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Cited by 2,347Renal Diseases and GlomerulopathiesSystemic Lupus Erythematosus ResearchVasculitis and related conditions

M-Type Phospholipase A 2 Receptor as Target Antigen in Idiopathic Membranous Nephropathy

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Beck, Laurence H., Bonegio, Ramon G.B., Lambeau, Gérard, Beck, David M., Powell, David W., Cummins, Timothy D., Klein, Jon B., Salant, David J.·2009·New England Journal of Medicine
DOI 10.1056/nejmoa0810457PMC PMC2762083
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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 A(2) receptor (PLA(2)R). Reactive serum specimens recognized recombinant PLA(2)R and bound the same 185-kD glomerular protein as did the monospecific anti-PLA(2)R antibody. Anti-PLA(2)R autoantibodies in serum samples from patients with membranous nephropathy were mainly IgG4, the predominant immunoglobulin subclass in glomerular deposits. PLA(2)R 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 PLA(2)R. CONCLUSIONS: A majority of patients with idiopathic membranous nephropathy have antibodies against a conformation-dependent epitope in PLA(2)R. PLA(2)R is present in normal podocytes and in immune deposits in patients with idiopathic membranous nephropathy, indicating that PLA(2)R is a major antigen in this disease.

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  • Several LPG cases have been discovered due to high serum ApoE even without hyperlipidemia.

    “In addition, several LPG cases have been discovered due to high serum ApoE even without hyperlipidemia [14, 15].”

    From Membranous Nephropathy-Like Apolipoprotein E Deposition Disease with Apolipoprotein E Toyonaka (Ser197Cys) and a Homozygous Apolipoprotein E2/2 (2018) · cites this paper as [14]

    The Results sections on target-protein identification and disease activity discuss PLA2R antibodies in idiopathic membranous nephropathy, not lipoprotein glomerulopathy (LPG). Searches for LPG, serum ApoE, and hyperlipidemia found no passage addressing the claimed cases. The passages have no page numbers in our copy. (LLM, conf=0.76)

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  1. [1]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 38 502 10 147961
  2. [2]Couser WG Steinmuller DR Stilmant MM Salant DJ Lowenstein LM Experimental glomerulonephritis in the isolated perfused rat kidney J Clin Invest 1978 62 1275 87 372233 PMC371893
  3. [3]Couser WG Salant DJ In situ immune complex formation and glomerular injury Kidney Int 1980 17 1 13 6990087
  4. [4]Kerjaschki D Farquhar MG The pathogenic antigen of Heymann nephritis is a membrane glycoprotein of the renal proximal tubule brush border Proc Natl Acad Sci U S A 1982 79 5557 61 6752952 PMC346943
  5. [5]Idem Immunocytochemical localization of the Heymann nephritis antigen (GP330) in glomerular epithelial cells of normal Lewis rats J Exp Med 1983 157 667 86 6337231 PMC2186920
  6. [6]Makker SP Singh AK Characterization of the antigen (gp600) of Heymann nephritis Lab Invest 1984 50 287 93 6199583
  7. [7]Raychowdhury R Niles JL McCluskey RT Smith JA Autoimmune target in Heymann nephritis is a glycoprotein with homology to the LDL receptor Science 1989 244 1163 5 2786251
  8. [8]Saito A Pietromonaco S Loo AK Farquhar MG Complete cloning and sequencing of rat gp330/“megalin,” a distinctive member of the low density lipoprotein receptor gene family Proc Natl Acad Sci U S A 1994 91 9725 9 7937880 PMC44889
  9. [9]Debiec H Guigonis V Mougenot B Antenatal membranous glomerulonephritis due to anti-neutral endopeptidase antibodies N Engl J Med 2002 346 2053 60 12087141
  10. [10]Debiec H Nauta J Coulet F Role of truncating mutations in MME gene in fetomaternal alloimmunisation and antenatal glomerulopathies Lancet 2004 364 1252 9 15464186
  11. [11]Salant DJ Cybulsky AV Experimental glomerulonephritis Methods Enzymol 1988 162 421 61 3265756
  12. [12]Zvaritch E Lambeau G Lazdunski M Endocytic properties of the M-type 180-kDa receptor for secretory phospholipases A2 J Biol Chem 1996 271 250 7 8550569
  13. [13]Powell DW Rane MJ Joughin BA Proteomic identification of 14-3-3zeta as a mitogen-activated protein kinase-activated protein kinase 2 substrate: role in dimer formation and ligand binding Mol Cell Biol 2003 23 5376 87 12861023 PMC165733
  14. [14]Powell DW Weaver CM Jennings JL Cluster analysis of mass spectrometry data reveals a novel component of SAGA Mol Cell Biol 2004 24 7249 59 15282323 PMC479721
  15. [15]Lambeau G Ancian P Barhanin J Lazdunski M Cloning and expression of a membrane receptor for secretory phospholipases A2 J Biol Chem 1994 269 1575 8 8294398
  16. [16]Doi T Mayumi M Kanatsu K Suehiro F Hamashima Y Distribution of IgG subclasses in membranous nephropathy Clin Exp Immunol 1984 58 57 62 6383668 PMC1576972
  17. [17]Kuroki A Iyoda M Shibata T Sugisaki T Th2 cytokines increase and stimulate B cells to produce IgG4 in idiopathic membranous nephropathy Kidney Int 2005 68 302 10 15954921
  18. [18]Brandslund I Siersted HC Jensenius JC Svehag SE Detection and quantitation of immune complexes with a rapid polyethylene glycol precipitation complement consumption method (PEG-CC) Methods Enzymol 1981 74 551 71 6459516
  19. [19]Saleem MA O’Hare MJ Reiser J A conditionally immortalized human podocyte cell line demonstrating nephrin and podocin expression J Am Soc Nephrol 2002 13 630 8 11856766
  20. [20]Makker SP Kanalas JJ Course of transplanted Heymann nephritis kidney in normal host: implications for mechanism of proteinuria in membranous glomerulonephropathy J Immunol 1989 142 3406 10 2654289
  21. [21]Haas M IgG subclass deposits in glomeruli of lupus and nonlupus membranous nephropathies Am J Kidney Dis 1994 23 358 64 8128936
  22. [22]East L Isacke CM The mannose receptor family Biochim Biophys Acta 2002 1572 364 86 12223280
  23. [23]Lambeau G Lazdunski M Receptors for a growing family of secreted phospholipases A2 Trends Pharmacol Sci 1999 20 162 70 10322502
  24. [24]Rouault M Le Calvez C Boilard E Recombinant production and properties of binding of the full set of mouse secreted phospholipases A2 to the mouse M-type receptor Biochemistry 2007 46 1647 62 17279628
  25. [25]Ancian P Lambeau G Mattéi MG Lazdunski M The human 180-kDa receptor for secretory phospholipases A2: molecular cloning, identification of a secreted soluble form, expression, and chromosomal localization J Biol Chem 1995 270 8963 70 7721806
  26. [26]Beck S Beck G Ostendorf T Up-regulation of group IB secreted phospholipase A(2) and its M-type receptor in rat ANTI-THY-1 glomerulonephritis Kidney Int 2006 70 1251 60 16900094
  27. [27]Hellmark T Burkhardt H Wieslander J Goodpasture disease: characterization of a single conformational epitope as the target of pathogenic autoantibodies J Biol Chem 1999 274 25862 8 10464328
  28. [28]Hudson BG The molecular basis of Goodpasture and Alport syndromes: beacons for the discovery of the collagen IV family J Am Soc Nephrol 2004 15 2514 27 15466256
  29. [29]Llorca O Extended and bent conformations of the mannose receptor family Cell Mol Life Sci 2008 65 1302 10 18193159 PMC11131820
  30. [30]Nangaku M Shankland SJ Couser WG Cellular response to injury in membranous nephropathy J Am Soc Nephrol 2005 16 1195 204 15800119
  31. [31]Cybulsky AV Quigg RJ Salant DJ Experimental membranous nephropathy redux Am J Physiol Renal Physiol 2005 289 F660 F671 16159900 PMC1325222
  32. [32]Granata F Petraroli A Boilard E Activation of cytokine production by secreted phospholipase A2 in human lung macrophages expressing the M-type receptor J Immunol 2005 174 464 74 15611272
  33. [33]Silliman CC Moore EE Zallen G Presence of the M-type sPLA(2) receptor on neutrophils and its role in elastase release and adhesion Am J Physiol Cell Physiol 2002 283 C1102 C1113 12225974

