Idiopathic membranous nephropathy: an autoimmune disease

Abstract

For more than 50 years researchers have debated the evidence for an autoimmune basis of human idiopathic membranous nephritis (MN). Work published in the past 2 years has substantially strengthened the belief that MN is indeed an autoimmune disease of the kidney. Autoantibodies of the IgG4 subclass to at least three podocyte membrane proteins including phospholipase A(2)-receptor, aldose reductase, and manganese superoxide dismutase have been detected by immunoblotting in sera as well as in acid eluates prepared from renal biopsy tissue of patients with this disease, using either whole tissue or microdissected glomeruli from frozen sections. In each case the podocyte antigen has been shown to co-localize with the subepithelial glomerular immune deposits in renal tissue of the same patients. It is not certain if any of these podocyte proteins is an inciting/primary autoantigen or whether they are secondary antigens recruited by intermolecular epitope-spreading, initiating from a yet-to-be-discovered autoantigen. Although it is clear that autoantibodies to podocyte membrane proteins are elicited in idiopathic MN and contribute to the formation of the subepithelial deposits, many questions remain concerning the triggers for their development and their contribution toward proteinuria and progression of the disease.

Figure 1

A. Frozen section of a normal human kidney is reacted with polyclonal phage from a Fab-phage expression library prepared from pooled peripheral blood B cells of patients with idiopathic MN and studied by indirect immunofluorescence microscopy. Reaction along the periphery of glomerular capillaries (presumably podocytes) can be seen. B. Paraformaldehyde fixed podocytes grown on cover slips are reacted with the earlier-described polyclonal phage and studied by indirect immunofluorescence microscopy. Reaction of phage on podocytes can be seen. C. Podocytes as in B described previously are reacted with purified soluble Fab expressed from the earlier-described polyclonal phage and studied by indirect immunofluorescence microscopy. Reaction on podocyte can be seen.