The molecular pathogenesis of idiopathic membranous nephropathy

Abstract

Idiopathic membranous nephropathy (IMN) is one of the common pathological types of adult nephrotic syndrome in the world. In China, the proportion of IMN among primary glomerular diseases increased obviously in recent years. Because the etiology and the pathogenesis of IMN are not well-known, and there is a lack of biomarkers for predicting activity of IMN, the economic burden and drugs toxicity caused by the treatment remain to be controversial and challenging. IMN is an organ-specific autoimmune disease, in which non-inflammatory autoantibodies can bind target antigens on podocytes, forming subepithelial in-situ immunocomplex on the outside of the glomerular basement membrane that provokes local complement activation so as to cause podocyte injury and proteinuria. The Heymann nephritis model is a classical animal model for MN. However, megalin, which was the target antigen of this model, was not the cause of human IMN. Then, neutral endopeptidase (NEP) was found to be the target antigen of maternal-fetal alloimmunization with antenatal MN. To 2009, phospholipase A2 receptor (PLA2R) was confirmed as the target antigen of IMN. Anti-PLA2R-IgG4 was detected in serum with high specificity of 100% and sensitivity of 70%-80% in IMN patients. Anti-PLA2R-IgG4 could bind PLA2R antigen. Complement lectin pathway was activated by these in-situ immune complex and C5b-9 was generated. C5b-9 membrane attack complex could cause podocytes injury and production of proteinuria. In addition, the level of anti-PLA2R antibodies can predict the activity of the disease. HLA-DQA1 and PLA2R loci are associated with the onset of IMN, and the risk allels of both genes have additive effects. All in all, many factors are involved in the onset of IMN, such as genetic predisposition, target antigens, autoantibodies and complement, etc. These findings are of great significance for the diagnosis and treatment of IMN . Key words: Idiopathic membranous nephropathy; Animal model; Podocyte; PLA2R; HLA-DQA1