Cited by

Sorted by citations

Authors
Beck, L. H., Bonegio, R. G. B., Lambeau, G., Beck, D. M., Powell, D. W., Cummins, T. D., Klein, J. B., & Salant, D. J.
Affiliations
  • Boston University (US)
  • University of Louisville (US)
ORCID
Venue
New England Journal of Medicine
Publisher
Massachusetts Medical Society
Published
2009-07-02
Volume
361
Issue
1
Pages
11-21
ISSN
  • 0028-4793 (ISSN-L)
  • 1533-4406
DOI
10.1056/nejmoa0810457
PMC
PMC2762083
OpenAlex
W2166822765
Cited by
2,347
References
0
Citations by year
2026: 134 · 2025: 164 · 2024: 189 · 2023: 195 · 2022: 162 · 2021: 161 · 2020: 159 · 2019: 146 · 2018: 132 · 2017: 108 · 2016: 133 · 2015: 144 · 2014: 121 · 2013: 145 · 2012: 94
FWCI
58.30
Type
journal article
Language
en
Open access
Locations
  • New England Journal of Medicine (publishedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
  • HAL (submittedVersion)
Funders
National Institute of Diabetes and Digestive and Kidney Diseases (DK067658, T32DK007053, R01DK030932, R21DK067658, DK30932, DK076743, K01DK076743, R56DK030932)
Topics
  • Health Sciences › Medicine › Nephrology › Renal Diseases and Glomerulopathies
  • Health Sciences › Medicine › Rheumatology › Systemic Lupus Erythematosus Research
  • Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Vasculitis and related conditions
Keywords
idiopathic membranous nephropathy, M-type phospholipase A2 receptor, target antigens, autoantibodies, IgG4, podocytes, glomerular immune deposits, conformational epitopes, nephrotic syndrome, IgA nephropathy
MeSH terms
Epitopes, Autoantibodies, Humans, Immunoglobulin G, Kidney Glomerulus, Mass Spectrometry, Blotting, Western, Glomerulonephritis, Membranous, Chi-Square Distribution, Receptors, Phospholipase A2

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