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Am J Pathol. Nov 1996; 149(5): 1695–1706.
PMCID: PMC1865281

Autoantibodies to myeloperoxidase aggravate mild anti-glomerular-basement-membrane-mediated glomerular injury in the rat.

Abstract

Autoantibodies to myeloperoxidase (MPO) are present in sera from patients with various forms of vasculitis-associated glomerulonephritis. Evidence for a pathogenic role of anti-MPO antibodies has been provided mainly by in vitro studies. We studied the pathogenic role of autoantibodies to MPO in a rat model of mild immune-mediated glomerular injury. Brown Norway rats were immunized with human MPO in complete Freund's adjuvant or with complete Freund's adjuvant alone. At 2 weeks after immunization, rats had developed antibodies to human and rat MPO as detected by indirect immunofluorescence, enzyme-linked immunosorbent assay, and immunoprecipitation. At this time point, rats were intravenously injected with a subnephritogenic dose of 150 micrograms of rabbit anti-rat GBM. Rats were sacrificed at 4 hours, 24 hours, 4 days, and 10 days after antibody administration. Control immunized rats developed mild glomerulonephritis characterized by slight proteinuria at day 10 (14.8 +/- 8.1 mg/24 hours) and moderate intraglomerular accumulation of ED1+ macrophages. Crescent formation, tuft necrosis, and tubular atrophy were not observed in those rats. In contrast, rats immunized with MPO developed severe glomerulonephritis characterized by the early occurrence of severe hematuria, marked proteinuria at day 10 (76.2 +/- 18.2 mg/24 hours), and massive glomerular deposition of fibrin. Complement and rat IgG were present in insudative lesions, but no linear pattern along the glomerular capillary wall was observed. By light microscopy, severe glomerular lesions were found at day 10 consisting of crescent formation and fibrinoid necrosis of capillary loops. In the interstitium, tubular necrosis and atrophy and marked interstitial mononuclear infiltration were found in conclusion, autoantibodies to MPO severely aggravate subclinical anti-GBM disease demonstrating their in vivo pathogenic potential.

