Abstract
To develop an animal model for antimyeloperoxidase (MPO)-associated necrotizing crescentic glomerulonephritis (NCGN), we immunized Brown Norway rats with MPO and localized a neutrophil lysosomal enzyme extract, primarily consisting of MPO and elastinolytic enzymes, plus H2O2, the substrate of MPO, to the glomerular basement membrane (GBM). Upon immunization rats developed antibodies and positive skin tests to MPO. After unilateral perfusion of the left kidney with the lysosomal enzyme extract and H2O2, MPO and immunoglobulin (Ig)G localized transiently along the GMB. At the time of maximal inflammation, at 4 and 10 d after perfusion, MPO, IgG, and C3 could not be detected anymore. MPO-immunized rats perfused with the lysosomal enzyme extract and H2O2, in contrast to control-immunized and/or control-perfused rats, developed a proliferative GN characterized by intra- and extracapillary cell proliferation, ruptured Bowman's capsule, periglomerular granulomatous inflammation, and formation of giant cells. Monocytes, polymorphonuclear leukocytes (PMN), and to a far lesser extent T cells were found in the glomeruli. Interstitial infiltrates consisted of monocytes, PMN, and T cells. Granulomatous vasculitis of small vessels was found at 10 d after perfusion. The proliferative NCGN in this rat model closely resembles human anti-MPO- associated pauci-immune NCGN, and enables the study of the pathophysiology of anti-MPO-associated NCGN.
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- Bhathena D. B., Migdal S. D., Julian B. A., McMorrow R. G., Baehler R. W. Morphologic and immunohistochemical observations in granulomatous glomerulonephritis. Am J Pathol. 1987 Mar;126(3):581–591. [PMC free article] [PubMed] [Google Scholar]
- Couser W. G. Idiopathic rapidly progressive glomerulonephritis. Am J Nephrol. 1982;2(2):57–69. doi: 10.1159/000166586. [DOI] [PubMed] [Google Scholar]
- Dijkstra C. D., Döpp E. A., Joling P., Kraal G. The heterogeneity of mononuclear phagocytes in lymphoid organs: distinct macrophage subpopulations in the rat recognized by monoclonal antibodies ED1, ED2 and ED3. Immunology. 1985 Mar;54(3):589–599. [PMC free article] [PubMed] [Google Scholar]
- Falk R. J. ANCA-associated renal disease. Kidney Int. 1990 Nov;38(5):998–1010. doi: 10.1038/ki.1990.304. [DOI] [PubMed] [Google Scholar]
- Falk R. J., Jennette J. C. 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. doi: 10.1056/NEJM198806233182504. [DOI] [PubMed] [Google Scholar]
- Falk R. J., Terrell R. S., Charles L. A., Jennette J. C. 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. doi: 10.1073/pnas.87.11.4115. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Fleuren G., Grond J., Hoedemaeker P. J. In situ formation of subepithelial glomerular immune complexes in passive serum sickness. Kidney Int. 1980 May;17(5):631–637. doi: 10.1038/ki.1980.74. [DOI] [PubMed] [Google Scholar]
- GODMAN G. C., CHURG J. Wegener's granulomatosis: pathology and review of the literature. AMA Arch Pathol. 1954 Dec;58(6):533–553. [PubMed] [Google Scholar]
- Germuth F. G., Jr, Valdes A. J., Taylor J. J., Wise O., Rodriguez E. Fatal immune complex glomerulonephritis without deposits. Johns Hopkins Med J. 1975 May;136(5):189–192. [PubMed] [Google Scholar]
- Goldschmeding R., van der Schoot C. E., ten Bokkel Huinink D., Hack C. E., van den Ende M. E., Kallenberg C. G., von dem Borne A. E. 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. doi: 10.1172/JCI114335. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Henson P. M., Johnston R. B., Jr Tissue injury in inflammation. Oxidants, proteinases, and cationic proteins. J Clin Invest. 1987 Mar;79(3):669–674. doi: 10.1172/JCI112869. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Horn R. G., Fauci A. S., Rosenthal A. S., Wolff S. M. Renal biopsy pathology in Wegener's granulomatosis. Am J Pathol. 1974 Mar;74(3):423–440. [PMC free article] [PubMed] [Google Scholar]
