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Molecular Pathomechanisms of Membranous Nephropathy: From Heymann Nephritis to Alloimmunization

INSERM Unit 489; University Pierre et Marie Curie; and Tenon Hospital (Assistance Publique-Hôpitaux de Paris), Paris, France

Address correspondence to: Dr. Pierre Ronco, INSERM Unit 489, Hôpital Tenon, 4 rue de la Chine, 75020 Paris, France. Phone: 33-1-56-01-66-39; Fax: 33-1-56-01-69-99; E-mail: pierre.ronco{at}tnn.ap-hop-paris.fr

Abstract

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.

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				C.-C. Wu, J.-S. Chen, S.-H. Lin, A. Chen, H.-K. Sytwu, and Y.-F. Lin Experimental model of membranous nephropathy in mice: sequence of histological and biochemical events Lab Anim, July 1, 2008; 42(3): 350 - 359. [Abstract] [Full Text] [PDF]

				P. Ronco and H. Debiec Molecular Dissection of Target Antigens and Nephritogenic Antibodies in Membranous Nephropathy: Towards Epitope-Driven Therapies J. Am. Soc. Nephrol., July 1, 2006; 17(7): 1772 - 1774. [Full Text] [PDF]

Copyright © 2008 by the American Society of Nephrology. Online ISSN: 1533-3450 Print ISSN: 1046-6673