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Previous studies show that the proliferation of human mesangial cells (HMCs) played a significant part in the pathogenesis of Henoch-Schönlein purpura nephritis (HSPN). The aim of this study was to explore the proliferation of HMCs induced by IgA1 isolated from the sera of HSP patients. HMCs were cultured in three different types of media, including IgA1 from patients with HSP (HSP IgA1 group), healthy children (healthy IgA1 group) and medium (control group). The proliferation of HMCs incubated with IgA1 was determined by cell counting kit-8 assay and bromodeoxyuridine incorporation. The expression of ERK1/2 and phosphatidylinositol 3 kinase/protein kinase B/mammalian targets of the rapamycin (PI3K/AKt/mTOR) signals and transferrin receptor (TfR/CD71) was detected with the methods of immunoblotting. The results indicated that the proliferation of HMCs significantly increased in the HSP IgA1 group compared with that in the control group or the healthy IgA1 group (P < 0.001). Moreover, we found that IgA1 isolated from HSP patients activated ERK and PI3K/AKt/mTOR signals, and markedly increased TfR/CD71 expression in HMCs. These effects induced by IgA1 isolated from patients with HSP were inhibited by human TfR polyclonal antibody (hTfR pAb) and soluble human transferrin receptor (sTfR), indicating that IgA1-induced HMC proliferation and ERK1/2 and PI3K/AKt/mTOR activation were dependent on TfR/CD71 engagement. Altogether, these data suggested that TfR/CD71 overexpression and ERK1/2 and PI3K/AKt/mTOR activation were engaged in HMC proliferation induced by IgA1 from HSP patients, which might be related to the mesangial injury of HSPN., (© 2019 International Federation for Cell Biology.)

IgA nephropathy, the most common primary glomerulonephritis in the world and a frequent cause of end-stage renal disease, is characterized by typical mesangial deposits of IgA1, as described by Berger and Hinglaise in 1968. Since then, it has been discovered that aberrant IgA1 O-glycosylation is involved in disease pathogenesis. Progress in glycomic, genomic, clinical, analytical, and biochemical studies has shown autoimmune features of IgA nephropathy. The autoimmune character of the disease is explained by a multihit pathogenesis model, wherein overproduction of aberrantly glycosylated IgA1, galactose-deficient in some O-glycans, by IgA1-secreting cells leads to increased levels of circulatory galactose-deficient IgA1. These glycoforms induce production of autoantibodies that subsequently bind hinge-region of galactose-deficient IgA1 molecules, resulting in the formation of nephritogenic immune complexes. Some of these complexes deposit in the kidney, activate mesangial cells, and incite glomerular injury. Thus, galactose-deficient IgA1 is central to the disease process. In this article, we review studies concerning IgA1 O-glycosylation that have contributed to the current understanding of the role of IgA1 in the pathogenesis of IgA nephropathy. [ABSTRACT FROM AUTHOR]

IgA nephropathy is the most common form of glomerulonephritis in many parts of the world and remains an important cause of end-stage renal disease. Current evidence suggests that IgA nephropathy is not due to a single pathogenic insult, but rather the result of multiple sequential pathogenic “hits”. An abnormally increased level of circulating poorly O-galactosylated IgA1 and the production of O-glycan-specific antibodies leads to the formation of IgA1-containing immune complexes, and their subsequent mesangial deposition results in inflammation and glomerular injury. While this general framework has formed the foundation of our current understanding of the pathogenesis of IgA nephropathy, much work is ongoing to try to precisely define the genetic, epigenetic, immunological, and molecular basis of IgA nephropathy. In particular, the precise origin of poorly O-galactosylated IgA1 and the inciting factors for the production of O-glycan-specific antibodies continue to be intensely evaluated. The mechanisms responsible for mesangial IgA1 deposition and subsequent renal injury also remain incompletely understood. In this review, we summarize the current understanding of the key steps involved in the pathogenesis of IgA nephropathy. It is hoped that further advances in our understanding of this common glomerulonephritis will lead to novel diagnostic and prognostic biomarkers, and targeted therapies to ameliorate disease progression. [ABSTRACT FROM AUTHOR]

IgA nephropathy (IgAN), the most common form of primary glomerulonephritis worldwide, is defined by predominant IgA1 deposits in the glomerular mesangium. Among abnormalities of the IgA immune system reported so far in IgAN, aberrant O-linked glycosylation in the hinge region of IgA1 is the most consistent finding. IgA1 molecules bearing abnormal glycosylation have been found in serum, in tonsillar lymphocytes, and in eluate from mesangial deposits, and characterized by decreased O-linked N-acetylgalactosamine residues with or without alteration in the terminal sialylation of the O-linked sugars. IgA1 with incomplete galactosylation has a tendency to accumulate in glomerular mesangium by self-aggregation or immune complex formation. Glomerular mesangial cells exposed to immune complexes of these IgA1 can proliferate and secrete cytokines, chemokines, growth factors, and extracellular matrix components promoting inflammatory reactions in the glomeruli. Although genes encoding enzymes involved in the O-glycosylation process, such as C1GALT1, have been reported to be responsible for susceptibility to IgAN, recent evidence suggests that the abnormality is restricted to a small fraction of B cell populations and arises from dysregulated IgA1 production and secretion in mucosal immune system. This review will focus on and discuss the role of incompleteness of IgA1 O-galactosylation in the pathogenesis of IgAN and propose a possible mechanism in which abnormal IgA1 occurs in IgAN. [ABSTRACT FROM AUTHOR]

