An update on the pathogenesis and treatment of IgA nephropathy

Boyd, Joanna; Cheung, Chee Kay; Molyneux, Karen; Feehally, John; Barratt, Jonathan

doi:10.1038/ki.2011.501

Cited by 148 publications

(127 citation statements)

References 106 publications

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“…Among other CNVs, we focused on an aberration containing a gene encoding for the TLR9 that was found involved in the IgAN 28,29 and that could also have a role in the T-cell-independent IgA secretion. 35,36 This suggests that mucosal pathogens may specifically stimulate IgA1 synthesis and modulate the glycosylation process of IgA. We confirmed, on two different cohorts from Italian and Greek populations, that IgAN patients with DRF carried low copy number of the variant containing the TLR9 gene and found that the TLR9 expression significantly correlated with the loss aberration in patients.…”

Section: Cnvs In Iga Nephropathysupporting

confidence: 73%

“…10,11 Mutations in MHC genes have been associated with several autoimmune conditions, consistently with the predisposition to develop IgA1 hinge region autoantibodies, at least in some cases. 35 Moreover, again in chromosome 6, we also found a CNV, the loss chr6.hg18:g.(?_33 229 433)_(33 246 998_? )del, in very close proximity to regions identified by three independent GWAS [10][11][12] and containing the gene COL11A2.…”

Section: Cnvs In Iga Nephropathymentioning

confidence: 54%

“…38 This may result in impaired elimination of mucosal antigens, prolonged antigen exposure to B cells and an increase in immunologic memory leading to deal with continuous antigenic challenge that triggers the production of nephritogenic IgA1. 35 In conclusion, we performed the first genome-wide CNV study in IgAN identifying some structural variants specific of IgAN patients and providing a collection of new candidate genes and loci that can help to dissect the complex genomic setting of the disease. Moreover, we identified a specific CNV, spanning the TLR9 gene, that could explain the disease severity in some IgAN patients.…”

Section: Cnvs In Iga Nephropathymentioning

confidence: 99%

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Genome-wide scan identifies a copy number variable region at 3p21.1 that influences the TLR9 expression levels in IgA nephropathy patients

et al. 2014

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on behalf of the European IgAN ConsortiumImmunoglobulin A nephropathy (IgAN) is a complex multifactorial disease characterized by genetic factors that influence the pathogenesis of the disease. In this context, an intriguing role could be ascribed to copy number variants (CNVs). We performed the whole-genome screening of CNVs in familial IgAN patients, their healthy relatives and healthy subjects (HSs). In the initial screening, we included 217 individuals consisting of 51 biopsy-proven familial IgAN cases and 166 healthy relatives. We identified 148 IgAN-specific aberrations, specifically 105 loss and 43 gain, using a new statistical approach that allowed us to identify aberrations that were concordant across multiple samples. Several CNVs overlapped with regions evidenced by previous genome-wide genetic studies. We focused our attention on a CNV located in chromosome 3, which contains the TLR9 gene and found that IgAN patients characterized by deteriorated renal function carried low copy number of this CNV. Moreover, the TLR9 gene expression was low and significantly correlated with the loss aberration. Conversely, IgAN patients with normal renal function had no aberration and the TLR9 mRNA was expressed at the same level as in HSs. We confirmed our data in another cohort of Greek subjects. In conclusion, here we performed the first genome-wide CNV study in IgAN identifying structural variants that could help the genetic dissection of this complex disease, and pointed out a loss aberration in the chromosome 3, which is responsible for the downregulation of TLR9 expression that, in turn, could contribute to the deterioration of the renal function in IgAN patients.

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Section: Cnvs In Iga Nephropathysupporting

confidence: 73%

Section: Cnvs In Iga Nephropathymentioning

confidence: 54%

Section: Cnvs In Iga Nephropathymentioning

confidence: 99%

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Genome-wide scan identifies a copy number variable region at 3p21.1 that influences the TLR9 expression levels in IgA nephropathy patients

et al. 2014

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“…Binding of IgA1 IC to mesangial cells with subsequent cell proliferation and release of proinflammatory and profibrotic mediators are widely accepted as key events in the pathogenesis of IgAN (15,28). Previous studies suggest that these mediators play a significant role in the pathogenesis and progression of IgAN.…”

Section: Discussionmentioning

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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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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“…These findings strongly support a predominant role of an autoimmune mechanism in the pathogenesis of IgAN, which remains partly unsolved. 33 …”

Section: Discussionmentioning

confidence: 99%

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

Berthoux

Suzuki

Thibaudin

et al. 2012

Journal of the American Society of Nephrology

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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An update on the pathogenesis and treatment of IgA nephropathy

Cited by 148 publications

References 106 publications

Genome-wide scan identifies a copy number variable region at 3p21.1 that influences the TLR9 expression levels in IgA nephropathy patients

Genome-wide scan identifies a copy number variable region at 3p21.1 that influences the TLR9 expression levels in 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

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

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