IgA1 immune complexes from pediatric patients with IgA nephropathy activate cultured human mesangial cells

Novák, Jan; Kafková, Leona Rašková; Suzuki, Hitoshi; Tomana, Milan; Matoušovic, K; Brown, Raymond Albert Joseph; Hall, Stacy; Sanders, John T.; Eison, T. Matthew; Moldoveanu, Zina; Novak, Lea; Novák, Zdeněk; Mayne, Richard; Julian, Bruce A.; Městecký, Jiří; Wyatt, Robert

doi:10.1093/ndt/gfr448

Cited by 65 publications

(70 citation statements)

References 36 publications

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“…3B). Apart from CIC levels, the nephritogenic activity of CIC depends also on molecular composition and molecular masses previously confirmed in vitro by MC proliferation response [25-27], which was not significantly reduced by prednisone therapy of our IgAN patients. Thus, we could not unambiguously conclude the corticosteroids’ effect on overall nephritogenic activity of CIC.…”

Section: Discussionsupporting

confidence: 58%

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Glucocorticoids Reduce Aberrant O-Glycosylation of IgA1 in IgA Nephropathy Patients

Kosztyu

Hill

Jemelkova

et al. 2018

Kidney Blood Press Res

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Background/Aims: IgA nephropathy is associated with aberrant O-glycosylation of IgA1, which is recognized by autoantibodies leading to the formation of circulating immune complexes. Some of them, after deposition into kidney mesangium, trigger glomerular injury. In patients with active disease nonresponding to angiotensin-converting enzyme inhibitors or angiotensin II blockers, corticosteroids are recommended. Methods: The relationship between the corticosteroid therapy and serum levels of IgA, aberrantly O-glycosylated IgA1, IgA-containing immune complexes and their mesangioproliferative activity was analyzed in IgA nephropathy patients and disease and healthy controls. Results: Prednisone therapy significantly reduced proteinuria and levels of serum IgA, galactose-deficient IgA1, and IgA-IgG immune complexes in IgA nephropathy patients and thus reduced differences in all of the above parameters between IgAN patients and control groups. A moderate but not significant reduction of mesangioproliferative potential of IgA-IgG immune complexes and IgA sialylation was detected. Conclusion: The prednisone therapy reduces overall aberrancy in IgA1 O-glycosylation in IgA nephropathy patients, but the measurement of IgA1 parameters does not allow us to predict the prednisone therapy outcome in individual patients.

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Section: Discussionsupporting

confidence: 58%

“…The MC proliferation was measured according to previously described protocol [25-27]. For analyses, 9 IgAN patients, 6 prednisone-treated controls, 6 untreated disease controls, and 6 healthy controls were evaluated.…”

Section: Methodsmentioning

confidence: 99%

Glucocorticoids Reduce Aberrant O-Glycosylation of IgA1 in IgA Nephropathy Patients

Kosztyu

Hill

Jemelkova

et al. 2018

Kidney Blood Press Res

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“…Based on the physical and biologic characteristics of the immune complexes, such as composition and size, 17,28 mesangial cells may be activated to proliferate and overproduce components of mesangial matrix, chemokines, and cytokines. 29,30 Overall, the serum levels of normalized IgG autoantibody and total IgA autoantibody steadily increased with the ARR level (ARR=3 . ARR=2 .…”

Section: Discussionmentioning

confidence: 98%

Autoantibodies Targeting Galactose-Deficient IgA1 Associate with Progression of IgA Nephropathy

Berthoux

Suzuki

Thibaudin

et al. 2012

Journal of the American Society of Nephrology

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225

155

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Mesangial and circulating IgA1 with aberrantly glycosylated hinge region O-glycans characterize IgA nephropathy (IgAN). Unlike healthy individuals, some IgA1 is galactose deficient in patients with IgAN, leaving terminal N-acetylgalactosamine residues in the hinge region exposed. Circulating autoantibodies that recognize such galactose-deficient IgA1 as an autoantigen, or the levels of the autoantigen itself, may allow prediction of disease progression. Here, we analyzed serum samples obtained at diagnosis for autoantigen and autoantibodies from 97 patients with IgAN selected from our prospective cohort according to their absolute renal risk for progression to dialysis or death (0, very low; 1, low; 2, high; 3, very high). We also analyzed samples from controls comprising 30 healthy volunteers and 30 patients with non-IgAN disease. The mean follow-up was 13.8 years. We found that mean serum levels of total autoantigen, normalized IgG autoantibody, and total IgA autoantibody were significantly higher in patients than in the combined controls (all P#0.01). Furthermore, increasing levels correlated with worse clinical outcomes. In Cox regression and Kaplan-Meier analyses, IgG autoantibody levels $1.33 predicted dialysis or death (both P#0.01). In conclusion, these data suggest that serum levels of IgG and IgA autoantibodies strongly associate with the progression of IgAN nephropathy.

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“…In vitro experiments have demonstrated the activation and proliferation of cultured mesangial cells stimulated by large immune complexes containing galactose-deficient IgA1 (Gd-IgA1). For the in vitro stimulatory activity, the size of the immune complexes needs to exceed 800 kDa [33,34]. The binding of IgG to Gd-IgA1 has been found to correlate with the level of proteinuria and also shown to be a specific test for the diagnosis of IgAN [35].…”

Section: Etiology and Pathophysiologymentioning

confidence: 99%

Henoch–Schönlein purpura nephritis

Pöhl

2014

Pediatr Nephrol

126

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Henoch-Schönlein purpura (HSP) is the one of most common types of systemic vasculitis in childhood. Glomerulonephritis (HSPN) occurs in 30-50 % of HSP patients, mostly in a mild form but a small percentage of patients present with nephrotic syndrome or renal failure. HSPN is caused by the glomerular deposition of immunoglobulin A1 (IgA1)-containing immune complexes in the mesangium, the subepithelial and the subendothelial space. Formation of the IgA1 immune complex is thought to be the consequence of aberrantly glycosylated IgA1 molecules secreted into the circulation and their subsequent recognition by IgG specific for galactose-deficient IgA1. Mesangial proliferation and renal damage are triggered by the deposited immune complexes, which likely require activation of the complement system. Whereas other organ manifestations of HSP are mostly benign and self-limiting, HSPN might lead to chronic renal disease and end stage renal failure, thereby justifying immunosuppressive treatment. Long-term renal outcome correlates to the severity of the initial clinical presentation and the extent of renal biopsy changes, both of which are used to decide upon a possible treatment. As there are no evidence-based treatment options for severe HSPN, a large variety of therapeutic regimens are used. Prospective randomized controlled treatment studies are needed, but the low incidence of severe HSPN renders such studies difficult.

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IgA1 immune complexes from pediatric patients with IgA nephropathy activate cultured human mesangial cells

Abstract: These data indicate that sera of pediatric IgAN patients contain biologically active CIC with Gal-deficient IgA1.

Cited by 65 publications

References 36 publications

Glucocorticoids Reduce Aberrant O-Glycosylation of IgA1 in IgA Nephropathy Patients

Glucocorticoids Reduce Aberrant O-Glycosylation of IgA1 in IgA Nephropathy Patients

Autoantibodies Targeting Galactose-Deficient IgA1 Associate with Progression of IgA Nephropathy

Henoch–Schönlein purpura nephritis

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