ArticleThe Journal of clinical investigation2021
Altered glycosylation of IgG4 promotes lectin complement pathway activation in anti-PLA2R1-associated membranous nephropathy.
Article in The Journal of clinical investigation, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 102 papers.
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Who cites it
102 citing papers in PubMed, 167 citations in OpenAlex.
- Article
- Serum PLA2R-IgG4/PLA2R-IgG ratio dynamics reveal pathogenic autoantibody subclass switch during progression of PLA2R-associated membranous nephropathy.Annals of medicine · 2026Article
- Distinct Complement Activation Profiles Between NELL1- and PLA2R-Associated Membranous Nephropathy: A Clinicopathological and Proteomic Study.Nephrology (Carlton, Vic.) · 2026Article
- Autoantibodies reactive with glomerular endothelial cells and podocytes in patients with membranous nephropathy.Journal of translational autoimmunity · 2026Article
- The evolving landscape of complement therapeutics in rheumatology.Annals of the rheumatic diseases · 2026Review
- PLA2R-Positive Membranous Nephropathy and AA Amyloidosis in an Ethiopian Patient With Chronic Hepatitis B: A Case Report.Clinical case reports · 2026Article
- Functional characterization of podocyte-expressed THSD7A in experimental membranous nephropathy.JCI insight · 2026Article
- Early kinetics of anti-PLA2R-IgG4 predicts rituximab response in membranous nephropathy: a prospective biomarker study.Scientific reports · 2026Article
- Proteomic Profiling of Complement Components in Glomerular Disease.Laboratory investigation; a journal of technical methods and pathology · 2026Article
- Complement role in kidney disease: a comprehensive review and therapeutic innovations.BMC nephrology · 2026Review
- Membranous Nephropathy: Antigenic Landscape and a Novel Pathogenetic Model.International journal of molecular sciences · 2026Review
- Article
- Complement-Mediated Kidney Diseases: Role of Alternative Pathway in Glomerular Inflammation.Kidney international reports · 2026Review
- Serum N-glycan NA3Fb identified as a prognostic biomarker of poor outcome in HBV-related hepatocellular carcinoma.Cancer cell international · 2026Article
- Commentary: Asymmetric adult-onset asthma with periocular xanthogranuloma associated with IgG4-related disease: a case report.Frontiers in surgery · 2026Article
- Treatment strategies for rituximab-resistant primary membranous nephropathy: from resistance mechanisms to emerging therapies.Frontiers in immunology · 2026Review
- Immune podocyte injury in autoimmune glomerular diseases.Frontiers in immunology · 2026Review
- The lipid-podocyte axis: emerging clues in membranous nephropathy pathogenesis.Frontiers in medicine · 2026Review
- Antibody-induced internalization and degradation of PLA2R amplifies CD4Theranostics · 2026Article
- Intercepting the complement amplification loop through podocyte MC5R signaling ameliorates membranous nephropathy.Molecular therapy : the journal of the American Society of Gene Therapy · 2025Article
42 more citing papers are in PubMed but not listed here.
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Authors and funding
18 authors at 7 institutions in 5 countries.
Funding
Abstract
Primary membranous nephropathy (pMN) is a leading cause of nephrotic syndrome in adults. In most cases, this autoimmune kidney disease is associated with autoantibodies against the M-type phospholipase A2 receptor (PLA2R1) expressed on kidney podocytes, but the mechanisms leading to glomerular damage remain elusive. Here, we developed a cell culture model using human podocytes and found that anti-PLA2R1-positive pMN patient sera or isolated IgG4, but not IgG4-depleted sera, induced proteolysis of the 2 essential podocyte proteins synaptopodin and NEPH1 in the presence of complement, resulting in perturbations of the podocyte cytoskeleton. Specific blockade of the lectin pathway prevented degradation of synaptopodin and NEPH1. Anti-PLA2R1 IgG4 directly bound mannose-binding lectin in a glycosylation-dependent manner. In a cohort of pMN patients, we identified increased levels of galactose-deficient IgG4, which correlated with anti-PLA2R1 titers and podocyte damage induced by patient sera. Assembly of the terminal C5b-9 complement complex and activation of the complement receptors C3aR1 or C5aR1 were required to induce proteolysis of synaptopodin and NEPH1 by 2 distinct proteolytic pathways mediated by cysteine and aspartic proteinases, respectively. Together, these results demonstrated a mechanism by which aberrantly glycosylated IgG4 activated the lectin pathway and induced podocyte injury in primary membranous nephropathy.
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