Exostosin 1/Exostosin 2–Associated Membranous Nephropathy

Sethi, Sanjeev; Madden, Benjamin J.; Dębiec, Hanna; Charlesworth, M. Cristine; Gross, Lou Ann; Ravindran, Aishwarya; Hummel, Amber M.; Specks, Ulrich; Fervenza, Fernando C.; Ronco, Pierre

doi:10.1681/asn.2018080852

Cited by 230 publications

(261 citation statements)

References 25 publications

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“…1 EXT1 and EXT2 have been recently identified as putative antigens in 30% to 40% of secondary autoimmune MN. 8 Thus, PLA2R-associated and EXT1/EXT2-associated MN are the 2 largest subgroups of MN.…”

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confidence: 99%

Proteomic Analysis of Complement Proteins in Membranous Nephropathy

Ravindran

Madden

Charlesworth

et al. 2020

Kidney International Reports

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Introduction: Membranous nephropathy (MN) is the most common cause of nephrotic syndrome in Caucasian adults. Phospholipase A2 receptor (PLA2R)-and exostosin 1 (EXT1)/exostosin 2 (EXT2)associated MN represent the most common primary and secondary forms of MN. The complement profile using a proteomics approach has not been studied in these 2 common forms of MN.Methods: We used laser microdissection and mass spectrometry (MS/MS) to dissect glomeruli and identify glomerular complement proteins in PLA2R-associated (n ¼ 7), EXT1/EXT2-associated MN (n ¼ 21), and 11 control cases (time 0 transplant biopsies).Results: MS/MS identified high total spectral counts for PLA2R and EXT1/EXT2 in corresponding cases of PLA2R-and EXT1/EXT2-positive MN. Both PLA2R-and EXT1/EXT2-associated MN had high spectral counts of complement proteins C3, C4, C5, C6, C7, C8, and C9. Complement protein C1 was present in low spectral counts in EXT1/EXT2-associated MN. Regulators of complement activation that were detected in MN included higher spectral counts of FH, FHR-1, FHR-5, clusterin, vitronectin and lower spectral counts of FHR-3, FHR-4, and CD59. Low spectral counts of FB and properdin, key components of the alternative pathway, also were detected. IgG4 and IgG1 were the most abundant IgG subclasses in PLA2R-and EXT1/ EXT2-associated MN. Lower spectral counts for C3, C4, and C5 were detected in control cases when compared with MN.Conclusion: Significant complement activation is present in MN as evidenced by large spectral counts of complement proteins from C3-and C4-based pathways, including regulatory proteins of complement pathways. These data suggest that anticomplement drugs may be effective in treatment for MN.Kidney Int Rep (2020) 5, 618-626; https://doi.

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confidence: 99%

Proteomic Analysis of Complement Proteins in Membranous Nephropathy

Ravindran

Madden

Charlesworth

et al. 2020

Kidney International Reports

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“…The most recently identified glomerular proteins involved in MN are EXT1/ EXT2 and NELL-1. Sethi et al [7] identified antibodies against EXT1/EXT2 in the GBM of 21 patients with PLA2R-negative MN using laser microdissection, mass spectrometry and immunohistochemistry. All control cases tested negative for EXT1/ EXT2.…”

Section: Antibodies Against Ext1/ext2 and Nell-1mentioning

confidence: 99%

“…Circulating antibodies against EXT1/EXT2 were not detected in any case, although very few patients had available serum. The authors proposed that EXT1/EXT2 proteins may represent biomarker proteins for MN associated with autoimmune disease rather than target antigens [7].…”

Section: Antibodies Against Ext1/ext2 and Nell-1mentioning

confidence: 99%

“…Histologic findings that should raise suspicion of secondary MN include preponderant deposition of IgG1 or IgG3, positivity for C1q or EXT1/EXT2, mesangial and subendothelial deposits, cellular proliferation in the glomeruli and endothelial tubuloreticular inclusions [7,9,10].…”

Section: Secondary Mnmentioning

confidence: 99%

“…On the other hand, approximately 20-25% of cases are collectively referred to as secondary MN as these cases have a recognizable etiology [5,6]. Recently, new antigens against exostosin 1 (EXT1)/exostosin 2 (EXT2) and neural epidermal growth factor-like 1 protein (NELL-1) were identified in a subgroup of patients with PLA2R1-negative MN [7,8].…”

Section: Introductionmentioning

confidence: 99%

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New Ways of Understanding Membranous Nephropathy

Trujillo

Alonso

Praga

2020

Nephron

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Background: In the last decade, great advances have been made in the field of membranous nephropathy (MN). The autoimmune nature of the disease has been confirmed with the description of diverse antigens, and few but very important prospective trials regarding treatment alternatives have been published, changing profoundly the way we understand this entity. Nowadays, an individualized therapeutic scheme based on clinical and serologic data appears to be the most appropriate method to manage patients with MN. Although there is still a long way to go, it is expected that future scientific progress will enable a patient-centered medicine based on concept-driven therapies. Summary: MN is the most common cause of nephrotic syndrome (NS) in white adults. Approximately one-third of patients achieve spontaneous remission, one-third remain stable, and onethird have an aggressive course with persistent NS and deterioration of renal function. About 80% of patients have circulating autoantibodies to phospholipase A2 receptor 1. Numerous therapies have been described including alkylating agents, rituximab, and calcineurin inhibitors, but new drugs are currently being explored. Here, we review the most important aspects regarding MN with an emphasis on results of the most recent clinical trials and pathophysiologic advances. Key Messages: 1. Evolving pathophysiologic concepts and recently published clinical trials have deeply changed our view of MN. 2. Most patients with MN present autoantibodies against diverse glomerular antigens. 3. Currently, an individual patient-centered management based on clinical and serologic markers is the most adequate approach to treat patients with MN.

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Epigenome‐wide three‐way interaction study identifies a complex pattern betweenTRIM27,KIAA0226, and smoking associated with overall survival of early‐stage NSCLC

Lin

Fan

et al. 2022

Molecular Oncology

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The interaction between DNA methylation of tripartite motif containing 27 (cg05293407TRIM27) and smoking has previously been identified to reveal histologically heterogeneous effects of TRIM27 DNA methylation on early‐stage non‐small‐cell lung cancer (NSCLC) survival. However, to understand the complex mechanisms underlying NSCLC progression, we searched three‐way interactions. A two‐phase study was adopted to identify three‐way interactions in the form of pack‐year of smoking (number of cigarettes smoked per day × number of years smoked) × cg05293407TRIM27 × epigenome‐wide DNA methylation CpG probe. Two CpG probes were identified with FDR‐q ≤ 0.05 in the discovery phase and P ≤ 0.05 in the validation phase: cg00060500KIAA0226 and cg17479956EXT2. Compared to a prediction model with only clinical information, the model added 42 significant three‐way interactions using a looser criterion (discovery: FDR‐q ≤ 0.10, validation: P ≤ 0.05) had substantially improved the area under the receiver operating characteristic curve (AUC) of the prognostic prediction model for both 3‐year and 5‐year survival. Our research identified the complex interaction effects among multiple environment and epigenetic factors, and provided therapeutic target for NSCLC patients.

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Exostosin 1/Exostosin 2–Associated Membranous Nephropathy

Cited by 230 publications

References 25 publications

Proteomic Analysis of Complement Proteins in Membranous Nephropathy

Proteomic Analysis of Complement Proteins in Membranous Nephropathy

New Ways of Understanding Membranous Nephropathy

Epigenome‐wide three‐way interaction study identifies a complex pattern betweenTRIM27,KIAA0226, and smoking associated with overall survival of early‐stage NSCLC

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