[HTML][HTML] M-Type Phospholipase A2 Receptor as Target Antigen in Idiopathic Membranous Nephropathy

LH Beck Jr, RGB Bonegio, G Lambeau… - … England Journal of …, 2009 - Mass Medical Soc
LH Beck Jr, RGB Bonegio, G Lambeau, DM Beck, DW Powell, TD Cummins, JB Klein
New England Journal of Medicine, 2009Mass Medical Soc
Background Idiopathic membranous nephropathy, a common form of the nephrotic
syndrome, is an antibody-mediated autoimmune glomerular disease. Serologic diagnosis
has been elusive because the target antigen is unknown. Methods We performed Western
blotting of protein extracts from normal human glomeruli with serum samples from patients
with idiopathic or secondary membranous nephropathy or other proteinuric or autoimmune
diseases and from normal controls. We used mass spectrometry to analyze the reactive …
Background
Idiopathic membranous nephropathy, a common form of the nephrotic syndrome, is an antibody-mediated autoimmune glomerular disease. Serologic diagnosis has been elusive because the target antigen is unknown.
Methods
We performed Western blotting of protein extracts from normal human glomeruli with serum samples from patients with idiopathic or secondary membranous nephropathy or other proteinuric or autoimmune diseases and from normal controls. We used mass spectrometry to analyze the reactive protein bands and confirmed the identity and location of the target antigen with a monospecific antibody.
Results
Serum samples from 26 of 37 patients (70%) with idiopathic but not secondary membranous nephropathy specifically identified a 185-kD glycoprotein in nonreduced glomerular extract. Mass spectrometry of the reactive protein band detected the M-type phospholipase A2 receptor (PLA2R). Reactive serum specimens recognized recombinant PLA2R and bound the same 185-kD glomerular protein as did the monospecific anti-PLA2R antibody. Anti-PLA2R autoantibodies in serum samples from patients with membranous nephropathy were mainly IgG4, the predominant immunoglobulin subclass in glomerular deposits. PLA2R was expressed in podocytes in normal human glomeruli and colocalized with IgG4 in immune deposits in glomeruli of patients with membranous nephropathy. IgG eluted from such deposits in patients with idiopathic membranous nephropathy, but not in those with lupus membranous or IgA nephropathy, recognized PLA2R.
Conclusions
A majority of patients with idiopathic membranous nephropathy have antibodies against a conformation-dependent epitope in PLA2R. PLA2R is present in normal podocytes and in immune deposits in patients with idiopathic membranous nephropathy, indicating that PLA2R is a major antigen in this disease.
The New England Journal Of Medicine