Glomerular deposition of mannose-binding lectin (MBL) indicates a novel mechanism of complement activation in IgA nephropathy

Endo, Morito

doi:10.1093/ndt/13.8.1984

Cited by 169 publications

(115 citation statements)

References 17 publications

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“…Therefore, activation of C4 by IgA via the lectin pathway, as demonstrated in the present study, may very well be the mechanism of C4 activation in IgA nephropathy. This hypothesis is strongly supported by the deposition of MBL in association with IgA in the mesangial area of patients with IgA nephropathy (19,20) and patients with Henoch-Schönlein purpura (32). The latter disease is also characterized by mesangial deposition of IgA and complement.…”

Section: Discussionmentioning

confidence: 84%

“…This is proposed for rheumatoid arthritis, and is suggested by the presence of MBL in renal biopsies from patients with IgA nephropathy, Henoch-Schönlein purpura, systemic lupus erythematosus, and poststreptococcal glomerulonephritis (19,20,32,40,44). IgA nephropathy is the leading cause of end stage renal disease worldwide.…”

Section: Discussionmentioning

confidence: 95%

“…A classical disease involving IgA and complement activation is primary IgA nephropathy, a common renal disease involving mesangial deposition of IgA and complement components, resulting in end stage renal failure in ϳ30% of the patients (18). Recent studies indicate the presence of MBL in association with IgA in the mesangial area of patients with IgA nephropathy (19,20).…”

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confidence: 99%

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Human IgA Activates the Complement System Via the Mannan-Binding Lectin Pathway

Roos

et al. 2001

The Journal of Immunology

388

286

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The recently identified lectin pathway of the complement system, initiated by binding of mannan-binding lectin (MBL) to its ligands, is a key component of innate immunity. MBL-deficient individuals show an increased susceptibility for infections, especially of the mucosal system. We examined whether IgA, an important mediator of mucosal immunity, activates the complement system via the lectin pathway. Our results indicate a dose-dependent binding of MBL to polymeric, but not monomeric IgA coated in microtiter plates. This interaction involves the carbohydrate recognition domain of MBL, because it was calcium dependent and inhibited by mannose and by mAb against this domain of MBL. Binding of MBL to IgA induces complement activation, as demonstrated by a dose-dependent deposition of C4 and C3 upon addition of a complement source. The MBL concentrations required for IgA-induced C4 and C3 activation are well below the normal MBL plasma concentrations. In line with these experiments, serum from individuals having mutations in the MBL gene showed significantly less activation of C4 by IgA and mannan than serum from wild-type individuals. We conclude that MBL binding to IgA results in complement activation, which is proposed to lead to a synergistic action of MBL and IgA in antimicrobial defense. Furthermore, our results may explain glomerular complement deposition in IgA nephropathy.

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Section: Discussionmentioning

confidence: 84%

Section: Discussionmentioning

confidence: 95%

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confidence: 99%

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Human IgA Activates the Complement System Via the Mannan-Binding Lectin Pathway

Roos

et al. 2001

The Journal of Immunology

388

286

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“…It is known that this local complement system in the glomeruli is activated via the alternative or mannose-binding lectin pathway in IgA nephropathy. 24,25 Complement by IgG antibodies proceeds through the classic pathway, as demonstrated by C1 binding. 26 In other words, IgG forms the classic pathway convertase C4bC2a through C1 fixation and subsequently cleaves C3 into C3a and C3b.…”

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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“…However, the mechanism and clinical significance of complement activation in IgA nephropathy is unclear. Activation may occur through an alternative pathway (20), but it has recently been proposed that the lectin pathway is involved in complement activation in IgA nephropathy (21,22). Furthermore, C4d deposition in glomeruli and activation of the lectin pathway influence the prognosis of IgA nephropathy and the severity of renal injury (23,24).…”

Section: Discussionmentioning

confidence: 99%

Correlation of serum levels of complement C4a desArg with pathologically estimated severity of glomerular lesions and mesangial hypercellularity scores in patients with IgA nephropathy

Sogabe

Uto

Kanmura

et al. 2013

International Journal of Molecular Medicine

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Abstract. The aim of the present study was to explore serum biomarkers for the pathology of IgA nephropathy using serum proteomics. The subjects were 57 patients with IgA nephropathy who were divided into two groups (group 1, n=25; group 2, n=32) and 14 healthy controls. Serum protein profiles were analyzed using the ProteinChip surface-enhanced laser desorption ionization (SELDI) system. Associations between signal intensities of proteins and histological findings in patients with IgA nephropathy were studied in group 1. Serum levels of a candidate biomarker protein (complement component C4a desArg) for IgA nephropathy were determined by enzyme linked-immunosorbent assay (ELISA) in group 2 and the relationships of these levels with histological findings were evaluated. There were significant differences in 93 protein signals between patients in group 1 and controls. Among these signals, 3 proteins at 8592, 8757 and 8806 m/z were significantly correlated with the severity of glomerular lesions. The protein at 8592 m/z was identified as C4a desArg and the signal intensity of 8592 m/z was strongly correlated with serum C4a levels, including C4a desArg, determined by ELISA. In addition, the serum levels of C4a (mainly C4a desArg) were significantly higher in patients in group 2 compared to controls and were correlated with the severity of glomerular lesions and with mesangial hypercellularity scores. In conclusion, the serum levels of complement C4a desArg are significantly higher in patients with IgA nephropathy compared to healthy controls and are significantly correlated with the severity of glomerular lesions and mesangial hypercellularity scores. Thus, serum C4a desArg is a potential biomarker for the severity of histological findings in patients with IgA nephropathy.

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Glomerular deposition of mannose-binding lectin (MBL) indicates a novel mechanism of complement activation in IgA nephropathy

Cited by 169 publications

References 17 publications

Human IgA Activates the Complement System Via the Mannan-Binding Lectin Pathway

Human IgA Activates the Complement System Via the Mannan-Binding Lectin Pathway

Glomerular IgG deposition predicts renal outcome in patients with IgA nephropathy

Correlation of serum levels of complement C4a desArg with pathologically estimated severity of glomerular lesions and mesangial hypercellularity scores in patients with IgA nephropathy

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