Gene/Protein Disease Symptom Drug Enzyme Compound
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This article reviews the considerable progress which has been made in the recent years in the understanding of the pathophysiology of membranous nephropathy, a model of organ-specific auto-immune disease. It shows how experimental models developed more than 30 years ago have led to the identification of several human antigens including neutral endopeptidase in the neonate, phospholipase A2 receptor, and thrombospondin 1 domain 7A in the adult, and cationic bovine serum albumin in children. Thanks to a successful GWAS performed in European Caucasians, the genetics of the disease begins to be understood. These groundbreaking findings already have a major impact on patients' care owing to the development of reliable ELISA and immunofluorescence test for the detection of PLA2R antibodies and of PLA2R antigen screening in biopsies. This review will tell the story from the careful clinical observation of cases to the most recent therapeutic perspectives which have been made possible by these advances. Advances in medical science often proceed by steps which are highly interdependent. New, groundbreaking findings with important clinical implications often result from the combination of faithful experimental models and careful clinical observations. This is well illustrated by the story of membranous nephropathy which started more than 50 years ago. It is remarkable that in this disease, the experimental models predicted the pathophysiology of the human glomerulopathy. The stories that we will tell in this article are aimed at young clinical investigators who are sometimes reluctant to embark on research projects. We hope that they will convince them that bedside research performed with intellectual curiosity and a bit of chance can lead to significant progress in clinical medicine.
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PMID:Membranous nephropathy: A fairy tale for immunopathologists, nephrologists and patients. 2659 9

Membranous nephropathy (MN) is characterized by an accumulation of immune deposits on the subepithelial side of the glomerular basement membrane, which results in complement activation and proteinuria. Since 2002, several major antigens of the podocyte have been identified in human MN, the first one being neutral endopeptidase (NEP), the alloantigen involved in neonatal cases of MN that occur in newborns from NEP-deficient mothers. This discovery opened the field to the major advances that have occurred since then in the pathophysiology and treatment of MN. It is remarkable that experimental models such as Heymann nephritis and cationic bovine serum albumin-induced MN in the rabbit predicted the pathomechanisms of the human glomerulopathy. The podocyte is at the center of the pathogenesis of MN either by providing a source of endogenous antigens or by creating an environment favorable to deposition and accumulation of immune complexes containing exogenous (non-podocyte) antigens. The podocyte is also a victim of complement activation and antibody blocking activity against enzymes or receptors. A search for innovative drugs aimed at protecting this cell against complement activation and the effects of prolonged ER stress has become a priority.
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PMID:A podocyte view of membranous nephropathy: from Heymann nephritis to the childhood human disease. 2859 89

Primary membranous nephropathy (MN) is the leading cause of nephrotic syndrome in adults. Discovery of several antibodies has contributed to an increased understanding of MN. Antibodies against the M-type phospholipase A2 receptor (PLA2R) are present in 50-100% with primary MN and are associated with a lower frequency of spontaneous remission. High levels are linked with a higher probability of treatment resistance, higher proteinuria, and impaired renal function, as well as a more rapid decline of kidney function during follow-up. Immunologic remission precedes reduction of proteinuria by months. Pretransplant evaluation of PLA2R antibodies is warranted to predict recurrence of disease following renal transplantation. Several risk alleles related to the PLA2R1 gene and within the HLA loci have been identified, whereas epitope spreading of PLA2R may predict treatment response. More recently, thrombospondin type 1 domain-containing 7A (THSD7A) antibodies have been discovered in primary MN. Several other rare antigens have been described, including antibodies against neutral endopeptidase as a cause of antenatal MN and circulating cationic bovine serum albumin as an antigen with implications in childhood MN. This review focuses on the progress with a special focus on diagnostic accuracy, predictive value, and treatment implications of the established and proposed antigens.
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PMID:Recent Progress in Deciphering the Etiopathogenesis of Primary Membranous Nephropathy. 2890 48


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