It has been clear for several decades from comparison with the rodent model disease Heymann nephritis that membranous glomerulonephritis (MGN) is an immune condition in which antibodies, usually autoantibodies, bind to targets on the surface of podocytes. However, the antigen in Heymann nephritis, megalin, is not present on human podocytes.
The first potential antigen was identified by studying rare examples of maternal alloimmunization, leading to congenital membranous nephropathy in the infant caused by antibodies to neutral endopeptidase. More recently, the target of autoantibody formation in most patients with primary MGN has been identified to be the phospholipase A2 receptor, PLA2R.
Genome-wide association studies identify predisposing genetic loci at HLADQ and at the locus encoding the autoantigen itself. So antibodies to at least two different molecular targets can cause MGN, and it seems likely that there may be other targets in secondary types of MGN, and possibly haptenized or otherwise modified molecules are implicated in drug- and toxin-induced MGN.
Once antibodies are fixed, animal models and human observations suggest that complement is involved in mediating tissue damage. However, immunoglobulin G4, not thought to fix complement, is the predominant isotype in human MGN, and the mechanisms are not fully unravelled. Podocyte injury is known to cause proteinuria. In MGN, antibody fixation or cell damage may stimulate production of extracellular matrix to account for the increased GBM thickness with ‘podocyte type’ basement membrane collagen isoforms, and ultimately cell death and glomerulosclerosis.