Altered glycosylation of IgG4 promotes lectin complement pathway activation in anti-PLA2R1–associated membranous nephropathy
| Autor: | Gérard Lambeau, Rudolf P. Wüthrich, Hong Ma, Andreas D. Kistler, Noortje de Haan, Harald Seeger, Manfred Wuhrer, Johan M. Lorenzen, Urs Wegmann, Péter Gál, David J. Salant, Gábor Pál, Christelle Zaghrini, Malte Kölling, Simone Brandt, George Haddad, Laurence H. Beck, Bence Kiss |
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| Přispěvatelé: | Institute of Physiology, University of Zurich, Zurich, Switzerland, Department of Medicine, Boston University School of Medicine, Boston, Massachusetts, USA, Center for Proteomics and Metabolomics, Leiden University Medical Center, Netherlands, Institut de pharmacologie moléculaire et cellulaire (IPMC), Centre National de la Recherche Scientifique (CNRS)-Université Nice Sophia Antipolis (... - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Université Côte d'Azur (UCA), Institute of Pathology, University Hospital of Zurich, Switzerland, Department of Biochemistry, Eötvös Loránd University, Budapest, Hungary, Institute of Enzymology, Research Centre for Natural Sciences, Budapest, Hungary, University of Zurich, Kistler, Andreas D |
| Rok vydání: | 2021 |
| Předmět: |
Adult
0301 basic medicine Nephrotic Syndrome [SDV]Life Sciences [q-bio] Proteolysis 610 Medicine & health 2700 General Medicine Complement Membrane Attack Complex Complement receptor Glomerulonephritis Membranous Autoimmune Diseases Podocyte 03 medical and health sciences 0302 clinical medicine Membranous nephropathy medicine Humans 10035 Clinic for Nephrology Receptor Anaphylatoxin C5a ComputingMilieux_MISCELLANEOUS Autoantibodies Cell Line Transformed biology medicine.diagnostic_test Podocytes Chemistry Receptors Phospholipase A2 Microfilament Proteins Membrane Proteins Lectin Complement Pathway Mannose-Binding Lectin General Medicine medicine.disease Receptors Complement 3. Good health Complement system Cell biology 030104 developmental biology medicine.anatomical_structure Immunoglobulin G 030220 oncology & carcinogenesis Lectin pathway biology.protein Synaptopodin Carrier Proteins Research Article |
| Zdroj: | J Clin Invest Journal of Clinical Investigation, 131(5). AMER SOC CLINICAL INVESTIGATION INC Journal of Clinical Investigation Journal of Clinical Investigation, American Society for Clinical Investigation, 2021, 131 (5), ⟨10.1172/JCI140453⟩ |
| ISSN: | 1558-8238 0021-9738 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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