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

Sallustio, Fabio; Cox, Sharon Natasha; Serino, Grazia; Curci, Claudia; Pesce, Francesco; Palma, Giuseppe De; Papagianni, Αikaterini; Kirmizis, Dimitrios; Falchi, Mario; Schena, Francesco Paolo

doi:10.1038/ejhg.2014.208

Cited by 24 publications

(24 citation statements)

References 41 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…23 Genome-wide scan identifies a copy number variable region at 3p21.1 that influences the TLR9 expression levels in patients with IgAN. 37 Accordingly, these findings suggest that tonsillar TLR9 signaling pathways may be involved in the pathogenesis of human IgAN. TLR9 ligand CpG-ODN increased the expressions of the APRIL receptors BCMA and TACI on B cells and enhanced B cell activation and Ig secretion.…”

Section: Discussionmentioning

confidence: 97%

Toll-Like Receptor 9 Stimulation Induces Aberrant Expression of a Proliferation-Inducing Ligand by Tonsillar Germinal Center B Cells in IgA Nephropathy

Muto

Manfroi

Suzuki

et al. 2016

JASN

110

View full text Add to dashboard Cite

The TNF family member a proliferation-inducing ligand (APRIL; also known as TNFSF13), produced by myeloid cells, participates in the generation and survival of antibody-producing plasma cells. We studied the potential role of APRIL in the pathogenesis of IgA nephropathy (IgAN). We found that a significant proportion of germinal centers (GCs) in tonsils of patients with IgAN contained cells aberrantly producing APRIL, contributing to an overall upregulation of tonsillar APRIL expression compared with that in tonsils of control patients with tonsillitis. In IgAN GC, antigen-experienced IgD+ B cells expressing a switched IgG/IgA B cell receptor produced APRIL. Notably, these GC B cells expressed mRNA encoding the common cleavable APRIL-a but also, the less frequent APRIL-d/z mRNA, which encodes a protein that lacks a furin cleavage site and is, thus, the uncleavable membrane-bound form. Significant correlation between TLR9 and APRIL expression levels existed in tonsils from patients with IgAN. In vitro, repeated TLR9 stimulation induced APRIL expression in tonsillar B cells from control patients with tonsillitis. Clinically, aberrant APRIL expression in tonsillar GC correlated with greater proteinuria, and patients with IgAN and aberrant APRIL overexpression in tonsillar GC responded well to tonsillectomy, with parallel decreases in serum levels of galactose-deficient IgA1. Taken together, our data indicate that antibody disorders in IgAN associate with TLR9-induced aberrant expression of APRIL in tonsillar GC B cells.

show abstract

Section: Discussionmentioning

confidence: 97%

Toll-Like Receptor 9 Stimulation Induces Aberrant Expression of a Proliferation-Inducing Ligand by Tonsillar Germinal Center B Cells in IgA Nephropathy

Muto

Manfroi

Suzuki

et al. 2016

JASN

110

View full text Add to dashboard Cite

show abstract

“…Together with CD40L and TCR, TGFβ is also necessary for the induction of T-cell-dependent IgA class switching [34,35]. Also genetic factors influence the physiopathology of IgAN [6][7][8][9][10] and, in this framework, DNA methylation can play an important role. The whole-genome DNA methylation screening in CD4 + Tcells allowed us to identify some DNA regions aberrantly methylated in IgAN patients.…”

Section: Discussionmentioning

confidence: 98%

“…IgAN has strong genetic components and seems to be influenced by genomic factors such as polymorphic loci and copy number variants [6][7][8][9][10]. On the other hand, it is clearly an immunologically mediated disease characterized by the deposition of IgA1-IgG immune complexes in the glomerular mesangium [11].…”