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  • Beirne GJ, Wagnild JP, Zimmerman SW, Macken PD, Burkholder PM. Idiopathic crescentic glomerulonephritis. Medicine (Baltimore) 1977 Sep;56(5):349–381. [PubMed]
  • Couser WG. Rapidly progressive glomerulonephritis: classification, pathogenetic mechanisms, and therapy. Am J Kidney Dis. 1988 Jun;11(6):449–464. [PubMed]
  • Falk RJ, Jennette JC. Anti-neutrophil cytoplasmic autoantibodies with specificity for myeloperoxidase in patients with systemic vasculitis and idiopathic necrotizing and crescentic glomerulonephritis. N Engl J Med. 1988 Jun 23;318(25):1651–1657. [PubMed]
  • Goldschmeding R, van der Schoot CE, ten Bokkel Huinink D, Hack CE, van den Ende ME, Kallenberg CG, von dem Borne AE. Wegener's granulomatosis autoantibodies identify a novel diisopropylfluorophosphate-binding protein in the lysosomes of normal human neutrophils. J Clin Invest. 1989 Nov;84(5):1577–1587. [PMC free article] [PubMed]
  • Niles JL, McCluskey RT, Ahmad MF, Arnaout MA. Wegener's granulomatosis autoantigen is a novel neutrophil serine proteinase. Blood. 1989 Nov 1;74(6):1888–1893. [PubMed]
  • Tervaert JW, Goldschmeding R, Elema JD, van der Giessen M, Huitema MG, van der Hem GK, The TH, von dem Borne AE, Kallenberg CG. Autoantibodies against myeloid lysosomal enzymes in crescentic glomerulonephritis. Kidney Int. 1990 Feb;37(2):799–806. [PubMed]
  • Jayne DR, Marshall PD, Jones SJ, Lockwood CM. Autoantibodies to GBM and neutrophil cytoplasm in rapidly progressive glomerulonephritis. Kidney Int. 1990 Mar;37(3):965–970. [PubMed]
  • O'Donoghue DJ, Short CD, Brenchley PE, Lawler W, Ballardie FW. Sequential development of systemic vasculitis with anti-neutrophil cytoplasmic antibodies complicating anti-glomerular basement membrane disease. Clin Nephrol. 1989 Dec;32(6):251–255. [PubMed]
  • Bosch X, Mirapeix E, Font J, Borrellas X, Rodríguez R, López-Soto A, Ingelmo M, Revert L. Prognostic implication of anti-neutrophil cytoplasmic autoantibodies with myeloperoxidase specificity in anti-glomerular basement membrane disease. Clin Nephrol. 1991 Sep;36(3):107–113. [PubMed]
  • Falk RJ, Terrell RS, Charles LA, Jennette JC. Anti-neutrophil cytoplasmic autoantibodies induce neutrophils to degranulate and produce oxygen radicals in vitro. Proc Natl Acad Sci U S A. 1990 Jun;87(11):4115–4119. [PMC free article] [PubMed]
  • Mulder AH, Heeringa P, Brouwer E, Limburg PC, Kallenberg CG. Activation of granulocytes by anti-neutrophil cytoplasmic antibodies (ANCA): a Fc gamma RII-dependent process. Clin Exp Immunol. 1994 Nov;98(2):270–278. [PMC free article] [PubMed]
  • Porges AJ, Redecha PB, Kimberly WT, Csernok E, Gross WL, Kimberly RP. Anti-neutrophil cytoplasmic antibodies engage and activate human neutrophils via Fc gamma RIIa. J Immunol. 1994 Aug 1;153(3):1271–1280. [PubMed]
  • Rischmueller M, McNeilage LJ, McCluskey J, Gordon T. Human autoantibodies directed against the RNA recognition motif of La (SS-B) bind to a conformational epitope present on the intact La (SS-B)/Ro (SS-A) ribonucleoprotein particle. Clin Exp Immunol. 1995 Jul;101(1):39–44. [PMC free article] [PubMed]
  • Vargunam M, Adu D, Taylor CM, Michael J, Richards N, Neuberger J, Thompson RA. Endothelium myeloperoxidase-antimyeloperoxidase interaction in vasculitis. Nephrol Dial Transplant. 1992;7(11):1077–1081. [PubMed]
  • Ewert BH, Jennette JC, Falk RJ. Anti-myeloperoxidase antibodies stimulate neutrophils to damage human endothelial cells. Kidney Int. 1992 Feb;41(2):375–383. [PubMed]
  • Savage CO, Pottinger BE, Gaskin G, Pusey CD, Pearson JD. Autoantibodies developing to myeloperoxidase and proteinase 3 in systemic vasculitis stimulate neutrophil cytotoxicity toward cultured endothelial cells. Am J Pathol. 1992 Aug;141(2):335–342. [PMC free article] [PubMed]
  • Ballieux BE, Hiemstra PS, Klar-Mohamad N, Hagen EC, van Es LA, van der Woude FJ, Daha MR. Detachment and cytolysis of human endothelial cells by proteinase 3. Eur J Immunol. 1994 Dec;24(12):3211–3215. [PubMed]
  • Brouwer E, Huitema MG, Klok PA, de Weerd H, Tervaert JW, Weening JJ, Kallenberg CG. Antimyeloperoxidase-associated proliferative glomerulonephritis: an animal model. J Exp Med. 1993 Apr 1;177(4):905–914. [PMC free article] [PubMed]
