Immunological Basis of Membranous Glomerulonephritis

Primary membranous glomerulonephritis (MGN) is a major glomerular disease causing proteinuria in humans (Jones, 1957). It is the prototype of an autoimmune disease (Couser, et al., 1978) characterized by sub-epithelial immune deposits within glomeruli. Its pathogenesis remains still unknown. Immune deposits are formed by IgG4, their respective antigen and complement. The definition of the immune deposit architecture has been a main focus of the pathology research for years but advances were restricted, until recently, to animal models of the disease, in particular to Heymann nephritis (HN) (Heymann, et al., 1959; Heymann, et al., 1952; Van Damme, et al., 1978). Unfortunately, results from experimental HN cannot be readily exported to human MGN since the major antigen of immune deposits in rat is not present in human glomeruli. Therefore different podocyte antigens are involved in human MGN and their identification is a fundamental step in understanding human pathology. Technology problems, mainly concerning dissection of glomeruli and purification/characterization of glomerular antibodies from human biopsies, have limited the experimental approach in humans for years. In the last 5 years, human MGN has become the topic of renewed nephrologic research. Debiec et al. (Debiec, et al., 2002, 2004) first showed that neutral endopeptidase (NEP) emerges as podocyte antigen in a rare form of congenital MGN due to maternal NEP deficiency and alloimmunization during pregnancy. More recently, the existence of three new glomerular auto-antigens, i.e. phospholipase A2 receptor (PLA2R), aldose reductase (AR) and superoxide dismutase 2 (SOD2) have been proposed by independent groups (Beck, et al., 2009; Prunotto, et al., 2010). Technology evolution in the field of laser capture and proteomics allowed a direct experimental approach in humans, a crucial step for a direct analysis ‘in vivo’. It is now clear that IgG4 eluted from glomeruli of MGN patients recognize a panel of podocyte proteins