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. 1990 Jun;87(11):4115–4119. doi: 10.1073/pnas.87.11.4115

Anti-neutrophil cytoplasmic autoantibodies induce neutrophils to degranulate and produce oxygen radicals in vitro.

R J Falk 1, R S Terrell 1, L A Charles 1, J C Jennette 1
PMCID: PMC54058  PMID: 2161532

Abstract

Anti-neutrophil cytoplasmic autoantibodies (ANCA) are in the circulation of most patients with pauci-immune necrotizing vasculitis and pauci-immune crescentic glomerulonephritis. The current study demonstrates an effect of these autoantibodies on neutrophil function in vitro. ANCA cause normal human neutrophils to undergo an oxidative burst and degranulate. Both ANCA phenotypes (i.e., cytoplasmic-pattern ANCA and myeloperoxidase-specific ANCA) induce neutrophil activation. ANCA sera and purified immunoglobulins significantly increase the release of reactive oxygen species when compared with controls. ANCA, in a dose-dependent manner, induce the release of primary granule contents. These effects are markedly enhanced by priming neutrophils with tumor necrosis factor. Flow cytometry studies demonstrate the presence of myeloperoxidase on the surface of neutrophils after cytokine priming, indicating that primed neutrophils have ANCA antigens at their surfaces to interact with ANCA. These observations suggest an in vivo pathogenetic role for ANCA. We propose that, in patients with necrotizing vasculitis, ANCA-induced release of toxic oxygen radicals and noxious granule enzymes from cytokine-primed neutrophils could be mediating vascular inflammation.

