Molecular pathomechanisms of membranous nephropathy: from Heymann nephritis to alloimmunization.
Membranous nephropathy (MN), the most common cause of idiopathic nephrotic syndrome in white adults, is characterized by an accumulation of immune deposits on the outer aspect of the glomerular basement membrane. In Heymann nephritis, the rat experimental model for MN, megalin--the target antigen of the nephritogenic antibodies--is expressed on the surface of podocytes, where immune complexes are formed, leading to complement activation and nephrotic-range proteinuria. However, megalin cannot be held responsible for human MN because it has not been found in human podocytes or detected in subepithelial immune deposits in patients with MN. Several potential antigens have been identified in so-called secondary forms of MN, but there is no real proof that these antigens are pathogenic. In a subgroup of infants with antenatal MN, neutral endopeptidase (NEP) has been identified as the first protein target on human podocytes of nephritogenic antibodies. The infants' mothers became immunized during pregnancy against NEP expressed on syncytiotrophoblastic cells because they were NEP deficient as a result of truncating mutations in the MME gene. Severity of neonatal renal disease was determined by the mothers' IgG response that led to the formation of the membrane attack complex of complement in the subepithelial deposits. Alloimmunization against NEP is a novel pathomechanism of MN that might also account for some cases of MN after renal or bone marrow transplantation. Other types of alloimmunization should be investigated in MN but also in other renal and nonrenal diseases, particularly those that affect the pediatric age.
Ronco
Pierre
P
INSERM Unit 489, Tenon Hôpital (Assistance Publique, Hôpitaux de Paris), 4 rue de la Chine, 75020 Paris, France. pierre.ronco@tnn.ap-hop-paris.fr
Debiec
Hanna
H
D005921:Glomerulonephritis / Q000235:genetics / Q000276:immunology* / Q000473:pathology*; D015433:Glomerulonephritis, Membranous / Q000235:genetics / Q000276:immunology* / Q000473:pathology*; D006801:Humans; D007519:Isoantigens / Q000276:immunology*; D010375:Pedigree
D007519:Isoantigens