IgA1-containing immune complexes in IgA nephropathy differentially affect proliferation of mesangial cells

Novák, Jan; Tomana, Milan; Matoušovic, K; Brown, Raymond Albert Joseph; Hall, Stacy; Novak, Lea; Julian, Bruce A.; Wyatt, Robert; Městecký, Jiří

doi:10.1111/j.1523-1755.2005.67107.x

Cited by 187 publications

(186 citation statements)

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“…Using total serum IgA1 purified from patients with IgAN, we were not able to induce proliferation of HMC. Previous study showed circulating IC containing aberrantly glycosylated IgA1 isolated from patients' sera stimulated mesangial cell proliferation (14). Because of technical issues, we were not able to isolate circulating IC from patients' sera.…”

Section: Discussionmentioning

confidence: 96%

“…Consequently, mesangial cells release proinflammatory and profibrogenic mediators, including IL-6, IL-8, IL-1b, IFN-g-inducible protein-10 (IP-10), TNF-a, MCP-1, macrophage migration inhibitory factor, and TGF-b (8)(9)(10)(11)(12). The IgA IC also modulates proliferation and apoptosis of human mesangial cells (HMC) (13,14). The subsequent inflammation, cellular proliferation, and synthesis of extracellular matrix lead to the progression of IgAN (15).…”

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confidence: 99%

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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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Section: Discussionmentioning

confidence: 96%

mentioning

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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“…IgA1 with aberrant hinge region glycans or IgA1 with antiglycan specificity binds to IgG and forms circulating or in situ immune complexes. 8 Novak et al 18 showed that immune complexes containing aberrantly glycosylated IgA1 bind to mesangial cells more efficiently than uncomplexed IgA. Eventually, subsequent deposition of immune complexes within the mesangium induces mesangial damage triggering kidney injury.…”

Section: Discussionmentioning

confidence: 99%

Glomerular IgG deposition predicts renal outcome in patients with IgA nephropathy

et al. 2016

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Glomerular IgG deposition is frequently observed in patients with IgA nephropathy. However, the association between glomerular IgG deposition and progression of IgA nephropathy is uncertain. Six hundred and twentyseven patients with biopsy-proven IgA nephropathy were recruited. Histological variables of the Oxford classification (Oxford-MEST) and the presence of glomerular IgG deposits were assessed. Renal progression defined as end-stage renal disease or 50% reduction in estimated glomerular filtration rate was analyzed using Kaplan-Meier methods and Cox regression analysis. Of the study population, 200 patients (31.9%) had glomerular IgG deposition on immunofluorescence staining. During a mean follow-up of 56.8 ± 37.5 months, the rate of renal progression was significantly higher in the IgA nephropathy patients with glomerular IgG deposition compared with the IgA nephropathy patients without glomerular IgG deposition (39.8 vs 12.3 per 1000 patientyears; Po 0.001). Of patients with IgG deposition, 178 (28.3%), 20 (3.2%), and 2 (0.3%) patients had mild, moderate, and marked glomerular IgG deposits, receptively. Kaplan-Meier analysis revealed that cumulative renal survival was significantly lower in IgA nephropathy patients with the higher intensity of glomerular IgG deposits (Po 0.001). In addition, Cox regression analysis revealed that moderate and marked glomerular IgG deposits significantly predicted renal outcome independent of Oxford-MEST and clinical variables (HR, 2.97; 95% CI, 1.01-8.77; P = 0.04). This study showed that that glomerular IgG deposition was independently associated with poor renal outcome in patient with IgA nephropathy.

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“…These complexes stimulate cultured human mesangial cells (3)(4)(5), resulting in activation of oxidative stress pathways (6 -8). Evidence of increased oxidative stress has been noted in renal tissue of patients with IgAN (9) as well as in their sera and/or erythrocytes (i.e., increased levels of lipoperoxide or malondialdehyde and reduced activity of superoxide dismutase, catalase, and glutathione peroxidase) (10,11).…”

Section: Introductionmentioning

confidence: 99%

Oxidative Stress and Galactose-Deficient IgA1 as Markers of Progression in IgA Nephropathy

Camilla

Suzuki

Daprà

et al. 2011

Clinical Journal of the American Society of Nephrology

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Summary Background and objectives We assessed the activation of the oxidative stress pathway in patients with IgA nephropathy (IgAN), while evaluating the classic marker of the disease (galactose-deficient serum IgA1). Design, setting, participants, & measurements Sera from 292 patients and 69 healthy controls from Italy and the United States were assayed for advanced oxidation protein products (AOPPs), free sulfhydryl groups on albumin (SH-Alb), and IgA1 with galactose-deficient hinge-region O-glycans (Gd-IgA1). Gd-IgA1 was detected by binding to Helix aspersa agglutinin (HAA) and expressed as total Gd-IgA1 or as degree of galactose deficiency relative to a standard Gd-IgA1 myeloma protein (%HAA). Results Sera from IgAN patients showed higher levels of Gd-IgA1, %HAA, and AOPPs, but lower levels of SH-Alb in comparison to that from healthy controls. Serum levels of AOPPs significantly correlated with serum Gd-IgA1 and %HAA. The relationship between these biomarkers and clinical features at sampling and during follow-up was assessed in 62 patients with long-term follow-up. AOPPs and %HAA correlated with proteinuria at sampling and independently associated with subsequent proteinuria. Levels of AOPPs correlated with rate of decline in renal function after sampling. The combination of a high level of AOPPs and a high level of %HAA associated with decline in estimated GFR. Conclusions Serum levels of aberrantly glycosylated IgA1 are elevated and oxidative stress pathways are activated in patients with IgAN; the intensity of the stress correlated with expression and progression of the disease. We speculate that oxidative stress may modulate the nephrotoxicity of aberrantly glycosylated IgA1 in IgAN.

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IgA1-containing immune complexes in IgA nephropathy differentially affect proliferation of mesangial cells

Abstract: Overall, these findings suggest that CIC containing aberrantly glycosylated IgA1 affect proliferation of MC in vitro and, thus, likely play a role in the pathogenesis of IgAN.

Cited by 187 publications

References 50 publications

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

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

Glomerular IgG deposition predicts renal outcome in patients with IgA nephropathy

Oxidative Stress and Galactose-Deficient IgA1 as Markers of Progression in IgA Nephropathy

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