Summary: Circulating immune complexes containing aberrantly glycosylated IgA1 play a pivotal role in the pathogenesis of IgA nephropathy (IgAN). A portion of IgA1 secreted by IgA1-producing cells in patients with IgAN is galactose-deficient and consequently recognized by anti-glycan IgG or IgA1 antibodies. Some of the resultant immune complexes in the circulation escape normal clearance mechanisms, deposit in the renal mesangium, and induce glomerular injury. Recent studies of the origin of these aberrant molecules, their glycosylation profiles, and mechanisms of biosynthesis have provided new insight into the autoimmune nature of the pathogenesis of this common renal disease. An imbalance in the activities of the pertinent glycosyltransferases in the IgA1-producing cells favors production of molecules with galactose-deficient O-linked glycans at specific sites in the hinge region of the α heavy chains. By using sophisticated analytic methods, it may be possible to define biomarkers for diagnostic purposes and identify new therapeutic targets for a future disease-specific therapy. [Copyright &y& Elsevier]

Human immunoglobulin A1 (IgA1), which is the predominant subtype to be deposited in glomeruli in IgA nephropathy (IgAN), has a unique mucine-like structure in its hinge region. Namely, it contains O -glycans and proline-rich peptides. We previously observed underglycosylation of the hinge region in serum and deposited IgA1 in IgAN. On the other hand, clinical development and exacerbation of IgAN are frequently preceded by episodes of upper respiratory tract infection, and palatine tonsils represent the predominant immunocompetent tissue of the upper respiratory tract. Therefore, we hypothesized that tonsils were one of the origins of glomerular IgA1 in IgAN, and investigated the O -glycan structure of IgA1 produced by tonsillar lymphocytes (tonsillar IgA1). A significant increase in asialo-agalacto type O -glycans was found in the tonsillar IgA1 hinge in IgAN. These results suggest that the tonsils produce underglycosylated IgA1 molecules, which enter the bloodstream and are then deposited in the glomeruli. [ABSTRACT FROM AUTHOR]

A predominant expression of IgA1 in mesangial deposits, serum, and bone marrow culture supernatants has been shown in IgA nephropathy (IgAN). Furthermore an excess of λ light chains in both mesangial deposits and serum IgA has been observed. However, the origin of mesangial IgA remains controversial. In the present study, we have examined the IgA1 light chain type in IgAN. Total IgA1, IgA1K and IgAlλ were measured by ELISA in serum and culture supernatants from spontaneous and pokeweed-mitogen (PWM)- stimulated peripheral blood mononuclear cells (PBMC). We observed an increase in IgA and IgAl serum concentrations in IgA nephropathy patients, with a ratio of serum IgA1 to total serum IgA identical between patients and controls. The concentration of serum IgAk did not differ between patients and controls but patients had a significantly higher concentration of serum IgAλ. The IgA1K to IgA1λ ratio was 1.06 ± 0.42 in IgAN patients versus 1.55 ± 0.36 in controls (P<0.01). By contrast, the concentrations of IgA1K and IgA1λ in PBMC culture supernatants, both spontaneous and PWM-stimulated, were identical in patients and controls.Therefore, there is a specific increase in IgA1λ in patients' sera. This contrasts with the normal IgA1 production by PBMC, which are derived from mucosal-associated lymphoid tissues. This suggests that IgA isotypic deregulation is confined to the bone marrow compartment and is not a generalised defect of the IgA system. [ABSTRACT FROM PUBLISHER]

Background: IgA nephropathy (IgAN) is characterized by mesangial deposition of polymeric IgA1 (pIgA1), yet the pathogeneic mechanism remains unresolved. In the present study, we examined the glycosylation profile of differently charged IgA1 from IgAN patients. The binding characteristics of these IgA1 fractions to cultured human mesangial cells (HMC) and hepatoma cell lines (HepG2) were studied. Methods: Differently charged IgA1 were isolated by ion exchange chromatography. The glycosylation profile in the carbohydrate moieties of these differently charged IgA1 was analyzed by galactose (Gal)-, galactose-acetylgalactosamine (Gal-GalNAc)-, or sialic acid-specific enzyme-linked lectin binding assays (ELLA). The binding characteristic of these IgA1 to HMC was examined by flow cytometry and competitive binding assay. Results: Anionic pIgA from IgAN patients showed less reactivity in (Gal)- and (Gal-GalNAc)-specific ELLA (p < 0.01). There was higher reactivity for anionic pIgA1 in α(2,6)-linked sialic acid-specific ELLA (p < 0.01). Anionic pIgA1 from IgAN patients exhibited increased binding to cultured HMC and the binding was significantly reduced after neuraminidase treatment (p < 0.05). In contrast, anionic pIgA1 from IgAN patients bound less to cultured HepG2 cells and the binding was enhanced following neuraminidase treatment (p < 0.05). Conclusions: We demonstrated an unusual glycosylation and sialylation pattern of anionic pIgA1 in IgAN which may have an important effect on its pathogenesis. Copyright © 2007 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]