Section: Introductionmentioning

confidence: 98%

Aberrantly methylated DNA regions lead to low activation of CD4+ T-cells in IgA nephropathy

et al. 2016

Self Cite

View full text Add to dashboard Cite

IgAN (IgA nephropathy) is the most common form of primary glomerulonephritis worldwide and has a strong genetic component. In this setting, DNA methylation could also be an important factor influencing this disease. We performed a genome-wide screening for DNA methylation in CD4(+) T-cells from IgAN patients and found three regions aberrantly methylated influencing genes involved in the response and proliferation of CD4(+) T-cells. Two hypomethylated regions codified genes involved in TCR (T-cell receptor) signalling, TRIM27 (tripartite motif-containing 27) and DUSP3 (dual-specificity phosphatase 3), and an hypermethylated region included the VTRNA2-1 (vault RNA 2-1) non-coding RNA, also known as miR-886 precursor. We showed that the aberrant methylation influences the expression of these genes in IgAN patients. Moreover, we demonstrated that the hypermethylation of the miR-886 precursor led to a decreased CD4(+) T-cell proliferation following TCR stimulation and to the overexpression of TGFβ (transforming growth factor β). Finally, we found a Th1/Th2 imbalance in IgAN patients. The IL (interleukin)-2/IL-5 ratio was notably higher in IgAN patients and clearly indicated a Th1 shift. In conclusion, we identified for the first time some specific DNA regions abnormally methylated in IgAN patients that led to the reduced TCR signal strength of the CD4(+) T-cells and to their anomalous response and activation that could explain the T-helper cell imbalance. The present study reveals new molecular mechanisms underlying the abnormal CD4(+) T-cell response in IgAN patients.

show abstract

“…Such studies are beginning to result in discoveries of both de novo and inherited CNV that are associated with risk of common disease [27]. A recent report in Italian patients with familial IgAN identified a copy number variable region at 3p21.1 that influenced toll-like receptor-9 (TLR9) expression levels [28]. Low copy number was associated with deterioration of renal function in IgAN.…”

Section: Are ‘Genetic Factors' Important In Igan?mentioning

confidence: 99%

The Genetics of IgA Nephropathy: An Overview from Western Countries

Feehally

Barratt

2015

Kidney Dis

View full text Add to dashboard Cite

Background: IgA nephropathy (IgAN) is the commonest primary glomerulonephritis worldwide and a significant cause of chronic kidney disease and end-stage renal disease. It is widely accepted that genetic factors play a role in the pathogenesis of IgAN. However, the identity of these genetic factors remains uncertain. Summary: Critical to all genetic studies is a precise phenotypic definition of the disease. It is well recognised that IgAN displays striking phenotypic variation, raising the possibility that it may not be a single disease and it may not be the same disease in different parts of the world. In this review, we discuss the challenges that this phenotypic variation poses to interpreting genetic data and the current evidence for specific gene involvement in IgAN, focusing particularly on data from European IgAN cohorts. Key Messages: With advances in genetic techniques, in particular next-generation sequencing, and an increased understanding of the importance of copy number variations, epigenetics and transcriptomics, it is likely that we will gain a greater understanding of the genetic basis for IgAN. However, due to the lack of consistency in epidemiological clinicopathological studies both within and between continents, this will only be achieved if we are able to more precisely phenotype IgAN populations. Facts from East and West: The reported prevalence of IgAN is higher in Asia than in Europe and North America. However, differences in use of biopsy for the diagnosis of IgAN should be taken into account in analysing data from both East and West. In Europe, IgAN affects men more frequently than women; this is not the case in Asia. Familial IgAN has been more frequently reported in Europe than in Asia. Within Europe, familial IgAN is more evident in southern than in northern populations. Changes in the pattern of serum IgA1 O-glycosylation is a common finding in IgAN patients in the East and West. SNPs within the gene coding for the enzyme C1GALT1 have been reported in Chinese and European patients. However, there is no evidence for a role of gene polymorphism of the C1GALT1 chaperone cosmc in Europeans. Genetic variants in the HLA gene family have been observed in populations from the East and West. Associations between IgAN and variants of the TAP1/PSMB and DEFA genes were observed in Asian but not in Western patients. Association with the angiotensin-converting enzyme gene was seen only in Asian patients.

show abstract

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

Cited by 24 publications

References 41 publications

Toll-Like Receptor 9 Stimulation Induces Aberrant Expression of a Proliferation-Inducing Ligand by Tonsillar Germinal Center B Cells in IgA Nephropathy

Toll-Like Receptor 9 Stimulation Induces Aberrant Expression of a Proliferation-Inducing Ligand by Tonsillar Germinal Center B Cells in IgA Nephropathy

Aberrantly methylated DNA regions lead to low activation of CD4+ T-cells in IgA nephropathy

The Genetics of IgA Nephropathy: An Overview from Western Countries

Contact Info

Product

Resources

About