Role of truncating mutations in MME gene in fetomaternal alloimmunisation and antenatal glomerulopathies

Dębiec, Hanna; Nauta, Jeroen; Coulet, Florence; Burg, Mirjam van der; Guigonis, Vincent; Schurmans, Thierry; Heer, Emile de; Soubrier, Florent; Janssen, Françoise; Ronco, Pierre

doi:10.1016/s0140-6736(04)17142-0

Cited by 196 publications

(196 citation statements)

References 26 publications

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“…Anti-PLA2R1 antibodies are directed to a reduction-sensitive epitope, 3 which might occur in only one of the two conformations. 1,14 The concept of the role of conformational changes in antibody formation was developed by Hudson's group, who demonstrated that changes in the molecular architecture of the a345-collagen IV autoantigen play a key role in eliciting an autoimmune response in Goodpasture syndrome. 15 The PLA2R1 sequencing data do not provide a simple genetic basis for iMN as another "conformeropathy."…”

Section: Discussionmentioning

confidence: 99%

Phospholipase A2 Receptor (PLA2R1) Sequence Variants in Idiopathic Membranous Nephropathy

Coenen

Hofstra

Dębiec

et al. 2013

Journal of the American Society of Nephrology

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108

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The M-type receptor for phospholipase A2 (PLA2R1) is the major target antigen in idiopathic membranous nephropathy (iMN). Our recent genome-wide association study showed that genetic variants in an HLA-DQA1 and phospholipase A2 receptor (PLA2R1) allele associate most significantly with biopsy-proven iMN, suggesting that rare genetic variants within the coding region of the PLA2R1 gene may contribute to antibody formation. Here, we sequenced PLA2R1 in a cohort of 95 white patients with biopsy-proven iMN and assessed all 30 exons of PLA2R1, including canonical (GT-AG) splice sites, by Sanger sequencing. Sixty patients had anti-PLA2R1 in serum or detectable PLA2R1 antigen in kidney tissue. We identified 18 sequence variants, comprising 2 not previously described, 7 reported as rare variants (,1%) in the Single Nucleotide Polymorphism Database or the 1000 Genomes project, and 9 known to be common polymorphisms. Although we confirmed significant associations among 6 of the identified common variants and iMN, only 9 patients had the private or rare variants, and only 4 of these patients were among the 60 who were PLA2R positive. In conclusion, rare variants in the coding sequence of PLA2R1, including splice sites, are unlikely to explain the pathogenesis of iMN.

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Section: Discussionmentioning

confidence: 99%

Phospholipase A2 Receptor (PLA2R1) Sequence Variants in Idiopathic Membranous Nephropathy

Coenen

Hofstra

Dębiec

et al. 2013

Journal of the American Society of Nephrology

Self Cite

108

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“…Such acquired CR1 deficiency could increase the susceptibility of podocytes to complement activation by antibodies in subepithelial immune deposits (82). As in experimental MN, C5b-9 is assembled on the podocytes of patients with MN, which is evident histologically (26,99) and by examining urine for C5b-9 (65,125). Complicating the utility of urinary C5b-9 measurement is alternative complement pathway activation on proximal tubular cells noted previously, which also can result in the appearance of C5b-9 in the urine of proteinuric patients, including those with MN (85,96).…”

Section: Implications For Human Mnmentioning

confidence: 97%

“…Serum from the mother and antiserum to NEP colocalized on podocytes of normal kidney sections, and the mother's serum formed membranous-type glomerular deposits of IgG when injected into rabbits. In follow-up studies, three individuals from two other families were identified with a similar pathogenesis (26). Interestingly, a NEP-deficient female from one of these families bore four children, none of whom developed MN; while she had measurable anti-NEP antibodies, these were IgG4 and not the complement-fixing IgG1 subclass, which the authors suggested could explain their lack of pathogenicity (26).…”

Section: Implications For Human Mnmentioning

confidence: 99%

“…In follow-up studies, three individuals from two other families were identified with a similar pathogenesis (26). Interestingly, a NEP-deficient female from one of these families bore four children, none of whom developed MN; while she had measurable anti-NEP antibodies, these were IgG4 and not the complement-fixing IgG1 subclass, which the authors suggested could explain their lack of pathogenicity (26). Whereas these reports support the concept of in situ immune deposit formation by circulating antibodies to a podocyte antigen in human MN, it is unlikely that NEP is the target antigen in the majority of cases of idiopathic MN.…”