- Hoyer J. R., Mauer S. M., Michael A. F. Unilateral renal disease in the rat. I. Clinical, morphologic, and glomerular mesangial functional features of the experimental model produced by renal perfusion with aminonucleoside. J Lab Clin Med. 1975 May;85(5):756–768. [PubMed] [Google Scholar]
- Johnson R. J., Couser W. G., Chi E. Y., Adler S., Klebanoff S. J. New mechanism for glomerular injury. Myeloperoxidase-hydrogen peroxide-halide system. J Clin Invest. 1987 May;79(5):1379–1387. doi: 10.1172/JCI112965. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Johnson R. J., Guggenheim S. J., Klebanoff S. J., Ochi R. F., Wass A., Baker P., Schulze M., Couser W. G. 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] [Google Scholar]
- Klebanoff S. J. Oxygen metabolism and the toxic properties of phagocytes. Ann Intern Med. 1980 Sep;93(3):480–489. doi: 10.7326/0003-4819-93-3-480. [DOI] [PubMed] [Google Scholar]
- Klebanoff S. J., Waltersdorph A. M., Rosen H. Antimicrobial activity of myeloperoxidase. Methods Enzymol. 1984;105:399–403. doi: 10.1016/s0076-6879(84)05055-2. [DOI] [PubMed] [Google Scholar]
- Lüdemann J., Utecht B., Gross W. L. Anti-neutrophil cytoplasm antibodies in Wegener's granulomatosis recognize an elastinolytic enzyme. J Exp Med. 1990 Jan 1;171(1):357–362. doi: 10.1084/jem.171.1.357. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Merrill D. P. Purification of human myeloperoxidase by Concanavalin A-Sepharose affinity chromatography. Prep Biochem. 1980;10(2):133–50. doi: 10.1080/00327488008061729. [DOI] [PubMed] [Google Scholar]
- Niles J. L., McCluskey R. T., Ahmad M. F., Arnaout M. A. Wegener's granulomatosis autoantigen is a novel neutrophil serine proteinase. Blood. 1989 Nov 1;74(6):1888–1893. [PubMed] [Google Scholar]
- Pinching A. J., Rees A. J., Pussell B. A., Lockwood C. M., Mitchison R. S., Peters D. K. Relapses in Wegener's granulomatosis: the role of infection. Br Med J. 1980 Sep 27;281(6244):836–838. doi: 10.1136/bmj.281.6244.836. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Pryzwansky K. B., Martin L. E., Spitznagel J. K. 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] [Google Scholar]
- Ronco P., Verroust P., Mignon F., Kourilsky O., Vanhille P., Meyrier A., Mery J. P., Morel-Maroger L. Immunopathological studies of polyarteritis nodosa and Wegener's granulomatosis: a report of 43 patients with 51 renal biopsies. Q J Med. 1983 Spring;52(206):212–223. [PubMed] [Google Scholar]
- Stilmant M. M., Bolton W. K., Sturgill B. C., Schmitt G. W., Couser W. G. Crescentic glomerulonephritis without immune deposits: clinicopathologic features. Kidney Int. 1979 Feb;15(2):184–195. doi: 10.1038/ki.1979.24. [DOI] [PubMed] [Google Scholar]
- Tervaert J. W., Goldschmeding R., Elema J. D., Limburg P. C., van der Giessen M., Huitema M. G., Koolen M. I., Hené R. J., The T. H., van der Hem G. K. Association of autoantibodies to myeloperoxidase with different forms of vasculitis. Arthritis Rheum. 1990 Aug;33(8):1264–1272. doi: 10.1002/art.1780330829. [DOI] [PubMed] [Google Scholar]
- Tervaert J. W., Goldschmeding R., Elema J. D., van der Giessen M., Huitema M. G., van der Hem G. K., The T. H., von dem Borne A. E., Kallenberg C. G. Autoantibodies against myeloid lysosomal enzymes in crescentic glomerulonephritis. Kidney Int. 1990 Feb;37(2):799–806. doi: 10.1038/ki.1990.48. [DOI] [PubMed] [Google Scholar]
- Weiss S. J. Tissue destruction by neutrophils. N Engl J Med. 1989 Feb 9;320(6):365–376. doi: 10.1056/NEJM198902093200606. [DOI] [PubMed] [Google Scholar]