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O-glycosylated IgA rheumatoid factor induces IgA deposits and glomerulonephritis.

ABSTRACT: 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.

SUBMITTER: Otani M

PROVIDER: S-EPMC3294307 | biostudies-literature | 2012 Mar

REPOSITORIES: biostudies-literature

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O-glycosylated IgA rheumatoid factor induces IgA deposits and glomerulonephritis.

Otani Masako M Nakata Junichiro J Kihara Masao M Leroy Valérie V Moll Solange S Wada Yoshinao Y Izui Shozo S

Journal of the American Society of Nephrology : JASN 20111222 3

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 ...[more]

PMID: 22193386

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Project description:Small glomerular IgA deposits have been reported in patients with liver cirrhosis, mainly as an incidental finding in autopsy studies. We recently encountered nine cirrhotic patients who presented with acute proliferative glomerulonephritis with unusually large, exuberant glomerular immune complex deposits, in the absence of systemic lupus erythematosus (SLE) or monoclonal gammopathy-related kidney disease. Deposits were typically IgA dominant/codominant. Our aim was to further elucidate the etiology, diagnostic pitfalls, and clinical outcomes.We present clinical features and kidney biopsy findings of nine cirrhotic patients with an unusual acute immune complex glomerulonephritis. We also identified native kidney biopsies from all patients with liver cirrhosis at our institution over a 13-year period (January 2004 to December 2016) to evaluate presence of glomerular IgA deposits in them (n = 118).Six of nine cirrhotic patients with the large immune deposits had a recent/concurrent acute bacterial infection, prompting a diagnosis of infection-associated glomerulonephritis and treatment with antibiotics. In the remaining three patients, no infection was identified and corticosteroids were initiated. Three of nine patients recovered kidney function (one recovered kidney function after liver transplant); three patients developed chronic kidney disease but remained off dialysis; two patients became dialysis-dependent and one patient developed sepsis and expired shortly after biopsy. Within the total cohort of 118 patients with cirrhosis, 67 others also showed IgA deposits, albeit small; and 42 patients had no IgA deposits.These cases provide support to the theory that liver dysfunction may compromise clearance of circulating immune complexes, enabling deposition in the kidney. At least in a subset of cirrhotic patients, a superimposed bacterial infection may serve as a "second-hit" and lead to acute glomerulonephritis with exuberant immune complex deposits. Therefore, a trial of antibiotics is recommended and caution is advised before immunosuppressive treatment is offered. Unfortunately, most of these patients have advanced liver failure; therefore both diagnosis and management remain a challenge.

Dataset Information

O-glycosylated IgA rheumatoid factor induces IgA deposits and glomerulonephritis.

Publications

O-glycosylated IgA rheumatoid factor induces IgA deposits and glomerulonephritis.

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