Section: Implications For Human Mnmentioning

confidence: 99%

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Experimental membranous nephropathy redux

Cybulsky

Quigg²,

Salant³

2005

American Journal of Physiology-Renal Physiology

115

133

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Membranous nephropathy (MN) is a common cause of nephrotic syndrome in adults. Active and passive Heymann nephritis (HN) in rats are valuable experimental models because their features so closely resemble human MN. In HN, subepithelial immune deposits form in situ as a result of circulating antibodies. Complement activation leads to assembly of C5b-9 on glomerular epithelial cell (GEC) plasma membranes and is essential for sublethal GEC injury and the onset of proteinuria. This review revisits HN and focuses on areas of substantial progress in recent years. The response of the GEC to sublethal C5b-9 attack is not simply due to disruption of the plasma membrane but is due to the activation of specific signaling pathways. These include activation of protein kinases, phospholipases, cyclooxygenases, transcription factors, growth factors, NADPH oxidase, stress proteins, proteinases, and others. Ultimately, these signals impact on cell metabolic pathways and the structure/function of lipids and key proteins in the cytoskeleton and slit-diaphragm. Some signals affect GEC adversely. Thus C5b-9 induces partial dissolution of the actin cytoskeleton. There is a decline in nephrin expression, reduction in F-actin-bound nephrin, and loss of slit-diaphragm integrity. Other signals, such as endoplasmic reticulum stress, may limit complement-induced injury, or promote recovery. The extent of complement activation and GEC injury is dependent, in part, on complement-regulatory proteins, which act at early or late steps within the complement cascade. Identification of key steps in complement activation, the cellular signaling pathways, and the targets will facilitate therapeutic intervention in reversing GEC injury in human MN.

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“…4 -6 The autoantigen in the common variety of idiopathic human membranous glomerulonephritis is unknown, although in a few neonatal cases, the neutral endopeptidase on podocytes was identified as the target antigen of maternal alloantibodies. 7 Megalin presents a complex immunologic target, presenting epitopes involved in propagating autoimmunity as well as those involved in deposition of autoAb. A structural organization consisting of four discrete ligand-binding domains (LBD I through IV) is critical to its function as an endocytic receptor.…”

mentioning

confidence: 99%

Intramolecular Epitope Spreading in Heymann Nephritis

Shah¹,

Tramontano²,

Makker³

2007

Journal of the American Society of Nephrology

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Immunization with megalin induces active Heymann nephritis, which reproduces features of human idiopathic membranous glomerulonephritis. Megalin is a complex immunological target with four discrete ligand-binding domains (LBDs) that may contain epitopes to which pathogenic autoantibodies are directed. Recently, a 236-residue N-terminal fragment, termed "L6," that spans the first LBD was shown to induce autoantibodies and severe disease. We used this model to examine epitope-specific contributions to pathogenesis. Sera obtained from rats 4 weeks after immunization with L6 demonstrated reactivity only with the L6 fragment on Western blot, whereas sera obtained after 8 weeks demonstrated reactivity with all four recombinant fragments of interest (L6 and LBDs II, III, and IV). We demonstrated that the L6 immunogen does not contain the epitopes responsible for the reactivity to the LBD fragments. Therefore, the appearance of antibodies directed at LBD fragments several weeks after the primary immune response suggests intramolecular epitope spreading. In vivo, we observed a temporal association between increased proteinuria and the appearance of antibodies to LBD fragments. These data implicate B cell epitope spreading in antibody-mediated pathogenesis of active Heymann nephritis, a model that should prove valuable for further study of autoimmune dysregulation.

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Role of truncating mutations in MME gene in fetomaternal alloimmunisation and antenatal glomerulopathies

Cited by 196 publications

References 26 publications

Phospholipase A2 Receptor (PLA2R1) Sequence Variants in Idiopathic Membranous Nephropathy

Phospholipase A2 Receptor (PLA2R1) Sequence Variants in Idiopathic Membranous Nephropathy

Experimental membranous nephropathy redux

Intramolecular Epitope Spreading in Heymann Nephritis

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