Identification of Antigen of Membranous Nephropathy

Sabine Karam MD
Saint George Hospital University Medical Center, Beirut, Lebanon

Up until the late 1970s, it was thought that all forms of immune-complex glomerulonephritis were due to circulating immune complexes passively trapped in glomeruli. This theory was challenged by works done by W.G. Couser and B.J. Van Damme on Heymann nephritis, a rat model of experimental membranous nephropathy (MN) that showed that deposits in experimental MN formed in situ when circulating immunoglobulin G (IgG) antibodies bound to an unknown glomerular antigen located in the subepithelial space (1-3). This hypothesis was only confirmed in a human model several years later when, in 2002, H.G. Debiec et al. described a case of neonatal MN in which transplacental passage of antineutral endopeptidase (NEP) antibodies from a pre-sensitized NEP-deficient mother bound to NEP on the baby’s podocytes(4). The pathogenesis of primary MN was finally elucidated in 2009 when D.J. Salant et al. found that the M-type phospholipase A2 receptor (PLA2R) expressed in podocytes of normal human glomeruli colocalized with IgG4 in immune deposits in the glomeruli of the majority of patients with idiopathic MN(5) and therefore constituted a major antigen in this disease. Salant had worked with Couser earlier in his career. Furthermore, this mechanism of adaptive immunity was found to have a genetic basis through the finding that the HLA-DQA1 allele on chromosome 6p21 was closely associated with idiopathic membranous nephropathy and could facilitate an autoimmune response against targets such as variants of PLA2R1(6).

Not only is the discovery seminal, but it’s also notable that Dr. Couser was President of the ISN from 2005-2007 and won the 2020 Hamburger Award.

References

  1. Couser WG, Steinmuller DR, Stilmant MM, Salant DJ, Lowenstein LM. Experimental glomerulonephritis in the isolated perfused rat kidney. J Clin Invest. 1978;62(6):1275-87. Epub 1978/12/01. doi: 10.1172/JCI109248. PubMed PMID: 372233; PubMed Central PMCID: PMCPMC371893.
  2. Van Damme BJ, Fleuren GJ, Bakker WW, Vernier RL, Hoedemaeker PJ. Experimental glomerulonephritis in the rat induced by antibodies directed against tubular antigens. V. Fixed glomerular antigens in the pathogenesis of heterologous immune complex glomerulonephritis. Lab Invest. 1978;38(4):502-10. Epub 1978/04/01. PubMed PMID: 147961.
  3. Couser WG, Salant DJ. In situ immune complex formation and glomerular injury. Kidney Int. 1980;17(1):1-13. Epub 1980/01/01. doi: 10.1038/ki.1980.1. PubMed PMID: 6990087.
  4. Debiec H, Guigonis V, Mougenot B, Decobert F, Haymann JP, Bensman A, et al. Antenatal membranous glomerulonephritis due to anti-neutral endopeptidase antibodies. N Engl J Med. 2002;346(26):2053-60. Epub 2002/06/28. doi: 10.1056/NEJMoa012895. PubMed PMID: 12087141.
  5. Beck LH, Jr., Bonegio RG, Lambeau G, Beck DM, Powell DW, Cummins TD, et al. M-type phospholipase A2 receptor as target antigen in idiopathic membranous nephropathy. N Engl J Med. 2009;361(1):11-21. Epub 2009/07/03. doi: 10.1056/NEJMoa0810457. PubMed PMID: 19571279; PubMed Central PMCID: PMCPMC2762083.
  6. Stanescu HC, Arcos-Burgos M, Medlar A, Bockenhauer D, Kottgen A, Dragomirescu L, et al. Risk HLA-DQA1 and PLA(2)R1 alleles in idiopathic membranous nephropathy. N Engl J Med. 2011;364(7):616-26. Epub 2011/02/18. doi: 10.1056/NEJMoa1009742. PubMed PMID: 21323541.

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