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Previous Volume 361:11-21 July 2, 2009 Number 1 Next

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ABSTRACT

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.

Source Information

From the Boston University School of Medicine, Boston (L.H.B., R.G.B.B., D.M.B., D.J.S.); Institut de Pharmacologie Moléculaire et Cellulaire, Unité Mixte de Recherche 6097, Centre National de la Recherche Scientifique, and Université de Nice Sophia Antipolis, Valbonne, France (G.L.); and the University of Louisville School of Medicine, Louisville, KY (D.W.P., T.D.C., J.B.K.).

Address reprint requests to Dr. Salant at Evans Biomedical Research Center, Rm. 504, 650 Albany St., Boston, MA 02118, or at djsalant{at}bu.edu.

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This article has been cited by other articles:

• Thongboonkerd, V. (2009). Current status of renal and urinary proteomics: ready for routine clinical application?. Nephrol Dial Transplant 0: gfp476v1-gfp476 [Full Text]  
• Glassock, R. J. (2009). Human Idiopathic Membranous Nephropathy -- A Mystery Solved?. NEJM 361: 81-83 [Full Text]