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Selected References

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  1. Allen R. C., Mills E. L., McNitt T. R., Quie P. G. Role of myeloperoxidase and bacterial metabolism in chemiluminescence of granulocytes from patients with chronic granulomatous disease. J Infect Dis. 1981 Oct;144(4):344–348. doi: 10.1093/infdis/144.4.344. [DOI] [PubMed] [Google Scholar]
  2. Andrassy K., Koderisch J., Waldherr R., Rufer M. Diagnostic significance of anticytoplasmatic antibodies (ACPA/ANCA) in detection of Wegener's granulomatosis and other forms of vasculitis. Nephron. 1988;49(3):257–258. doi: 10.1159/000185068. [DOI] [PubMed] [Google Scholar]
  3. Babior B. M., Kipnes R. S., Curnutte J. T. Biological defense mechanisms. The production by leukocytes of superoxide, a potential bactericidal agent. J Clin Invest. 1973 Mar;52(3):741–744. doi: 10.1172/JCI107236. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Berkow R. L., Dodson M. R. Biochemical mechanisms involved in the priming of neutrophils by tumor necrosis factor. J Leukoc Biol. 1988 Nov;44(5):345–352. doi: 10.1002/jlb.44.5.345. [DOI] [PubMed] [Google Scholar]
  5. Borregaard N., Heiple J. M., Simons E. R., Clark R. A. Subcellular localization of the b-cytochrome component of the human neutrophil microbicidal oxidase: translocation during activation. J Cell Biol. 1983 Jul;97(1):52–61. doi: 10.1083/jcb.97.1.52. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Charles L. A., Falk R. J., Jennette J. C. Reactivity of anti-neutrophil cytoplasmic autoantibodies with HL-60 cells. Clin Immunol Immunopathol. 1989 Nov;53(2 Pt 1):243–253. doi: 10.1016/0090-1229(89)90054-8. [DOI] [PubMed] [Google Scholar]
  7. Clark R. A., Borregaard N. Neutrophils autoinactivate secretory products by myeloperoxidase-catalyzed oxidation. Blood. 1985 Feb;65(2):375–381. [PubMed] [Google Scholar]
  8. Couser W. G. Rapidly progressive glomerulonephritis: classification, pathogenetic mechanisms, and therapy. Am J Kidney Dis. 1988 Jun;11(6):449–464. doi: 10.1016/s0272-6386(88)80079-9. [DOI] [PubMed] [Google Scholar]
  9. Davies D. J., Moran J. E., Niall J. F., Ryan G. B. Segmental necrotising glomerulonephritis with antineutrophil antibody: possible arbovirus aetiology? 1982 Aug 28-Sep 4Br Med J (Clin Res Ed) 285(6342):606–606. doi: 10.1136/bmj.285.6342.606. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. DeChatelet L. R., Long G. D., Shirley P. S., Bass D. A., Thomas M. J., Henderson F. W., Cohen M. S. Mechanism of the luminol-dependent chemiluminescence of human neutrophils. J Immunol. 1982 Oct;129(4):1589–1593. [PubMed] [Google Scholar]
  11. DiPersio J. F., Billing P., Williams R., Gasson J. C. Human granulocyte-macrophage colony-stimulating factor and other cytokines prime human neutrophils for enhanced arachidonic acid release and leukotriene B4 synthesis. J Immunol. 1988 Jun 15;140(12):4315–4322. [PubMed] [Google Scholar]
  12. Diagnosis of pheochromocytoma. N Engl J Med. 1988 Nov 24;319(21):1417–1418. doi: 10.1056/NEJM198811243192115. [DOI] [PubMed] [Google Scholar]
  13. 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]
  14. Gallin J. I., Fletcher M. P., Seligmann B. E., Hoffstein S., Cehrs K., Mounessa N. Human neutrophil-specific granule deficiency: a model to assess the role of neutrophil-specific granules in the evolution of the inflammatory response. Blood. 1982 Jun;59(6):1317–1329. [PubMed] [Google Scholar]
  15. 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]
  16. Goldstein I., Hoffstein S., Gallin J., Weissmann G. Mechanisms of lysosomal enzyme release from human leukocytes: microtubule assembly and membrane fusion induced by a component of complement. Proc Natl Acad Sci U S A. 1973 Oct;70(10):2916–2920. doi: 10.1073/pnas.70.10.2916. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. Hall J. B., Wadham B. M., Wood C. J., Ashton V., Adam W. R. Vasculitis and glomerulonephritis: a subgroup with an antineutrophil cytoplasmic antibody. Aust N Z J Med. 1984 Jun;14(3):277–278. doi: 10.1111/j.1445-5994.1984.tb03769.x. [DOI] [PubMed] [Google Scholar]
  18. Jandl R. C., André-Schwartz J., Borges-DuBois L., Kipnes R. S., McMurrich B. J., Babior B. M. Termination of the respiratory burst in human neutrophils. J Clin Invest. 1978 May;61(5):1176–1185. doi: 10.1172/JCI109033. [DOI] [PMC free article] [PubMed] [Google Scholar]
  19. Jennette J. C., Falk R. J. Antineutrophil cytoplasmic autoantibodies and associated diseases: a review. Am J Kidney Dis. 1990 Jun;15(6):517–529. doi: 10.1016/s0272-6386(12)80521-x. [DOI] [PubMed] [Google Scholar]
  20. Jennette J. C., Wilkman A. S., Falk R. J. Anti-neutrophil cytoplasmic autoantibody-associated glomerulonephritis and vasculitis. Am J Pathol. 1989 Nov;135(5):921–930. [PMC free article] [PubMed] [Google Scholar]
  21. Klebanoff S. J., Vadas M. A., Harlan J. M., Sparks L. H., Gamble J. R., Agosti J. M., Waltersdorph A. M. Stimulation of neutrophils by tumor necrosis factor. J Immunol. 1986 Jun 1;136(11):4220–4225. [PubMed] [Google Scholar]
  22. Klebanoff S. J., Vadas M. A., Harlan J. M., Sparks L. H., Gamble J. R., Agosti J. M., Waltersdorph A. M. Stimulation of neutrophils by tumor necrosis factor. J Immunol. 1986 Jun 1;136(11):4220–4225. [PubMed] [Google Scholar]
  23. Lockwood C. M., Bakes D., Jones S., Whitaker K. B., Moss D. W., Savage C. O. Association of alkaline phosphatase with an autoantigen recognised by circulating anti-neutrophil antibodies in systemic vasculitis. Lancet. 1987 Mar 28;1(8535):716–720. doi: 10.1016/s0140-6736(87)90357-6. [DOI] [PubMed] [Google Scholar]
  24. Lüdemann G., Gross W. L. Autoantibodies against cytoplasmic structures of neutrophil granulocytes in Wegener's granulomatosis. Clin Exp Immunol. 1987 Aug;69(2):350–357. [PMC free article] [PubMed] [Google Scholar]
  25. 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]
  26. Nauseef W. M., Metcalf J. A., Root R. K. Role of myeloperoxidase in the respiratory burst of human neutrophils. Blood. 1983 Mar;61(3):483–492. [PubMed] [Google Scholar]
  27. Newburger P. E., Chovaniec M. E., Cohen H. J. Activity and activation of the granulocyte superoxide-generating system. Blood. 1980 Jan;55(1):85–92. [PubMed] [Google Scholar]
  28. 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]
  29. Pryzwansky K. B., MacRae E. K., Spitznagel J. K., Cooney M. H. Early degranulation of human neutrophils: immunocytochemical studies of surface and intracellular phagocytic events. Cell. 1979 Dec;18(4):1025–1033. doi: 10.1016/0092-8674(79)90215-0. [DOI] [PubMed] [Google Scholar]
  30. 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]
  31. Specks U., Wheatley C. L., McDonald T. J., Rohrbach M. S., DeRemee R. A. Anticytoplasmic autoantibodies in the diagnosis and follow-up of Wegener's granulomatosis. Mayo Clin Proc. 1989 Jan;64(1):28–36. doi: 10.1016/s0025-6196(12)65300-2. [DOI] [PubMed] [Google Scholar]
  32. Venning M. C., Arfeen S., Bird A. G. Antibodies to neutrophil cytoplasmic antigen in systemic vasculitis. Lancet. 1987 Oct 10;2(8563):850–850. doi: 10.1016/s0140-6736(87)91030-0. [DOI] [PubMed] [Google Scholar]
  33. Wathen C. W., Harrison D. J. Circulating anti-neutrophil antibodies in systemic vasculitis. Lancet. 1987 May 2;1(8540):1037–1037. doi: 10.1016/s0140-6736(87)92310-5. [DOI] [PubMed] [Google Scholar]
  34. Weiss M. A., Crissman J. D. Segmental necrotizing glomerulonephritis: diagnostic, prognostic, and therapeutic significance. Am J Kidney Dis. 1985 Oct;6(4):199–211. doi: 10.1016/s0272-6386(85)80174-8. [DOI] [PubMed] [Google Scholar]
  35. Zurier R. B., Hoffstein S., Weissmann G. Cytochalasin B: effect on lysosomal enzyme release from human leukocytes. Proc Natl Acad Sci U S A. 1973 Mar;70(3):844–848. doi: 10.1073/pnas.70.3.844. [DOI] [PMC free article] [PubMed] [Google Scholar]
  36. van der Woude F. J., Rasmussen N., Lobatto S., Wiik A., Permin H., van Es L. A., van der Giessen M., van der Hem G. K., The T. H. Autoantibodies against neutrophils and monocytes: tool for diagnosis and marker of disease activity in Wegener's granulomatosis. Lancet. 1985 Feb 23;1(8426):425–429. doi: 10.1016/s0140-6736(85)91147-x. [DOI] [PubMed] [Google Scholar]

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