overexpressing BAFF develop a commensal flora–dependent, IgA-associated nephropathy

McCarthy¹,

Kujawa²,

Wilson³

et al. 2011

J. Clin. Invest.

237

165

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B cell activation factor of the TNF family (BAFF) is a potent B cell survival factor. BAFF overexpressing transgenic mice (BAFF-Tg mice) exhibit features of autoimmune disease, including B cell hyperplasia and hypergammaglobulinemia, and develop fatal nephritis with age. However, basal serum IgA levels are also elevated, suggesting that the pathology in these mice may be more complex than initially appreciated. Consistent with this, we demonstrate here that BAFF-Tg mice have mesangial deposits of IgA along with high circulating levels of polymeric IgA that is aberrantly glycosylated. Renal disease in BAFF-Tg mice was associated with IgA, because serum IgA was highly elevated in nephritic mice and BAFF-Tg mice with genetic deletion of IgA exhibited less renal pathology. The presence of commensal flora was essential for the elevated serum IgA phenotype, and, unexpectedly, commensal bacteria-reactive IgA antibodies were found in the blood. These data illustrate how excess B cell survival signaling perturbs the normal balance with the microbiota, leading to a breach in the normal mucosal-peripheral compartmentalization. Such breaches may predispose the nonmucosal system to certain immune diseases. Indeed, we found that a subset of patients with IgA nephropathy had elevated serum levels of a proliferation inducing ligand (APRIL), a cytokine related to BAFF. These parallels between BAFF-Tg mice and human IgA nephropathy may provide a new framework to explore connections between mucosal environments and renal pathology.

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Section: Figurementioning

confidence: 99%

Mice overexpressing BAFF develop a commensal flora–dependent, IgA-associated nephropathy

McCarthy¹,

Kujawa²,

Wilson³

et al. 2011

J. Clin. Invest.

237

165

View full text Add to dashboard Cite

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“…These data indicate that Gal deficiency in N-glycans of IgA is not essential for the development of the 6-19 model of GN, although Gal deficiency of serum IgA has previously been reported to be associated with the development of glomerular lesions in other murine models of IgAN. [14][15][16] The possibility of a critical pathogenic role of O-glycans present in the 6-19 IgA hinge region for the development of glomerular lesions remains to be tested. It should be stressed that 6-19 IgA O-glycans were highly galactosylated, in contrast to the hypogalactosylated O-glycans of IgA1 in patients with IgAN.…”

Section: Discussionmentioning

confidence: 99%

“…The peptide fraction containing the 62-amino acid hinge peptide of each IgA mAb obtained by treatment with trypsin and lysylendopeptidase ( Figure 4) was collected by HPLC and subjected to matrix-assisted laser desorption/ionization-time-of-flight mass spectrometry (MALDI-TOF MS). The analysis of [6][7][8][9][10][11][12][13][14][15][16][17][18][19] IgA RF mAb identified, in addition to a peak containing the nonglycosylated hinge peptide at m/z 6627, four additional peaks of O-glycosylated hinge peptides, which contained GalNAc monosaccharide, GalNAc-Gal disaccharide, and its monoand disialylated forms ( Figure 5). The prevailing form of the carbohydrate composition of O-glycans was GalNAc-Gal disaccharide at m/z 6992, and the abundance of the glycosylated peptide ions at this peak was similar to that of the nonglycosylated ones.…”

Section: Similar Proportion Of Polymeric and Monomericmentioning

confidence: 99%

“…12 In contrast, murine IgA carries at least two N-linked oligosaccharide side chains in CH1 and CH3 domains, 8,9,13 and Gal deficiency of N-linked glycans (N-glycans) has been reported to be associated with the development of glomerular lesions in murine models of IgAN. [14][15][16] In the present study, we explored the nephritogenic potential of two different monoclonal IgA anti-IgG2a rheumatoid factors (RFs) bearing the Igh-2 a allotype (6-19 and 46-42) in relation to the possible presence of O-glycans in their hinge regions and to the structural abnormality of N-glycans in their CH1 and CH3 domains. We observed that only 6-19 IgA RF mAb carrying O-glycans in the hinge region is able to induce severe glomerular lesions characterized by mesangial IgA deposits, although its O-glycans are highly galactosylated, and that the structure of N-glycans present in the CH1 domain of 6-19 IgA RF is also markedly different from that of non-nephritogenic 46-42 IgA RF.…”