  • Brouwer E, Weening JJ, Klok PA, Huitema MG, Tervaert JW, Kallenberg CG. Induction of an humoral and cellular (auto) immune response to human and rat myeloperoxidase(MPO) in Brown-Norway(BN), Lewis and Wistar Kyoto(WKY) rat strains. Adv Exp Med Biol. 1993;336:139–142. [PubMed]
  • Meezan E, Hjelle JT, Brendel K, Carlson EC. A simple, versatile, nondisruptive method for the isolation of morphologically and chemically pure basement membranes from several tissues. Life Sci. 1975 Dec 1;17(11):1721–1732. [PubMed]
  • Langeveld JP, Veerkamp JH, Duyf CM, Monnens LH. Chemical characterization of glomerular and tubular basement membranes of men of different age. Kidney Int. 1981 Jul;20(1):104–114. [PubMed]
  • van Goor H, van der Horst ML, Fidler V, Grond J. Glomerular macrophage modulation affects mesangial expansion in the rat after renal ablation. Lab Invest. 1992 May;66(5):564–571. [PubMed]
  • Hünig T, Wallny HJ, Hartley JK, Lawetzky A, Tiefenthaler G. A monoclonal antibody to a constant determinant of the rat T cell antigen receptor that induces T cell activation. Differential reactivity with subsets of immature and mature T lymphocytes. J Exp Med. 1989 Jan 1;169(1):73–86. [PMC free article] [PubMed]
  • Pryzwansky KB, Martin LE, Spitznagel JK. Immunocytochemical localization of myeloperoxidase, lactoferrin, lysozyme and neutral proteases in human monocytes and neutrophilic granulocytes. J Reticuloendothel Soc. 1978 Sep;24(3):295–310. [PubMed]
  • Brouwer E, Huitema MG, Mulder AH, Heeringa P, van Goor H, Tervaert JW, Weening JJ, Kallenberg CG. Neutrophil activation in vitro and in vivo in Wegener's granulomatosis. Kidney Int. 1994 Apr;45(4):1120–1131. [PubMed]
  • Kinjoh K, Kyogoku M, Good RA. Genetic selection for crescent formation yields mouse strain with rapidly progressive glomerulonephritis and small vessel vasculitis. Proc Natl Acad Sci U S A. 1993 Apr 15;90(8):3413–3417. [PMC free article] [PubMed]
  • Kettritz R, Yang JJ, Kinjoh K, Jennette JC, Falk RJ. Animal models in ANCA-vasculitis. Clin Exp Immunol. 1995 Jul;101 (Suppl 1):12–15. [PMC free article] [PubMed]
  • Esnault VL, Mathieson PW, Thiru S, Oliveira DB, Martin-Lockwood C. Autoantibodies to myeloperoxidase in brown Norway rats treated with mercuric chloride. Lab Invest. 1992 Jul;67(1):114–120. [PubMed]
  • Mathieson PW, Thiru S, Oliveira DB. Mercuric chloride-treated brown Norway rats develop widespread tissue injury including necrotizing vasculitis. Lab Invest. 1992 Jul;67(1):121–129. [PubMed]
  • Yang JJ, Jennette JC, Falk RJ. Immune complex glomerulonephritis is induced in rats immunized with heterologous myeloperoxidase. Clin Exp Immunol. 1994 Sep;97(3):466–473. [PMC free article] [PubMed]
  • Wilson CB. Nephritogenic antibody mechanisms involving antigens within the glomerulus. Immunol Rev. 1981;55:257–297. [PubMed]
  • Vissers MC, Wiggins R, Fantone JC. Comparative ability of human monocytes and neutrophils to degrade glomerular basement membrane in vitro. Lab Invest. 1989 Jun;60(6):831–838. [PubMed]
  • Johnson RJ, Couser WG, Chi EY, Adler S, Klebanoff SJ. New mechanism for glomerular injury. Myeloperoxidase-hydrogen peroxide-halide system. J Clin Invest. 1987 May;79(5):1379–1387. [PMC free article] [PubMed]
  • Johnson RJ, Guggenheim SJ, Klebanoff SJ, Ochi RF, Wass A, Baker P, Schulze M, Couser WG. Morphologic correlates of glomerular oxidant injury induced by the myeloperoxidase-hydrogen peroxide-halide system of the neutrophil. Lab Invest. 1988 Mar;58(3):294–301. [PubMed]
  • Rehan A, Johnson KJ, Kunkel RG, Wiggins RC. Role of oxygen radicals in phorbol myristate acetate-induced glomerular injury. Kidney Int. 1985 Mar;27(3):503–511. [PubMed]
  • Kobayashi K, Shibata T, Sugisaki T. Aggravation of rat nephrotoxic serum nephritis by anti-myeloperoxidase antibodies. Kidney Int. 1995 Feb;47(2):454–463. [PubMed]
  • Tomosugi NI, Cashman SJ, Hay H, Pusey CD, Evans DJ, Shaw A, Rees AJ. Modulation of antibody-mediated glomerular injury in vivo by bacterial lipopolysaccharide, tumor necrosis factor, and IL-1. J Immunol. 1989 May 1;142(9):3083–3090. [PubMed]
  • Casselman BL, Kilgore KS, Miller BF, Warren JS. Antibodies to neutrophil cytoplasmic antigens induce monocyte chemoattractant protein-1 secretion from human monocytes. J Lab Clin Med. 1995 Nov;126(5):495–502. [PubMed]

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