Abstract
Over the past few years, considerable advances have been made in our understanding of the molecular pathomechanisms of human membranous nephropathy, inspired by studies of Heymann nephritis, a faithful experimental model of this disease. This research led to the identification of neutral endopeptidase, the M-type receptor for secretory phospholipase A2 (PLA2R1) and cationic bovine serum albumin as target antigens of circulating and deposited antibodies in alloimmune neonatal, adult 'idiopathic' and early-childhood membranous nephropathy, respectively. A genome-wide association study has provided further evidence for a highly significant association between PLA2R1 and HLA-DQA1 loci and idiopathic membranous nephropathy in patients of white ancestry. Additional antibody specificities for cytoplasmic antigens have also been identified, but their pathogenic role is uncertain. The time has come to revisit the spectrum of membranous nephropathies based on the newly identified antigen–antibody systems that should be considered as molecular signatures of the disease and that challenge the uniform histological definition. These signatures will soon have a major impact on patient care.
Key Points
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Antibodies to neutral endopeptidase, the first podocyte antigen described in human membranous nephropathy, are responsible for alloimmune neonatal membranous nephropathy, which develops in children of mothers deficient in this enzyme
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The secretory phospholipase A2 receptor (PLA2R1) is a major target antigen in idiopathic membranous nephropathy in adults, and antibodies to PLA2R1 are detected in 60–80% of these patients before immunosuppressive treatment
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In addition to their diagnostic value, anti-PLA2R1 antibodies can be used to monitor response to treatment
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Variants in PLA2R1 and HLA-DQA1 are strongly associated with idiopathic membranous nephropathy in patients of white ancestry
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Immunization against cationic bovine serum albumin is a cause of early-childhood membranous nephropathy, which points to a possible role for food and environmental antigens in membranous nephropathy
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The newly identified antigen–antibody systems should be considered as molecular signatures of membranous nephropathy that challenge the uniform histological definition and will have a major impact on patient care in the near future
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The research of the authors is supported by grants from Agence Nationale de la Recherche (ANR-07-Physio-016–01), and Coordination Theme 1 (Health) of the European Community's Seventh Framework Programme, grant agreement number HEALTH-F2-2007-201,590. The authors thank C. Vial for assistance with language editing.
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Ronco, P., Debiec, H. Pathogenesis of membranous nephropathy: recent advances and future challenges. Nat Rev Nephrol 8, 203–213 (2012). https://doi.org/10.1038/nrneph.2012.35
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DOI: https://doi.org/10.1038/nrneph.2012.35
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