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confidence: 99%

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O-Glycosylated IgA Rheumatoid Factor Induces IgA Deposits and Glomerulonephritis

Otani

Nakata²,

Kihara³

et al. 2012

Journal of the American Society of Nephrology

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Structural aberrations of O-linked glycans present in the IgA1 hinge region are associated with IgA nephropathy, but their contribution to its pathogenesis remains incompletely understood. In this study, mice implanted with hybridoma secreting 6-19 IgA anti-IgG2a rheumatoid factor, but not 46-42 IgA rheumatoid factor bearing the same IgA allotype, developed mesangial deposits consisting of IgA, IgG2a, and C3. Studies in immunoglobulin-and C3-deficient mice revealed that the development of these glomerular lesions required the formation of IgA-IgG2a immune complexes and subsequent activation of complement. The proportion of polymeric and monomeric forms, the IgG2a-binding affinity, and the serum levels of IgA-IgG2a immune complexes were similar between 6-19 IgA-and 46-42 IgA-injected mice. In contrast, the analysis of oligosaccharide structures revealed highly galactosylated O-linked glycans in the hinge region of 6-19 IgA and poorly O-glycosylated in the hinge region of 46-42 IgA. Furthermore, the structure of N-linked glycans in the CH1 domain was the complex type in 6-19 IgA and the hybrid type in 46-42 IgA. In summary, this study demonstrates the presence of O-linked glycans in the hinge region of mouse IgA and suggests that 6-19 IgA rheumatoid factor-induced GN could serve as an experimental model for IgA nephropathy.

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“…These data argue against a primary role of Nglycans present in the Fc region of IgA for the development of IgAN-like glomerular lesions induced by the 6-19 IgA RF mAb. However, because it was previously reported that hypogalactosylation of N-glycans of serum IgA was associated with the development of glomerular lesions in other murine models of IgAN, [19][20][21] one cannot exclude the possibility that aberrant glycosylation of N-glycans could play an additional role in the development of IgAN-like glomerular lesions. In this regard, it should be stressed that the development of IgAN-like glomerular lesions has been reported in ddY-A mice bearing the Igh-2 b allotype, in which IgA lacks the O-glycosylation acceptor site, whereas a more rapid and severe disease was developed in ddY-B mice, in which IgA are potentially O-glycosylated.…”

Section: Discussionmentioning

confidence: 99%

O-Linked Glycosylation Determines the Nephritogenic Potential of IgA Rheumatoid Factor

Kihara

Ito

Nakata

et al. 2014

Journal of the American Society of Nephrology

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Deficient glycosylation of O-linked glycans in the IgA1 hinge region is associated with IgA nephropathy in humans, but the pathogenic contribution of the underlying structural aberrations remains incompletely understood. We previously showed that mice implanted with cells secreting the class-switch variant 6-19 IgA anti-IgG2a rheumatoid factor, but not 46-42 IgA anti-IgG2a rheumatoid factor, develop glomerular lesions resembling IgA nephropathy. Because the levels of O-linked glycosylation in the hinge region and the structures of N-linked glycans in the CH1 domain differ in 6-19 IgA and 46-42 IgA, we determined the respective contributions of O-and N-linked glycans to the nephritogenic potential of the 6-19 IgA rheumatoid factor in mice. Wild-type 6-19 IgA secreted by implanted cells induced significant formation of glomerular lesions, whereas poorly O-glycosylated 6-19 IgA glycovariants or a 6-19 IgA hinge mutant lacking O-linked glycans did not. However, we observed no apparent heterogeneity in the structure of N-linked glycans attached to three different sites of the Fc regions of nephritogenic and non-nephritogenic 6-19 IgAs. Collectively, our data suggest a critical role of O-linked glycans attached to the hinge region in the development of IgA nephropathy-like GN induced by 6-19 IgA rheumatoid factor in mice.

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Development of Immunoglobulin A Nephropathy- Like Disease in β-1,4-Galactosyltransferase-I-Deficient Mice

Cited by 66 publications

References 54 publications

Mice overexpressing BAFF develop a commensal flora–dependent, IgA-associated nephropathy

Mice overexpressing BAFF develop a commensal flora–dependent, IgA-associated nephropathy

O-Glycosylated IgA Rheumatoid Factor Induces IgA Deposits and Glomerulonephritis

O-Linked Glycosylation Determines the Nephritogenic Potential of IgA Rheumatoid Factor

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